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Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: A

double-blind, randomised clinical trial
Huajun Xu, MD, PhD, Chujun Zhang, MD, Yingjun Qian, MD, PhD, Jianyin Zou, MD,
PhD, Xinyi Li, MD, PhD, Yupu Liu, MD, PhD, Huaming Zhu, MD, PhD, Lili Meng, MD,
Suru Liu, MD, PhD, Weitian Zhang, Hongliang Yi, MD, PhD, Jian Guan, MD, PhD,
Zhengnong Chen, MD, PhD, Shankai Yin, MD, PhD
PII: S1389-9457(20)30474-3
DOI: https://doi.org/10.1016/j.sleep.2020.10.018
Reference: SLEEP 4621
To appear in: Sleep Medicine
Received Date: 30 July 2020

Revised Date: 15 October 2020
Accepted Date: 16 October 2020
Please cite this article as: Xu H, Zhang C, Qian Y, Zou J, Li X, Liu Y, Zhu H, Meng L, Liu S, Zhang W, Yi
H, Guan J, Chen Z, Yin S, Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia:
A double-blind, randomised clinical trial, Sleep Medicine, https://doi.org/10.1016/j.sleep.2020.10.018.
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© 2020 Published by Elsevier B.V.

Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: A
double-blind, randomised clinical trial
Huajun Xu 1,2,3*, MD, PhD; Chujun Zhang1,2,3*, MD; Yingjun Qian1,2,3, MD, PhD;
Jianyin Zou1,2,3, MD, PhD; Xinyi Li1,2,3, MD, PhD; Yupu Liu1,2,3, MD, PhD; Huaming
Zhu1,2,3†, MD,PhD; Lili Meng1,2,3, MD; Suru Liu1,2,3, MD, PhD; Weitian Zhang1,2,3†;
Hongliang Yi1,2,3, MD, PhD; Jian Guan†1,2,3, MD, PhD; Zhengnong Chen1,2,3, MD,
PhD; Shankai Yin1,2,3, MD, PhD
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1. Department of Otolaryngology Head and Neck Surgery & Center of Sleep
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Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600
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Yishan Road, 200233，Shanghai, China.
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2. Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
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3. Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai, China.

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*These authors contributed equally to this article.

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†Corresponding to
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Dr. Huaming Zhu. Address: 600 Yishan Road, 200233, Shanghai, China. Email:
zhmtiger@126.com. Tel: 008602124058706.
Dr. Weitian Zhang. Address: 600 Yishan Road, 200233, Shanghai, China.
Email:drzhangwt@163.com. Tel: 008602124058706
and Dr Jian Guan. Address: 600 Yishan Road, 200233, Shanghai, China.
Email:guanjian0606@sina.com. Tel: 008602124058706.

Abstract
Background: The aim of this study was to determine the efficacy of exogenous
melatonin supplementation for sleep disturbances in patients with middle-aged
primary insomnia.
Methods: This is a randomized double-blind, placebo-controlled parallel study.
Participants were recruited from Tianlin community, Xuhui district, Shanghai.
Ninety-seven consecutive middle-aged patients with primary insomnia were
randomized to receive 3 mg fast-release melatonin (n = 51) or placebo (n=46) for
4-weeks. Objective sleep parameters tested by overnight polysomnography, subjective
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sleep performance and daytime somnolence obtained from the Pittsburgh Sleep
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Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale
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(ESS) were obtained at baseline and after treatment. Treatment was taken daily one
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hour before bedtime. Serious adverse events and side-effects were monitored.
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Results: Melatonin supplementation significantly decreased early wake time

(-30.63min [95% CI, -53.92 to -7.34]; P = 0.001) and percentage of N2 sleep (-7.07%
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[95% CI, -13.47% to -0.68%]; P = 0.031). However, melatonin had no significant

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effect on other objective sleep parameters including sleep latency, sleep efficiency,
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wake during the sleep and percent of N1, N3 and REM sleep. Melatonin had no effect
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on insomnia symptoms and severity on the PSQI (1.53[95% CI, -0.55 to 3.61];
p=0.504); ISI (0.81 [95% CI, -2.27 to 3.88]; p=0.165) and ESS (-0.83 [95% CI, -3.53
to 1.88]; p=0.147). No serious adverse events were reported.
Conclusions: Melatonin supplementation over a 4-week period is effective and safe
in improving some aspects of objective sleep quality such as total sleep time,
percentage of rapid eye movement and early morning wake time in middle-aged
patients with insomnia.
Trial registration: Identifier: ChiCTR-TRC-13003997; Prospectively registered on 2
December 2013.
Keywords: primary insomnia, melatonin, randomized, polysomnography, Pittsburgh
Sleep Quality Index
Introduction
Insomnia is one of the most common sleep disorders, characterized by complaint
of difficulty in initiating or maintaining sleep, or non-restorative sleep, for at least one
month. The worldwide prevalence of insomnia was reported to be about 10%-40%[1,
2]. Insomnia can result in various adverse consequences such as fatigue, mood
disturbance, interrelationship problems, metabolic disorders, occupational difficulty,
and reduced quality of life.[3] Among insomnia category, those unrelated with a
medical condition, substance use or concurrent psychological disorder are considered
as primary insomnia.
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Melatonin is synthesized in the pineal gland driven by the biological clock
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residing in the suprachiasmatic nucleus(SCN).[4] Melatonin acts as a sleep regulator
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in promoting of sleep by induction of sleep and inhibiting of wake-promoting signals
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with its MT1 and MT2 receptors.[5, 6] Thus, the circadian rhythm of melatonin
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synthesis and secretion might influence the sleep rhythm. Endogenous melatonin
levels decrease gradually with age, presumably due to an age-related decline in SCN
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circadian rhythmic functions or the calcification of the pineal gland.[7-9] As

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melatonin has the effect of promoting sleep, the decline in melatonin with increased
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age might contribute to insomnia in elderly subjects.[10, 11] Thus exogenous

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melatonin has been prompt to make benefits on sleep in insomnia patients.[12]

Previous study revealed that the melatonin treatment on primary insomnia might
be age dependent.[13] Most previous randomized controlled studies (RCTs) on the
effect of melatonin in insomnia patients focused on elderly population.[14-17] Few
small-sample-size studies found melatonin could improve objective or subjective
sleep outcome measurements in elderly.[14, 16, 18] Considering melatonin
production begins declining in early midlife, however few studies focused on such
population. Thus, the aim of the current study was to evaluate the effect of exogenous
melatonin supplementation (3 mg/d) on objective and subjective sleep performance in
middle-aged primary insomnia population.
Method
Study design
This was a randomized, double blind, placebo controlled, parallel clinical trial
conducted in a tertiary hospital (Shanghai Jiao Tong University affiliated Sixth
People’s Hospital, Shanghai, China). The study compromised a 4-week double-blind
period, in which participants were randomized in 1:1 ratio to take fast-release
melatonin(3mg) or placebo with identical appearance, given orally as one tablet per
night 1 hour before bedtime. This study was conducted in accordance with the
International conference on Harmonized Tripartite guideline for good clinical practice.
All patients provided written informed consent prior to study participation. The
protocol and the statement of informed consent were approved by the Ethics
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Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital prior
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to initiation. Patients were reimbursed for travel expenses to the hospital.
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Participants
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Participants were recruited from the Tianlin community, Xuhui district, Shanghai and
were pre-screened by the general practitioners using Self-Rating Scale of Sleep
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(SRSS). The SRSS was a questionnaire designed for screening insomnia in Chinese
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population.[19] A patient with SRSS score of ≥20 was suspected to have insomnia
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and were arranged to pay a screening visit to the study center within 2 weeks.
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During the screening visit, demographic data; medical histories, psychiatric status
and medication; and symptoms of primary insomnia according to the DSM-IV
criteria[20] [difficulty in initiating and/or maintaining and/or poor quality of sleep
(QOS) for 1 month or more with significant daytime distress] were assessed. Besides,
a physical examination was conducted by a qualified clinician. Questionnaires
including Beck Depression Inventory,[21] State-Trait Anxiety Inventory,[22] and
Mini Mental State[23] were used to rule out other psychological disorders (e.g.
depression, anxiety, dementia).
Eligible patients were Chinese individuals aged 45-60 years who suffered from
primary insomnia according to the DSM-IV criteria. Exclusion criteria included use of
hypnotics within the previous 1 month or any psychoactive treatment, had drugs such
as neuroleptic, antidepressants and anticholinergic agents which could interfere on
sleep structure within the previous 3 months; moderate-severe OSA or relevant
periodic leg movements; sleep disorders associated with a psychiatric disorder; severe
psychiatric disorders, especially psychosis, anxiety and depression; sleep disorders
secondary to another medical condition; a lifestyle likely to interfere with sleep
patterns; use of prohibited medication or alcoholism; patients with severe organic
diseases or with other conditions not suitable for participating in the study at the
investigator's discreet.
Outcome measures
Age and percentage of male participants were recorded at baseline. Sleep quality
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measured by overnight polysomnography (PSG) and Pittsburgh Sleep Quality Index
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(PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) were also
recorded.
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Objective sleep study
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The PSG (Alice 5; Respironics, Pittsburgh, PA, USA) was performed in all the
included patients on the first and last night of treatment period in Shanghai Jiao Tong
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University Affiliated Sixth People’s Hospital sleep center to assess sleep objectively.
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The PSG was equipped with electroencephalography (EEG) channels, submental

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electromyography (EMG) channels, bilateral electrooculogram (EOG) channels, and

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electrocardiography (ECG) channels, nasal pressure transducer, oronasal thermistor,

piezo belts, snoring sound detector, leg movement detector and pulse oximetry
sensors. The light-off and beginning of PSG recordings were set at 22:30; the light-on
and termination of PSG recordings were set at 6:30. Scoring was performed
automatically using a computer software and were subsequently checked manually by
a skilled technician in 30-s epochs, following the 2012 guidelines of the American
Academy of Sleep Medicine (AASM)[24]. Apnea was defined as an at-least 90%
reduction in airflow for at least 10 s; hypopnea was defined as an at-least 30%
reduction in airflow for at least 10 s, accompanied by an at-least 3% reduction in
oxygen saturation or an event-related arousal. Apnea-hypopnea index (AHI) was
calculated as the average number of apnea and hypopnea per hour of sleep. An
arousal was defined as an abrupt shift in the electroencephalogram (EEG) frequency
that lasted ≥ 3 s. Arousal index (ArI) was defined as the average number of arousals
per hour of sleep. Sleep onset was defined as the occurrence of stage 2 (or higher
sleep stage). End of the sleep period was defined as the last sleep epoch. Sleep onset
latency was calculated as the time elapsed between light off and sleep on set, which
was regarded as the primary outcome; Total sleep time (TST) was calculated as time
spent in rapid eye movement (REM) plus non-REM (NREM) sleep; sleep efficiency
was calculated as 100*TST/time in bed; early wake time was defined as light-on time
of PSG recording minus wake up time; wake during sleep was defined as total time of
awakenings (wake was scored as at least 30-s epochs); wake after sleep onset (WASO)
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was defined as the total amount of awake time. Percentage of each sleep stage
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(including N1-N3 and REM) were also calculated.
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Subjective sleep study
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Subjective efficacy variables including PSQI, ISI and ESS were recorded in all the
included patients at baseline and the last day of treatment period.
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The PSQI has been recommended as an essential measure for global insomnia
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symptoms[25]. The PSQI is a self-rating scale, composed of 19 self-rated items (0-3

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scale) assessing 7 domains of sleep (including sleep latency, sleep duration, sleep
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efficiency, sleep quality, sleep disturbances, medication, and daytime dysfunction) in

the prior one month. A summation of these 7 domains scores yields a global score,
ranging from 0 to 21. Insomnia was defined as a global score of >5 (sensitivity of 90%
and specificity of 87% in the general population)[26].
ISI is a reliable and valid instrument to quantify perceived insomnia severity and a
useful tool in outcome measuring after insomnia treatment.[27] This questionnaire has
seven items which evaluates insomnia symptoms (initial, middle, late), the degree of
satisfaction with sleep, interference with daytime functioning, noticeability of
impairment, and concern caused by the sleep problem over the past 2 or 4 weeks with a
Likert scale of 5 points (0 = none; 4 = extremely severe), yielding a total score between
0 and 28. And a score of 14 provides the best cutoff to optimize sensitivity and
specificity.
For measurement of subjective sleepiness, the ESS is the preferred self-report
measure of sleepiness[28]. ESS is a subjective approach to evaluate daytime sleepiness
in the form of a self-reported 8-item questionnaire evaluating sleep propensity in eight
daily situations. And, ESS score is calculated by totaling the sub-scores with a response
format of 4-point Likert (0 = none drowsiness, 1 = slight drowsiness, 2 = moderate
drowsiness, and 3 = severe drowsiness). In addition, the total score ranges from 0 to 24.
The higher the score, the higher the level of severity for daytime sleepiness.
Randomisation and blinding
The random allocation of the patients into the melatonin or placebo group was
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conducted using the random number method by the responsible clinician.
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Randomized allocation was concealed in sequentially numbered, opaque, sealed
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envelopes. The allocation group was not revealed until an investigator provided the
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data of a fully eligible patient, which guaranteed the concealment of the
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randomization sequence. The patients and investigators that assessing outcomes were
blind to the random allocation of the treatment group (double-blind). Blinding was
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kept by using placebo with identical appearance, smell and taste of the melatonin
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tablet. The blinding was not to be broken (unless in emergency) until the data was
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collected and verified for analyses.

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Safety measurement
Safety measures included reported symptoms, pulse rate, blood pressure, physical
examination, blood and urine laboratory measures and adverse events.
Statistical Analyses
Baseline characteristics are summarized as mean± standard for continuous variables,
and counts (percentages) for categorical variables. The statistical analyses of
endpoints were based on patients who met the entry criteria, were randomized and
provided outcome data after treatment period. For endpoints including PSQI, ISI, ESS
and PSG variables, the outcomes statistical analysis comprised Student’s t-test to
verify the homogeneity between melatonin and placebo group, and Student’s t-test to
compare the difference in change between the melatonin and placebo group.
Calculation of the sample size aimed to detect a reduction in sleep onset latency of 7
min or more, assuming a pooled standard deviation of 6[16], an α error of 5%, and a
statistical power of 80%, with a total of 92 patients needed per randomized treatment
group after considering a 10% loss to follow-up [29]. Chi-square test was used to
assess safety measures including adverse events. All statistical tests were performed
two-tailed at the 5% level of significance with the use of SPSS 22.0 software (SPSS
Inc., Chicago, IL).
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Results
Participant flowchart
A total of 563 subjects were pre-screened by the general practitioners. 353 volunteers
had a SRSS score no less than 20 and paid the first visit to the research center. Of
these, 252 patients failed to meet the inclusion/exclusion criteria. The remaining 111
patients were eligible for inclusion in the study and were then randomized to the
placebo and melatonin group. 56 patients were included in the melatonin group and
55 patients were included in the placebo group. Of the 111 randomized patients, 97
patients (51 with melatonin and 46 with placebo) completed the study and had valid
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measurements. By excluding patients that showed moderate-severe OSA or relevant
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periodic leg movements on polysomnographic results, 61 patients (29 with melatonin
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and 32 with placebo) were finally included for statistical analyses (Figure 1).
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Patient characteristics
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The demographic data at baseline in the placebo, melatonin groups are presented in
table 1. Values of questionnaires and PSG parameters at baseline in the two treatment
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groups are also shown in Table 1. There were no significant differences in baseline
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demographic and sleep data between the two treatment groups (Table 1).
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Efficacy
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Polysomnographic sleep variable: For sleep induction variables, there were no

significant differences of outcome in sleep onset latency and latency to REM stage
between the placebo and melatonin treatment groups (sleep onset latency, p=0.262;
REM latency, p=0.534) (Table2).
For sleep continuity variables, the melatonin group achieved a greater decrease
in early wake time (-30.63min [95% CI, -53.92 to -7.34]; P = 0.001). There were no
significant differences in total sleep time, wake during sleep, and sleep efficiency
(total sleep time, p=0.218; wake during sleep, p=0.862; sleep efficiency, p=0.324)
(Table2).
Sleep architecture: Regarding the percentage of each sleep stages, N2% decrease was
greater in the melatonin group than in the placebo group (-7.07% [95% CI, -13.47%
to -0.68%]; P = 0.031). There were no differences in the other sleep stages including
percentage of N1, N3 and REM (Table2).
Subjective assessment: The mean effect of PSQI (1.53[95% CI, -0.55 to 3.61];
p=0.504); ISI (0.81 [95% CI, -2.27 to 3.88]; p=0.165) and ESS (-0.83 [95% CI, -3.53
to 1.88]; p=0.147) changes did not significantly differ between the placebo and
melatonin groups. Besides, only the component 6 in PSQI showed difference (0.13
[95% CI, -0.27 to 0.54]; p=0.030) between the melatonin and placebo groups (Table
3).
Safety:
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There was no significant difference in regard to the incidence of adverse events. The
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study melatonin was well tolerated and no clinically relevant changes in vital signs
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and laboratory blood and urine tests were observed.
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Discussion
The effect of melatonin on primary insomnia has been widely studied. However, the
results were inconsistent.[17, 30] Many factors might have contributed to the
heterogeneity of the results, such as different study types (RCT or non-RCT), sample
size, outcome assessing methods (objective and subjective sleep assessments), and
characteristics of study population such as age, gender and race. So, there arise the
need for analysis of subgroups of insomnia patients who could potentially benefit
from melatonin treatment with enough sample size, using objective sleep
measurements. Considering these aforementioned factors existed, our study was the
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first to investigate the efficacy of melatonin in alleviating objective sleep disturbance
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in middle-aged patients with primary insomnia, We found that melatonin improved
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several objective sleep variables tested by overnight PSG, such as decreased
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early-morning wake and percentage of N2 sleep; but not subjective sleep performance
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evidenced by the PSQI, ISI and ESS. The results suggest that melatonin might be
useful in treating sleep disturbances in middle-aged patients with primary insomnia.
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On polysomnographic recordings, sleep onset latency was not improved in

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middle-aged patients with primary insomnia after melatonin treatment in our study.
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The result is in agreement with previous study conducted by Irina and Luis, who also
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used one-night PSG in recording of sleep.[18] Although some other studies have
reported benefit of melatonin on sleep latency, meta-analysis has yielded limited
decease of sleep onset latency in primary insomnia patients, in contrast to decrease of
sleep onset latency in the delayed sleep phase syndrome.[30] This might be partly
explained by the differences of a circadian abnormality presented in the delayed sleep
phase syndrome but not in the primary insomnia.
Early awakening in the morning is one of the insomnia types.[31] Chronic early
morning awakening insomnia has been associated with significantly advanced
melatonin rhythms.[8] But whether melatonin treatment could facilitate some effect
on this type of insomnia has hardly ever been investigated. In our population, we
observed a reduction in morning early awakening after treatment of melatonin.
Besides, since early morning awakening could lead to the reduction on total sleep
time, the total sleep time that also increased in our population might be due to the
improvement in early morning awakening.
Regrettably, we found almost all subjective sleep variables were not improved by
melatonin treatment. Discrepancy was reported to exist between subjective and
objective sleep, especially in patients with insomnia,[32] so the response of objective
sleep and subjective sleep performance differed. Researches showed that patients with
insomnia tend to have great negative sleep discrepancy, which is characterized by
self-reports of sleep features being in the direction of greater sleep impairment than
corresponding objectively measures, that might partly explain the negative findings.
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In our study, we used a dosage of 3 mg fast-release melatonin as an treatment.
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Indeed, recent studies demonstrated that different formulations and timing of
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administration of melatonin could significantly influence the effect of this molecule.
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Moreover, currently only the formulation of prolonged release of melatonin 2 mg is
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approved for the treatment of chronic insomnia characterized by poor quality of sleep
in people aged ≥ 55. This because prolonged release of melatonin 2 mg showed to
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mimic the physiological release of melatonin by releasing melatonin gradually and

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acting on melatonin receptors. Thus, it could be more useful to see whether prolonged
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release of melatonin 2 mg was effective in younger adult patients with insomnia, we

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will further confirm this in future studies through conducting another RCT.
Our study has several limitations should be addressed. First, endogenous
melatonin concentration was not measured in our study, thus, the association between
melatonin excretion level and its treatment effect could not be concluded. As shown
in previous studies, melatonin level has great inter-individual variability. The
endogenous melatonin level tested before administration of melatonin could not
predict responses to melatonin treatment.[13] Second, melatonin phase was not
captured, we are unable to determine to what extent changes of sleep quality were
mitigated by alterations in circadian phase. Third, four-weeks’ follow-up time is short,
whether longer intervention time bring better therapeutic effects till not be determined.
Fourth, the age cut-off for response warrants further investigation. The sleep variables
that improved after melatonin treatment in the subgroup of middle-aged insomnia in
this study might be different from that in the more aged patients with the age of over
55 or even over 65 as previously reported. Thus, for which age group, the treatment
effect of melatonin is better is still needed for evidence-based recommendations.
Fourth, due to only 29 participants received treatment of melatonin were finally
included for statistical analysis, thus it is difficult to investigate the effect of
melatonin on different insomnia subtypes such as difficulty in initiating, difficulty in
maintaining sleep or early morning awakenings (the sample size in each subtype
group is relatively small). Fifth, the chronotype of patients by means of melatonin
assessment (DLMO) or questionnaire were not investigated.
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Conclusions
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In conclusion, our study first provides evidence for the efficacy of melatonin in
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alleviating objective sleep disturbances in middle-aged patients with primary
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insomnia. Future studies should investigate whether melatonin combined with
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cognitive behavioral therapy for insomnia (CBT-I) or light therapy will improve sleep
performance for such a population than melatonin supplementation alone.
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Abbreviations
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CI: Confidence interval; PSQI: Pittsburgh Sleep Quality Index; ISI: Insomnia Severity
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Index; ESS: Epworth Sleepiness Scale (ESS); N1: None rapid eye movement 1; N2:
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None rapid eye movement 2; N3: None rapid eye movement 3; REM: Rapid eye
movement; CBT-I: cognitive behavioral therapy for insomnia; PSG:
polysomnography
Acknowledgements
We thank each and every participant for contributing their time to this study. We
would also like to thank all the doctors and nurses of our department.
Funding
This study was supported by grants-in-aid from Shanghai Municipal Commission of
Science and Technology (Grant No.18DZ2260200). The funder was not involved in
study design, and collection, analysis or interpretation of the data. The funder also
played no role in the preparation, review, writing or approval of the manuscript.
Authors’ contributions
The authors take responsibility and vouch for the accuracy and completeness of the
data and analyses. Prof. HZ, ZC and WZ had full access to all of the data in the study
and took responsibility for the integrity of the data and the accuracy of the data
analysis. Study design: JG, HY and SY; Data collection: HX, YQ, CZ, JZ, XL,YL,
LM, SL, and HZ; Statistical analysis: HX, YQ; Manuscript draft: HX, YQ，JG, HY
and SY. All authors have seen and approved the manuscript.
Ethics approval and consent to participate
The study was prospectively approved by the ethics committee of shanghai jiaotong
university affiliated sixth people’s hospital (2013-64), and participant consent was
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obtained from each participant before enrolment into the study.
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Consent for publication
Not applicable.
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Competing interests
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The authors have nothing to disclose.

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al
u rn
Jo
Table 1. Comparisons of demographic and bassline sleep data between placebo and melatonin group
Placebo(N=32) Melatonin(N=29) P-value
Age, y 56.53±4.65 57.24±5.59 0.590
Male, No. (%) 17(53.13) 12(41.38) 0.444
Sleep Latency 51.01±39.44 59.28±55.35 0.501
REM Latency 159.11±73.50
f
189.31±84.83
o 0.142
Total Sleep Time 360.62±75.59 364.37±68.95
o 0.841
Sleep Efficiency (%) 75.01±15.51 r 73.93±15.29 0.786
Micro-arousal Index 9.92±7.27 -p 10.97±8.58 0.606
Wake during sleep(min) 47.64±46.84 e 42.47±47.44 0.670
Wake after sleep onset (min) 69.78±54.25r 73.17±55.99 0.811
Early wake (min) 38.94±41.18
P 42.88±30.55 0.675
N1%
a l
13.69±13.70 14.04±12.48 0.917
N2% n47.48±10.04 54.48±10.78 0.011
N3% r 20.82±11.41 15.61±9.86 0.063
REM% u 18.01±7.69 15.34±7.52 0.177
PSQI-Component 1 Jo 1.47±0.72 1.48±0.74 0.940
PSQI-Component 2 1.81±0.97 1.86±0.88 0.835
PSQI-Component 3 1.53±1.08 2.03±0.87 0.048
PSQI-Component 4 1.47±1.24 1.83±1.28 0.272
PSQI-Component 5 1.41±0.50 1.52±0.74 0.499
PSQI-Component 6 0.47±1.02 0.41±0.87 0.822
PSQI-Component 7 1.97±0.86 1.69±0.85 0.208
PSQI total score 10.12±4.32 10.83±4.36 0.530
ISI 13.28±5.26 12.52±4.93 0.561
ESS 8.84±5.73 8.59±5.61 0.860
Abbreviations: PSQI= Pittsburgh Sleep Quality Index, ISI= Insomnia Severity Index, ESS= Epworth Sleepiness Scale (ESS). N1= None rapid
eye movement 1; N2= None rapid eye movement 2; N3= None rapid eye movement 3; REM= Rapid eye movement.
f
o o
Table 2. Effect of melatonin treatment on objective sleep parameters.
r
Placebo(N=32) -p
Melatonin(N=29) Difference in change
r e P-value
Baseline Follow-up Baseline Follow-up (95% CI)
Sleep latency (min) 51.01±39.44 31.80±24.49 l P

59.28±55.35 44.32±35.46 53.89(-41.27, 149.05) 0.262
REM latency (min) 159.11±73.50 129.96±48.19
n a 189.31±84.83 148.06±55.65 -13.17(-55.24, 28.91) 0.534
Total sleep time (min) 360.62±75.59 u r
352.03±80.57 364.37±68.95 376.68±58.46 20.90(-12.67, 54.47) 0.218
Sleep efficiency (%) 75.01±15.51 77.58±17.39
Jo 73.93±15.29 79.69±12.93 3.19(-3.23, 9.60) 0.324
Micro-arousal index 9.92±7.27 7.23±4.56 10.97±8.58 8.29±6.14 0.00(-4.67, 4.68) 0.998
Wake during sleep (min) 47.64±46.84 35.00±41.83 42.47±47.44 31.57±26.93 1.74(-18.22, 21.71) 0.862
Wake after sleep onset(min) 69.78±54.25 71.50±59.66 73.17±55.99 54.07±52.30 -20.84(-46.14, 4.46) 0.105
Early wake (min) 38.94±41.18 72.13±62.04 42.88±30.55 45.45±44.08 -30.63(-53.92, -7.34) 0.011
N1% 13.69±13.70 10.88±8.88 14.04±12.48 8.36±10.02 -2.87(-8.74, 3.00) 0.332
N2% 47.48±10.04 51.53±11.25 54.48±10.78 51.46±10.96 -7.07(-13.47, -0.68) 0.031
N3% 20.82±11.41 19.14±14.21 15.61±9.86 18.57±10.95 4.63(-0.78, 10.05) 0.262
REM% 18.01±7.69 18.42±6.65 15.34±7.52 21.58±7.57 5.82(0.54, 11.10) 0.534
Difference in change was calculated as (change in melatonin group) − (change in placebo group). Abbreviations: N1= None rapid eye movement
f
1; N2= None rapid eye movement 2; N3= None rapid eye movement 3; REM= Rapid eye movement; CI= confidence interval.
o
r o
p
Table 3. Effect of melatonin treatment on subjective sleep parameters.
-
Placebo(N=32) r e Melatonin(N=29) Difference in change
P-value
Baseline Follow-up
l P Baseline Follow-up (95% CI)
Component 1 1.47±0.72 1.31±0.59 a 1.48±0.74 1.28±0.53 -0.05(-0.45, 0.34) 0.092

Component 2 1.81±0.97 1.22±0.97
rn 1.86±0.88 1.55±0.83 0.28(-0.19, 0.76) 0.031
Component 3 1.53±1.08
u
1.31±0.82 2.03±0.87 2.00±0.85 0.18(-0.34, 0.71) 0.798
Component 4 1.47±1.24
Jo
0.84±1.02 1.83±1.28 1.93±1.07 0.73(0.07, 1.38) 0.234
Component 5 1.41±0.50 1.22±0.42 1.52±0.74 1.24±0.51 -0.09(-0.34, 0.17) 0.488
Component 6 0.47±1.02 0.44±0.88 0.41±0.87 0.52±0.99 0.13(-0.27, 0.54) 0.030
Component 7 1.97±0.86 1.56±0.84 1.69±0.85 1.62±0.90 0.34(-0.14, 0.82) 0.492
PSQI total score 10.12±4.32 7.91±3.50 10.83±4.36 10.14±3.94 1.53(-0.55, 3.61) 0.504
ISI 13.28±5.26 9.41±4.98 12.52±4.93 9.45±4.76 0.81(-2.27, 3.88) 0.165
ESS 8.84±5.73 7.84±4.42 8.59±5.61 6.76±4.19 -0.83(-3.53, 1.88) 0.147
Difference in change was calculated as (change in melatonin group) − (change in placebo group). Abbreviations: PSQI= Pittsburgh Sleep
Quality Index; ISI= Insomnia Severity Index; ESS= Epworth Sleepiness Scale (ESS); CI= confidence interval.
o f
Figure legends r o
p
Figure 1. Flowchart of the study. A total of 563 participants were prescreened and 97 of them were randomized to treatment, and 61 participants
-
were finally included for stastistical analysis. r e
l P
n a
u r
Jo
Highlights
1) This is a randomized double-blind, placebo-controlled parallel study to explore
efficacy of melatonin for sleep disturbance.
2) Few studies have assessed objective sleep disturbance using standard
polysomnography.
3) Most of previous studies focused on the elderly, few studies focused on
middle-aged primary insomnia population.
o of
pr
e-
Pr
al
u rn
Jo
Pre-screened (N=563)
Excluded (N=210):
-Did not satisfy sleep history requirements (N=52)
-SRSS scored less than 20 (N=158)
Attended visit 1 (N=353)
Excluded (N=242): of
ro
-Unsuitable age (N=71); Use of hypnotics (N=27)
-p
-Unsuitable lifestyle (N=8);Did not consent (N=136)
re
lP
na
Randomized (N=111)
ur
Jo
Allocated to Melatonin (N=56) Allocated to placebo (n=55)
Lost to follow-up (N=1) Lost to follow-up (N=2)
Refused to continue (N=4) Refused to continue (N=7)
Excluded due to Excluded due to moderate-
moderate-severe OSA severe OSA and relevant
and relevant PLM (N=22) PLM (N=14)
Analyzed (N=29) Analyzed (N=32)
Escala de PEDro – Português (Brasil)
1. Os critérios de elegibilidade foram especificados não! sim! onde:
2. Os sujeitos foram aleatoriamente distribuídos por grupos (num estudo

cruzado, os sujeitos foram colocados em grupos de forma aleatória de
acordo com o tratamento recebido) não! sim! onde:
3. A alocação dos sujeitos foi secreta não! sim! onde:
4. Inicialmente, os grupos eram semelhantes no que diz respeito aos

indicadores de prognóstico mais importantes não! sim! onde:
5. Todos os sujeitos participaram de forma cega no estudo não! sim! onde:
6. Todos os terapeutas que administraram a terapia fizeram-no de forma

cega não! sim! onde:
7. Todos os avaliadores que mediram pelo menos um resultado-chave,

fizeram-no de forma cega não! sim! onde:
8. Mensurações de pelo menos um resultado-chave foram obtidas em mais de

85% dos sujeitos inicialmente distribuídos pelos grupos não! sim! onde:
9. Todos os sujeitos a partir dos quais se apresentaram mensurações de resultados

receberam o tratamento ou a condição de controle conforme a alocação
ou, quando não foi esse o caso, fez-se a análise dos dados para pelo menos
um dos resultados-chave por “intenção de tratamento” não! sim! onde:
10. Os resultados das comparações estatísticas inter-grupos foram descritos

para pelo menos um resultado-chave não! sim! onde:
11. O estudo apresenta tanto medidas de precisão como medidas de

variabilidade para pelo menos um resultado-chave não! sim! onde:
A escala PEDro baseia-se na lista de Delphi, desenvolvida por Verhagen e colegas no Departamento de Epidemologia, da
Universidade de Maastricht (Verhagen AP et al (1988). The Delphi list: a criteria list for quality assessment of randomised
clinical trials for conducting systematic reviews developed by Delphi consensus. Journal of Clinical Epidemiology,
51(12):1235-41). A lista, na sua maior parte, baseia-se num “consenso de peritos” e não em dados empíricos. Incluíram-se na
escala de PEDro dois itens adicionais, que não constavam da lista de Delphi (os itens 8 e 10 da escala de PEDro). À medida
que forem disponibilizados mais dados empíricos, pode vir a ser possível ponderar os itens da escala de forma a que a
pontuação obtida a partir da aplicação da escala PEDro reflita a importância de cada um dos itens da escala.
O objetivo da escala PEDro consiste em auxiliar os utilizadores da base de dados PEDro a identificar rapidamente quais dos
estudos controlados aleatorizados, ou quase-aleatorizqados, (ou seja, ECR ou ECC) arquivados na base de dados PEDro
poderão ter validade interna (critérios 2-9), e poderão conter suficiente informação estatística para que os seus resultados
possam ser interpretados (critérios 10-11). Um critério adicional (critério 1) que diz respeito à validade externa (ou “potencial
de generalização” ou “aplicabilidade” do estudo clínico) foi mantido para que a Delphi list esteja completa, mas este critério
não será usado para calcular a pontuação PEDro apresentada no endereço PEDro na internet.
A escala PEDro não deverá ser usada como uma medida da “validade” das conclusões de um estudo. Advertimos, muito
especialmente, os utilizadores da escala PEDro de que estudos que revelem efeitos significativos do tratamento e que obtenham
pontuação elevada na escala PEDro não fornecem, necessariamente, evidência de que o tratamento seja clinicamente útil.
Adicionalmente, importa saber se o efeito do tratamento foi suficientemente expressivo para poder ser considerado
clinicamente justificável, se os efeitos positivos superam os negativos, e aferir a relação de custo-benefício do tratamento. A
escala não deve ser utilizada para comparar a “qualidade” de estudo clínicos realizados em diferentes áreas de terapia,
principalmente porque algumas áreas da prática da fisioterapia não é possível satisfazer todos os itens da escala.
Modificada pela última vez em 21 de Junho de 1999

Tradução em Português vez em 13 de Maio de 2009
Ajustes ortográficos para a versão Português-Brasileiro em 12 de Agosto de 2010
Indicações para a administração da escala PEDro:
Todos os critérios A pontuação só será atribuída quando um critério for claramente satisfeito. Se numa leitura literal do
relatório do ensaio existir a possibilidade de um critério não ter sido satisfeito, esse critério não deve
receber pontuação.
Critério 1 Este critério pode considerar-se satisfeito quando o relatório descreve a origem dos sujeitos e a lista de
requisitos utilizados para determinar quais os sujeitos eram elegíveis para participar no estudo.
Critério 2 Considera-se que num determinado estudo houve alocação aleatória se o relatório referir que a alocação
dos sujeitos foi aleatória. O método de aleatoriedade não precisa de ser explícito. Procedimentos tais como
lançamento de dados ou moeda ao ar podem ser considerados como alocação aleatória. Procedimentos de
alocação quase-aleatória tais como os que se efetuam a partir do número de registo hospitalar, da data de
nascimento, ou de alternância, não satisfazem este critério.
Critério 3 Alocação secreta significa que a pessoa que determinou a elegibilidade do sujeito para participar no ensaio
desconhecia, quando a decisão foi tomada, o grupo a que o sujeito iria pertencer. Deve atribuir-se um
ponto a este critério, mesmo que não se diga que a alocação foi secreta, quando o relatório refere que a
alocação foi feita a partir de envelopes opacos fechados ou que a alocação implicou o contato com o
responsável pela alocação dos sujeitos por grupos, e este último não participou do ensaio.
Critério 4 No mínimo, nos estudos de intervenções terapêuticas, o relatório deve descrever pelo menos uma medida
da gravidade da condição a ser tratada e pelo menos uma (diferente) medida de resultado-chave que
caracterize a linha de base. O examinador deve assegurar-se de que, com base nas condições de
prognóstico de início, não seja possível prever diferenças clinicamente significativas dos resultados, para
os diversos grupos. Este critério é atingido mesmo que somente sejam apresentados os dados iniciais do
estudo.
Critérios 4, 7-11 Resultados-chave são resultados que fornecem o indicador primário da eficácia (ou falta de eficácia) da
terapia. Na maioria dos estudos, utilizam mais do que uma variável como medida de resultados.
Critérios 5-7 Ser cego para o estudo significa que a pessoa em questão (sujeito, terapeuta ou avaliador) não conhece
qual o grupo em que o sujeito pertence. Mais ainda, sujeitos e terapeutas só são considerados “cegos” se
for possível esperar-se que os mesmos sejam incapazes de distinguir entre os tratamentos aplicados aos
diferentes grupos. Nos ensaios em que os resultados-chave são relatados pelo próprio (por exemplo, escala
visual análoga, registo diário da dor), o avaliador é considerado “cego” se o sujeito foi “cego”.
Critério 8 Este critério só se considera satisfeito se o relatório referir explicitamente tanto o número de sujeitos
inicialmente alocados nos grupos como o número de sujeitos a partir dos quais se obtiveram medidas de
resultados-chave. Nos ensaios em que os resultados são medidos em diferentes momentos no tempo, um
resultado-chave tem de ter sido medido em mais de 85% dos sujeitos em algum destes momentos.
Critério 9 Uma análise de intenção de tratamento significa que, quando os sujeitos não receberam tratamento (ou a
condição de controle) conforme o grupo atribuído, e quando se encontram disponíveis medidas de
resultados, a análise foi efetuada como se os sujeitos tivessem recebido o tratamento (ou a condição de
controle) que lhes foi atribuído inicialmente. Este critério é satisfeito, mesmo que não seja referida a
análise por intenção de tratamento, se o relatório referir explicitamente que todos os sujeitos receberam o
tratamento ou condição de controle, conforme a alocação por grupos.
Critério 10 Uma comparação estatística inter-grupos implica uma comparação estatística de um grupo com outro.
Conforme o desenho do estudo, isto pode implicar uma comparação de dois ou mais tratamentos, ou a
comparação do tratamento com a condição de controle. A análise pode ser uma simples comparação dos
resultados medidos após a administração do tratamento, ou a comparação das alterações num grupo em
relação às alterações no outro (quando se usou uma análise de variância para analisar os dados, esta última
é frequentemente descrita como interação grupo versus tempo). A comparação pode apresentar-se sob a
forma de hipóteses (através de um valor de p, descrevendo a probabilidade dos grupos diferirem apenas
por acaso) ou assumir a forma de uma estimativa (por exemplo, a diferença média ou a diferença mediana,
ou uma diferença nas proporções, ou um número necessário para tratar, ou um risco relativo ou um razão
de risco) e respectivo intervalo de confiança.
Critério 11 Uma medida de precisão é uma medida da dimensão do efeito do tratamento. O efeito do tratamento pode
ser descrito como uma diferença nos resultados do grupo, ou como o resultado em todos os (ou em cada
um dos) grupos. Medidas de variabilidade incluem desvios-padrão (DP’s), erros-padrão (EP’s), intervalos
de confiança, amplitudes interquartis (ou outras amplitudes de quantis), e amplitudes de variação. As
medidas de precisão e/ou as medidas de variabilidade podem ser apresentadas graficamente (por exemplo,
os DP’s podem ser apresentados como barras de erro numa figura) desde que aquilo que é representado
seja inequivocamente identificável (por exemplo, desde que fique claro se as barras de erro representam
DP’s ou EP’s). Quando os resultados são relativos a variáveis categóricas, considera-se que este critério foi
cumprido se o número de sujeitos em cada categoria é apresentado para cada grupo.
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Published in final edited form as:

N Engl J Med. 2019 August 08; 381(6): 520–530. doi:10.1056/NEJMoa1900906.
Vitamin D Supplementation and Prevention of Type 2 Diabetes

Anastassios G. Pittas, M.D., Bess Dawson-Hughes, M.D., Patricia Sheehan, R.N., M.P.H.,
M.S., James H. Ware, Ph.D.*, William C. Knowler, M.D., Dr.P.H., Vanita R. Aroda, M.D., Irwin
Brodsky, M.D., Lisa Ceglia, M.D., Chhavi Chadha, M.D., Ranee Chatterjee, M.D., M.P.H.,
Cyrus Desouza, M.B., B.S., Rowena Dolor, M.D., John Foreyt, Ph.D., Paul Fuss, B.A., Adline
Ghazi, M.D., Daniel S. Hsia, M.D., Karen C. Johnson, M.D., M.P.H., Sangeeta R. Kashyap,
M.D., Sun Kim, M.D., Erin S. LeBlanc, M.D., M.P.H., Michael R. Lewis, M.D., Emilia Liao,
Author Manuscript
M.D., Lisa M. Neff, M.D., Jason Nelson, M.P.H., Patrick O’Neil, Ph.D., Jean Park, M.D., Anne
Peters, M.D., Lawrence S. Phillips, M.D., Richard Pratley, M.D., Philip Raskin, M.D., Neda
Rasouli, M.D., David Robbins, M.D., Clifford Rosen, M.D., Ellen M. Vickery, M.S., Myrlene
Staten, M.D., D2d Research Group†
Tufts Medical Center (A.G.P., L.C., P.F., J.N., E.M.V.), the Jean Mayer USDA Human Nutrition
Research Center on Aging at Tufts University (B.D.-H.), Brigham and Women’s Hospital (V.R.A.),
and Harvard School of Public Health (J.H.W.), Boston, and the Spaulding Rehabilitation Network,
Charlestown (P.S.) — all in Massachusetts; National Institute of Diabetes and Digestive and
Kidney Diseases, Phoenix, AZ (W.C.K.); the Maine Medical Center (I.B.) and the Maine Medical
Center Research Institute (C.R.) — both in Scarborough; HealthPartners Institute, Minneapolis
(C.C.); Duke University Medical Center, Durham, NC (R.C., R.D.); the University of Nebraska
Medical Center and Omaha Veterans Affairs Medical Center, Omaha (C.D.); Baylor College of
Author Manuscript
Medicine, Houston (J.F.), and the University of Texas Southwestern Medical Center, Dallas (P.R.)
— both in Texas; MedStar Good Samaritan Hospital, Baltimore (A.G.), MedStar Health Research
Institute, Hyattsville (J.P.), and the National Institute of Diabetes and Digestive and Kidney
Diseases, Bethesda (M.S.) — all in Maryland; Pennington Biomedical Research Center, Baton
Rouge, LA (D.S.H.); the University of Tennessee Health Science Center, Memphis (K.C.J.);
Cleveland Clinic, Cleveland (S.R.K.); Stanford University Medical Center, Stanford (S.K.), and the
Keck School of Medicine of the University of Southern California, Los Angeles (A.P.) — both in
California; Kaiser Permanente Center for Health Research–Northwest, Portland, OR (E.S.L.); the
University of Vermont, Burlington (M.R.L.); Northwell Health Lenox Hill Hospital, New York (E.L.);
Northwestern University, Chicago (L.M.N.); the Medical University of South Carolina, Charleston
(P.O.); Emory University School of Medicine, Atlanta, and the Atlanta Veterans Affairs Medical
Center, Decatur — both in Georgia (L.S.P.); AdventHealth Translational Research Institute for
Author Manuscript
Metabolism and Diabetes, Orlando, FL (R.P.); the University of Colorado Denver and the Veterans
Address reprint requests to Dr. Pittas at the Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, 800
Washington St., Box 268, Boston, MA 02111, or at apittas@tuftsmedicalcenter.org.
*Deceased.
†A list of the members of the D2d Research, Group is provided in the Supplementary Appendix, available at NEJM.org.
The views expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of
Health.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Pittas et al. Page 2
Affairs Eastern Colorado Health Care System, Denver (N.R.); and the University of Kansas
Author Manuscript
Medical Center, Kansas City (D.R.).
Abstract
BACKGROUND—Observational studies support an association between a low blood 25-
hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D
supplementation lowers the risk of diabetes is unknown.
METHODS—We randomly assigned adults who met at least two of three glycemic criteria for
prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2
hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level,
5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or
placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this
time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target
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number of diabetes events of 508.
RESULTS—A total of 2423 participants underwent randomization (1211 to the vitamin D group
and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the
vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared
with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a
median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the
vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years,
respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence
interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly
between the two groups.
CONCLUSIONS—Among persons at high risk for type 2 diabetes not selected for vitamin D
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insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a
significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and
Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, .)
MORE THAN 84 MILLION ADULTS IN the United States have an increased risk of type 2
diabetes, based on a fasting glucose or glycated hemoglobin level above the normal range
but below the threshold for diabetes.1 Persons at high risk for type 2 diabetes who are
overweight or obese and who have elevated fasting glucose levels and glucose intolerance
(according to a 75-g oral glucose-tolerance test) can slow progression to diabetes with
lifestyle changes.2 However, achieving and maintaining sufficient lifestyle change is
challenging, and the residual risk of diabetes remains elevated, even after successful weight
loss.
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Over the past decade, a low blood 25-hydroxyvitamin D level has emerged as a possible risk
factor for type 2 diabetes, and vitamin D supplementation has been proposed as a potential
intervention to lower diabetes risk.3,4 The hypothesis that vitamin D status may influence the
risk of type 2 diabetes is biologically plausible, because both impaired pancreatic beta-cell
function and insulin resistance have been reported with low blood 25-hydroxyvitamin D
levels.5 Observational studies support an association between a low blood 25-
hydroxyvitamin D level and the risk of diabetes.6 In short-term mechanistic studies, vitamin

D supplementation improved the disposition index, a measure of pancreatic beta-cell

function, by 40%.7 However, whether vitamin D supplementation lowers the risk of diabetes
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is unclear.8–10 The Vitamin D and Type 2 Diabetes (D2d) trial was conducted to test whether
vitamin D supplementation reduces the risk of type 2 diabetes among adults at high risk for
the disorder.
METHODS
TRIAL DESIGN
This randomized, double-blind, placebo-controlled clinical trial evaluated the safety and
efficacy of oral administration of vitamin D3 (cholecalciferol; 4000 IU per day) for diabetes
prevention in adults at high risk for type 2 diabetes.11 The trial protocol (available with the
full text of this article at NEJM.org) was designed by the planning committee and the
primary sponsor (National Institute of Diabetes and Digestive and Kidney Diseases) without
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input from manufacturers11 and involved collaboration among 22 academic medical centers
in the United States (https://d2dstudy.org/sites). A sponsor-appointed data and safety
monitoring board approved the protocol and provided independent monitoring of the trial.
The institutional review board at each clinical site also approved the protocol, and all the
participants provided written informed consent. The data were collected by trial-site
personnel and stored in an electronic data-capture database. The statistical team at the
coordinating center analyzed the data and vouches for its accuracy. All the authors vouch for
the accuracy and completeness of the data and for the fidelity of the trial to the protocol.
They also contributed to the interpretation of the results and the preparation, review, and
approval of the manuscript and made the decision to submit the manuscript for publication.
No pharmaceutical manufacturers contributed to the planning, design, or conduct of the trial.

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Trial pills were purchased from an independent nutritional-supplement manufacturing

company that has no association with any members of the D2d Research Group.
PARTICIPANTS
Participants met at least two of three glycemic criteria for prediabetes as defined by the 2010
American Diabetes Association (ADA) guidelines: fasting plasma glucose level, 100 to 125
mg per deciliter (5.6 to 6.9 mmol per liter); plasma glucose level 2 hours after a 75-g oral
glucose load, 140 to 199 mg per deciliter (7.8 to 11.0 mmol per liter); and glycated
hemoglobin level, 5.7 to 6.4% (39 to 47 mmol per mole).12 Other inclusion criteria were an
age of 30 years or older (25 years or older for American Indians, Alaska Natives, or Native
Hawaiians or other Pacific Islanders) and a body-mass index (BMI, the weight in kilograms
divided by the square of the height in meters) of 24 to 42 (22.5 to 42 for Asian Americans).
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A low serum 25-hydroxyvitamin D level was not an inclusion criterion.
Key exclusion criteria were any glycemic criterion in the diabetes range,12 factors (other
than hyperglycemia and race) affecting the glycated hemoglobin level, use of diabetes or
weight-loss medications, or use of supplements containing vitamin D at a dose of more than
1000 IU per day or calcium at a dose of more than 600 mg per day. For a complete list of
eligibility criteria, see the Supplementary Appendix (available at NEJM.org). The

recruitment process relied primarily on electronic-health-record identification of potentially

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eligible adults who were then screened in person and, if qualified, had a second screening
visit to determine final eligibility according to measured fasting plasma glucose, 2-hour
post-load plasma glucose, and glycated hemoglobin at the central laboratory of the trial.13
INTERVENTION AND PROCEDURES

Participants were randomly assigned to take a single, once-daily soft-gel pill containing
either 4000 IU of vitamin D3 or matching placebo. Randomization was block-stratified
according to trial site, BMI (<30 or ≥30), and race (white or nonwhite). Participants received
a bottle of trial pills at the time of randomization and every 6 months thereafter. Bottles with
unused pills were returned at each visit to estimate adherence.
To maximize the ability of the trial to observe a treatment effect, participants were asked to
refrain from using diabetes-specific or weight-loss medications during the trial and to limit
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the use of outside-of-trial vitamin D to 1000 IU per day from all supplements, including
multivitamins. Because of concern that high intake of calcium from supplements may be
associated with adverse outcomes, participants were asked to limit calcium supplements to
600 mg per day. During the trial, participants were provided with information on diabetes
prevention through information sheets and twice-yearly group meetings.
Follow-up visits occurred at month 3, month 6, and twice per year thereafter. Midway
between the in-person visits, an interim contact (telephone or email) took place. All visits
and contacts were designed to promote retention, encourage adherence to the trial regimen,
and assess for diabetes, occurrence of adverse events, and use of high-dose vitamin D
supplements, diabetes medications, and weight-loss medications.
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OUTCOMES
The primary outcome in this time-to-event analysis was new-onset diabetes, based on annual
glycemic testing of fasting plasma glucose, glycated hemoglobin, and 2-hour post-load
plasma glucose and semiannual testing of fasting plasma glucose and glycated hemoglobin.
If two or three of the glycemic measures met the 2010 ADA thresholds for diabetes,12 the
participant was considered to have met the diabetes outcome. When only the measure for
fasting plasma glucose or glycated hemoglobin met the threshold, confirmatory testing was
performed for the positive measure within 8 weeks. If only the measure for 2-hour post-load
plasma glucose met the threshold, then a 75-g oral glucose-tolerance test to reassess all three
glycemic measures was repeated. If the repeat measure was positive or both fasting plasma
glucose and glycated hemoglobin were positive (in the case of a repeat oral glucose-
tolerance test), then the participant was considered to have met the diabetes outcome. A
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diagnosis of diabetes that was made outside the trial was validated by in-trial laboratory
testing or adjudicated by an independent clinical-outcomes committee.
During the trial, research staff, caregivers, and participants were unaware of glycemic test
results until a participant met the diabetes outcome. Safety was assessed by means of
participant report and annual fasting measurements of serum calcium, serum creatinine, and
morning spot urine calcium:creatinine ratio (a rough estimate of urine calcium excretion).14

LABORATORY TESTING
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Serum calcium and creatinine were analyzed locally at each site, and the estimated
glomerular filtration rate was calculated.15 Other blood and urine specimens were processed
locally and shipped to the central laboratory. Glycated hemoglobin was measured with the
use of an ion-exchange high-performance liquid chromatography method certified by the
National Glyco-hemoglobin Standardization Program.16 Plasma glucose was measured with
the use of a hexokinase method. Stored serum samples from the baseline, month 12, and
month 24 visits were used to measure 25-hydroxyvitamin D by liquid chromatography–
tandem mass spectrometry validated by a quarterly proficiency-testing program administered
by the Vitamin D External Quality Assessment Scheme.17,18
STATISTICAL ANALYSIS
The trial was designed as an event-driven trial with a target of 508 diabetes events and a total
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sample size of 2382 participants assigned equally to the vitamin D group and placebo group,
on the basis of a hypothesized hazard ratio of 0.75 in the vitamin D group, an incidence of
diabetes of 10% per year in the placebo group, a type I error rate of 0.0501 (with a single
interim analysis taken into account), a power of 90%, a recruitment period of 2 years, a trial
duration of 4 years, and a withdrawal rate of 5% per year of follow-up.19
Intention-to-treat analyses compared groups defined by the randomization procedure and

included all participants irrespective of adherence to the assigned intervention or to the
protocol (e.g., use of diabetes or weight-loss medications). Follow-up time for all analyses
was calculated as the time from randomization until the occurrence of the primary outcome,
death, withdrawal, or last follow-up encounter free from diabetes. No imputation was
performed for missing data, but we conducted a sensitivity analysis to assess for
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noninformative censoring of incomplete data (see the Supplementary Appendix).
Because the use of a diabetes-specific medication would be considered a “competing event”

for the primary outcome, we prespecified a sensitivity analysis in which the primary
outcome was the time to new-onset diabetes according to trial criteria or use of a diabetes-
specific medication. As planned in the protocol, we conducted an exploratory per-protocol
analysis that censored follow-up data when a participant stopped the trial pills, started a
diabetes or weight-loss medication, or took out-of-trial vitamin D from supplements above
the trial limit of 1000 IU per day.
The protocol specified that this event-driven trial would continue until the required number
of diabetes events (508) was reached. A prespecified interim analysis for the data and safety
monitoring board to examine harm or superior efficacy with the use of a Haybittle–Peto
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boundary20 was conducted when approximately 70% of the required events (364 of 508) had
accrued, and the data and safety monitoring board recommended that the trial proceed to its
planned conclusion. Because the efficiency of event-driven trials is increased by stopping
when the required number of events is achieved,21 we conducted blinded monitoring of
event count and specified that when the trial was within approximately 2 months of reaching
508 events, the subsequent scheduled follow-up visit for each participant would be
considered the last visit. All events that occurred during the trial, including those that

occurred after the target of 508 events was reached, were used to generate the primary
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results.
Kaplan–Meier estimates were plotted for each group. Cox proportional-hazards models were
used to calculate the hazard ratio for new-onset diabetes between the two groups.22 The
model included group assignment as its main predictor variable and the stratification
variables (trial site, BMI, and race). We also show a model without the stratification
variables. Comparisons between the two groups at baseline and with respect to the rate of
withdrawal, discontinuation of trial pills, use of diabetes or weight-loss medications, and
supplemental intake above the trial limit used Fisher’s exact test, the chi-square test, the
Wilcoxon rank-sum test, or the pooled-variance t-test.
Variability of response to vitamin D supplementation was assessed in prespecified subgroups

defined by key baseline variables. Rates of adverse events were compared between the two
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groups. When evaluating the significance of the prespecified subgroup analyses, we used the
Hochberg sequential procedure to adjust for multiple comparisons, if necessary. No
adjustments were made for the safety analyses or the planned exploratory or post hoc
analyses for the primary outcome; therefore, only point estimates and 95% confidence
intervals are presented without P values.
RESULTS
PARTICIPANTS
From October 2013 through February 2017, a total of 7133 persons were screened (Fig. 1),
and 2423 were randomly assigned to receive vitamin D (1211 participants) or placebo (1212
participants); these participants were included in the intention-to-treat population (Table 1,
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and Table S1 in the Supplementary Appendix). A total of 44.8% of the participants were
women, 33.3% were of non-white race, and 9.3% were of Hispanic ethnic background.24
The participants had a mean age of 60.0 years, a mean BMI of 32.1, and a mean glycated
hemoglobin level of 5.9% (48 mmol per mole). A total of 84.2% of the participants met the
glycemic criteria for both fasting plasma glucose and glycated hemoglobin; approximately
one third met all three glycemic criteria.
The last trial encounter was in November 2018. In the two groups, the median follow-up was
2.5 years (interquartile range, 1.9 to 3.5 [vitamin D] and 1.7 to 3.5 [placebo]). Before
reaching a primary outcome event, 10 participants (5 in each group) died, and 62 (34 in the
vitamin D group and 28 in the placebo group) withdrew consent (Fig. 1). In total, 99.1% of
the cohort (1201 participants in the vitamin D group and 1199 in the placebo group)
contributed follow-up data, through either a visit that included central-laboratory testing or a
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nonvisit encounter to capture a diagnosis of diabetes outside the trial.
The mean baseline level of serum 25-hydroxyvitamin D was 28.0 ng per milliliter (69.9
nmol per liter), with no significant difference between the two groups; 78.3% of the
participants had a level equal to or greater than 20 ng per milliliter (50 nmol per liter) (Table
1). The mean 25-hydroxyvitamin D levels in the vitamin D group at month 12 (52.3 ng per
milliliter [130.5 nmol per liter]) and month 24 (54.3 ng per milliliter [135.5 nmol per liter])

were higher than those in the placebo group (28.1 ng per milliliter [70.1 nmol per liter] and
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28.8 ng per milliliter [71.9 nmol per liter], respectively) (Fig. S1 in the Supplementary
Appendix).
PRIMARY OUTCOME
By the end of the trial, diabetes had developed in 616 patients. New-onset diabetes (the
primary outcome) occurred in 293 participants (273 cases diagnosed by trial-specific
laboratory testing and 20 diagnosed by adjudication) in the vitamin D group and 323
patients (305 cases diagnosed by trial-specific laboratory testing and 18 diagnosed by
adjudication) in the placebo group (9.39 events and 10.66 events per 100 person-years,
respectively). The hazard ratio in the vitamin D group was 0.88 (95% confidence interval
[CI], 0.75 to 1.04; P = 0.12) (Fig. 2). When the stratification variables were not included in
the model, the hazard ratio in the vitamin D group was 0.87 (95% CI, 0.75 to 1.02). In a
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sensitivity analysis to account for missing data, the hazard ratio did not change substantially
(see the Supplementary Appendix).
In the sensitivity analysis in which diabetes was defined as new-onset diabetes according to
trial criteria or the use of a diabetes-specific medication, the hazard ratio in the vitamin D
group was 0.88 (95% CI, 0.75 to 1.02). The results of the subgroup analyses were consistent
with the findings of the main analysis; there was no apparent heterogeneity of treatment
effect across the prespecified subgroups (Fig. 3). In a post hoc analysis of data from
participants with a baseline 25-hydroxyvitamin D level of less than 12 ng per milliliter (30
nmol per liter) (103 participants), the hazard ratio in the vitamin D group was 0.38 (95% CI,
0.18 to 0.80). Among those with a baseline 25-hydroxyvitamin D level equal to or greater
than 12 ng per milliliter (2319 participants), the hazard ratio in the vitamin D group was
0.92 (95% CI, 0.78 to 1.08).
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ADHERENCE
A total of 170 participants (14.0%) in the vitamin D group and 172 (14.2%) in the placebo
group stopped trial pills, took diabetes or weight-loss medications, or took outside-of-trial
vitamin D supplements above the trial limit before the diagnosis of diabetes. During the trial,
more participants in the placebo group than in the vitamin D group started diabetes or
weight-loss medications (Fig. S2 in the Supplementary Appendix). Although overall
adherence to the trial regimen was high (85.8% of prescribed pills were taken), more
participants in the vitamin D group (11.3%) than in the placebo group (8.9%) stopped trial
pills (difference, 2.4 percentage points; 95% CI, 0.0 to 4.8) (Fig. S3 in the Supplementary
Appendix). During follow-up, more participants in the placebo group (5.2%) than in the
vitamin D group (2.6%) reported use of outside-of-trial vitamin D supplements above the
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trial limit of 1000 IU per day (difference, 2.6 percentage points; 95% CI, 1.1 to 4.2) (Fig. S2
in the Supplementary Appendix). There was no significant difference between the two
groups in the use of outside-of-trial calcium supplements above the trial limit.
In the exploratory per-protocol analysis that censored follow-up data when a participant
started a diabetes or weight-loss medication, stopped the trial pills, or took out-of-trial
vitamin D from supplements above the trial limit of 1000 IU per day, the primary outcome

occurred in 265 participants (21.9%) in the vitamin D group and 304 (25.1%) in the placebo
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group (hazard ratio, 0.84; 95% CI, 0.71 to 1.00).
SAFETY
There were no significant between-group differences in the protocol-specified adverse
events of interest: hypercalcemia, a fasting urine calcium:creatinine ratio of more than 0.375,
a low estimated glomerular filtration rate, and nephrolithiasis (Table 2). Overall, 47
participants (3.9%) in the vitamin D group stopped the trial pills because of an adverse
event, as compared with 37 (3.1%) in the placebo group (difference, 0.8 percentage points;
95% CI, −0.7 to 2.3).
DISCUSSION
In this multicenter, randomized, placebo-controlled trial involving persons at high risk for
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type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a

dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo
after a median follow-up of 2.5 years.
While our trial was being conducted, two other trials that were designed to test whether
vitamin D supplementation lowers the risk of type 2 diabetes among persons at risk showed
hazard ratios with vitamin D that were similar to those in our trial.25,26 In the Tromsø
Vitamin D and T2DM Trial (Norway), which randomly assigned 511 white adults with
prediabetes to 20,000 IU per week (approximately 2900 IU per day) of vitamin D3 or
placebo, the risk of diabetes was numerically lower in the vitamin D group than in the
placebo group, but the difference was not significant (hazard ratio, 0.90; 95% CI, 0.69 to
1.18).25 In the Diabetes Prevention with Active Vitamin D study (Japan), which randomly
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assigned 1256 adults with prediabetes to an active form of vitamin D analogue (eldecalcitol)
or placebo, the risk of diabetes was also lower in the vitamin D group than in the placebo
group, but the difference was again not significant (hazard ratio, 0.87; 95% CI, 0.68 to 1.09).
27 We powered our trial to detect a 25% lower risk of diabetes with vitamin D than with
placebo. On the basis of the results from all three trials, vitamin D supplementation may
decrease diabetes risk among persons at risk for diabetes not selected for vitamin D
insufficiency by a smaller effect size (10 to 15%), but none of these trials were powered to
test this effect size.
Our trial has several strengths. We used contemporary glycemic criteria to assemble a
diverse cohort at high risk for diabetes with a hyperglycemic pattern closely matching how
prediabetes is diagnosed in clinical practice, most commonly with fasting plasma glucose
and glycated hemoglobin. The vitamin D dose of 4000 IU per day was selected to balance
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safety and efficacy and resulted in a large difference in the serum 25-hydroxyvitamin D level
between the trial groups in the first 2 years of follow-up. In 94% of cases, the primary
outcome was ascertained by trial-specific laboratory testing based on current ADA criteria
and required two tests in the diabetes range for diagnosis. Our cohort was recruited at a
constant rate throughout the calendar year, which reduced the potential of confounding by
seasonal variability. Finally, the observed rate of new-onset diabetes in the placebo group

(10.7 events per 100 person-years) was consistent with our estimate of 10 events per 100
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person-years.
Overall adherence was high, and overall use of off-protocol concomitant therapies was low.
However, among nonadherent participants, more in the placebo group started diabetes or
weight-loss medications and took outside-of-trial vitamin D supplements above the trial
limit, whereas more in the vitamin D group stopped the trial pills for any reason. Whether
these differences among nonadherent participants shifted the risk difference between the two
groups toward or away from null in the intention-to-treat or per-protocol analysis is
unknown.
Response to a nutritional intervention depends on nutritional status at baseline; thus, if

vitamin D has an effect on diabetes prevention, persons with a higher baseline level of serum
25-hydroxy vitamin D would be expected to have less effect from supplementation than
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those with a lower baseline level.28 Owing to ethical and practical considerations, a lack of
consensus on the preferred 25-hydroxyvitamin D level, and our desire to maximize the
external validity of the trial, we specifically did not include serum 25-hydroxyvitamin D as
an eligibility criterion. Because vitamin D supplements are used increasingly in the U.S.
adult population,29 approximately 8 of 10 participants had a baseline serum 25-hydroxy
vitamin D level that was considered to be sufficient according to current recommendations
(≥20 ng per milliliter) to reduce the risk of many outcomes,23,30 including diabetes.6 The
high percentage of participants with adequate levels of vitamin D may have limited the
ability of the trial to detect a significant effect.
The vitamin D dose of 4000 IU per day is the recommended upper intake level to avert
potential toxicity,23 although data from large trials on the safety on this dose have been
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scant. There is concern that 25-hydroxyvitamin D levels above 50 ng per milliliter (125
nmol per liter) may be associated with adverse effects.23,30 In our trial, vitamin D3
supplementation at a dose of 4000 IU per day resulted in no significant differences between
the two groups in the protocol-specified adverse events of interest (hypercalcemia, a fasting
urine calcium:creatinine ratio of >0.375, a low estimated glomerular filtration rate, and
nephrolithiasis). The 24-hour urine calcium level was not measured.31
In conclusion, among persons at high risk for type 2 diabetes not selected for vitamin D
insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a
significantly lower risk of diabetes than placebo.
Supplementary Material
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Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
The planning phase of the D2d trial was funded by the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) through a multicenter clinical study implementation planning grant to Tufts Medical Center in
Boston (U34DK091958; principal investigator, Dr. Pittas). Planning was also supported, in part, by the Intramural
Research Program of the NIDDK. The conduct of the trial was supported primarily by the NIDDK and the Office of
Dietary Supplements of the National Institutes of Health through the multicenter clinical study cooperative
agreement (U01DK098245; principal investigator, Dr. Pittas) to Tufts Medical Center, where the D2d Coordinating

Center is based. The U01 grant mechanism establishes the NIDDK project scientist (Dr. Staten) as a member of the
D2d Research Group. The trial also received secondary funding from the American Diabetes Association to Tufts
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Medical Center (1-14-D2d-01; principal investigator, Dr. Pittas). Educational materials were provided by the
National Diabetes Education Program.
Dr. Dawson-Hughes reports receiving grant support, paid to Tufts University, from Pfizer and DSM and travel
support from Abiogen Pharma; Dr. Aroda, receiving consulting fees, paid to her institution, from Adocia, grant
support, paid to her institution, and consulting fees from AstraZeneca/Bristol-Myers Squibb, Novo Nordisk, and
Sanofi, consulting fees from BD and Zafgen, and grant support, paid to her institution, from Calibra Medical, Eisai,
Janssen, and Theracos; Dr. Ceglia, receiving grant support from DSM; Dr. Desouza, receiving advisory board fees
from Novo Nordisk; Dr. Kim, receiving consulting fees from Sanofi; Dr. LeBlanc, receiving grant support, paid to
her institution, from Merck; Dr. Neff, receiving grant support from GI Dynamics; Dr. O’Neil, receiving grant
support from Weight Watchers International, advisory board fees from Janssen, advisory board fees and fees for
presentations from Vindico Medical Education, fees for CME programs from WebMD, lecture fees from Robard,
and grant support and lecture fees from Novo Nordisk; Dr. Phillips, receiving grant support and advisory board fees
from Janssen Pharmaceuticals, receiving advisory board fees from Profil Institute for Clinical Research, receiving
grant support from Merck, Amylin Pharmaceuticals, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, AbbVie,
Vascular Pharmaceuticals, GlaxoSmithKline, Pfizer, and Kowa Research Institute, and serving as cofounder, officer,
and board member of and holding stock in Diasyst; and Dr. Pratley, receiving lecture fees, paid to his institution,
and consulting fees, paid to his institution, from AstraZeneca, consulting fees, paid to his institution, from
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Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Janssen, Mundipharma, and Pfizer, grant support, paid to
his institution, from Lexicon Pharmaceuticals, grant support, paid to his institution, and consulting fees, paid to his
institution, from Ligand Pharmaceuticals, Eli Lilly, Merck, and Sanofi, grant support, paid to his institution, and
lecture fees, paid to his institution, from Novo Nordisk and Takeda, and consulting fees from Sanofi US Services.
No other potential conflict of interest relevant to this article was reported.
We thank the D2d investigators, staff, and trial participants for their dedication and commitment to the trial.
Appendix
The authors’ affiliations are as follows: Tufts Medical Center (A.G.P., L.C., P.F., J.N.,
E.M.V.), the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts
University (B.D.-H.), Brigham and Women’s Hospital (V.R.A.), and Harvard School of
Public Health (J.H.W.), Boston, and the Spaulding Rehabilitation Network, Charlestown
(P.S.) — all in Massachusetts; National Institute of Diabetes and Digestive and Kidney
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Diseases, Phoenix, AZ (W.C.K.); the Maine Medical Center (I.B.) and the Maine Medical
Center Research Institute (C.R.) — both in Scarborough; HealthPartners Institute,
Minneapolis (C.C.); Duke University Medical Center, Durham, NC (R.C., R.D.); the
University of Nebraska Medical Center and Omaha Veterans Affairs Medical Center, Omaha
(C.D.); Baylor College of Medicine, Houston (J.F.), and the University of Texas
Southwestern Medical Center, Dallas (P.R.) — both in Texas; MedStar Good Samaritan
Hospital, Baltimore (A.G.), MedStar Health Research Institute, Hyattsville (J.P.), and the
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda (M.S.) — all in
Maryland; Pennington Biomedical Research Center, Baton Rouge, LA (D.S.H.); the
University of Tennessee Health Science Center, Memphis (K.C.J.); Cleveland Clinic,
Cleveland (S.R.K.); Stanford University Medical Center, Stanford (S.K.), and the Keck
School of Medicine of the University of Southern California, Los Angeles (A.P.) — both in
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California; Kaiser Permanente Center for Health Research-Northwest, Portland, OR

(E.S.L.); the University of Vermont, Burlington (M.R.L.); Northwell Health Lenox Hill
Hospital, New York (E.L.); Northwestern University, Chicago (L.M.N.); the Medical
University of South Carolina, Charleston (P.O.); Emory University School of Medicine,
Atlanta, and the Atlanta Veterans Affairs Medical Center, Decatur — both in Georgia
(L.S.P.); AdventHealth Translational Research Institute for Metabolism and Diabetes,
Orlando, FL (R.P.); the University of Colorado Denver and the Veterans Affairs Eastern

Colorado Health Care System, Denver (N.R.); and the University of Kansas Medical Center,
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Kansas City (D.R.).
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7. Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on
pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the
Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin
Nutr 2011; 94: 486–94. [PubMed: 21715514]
8. Seida JC, Mitri J, Colmers IN, et al. Effect of vitamin D3 supplementation on improving glucose
homeostasis and preventing diabetes: a systematic review and meta-analysis. J Clin Endocrinol
Metab 2014; 99: 3551–60. [PubMed: 25062463]
9. Mirhosseini N, Vatanparast H, Mazidi M, Kimball SM. Vitamin D supplementation, glycemic
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11. Pittas AG, Dawson-Hughes B, Sheehan PR, et al. Rationale and design of the Vitamin D and Type
2 Diabetes (D2d) study: a diabetes prevention trial. Diabetes Care 2014; 37: 3227–34. [PubMed:
25205139]
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2010; 33: Suppl 1: S11–S61. [PubMed: 20042772]
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approach for outreach to and recruitment of persons at high risk of type 2 diabetes in clinical trials:
the Vitamin D and Type 2 diabetes (D2d) study experience. Clin Trials 2019; 16: 308–15.
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National Academies Press, 2011.
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26829443]
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Vitamin D (DPVD): a randomised, double-blind, placebo-controlled study. BMJ Open 2016; 6(7):
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content/67/Supplement_1/120-LB).
28. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on
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29. Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in use of high-
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factsheets/VitaminD-HealthProfessional/).
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[PubMed: 21347742]
Author Manuscript

Author Manuscript
Author Manuscript
Author Manuscript
Figure 1. Screening, Randomization, and Follow-up.

One participant in the vitamin D group was withdrawn administratively after a clinical site
closed down early in the trial. Protocol-specified adverse events that led to discontinuation
of the trial pills were hypercalcemia, a fasting urine calcium:creatinine ratio of more than
0.375, a low estimated glomerular filtration rate, and nephrolithiasis. Of the 2423
participants who underwent randomization, 14 (9 in the vitamin D group and 5 in the
Author Manuscript
placebo group) were subsequently found not to meet all eligibility criteria.

Author Manuscript
Author Manuscript
Author Manuscript
Figure 2. Kaplan–Meier Curves for Survival Free from Diabetes among Adults at Risk for Type
2 Diabetes.
The hazard ratio for new-onset diabetes between the vitamin D group and the placebo group
is derived from Cox regression, with stratification according to trial site, body-mass index,
and race.
Author Manuscript

Author Manuscript
Author Manuscript
Author Manuscript
Figure 3. Prespecified Subgroup Analyses.

Participants met at least two of three glycemic criteria for prediabetes: fasting plasma
glucose level, 100 to 125 mg per deciliter (5.6 to 6.9 mmol per liter); plasma glucose level 2
hours after a 75-g oral glucose load, 140 to 199 mg per deciliter (7.8 to 11.0 mmol per liter)
(impaired glucose tolerance); and glycated hemoglobin level, 5.7 to 6.4% (39 to 47 mmol
per mole). To convert the values for 25-hydroxyvitamin D to nanomoles per liter, multiply
by 2.496.
Author Manuscript

Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Table 1.
Baseline Characteristics of the Participants.*
Characteristic Overall (N = 2423) Vitamin D (N = 1211) Placebo (N = 1212)

Pittas et al.
Demographic
Age — yr 60.0+9.9 59.6+9.9 60.4+10.0
Female sex — no. (%) 1086 (44.8) 541 (44.7) 545 (45.0)
Race — no. (%)†

Asian 130 (5.4) 66 (5.5) 64 (5.3)
Black 616 (25.4) 301 (24.9) 315 (26.0)
White 1616 (66.7) 810 (66.9) 806 (66.5)
Other 61 (2.5) 34 (2.8) 27 (2.2)
Hispanic or Latino ethnic group — no. (%)† 225 (9.3) 120 (9.9) 105 (8.7)
Body-mass index 32.1+4.5 32.0+4.5 32.1+4.4

Laboratory assessments
Fasting plasma glucose — mg/dl 107.9+7.4 108.0+7.4 107.8+7.4
2-Hr post-load plasma glucose — mg/dl 137.2+34.3 136.9+34.3 137.6+34.3
Glycated hemoglobin — % 5.9+0.2 5.9+0.2 5.9+0.2
Serum 25-hydroxyvitamin D
Mean — ng/ml 28.0+10.2 27.7+10.2 28.2+10.1
Distribution — no./total no. (%)‡

<12 ng/ml 103/2422 (4.3) 60/1211 (5.0) 43/1211 (3.6)
12–19 ng/ml 422/2422 (17.4) 216/1211 (17.8) 206/1211 (17.0)

20–29 ng/ml 876/2422 (36.2) 453/1211 (37.4) 423/1211 (34.9)
≥30 ng/ml 1021/2422 (42.2) 482/1211 (39.8) 539/1211 (44.5)
*
Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for 25-
hydroxyvitamin D to nanomoles per liter, multiply by 2.496.
†
Race and ethnic group were reported by the participant. The category “other” includes American Indian or Alaska Native; Native Hawaiian or other Pacific Islander; and other race. Ethnic group includes
any race.
‡
Categories of serum 25-hydroxyvitamin D are based on the 2010 Dietary Reference Intakes for calcium and vitamin D recommended by the Food and Nutrition Board of the Institute of Medicine.23
Page 16
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Table 2.
Protocol-Specified Adverse Events.
Incidence Rate Ratio for

Pittas et al.
Event Vitamin D (N = 1211) Placebo (N =1212) Vitamin D vs. Placebo

(95% Cl)
Participants with ≥1 Participants with
No. of Events Event Rate No. of Events Event Rate
Event ≥1 Event
no./100 person-
no./100 person-yr no. no.
yr
Any adverse event leading to
47 1.51 37 1.22 1.23 (0.80–1.90)
discontinuation of the trial pills
Within-trial laboratory evaluation*

Hypercalcemia 5 0.16 5 3 0.10 3 1.62 (0.39–6.77)
Fasting urine calcium:creatinine ratio
1 0.03 1 1 0.03 1 0.97 (0.06–15.52)
>0.375
Low estimated glomerular filtration
1 0.03 1 2 0.07 2 0.48 (0.04–5.36)
rate
Nephrolithiasis, participant-reported 25 0.80 24 21 0.69 20 1.16 (0.65–2.07)
Serious adverse event 235 7.53 173 228 7.52 153 1.00 (0.83–1.20)
Death 5 0.16 5 0.17 0.97 (0.28–3.35)
*
Hypercalcemia was defined as a serum calcium level (uncorrected for albumin level) higher than the upper limit of the normal range for the clinical laboratory at each clinical site. The fasting morning
urine calcium:creatinine ratio was measured by the central laboratory. A low estimated glomerular filtration rate was defined as a rate equal to or lower than 30 ml per minute per 1.73 m2 of body-surface
area based on serum creatinine measured at the clinical laboratory at each clinical site.

Page 17
Escala de PEDro – Português (Brasil)
1. Os critérios de elegibilidade foram especificados não! sim! onde:
2. Os sujeitos foram aleatoriamente distribuídos por grupos (num estudo

cruzado, os sujeitos foram colocados em grupos de forma aleatória de
acordo com o tratamento recebido) não! sim! onde:
3. A alocação dos sujeitos foi secreta não! sim! onde:
4. Inicialmente, os grupos eram semelhantes no que diz respeito aos

indicadores de prognóstico mais importantes não! sim! onde:
5. Todos os sujeitos participaram de forma cega no estudo não! sim! onde:
6. Todos os terapeutas que administraram a terapia fizeram-no de forma

cega não! sim! onde:
7. Todos os avaliadores que mediram pelo menos um resultado-chave,

fizeram-no de forma cega não! sim! onde:
8. Mensurações de pelo menos um resultado-chave foram obtidas em mais de

85% dos sujeitos inicialmente distribuídos pelos grupos não! sim! onde:
9. Todos os sujeitos a partir dos quais se apresentaram mensurações de resultados

receberam o tratamento ou a condição de controle conforme a alocação
ou, quando não foi esse o caso, fez-se a análise dos dados para pelo menos
um dos resultados-chave por “intenção de tratamento” não! sim! onde:
10. Os resultados das comparações estatísticas inter-grupos foram descritos

para pelo menos um resultado-chave não! sim! onde:
11. O estudo apresenta tanto medidas de precisão como medidas de

variabilidade para pelo menos um resultado-chave não! sim! onde:
A escala PEDro baseia-se na lista de Delphi, desenvolvida por Verhagen e colegas no Departamento de Epidemologia, da
Universidade de Maastricht (Verhagen AP et al (1988). The Delphi list: a criteria list for quality assessment of randomised
clinical trials for conducting systematic reviews developed by Delphi consensus. Journal of Clinical Epidemiology,
51(12):1235-41). A lista, na sua maior parte, baseia-se num “consenso de peritos” e não em dados empíricos. Incluíram-se na
escala de PEDro dois itens adicionais, que não constavam da lista de Delphi (os itens 8 e 10 da escala de PEDro). À medida
que forem disponibilizados mais dados empíricos, pode vir a ser possível ponderar os itens da escala de forma a que a
pontuação obtida a partir da aplicação da escala PEDro reflita a importância de cada um dos itens da escala.
O objetivo da escala PEDro consiste em auxiliar os utilizadores da base de dados PEDro a identificar rapidamente quais dos
estudos controlados aleatorizados, ou quase-aleatorizqados, (ou seja, ECR ou ECC) arquivados na base de dados PEDro
poderão ter validade interna (critérios 2-9), e poderão conter suficiente informação estatística para que os seus resultados
possam ser interpretados (critérios 10-11). Um critério adicional (critério 1) que diz respeito à validade externa (ou “potencial
de generalização” ou “aplicabilidade” do estudo clínico) foi mantido para que a Delphi list esteja completa, mas este critério
não será usado para calcular a pontuação PEDro apresentada no endereço PEDro na internet.
A escala PEDro não deverá ser usada como uma medida da “validade” das conclusões de um estudo. Advertimos, muito
especialmente, os utilizadores da escala PEDro de que estudos que revelem efeitos significativos do tratamento e que obtenham
pontuação elevada na escala PEDro não fornecem, necessariamente, evidência de que o tratamento seja clinicamente útil.
Adicionalmente, importa saber se o efeito do tratamento foi suficientemente expressivo para poder ser considerado
clinicamente justificável, se os efeitos positivos superam os negativos, e aferir a relação de custo-benefício do tratamento. A
escala não deve ser utilizada para comparar a “qualidade” de estudo clínicos realizados em diferentes áreas de terapia,
principalmente porque algumas áreas da prática da fisioterapia não é possível satisfazer todos os itens da escala.
Modificada pela última vez em 21 de Junho de 1999

Tradução em Português vez em 13 de Maio de 2009
Ajustes ortográficos para a versão Português-Brasileiro em 12 de Agosto de 2010
Indicações para a administração da escala PEDro:
Todos os critérios A pontuação só será atribuída quando um critério for claramente satisfeito. Se numa leitura literal do
relatório do ensaio existir a possibilidade de um critério não ter sido satisfeito, esse critério não deve
receber pontuação.
Critério 1 Este critério pode considerar-se satisfeito quando o relatório descreve a origem dos sujeitos e a lista de
requisitos utilizados para determinar quais os sujeitos eram elegíveis para participar no estudo.
Critério 2 Considera-se que num determinado estudo houve alocação aleatória se o relatório referir que a alocação
dos sujeitos foi aleatória. O método de aleatoriedade não precisa de ser explícito. Procedimentos tais como
lançamento de dados ou moeda ao ar podem ser considerados como alocação aleatória. Procedimentos de
alocação quase-aleatória tais como os que se efetuam a partir do número de registo hospitalar, da data de
nascimento, ou de alternância, não satisfazem este critério.
Critério 3 Alocação secreta significa que a pessoa que determinou a elegibilidade do sujeito para participar no ensaio
desconhecia, quando a decisão foi tomada, o grupo a que o sujeito iria pertencer. Deve atribuir-se um
ponto a este critério, mesmo que não se diga que a alocação foi secreta, quando o relatório refere que a
alocação foi feita a partir de envelopes opacos fechados ou que a alocação implicou o contato com o
responsável pela alocação dos sujeitos por grupos, e este último não participou do ensaio.
Critério 4 No mínimo, nos estudos de intervenções terapêuticas, o relatório deve descrever pelo menos uma medida
da gravidade da condição a ser tratada e pelo menos uma (diferente) medida de resultado-chave que
caracterize a linha de base. O examinador deve assegurar-se de que, com base nas condições de
prognóstico de início, não seja possível prever diferenças clinicamente significativas dos resultados, para
os diversos grupos. Este critério é atingido mesmo que somente sejam apresentados os dados iniciais do
estudo.
Critérios 4, 7-11 Resultados-chave são resultados que fornecem o indicador primário da eficácia (ou falta de eficácia) da
terapia. Na maioria dos estudos, utilizam mais do que uma variável como medida de resultados.
Critérios 5-7 Ser cego para o estudo significa que a pessoa em questão (sujeito, terapeuta ou avaliador) não conhece
qual o grupo em que o sujeito pertence. Mais ainda, sujeitos e terapeutas só são considerados “cegos” se
for possível esperar-se que os mesmos sejam incapazes de distinguir entre os tratamentos aplicados aos
diferentes grupos. Nos ensaios em que os resultados-chave são relatados pelo próprio (por exemplo, escala
visual análoga, registo diário da dor), o avaliador é considerado “cego” se o sujeito foi “cego”.
Critério 8 Este critério só se considera satisfeito se o relatório referir explicitamente tanto o número de sujeitos
inicialmente alocados nos grupos como o número de sujeitos a partir dos quais se obtiveram medidas de
resultados-chave. Nos ensaios em que os resultados são medidos em diferentes momentos no tempo, um
resultado-chave tem de ter sido medido em mais de 85% dos sujeitos em algum destes momentos.
Critério 9 Uma análise de intenção de tratamento significa que, quando os sujeitos não receberam tratamento (ou a
condição de controle) conforme o grupo atribuído, e quando se encontram disponíveis medidas de
resultados, a análise foi efetuada como se os sujeitos tivessem recebido o tratamento (ou a condição de
controle) que lhes foi atribuído inicialmente. Este critério é satisfeito, mesmo que não seja referida a
análise por intenção de tratamento, se o relatório referir explicitamente que todos os sujeitos receberam o
tratamento ou condição de controle, conforme a alocação por grupos.
Critério 10 Uma comparação estatística inter-grupos implica uma comparação estatística de um grupo com outro.
Conforme o desenho do estudo, isto pode implicar uma comparação de dois ou mais tratamentos, ou a
comparação do tratamento com a condição de controle. A análise pode ser uma simples comparação dos
resultados medidos após a administração do tratamento, ou a comparação das alterações num grupo em
relação às alterações no outro (quando se usou uma análise de variância para analisar os dados, esta última
é frequentemente descrita como interação grupo versus tempo). A comparação pode apresentar-se sob a
forma de hipóteses (através de um valor de p, descrevendo a probabilidade dos grupos diferirem apenas
por acaso) ou assumir a forma de uma estimativa (por exemplo, a diferença média ou a diferença mediana,
ou uma diferença nas proporções, ou um número necessário para tratar, ou um risco relativo ou um razão
de risco) e respectivo intervalo de confiança.
Critério 11 Uma medida de precisão é uma medida da dimensão do efeito do tratamento. O efeito do tratamento pode
ser descrito como uma diferença nos resultados do grupo, ou como o resultado em todos os (ou em cada
um dos) grupos. Medidas de variabilidade incluem desvios-padrão (DP’s), erros-padrão (EP’s), intervalos
de confiança, amplitudes interquartis (ou outras amplitudes de quantis), e amplitudes de variação. As
medidas de precisão e/ou as medidas de variabilidade podem ser apresentadas graficamente (por exemplo,
os DP’s podem ser apresentados como barras de erro numa figura) desde que aquilo que é representado
seja inequivocamente identificável (por exemplo, desde que fique claro se as barras de erro representam
DP’s ou EP’s). Quando os resultados são relativos a variáveis categóricas, considera-se que este critério foi
cumprido se o número de sujeitos em cada categoria é apresentado para cada grupo.

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Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: A

To appear in: Sleep Medicine

Received Date: 30 July 2020

© 2020 Published by Elsevier B.V.

3. Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai, China.

*These authors contributed equally to this article.

zhmtiger@126.com. Tel: 008602124058706.

Email:drzhangwt@163.com. Tel: 008602124058706

Email:guanjian0606@sina.com. Tel: 008602124058706.

Results: Melatonin supplementation significantly decreased early wake time

[95% CI, -13.47% to -0.68%]; P = 0.031). However, melatonin had no significant

circadian rhythmic functions or the calcification of the pineal gland.[7-9] As

age might contribute to insomnia in elderly subjects.[10, 11] Thus exogenous

melatonin has been prompt to make benefits on sleep in insomnia patients.[12]

The PSG was equipped with electroencephalography (EEG) channels, submental

electromyography (EMG) channels, bilateral electrooculogram (EOG) channels, and

electrocardiography (ECG) channels, nasal pressure transducer, oronasal thermistor,

symptoms[25]. The PSQI is a self-rating scale, composed of 19 self-rated items (0-3

efficiency, sleep quality, sleep disturbances, medication, and daytime dysfunction) in

collected and verified for analyses.

Polysomnographic sleep variable: For sleep induction variables, there were no

On polysomnographic recordings, sleep onset latency was not improved in

mimic the physiological release of melatonin by releasing melatonin gradually and

release of melatonin 2 mg was effective in younger adult patients with insomnia, we

The authors have nothing to disclose.

1995/07/01. PubMed PMID: 7481413.

psychopharmacology. 2009;24(5):239-49. doi: 10.1097/YIC.0b013e32832e9b08. PubMed PMID:

polysomnographic randomized controlled trials. CNS drugs. 2014;28(9):799-816. doi:

10.1007/s40263-014-0198-7. PubMed PMID: 25168785.

double-blind, placebo-controlled, crossover study. 2003;28(3):191-6.

Sleep latency (min) 51.01±39.44 31.80±24.49 l P

Component 1 1.47±0.72 1.31±0.59 a 1.48±0.74 1.28±0.53 -0.05(-0.45, 0.34) 0.092

1. Os critérios de elegibilidade foram especificados não! sim! onde:

2. Os sujeitos foram aleatoriamente distribuídos por grupos (num estudo

3. A alocação dos sujeitos foi secreta não! sim! onde:

4. Inicialmente, os grupos eram semelhantes no que diz respeito aos

5. Todos os sujeitos participaram de forma cega no estudo não! sim! onde:

6. Todos os terapeutas que administraram a terapia fizeram-no de forma

7. Todos os avaliadores que mediram pelo menos um resultado-chave,

8. Mensurações de pelo menos um resultado-chave foram obtidas em mais de

9. Todos os sujeitos a partir dos quais se apresentaram mensurações de resultados

10. Os resultados das comparações estatísticas inter-grupos foram descritos

11. O estudo apresenta tanto medidas de precisão como medidas de

Modificada pela última vez em 21 de Junho de 1999

Published in final edited form as:

Vitamin D Supplementation and Prevention of Type 2 Diabetes

Medical Center, Kansas City (D.R.).

number of diabetes events of 508.

N Engl J Med. Author manuscript; available in PMC 2020 February 08.

D supplementation improved the disposition index, a measure of pancreatic beta-cell

No pharmaceutical manufacturers contributed to the planning, design, or conduct of the trial.

Trial pills were purchased from an independent nutritional-supplement manufacturing

A low serum 25-hydroxyvitamin D level was not an inclusion criterion.

N Engl J Med. Author manuscript; available in PMC 2020 February 08.

recruitment process relied primarily on electronic-health-record identification of potentially

INTERVENTION AND PROCEDURES

N Engl J Med. Author manuscript; available in PMC 2020 February 08.

Intention-to-treat analyses compared groups defined by the randomization procedure and

noninformative censoring of incomplete data (see the Supplementary Appendix).

Because the use of a diabetes-specific medication would be considered a “competing event”

N Engl J Med. Author manuscript; available in PMC 2020 February 08.

Variability of response to vitamin D supplementation was assessed in prespecified subgroups