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ARTICLE IN PRESS

Sleep Medicine ■■ (2015) ■■–■■

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Sleep Medicine
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p

Original Article

Management of augmentation of restless legs syndrome with


rotigotine: a 1-year observational study
Claudia Trenkwalder a,*, Monica Canelo b, Michael Lang c, Hanna Schroeder d,
Daniela Kelling d, Reinhard Berkels d, Erwin Schollmayer d, Tanja Heidbrede d,
Heike Benes e
a
UMG Department of Neurosurgery, Göttingen and Paracelsus-Elena-Klinik, Kassel, Germany
b Paracelsus-Elena-Klinik, Kassel, Germany
c
NeuroPoint Patient Academy and Neurological Practice, Ulm, Germany
d UCB Pharma, Monheim am Rhein, Germany
e
Somni Bene Institut fur Medizinische Forschung und Schlafmedizin, Schwerin, Germany and Rostock University, Medical Center, Rostock, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Aim: The aim of this study is to assess the effect of switching to rotigotine transdermal patch on sever-
Received 28 April 2015 ity of restless legs syndrome (RLS) in patients who experienced acute augmentation with previous oral
Received in revised form 20 October 2015 dopaminergics.
Accepted 27 October 2015
Methods: In this 13-month observational study, adults with moderate-to-severe RLS and augmentation
Available online
were switched to rotigotine per the physician’s independent decision. Assessments included Clinical Global
Impression severity score (CGI-1); (primary), treatment regimen for switching (secondary), RLS-6,
Keywords:
International RLS Study Group Rating Scale (IRLS), and augmentation severity rating scale (ASRS).
Restless legs syndrome
Augmentation Results: A total of 99 patients received rotigotine, of whom 46 completed observational period, and 43
Dopamine receptor agonist were assessed for effectiveness. A total of 5 patients switched to rotigotine after a >1-day drug holiday,
23 switched overnight, 9 had an overlapping switch, and 6 received ongoing oral dopaminergics with
rotigotine for ≥28 days. Of the 99 patients, 57 took concomitant RLS medications (excluding switching
medications) on at least 1 day. At the final visit, median change in CGI-1 (Hodges–Lehman estimate [95%
CI]) was −2.0 (–2.5, −1.50); 37 of the 43 patients improved by ≥1 CGI-1 category, and 16 of 43 were re-
sponders (≥50% improvement). RLS-6 and IRLS scores also improved. Patients had median ASRS of 0 at
the final visit indicating “no worsening/occurrence of augmentation.” ASRS item 1 showed a shift in mean
time of symptom onset (24-h clock) from 12:38 (baseline) to 18:25 (final visit). Most common reasons
for withdrawal of rotigotine were adverse events (26 patients) and lack of efficacy (14 patients).
Conclusions: Switching from oral therapies to rotigotine was effective in improving RLS symptoms in 37
of the 43 patients (from the original population of 99 patients) who remained in the study over 13 months.
Clinical trial registration: ClinicalTrials.gov NCT01386944.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction for RLS in certain European countries, including Germany [2].


A recent meta-analysis confirmed the efficacy of these therapies
Three non-ergot dopamine receptor agonists (ropinirole [3]. Augmentation can be a major complication of long-term
immediate-release [IR], pramipexole IR, and rotigotine transder- dopaminergic therapy for RLS, and is characterized by an overall
mal patch) are approved for the symptomatic treatment of moderate worsening of symptoms beyond the severity experienced
to severe idiopathic restless legs syndrome (RLS) in the European before treatment [4]. Clinical features of augmentation, defined
Union and in the USA, and are recommended as first-line thera- by the International Restless Legs Syndrome Study Group (IRLSSG),
pies [1]. In addition, the dopamine precursor levodopa is indicated include increased symptom intensity, the emergence of symp-
toms earlier in the day, a shorter latency to symptom onset during
periods of inactivity, the spread of symptoms to areas of the body
that were previously unaffected, and a shorter duration of medi-
* Corresponding author. Center of Parkinsonism and Movement Disorders,
cation effect [4].
Paracelsus Elena-Klinik Kassel, Klinikstrasse 16, Kassel, Germany. Tel.: +49 (0) 561
600 9201; fax: +49 (0) 561 600 9126. While the pathophysiology of augmentation is still not fully
E-mail address: ctrenkwalder@gmx.de (C. Trenkwalder). understood, dopaminergic hyperstimulation is thought to play a key

http://dx.doi.org/10.1016/j.sleep.2015.10.006
1389-9457/© 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006
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role [5], and dopaminergic therapy appears to be the main risk factor. patient. Visit 1 (baseline) took place at the time of the decision to
With the exception of a few documented cases with the α-2-δ ligand switch to rotigotine, Visit 2 around 1–7 days post baseline (corre-
pregabalin [6] and the opioid tramadol [7], augmentation has not sponding to withdrawal from oral dopaminergic treatment, with or
been reported with non-dopaminergic agents. It should be noted without concomitant rotigotine), and Visit 3 up to 28 days post base-
that this treatment complication has been seen under placebo treat- line (corresponding to the end of the rotigotine titration phase),
ment in several double-blind studies, indicating limited specificity followed by four quarterly visits in accordance with routine medical
of the currently available assessment methods [8]. Potential risk practice (eg, Visit 4: ~ 4 months, Visit 5: ~ 7 months, Visit 6: ~ 10
factors for augmentation include dopaminergic treatment, dose and months, and Visit 7: ~ 13 months post baseline). As the study was
duration of treatment, and low ferritin levels [5,9–11]. Although observational, no washout of previous dopaminergic medications
comparative data are limited, the incidence of augmentation appears was conducted, and all changes in treatment regimen were at the
to be higher with levodopa than with longer-acting dopamine physician’s discretion.
receptor agonists [8,12]. As higher dopaminergic dosages may in-
crease the likelihood of developing augmentation [13,14], doses 2.2. Patients
should be kept as low as possible and should not exceed the limit
recommended by regulatory authorities [12,15]. Inclusion criteria were as follows: (1) adult patients with a
According to present recommendations, RLS treatment may be diagnosis of moderate or severe RLS; (2) augmentation due to pre-
initiated with either a dopaminergic receptor agonist or an α-2-δ vious oral dopaminergic therapy; (3) the physician’s treatment
ligand (gabapentin enacarbil, approved in the USA and Japan only) decision was made before the patient was included in the study and
[12,16]. Should clinically significant augmentation develop, a change was independent of study participation; and (4) the patient had
in treatment regimen may be required [17]. With the exception of been informed and had given written informed consent for the
case studies [18–20], no data are presently available on when and additional use of his/her medical data. Patients were excluded if they
how to switch patients with augmentation to an alternative therapy. had a diagnosis of secondary RLS or a confirmed iron deficiency
Therefore, recommendations for augmentation management are (serum ferritin levels were documented if available). The study
based on clinical experience. According to expert opinion, was conducted in accordance with Good Clinical Practice and the
patients on levodopa are advised to switch to a dopamine recep- Declaration of Helsinki, and the observational plan was reviewed
tor agonist or a non-dopaminergic agent such as an opioid or α-2-δ by national and local Independent ethics committees.
ligand [2,13].
Clinical studies have indicated low incidence of augmentation 2.3. Outcome measures
with rotigotine, the only long-acting dopamine agonist approved
for RLS [14,21]. Continuous delivery of rotigotine via a transder- The primary outcome measure was the change from baseline in
mal patch maintains stable plasma levels over 24 h [22] In a 5-year Clinical Global Impression severity score (CGI-1; seven-point scale)
open-label study, clinically significant augmentation (Max Planck [25] over the course of the study. The change in treatment regimen
Institute criteria) was seen in 39 (13%) patients on rotigotine, of used for switching to rotigotine (assessed up to 28 days after
whom 15 (5%) were administered a dose within the licensed range entering the study) was defined as the secondary outcome. Other
of 1–3 mg/24 h [14]. The present pilot study was conducted to offer variables included CGI-1 responders (≥50% decrease in CG1-1 score
exploratory data for rotigotine in patients who experienced relative to baseline), the time taken to switch to rotigotine, change
augmentation with their previous oral dopaminergic therapy. This in RLS-6 Scale [26] scores over the course of the study, and change
observational study was conducted to assess the effects of switch- in International RLS Study Group Rating Scale (IRLS) [27] scores at
ing to the rotigotine patch on RLS symptom severity in patients with Visit 5 (~7 months) and 7 (~13 months). Augmentation Severity
augmentation and report data on the management of augmenta- Rating Scale (ASRS)[ [28] total score over the course of the study
tion in routine clinical practice. was assessed in comparison to RLS symptom severity at the base-
line visit, although this use of the scale has not been validated. In
2. Methods addition to the predefined study outcomes, a post hoc assessment
of ASRS item 1 (“During the past week, at what time did your RLS
2.1. Design symptoms usually start?”) was performed. Safety assessments in-
cluded incidence of adverse events (AEs) and serious AEs. AEs were
AURORA (ClinicalTrials.gov: NCT01386944) was a 13-month coded using Medical Dictionary for Regulatory Activities (MedDRA).
observational study conducted in German neurology centers. Serious AEs were defined as any AEs (irrespective of a suspected
Feasibility assessments were carried out to ensure that all partici- causal relationship to rotigotine) that led to death or were life threat-
pating physicians had particular expertise in the diagnosis and ening, required inpatient hospitalization or prolonged existing
treatment of patients with RLS and augmentation. Physicians fol- hospitalization, led to persistent or significant disability or inca-
lowed routine practice in reaching treatment decisions and treating pacity, led to a congenital anomaly or birth defect, or were considered
their patients. Due to preexisting augmentation, the physician made to be clinically significant or important. Finally, we performed a post
the decision to switch to treatment with rotigotine. This decision hoc analysis of the doses of oral dopaminergic medications taken
was made before including the patients in the study; therefore, study at the time of initiation of rotigotine. Levodopa-equivalent doses
participation did not influence the patient’s medical treatment. Pa- were calculated per Tomlinson et al [29].
tients received oral dopaminergic therapy as either monotherapy
or in combination with other medications up to the time of the 2.4. Statistical analyses
switch. According to the routine medical practice, characteristics
of augmentation (National Institutes of Health [NIH] minimal Following an amendment to the original observational plan, ob-
criteria) were documented at baseline [23]. Treatment according to servation of 120 patients was planned with the goal of obtaining
the European Summary of Product Characteristics for rotigotine valid data from at least 60 patients at the end of the study. Based
transdermal patch was recommended [24]. Patients were evalu- on the 40% withdrawal rate observed in a 3-month observational
ated per routine medical practice and no additional diagnostic or study of rotigotine in RLS, a withdrawal rate of 50% was assumed
monitoring procedures were applied. A total of seven study visits [30]. All statistical analyses of the study variables were explorato-
were recommended, with an observational period of 13 months per ry in nature. Therefore, no references to statistical significance levels

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006
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are presented. Absolute and relative frequencies were calculated for Enrolment
categorical variables, and summary statistics were provided for con- 102 patients
tinuous variables. Data were reported “as observed,” that is, no
missing value imputations were performed. For the primary outcome, Baseline
the Hodges–Lehmann method was used to construct the exact 99 patients
95% confidence interval (CI) around the median change in CGI-1
Discontinuationsa
from baseline to each post-baseline visit. An exact 95% CI for the
Rotigotine withdrawn: 45 patients
probability of a CGI-1 response was calculated using the method Due to adverse events: 26 patients
of Clopper–Pearson. Lack of efficacy: 14 patients
Analyses of effectiveness were performed for the eligibility com- Other reason: 5 patients
pleter set, which included all patients who received treatment with Lost to follow-up: 8 patients
rotigotine at least once and completed the study (i.e., had a Other: 3 patients
measurement for the primary outcome at the last visit (Visit 7), and
Completed study period
excluded those with concomitant Parkinson’s disease or treated for 46 patients
polyneuropathy. In addition, an analysis of effectiveness was
performed for the full analysis set, which included all patients who Analyzed for effectiveness
received treatment with rotigotine at least once, and who had a Full analysis set: 97 patients
baseline measurement and at least one post-baseline measure- Eligibility completer set: 43 patientsb
ment for the primary outcome. Safety data were reported for all aIncludes 3 patients who discontinued prior to baseline.
patients who received at least one application of the rotigotine patch. bThree study completers were excluded from the eligibility completer set due to concomitant
Parkinson’s disease.
3. Results
Fig. 1. Patient disposition.

3.1. Patients

This study was conducted between July 2011 and August 2013. benserazide/levodopa (20 patients), pramipexole (16), tilidine (10),
A total of 102 patients were included from 18 sites in Germany, of ropinirole (eight), and pregabalin (six). Few patients took opiates/
whom 99 received rotigotine. Patients had a median RLS duration opioids other than tilidine (oxycodone: four patients; tramadol: four
of 5.8 years and had received their preexisting oral dopaminergic patients; morphine: one patient) and/or benzodiazipines
therapy for a median of 513.5 days (~73.4 weeks). Baseline CGI-1, (bromazepam: one patient; clonazepam: one patient; oxazepam:
RLS-6, and IRLS scores indicated severe RLS symptoms consistent one patient). Supplementary Table S1 shows concomitant medica-
with augmentation (Table 1). tions with regular intake (treatment duration of ≥1 week) used for
During the observational period, 57 of the 99 patients received the treatment of RLS (following international guidelines).
concomitant medications for RLS (excluding medications to be Discontinuation before the end of the 13-month observational
switched) on at least one day; medications taken by ≥5 patients were period was documented in 56 of the 102 enrolled patients, of whom
45 were withdrawn from rotigotine therapy (26 due to AEs; 14 due
to lack of efficacy; five due to other reasons); eight patients were
lost to follow-up, and three withdrew due to unknown reasons. A
Table 1
Baseline characteristics.
total of 46 patients completed the 13-month study (Fig. 1). The el-
igibility completer set consisted of 43 patients, as three study
All patients (n = 99)
completers were excluded due to concomitant Parkinson’s disease.
Age, mean ± SD, years 64.2 ± 11.1 In total, 97 patients were included in the full analysis set.
Age ≥65 years, n (%) 53 (53.5)
Female, n (%) 68 (68.7)
Duration of RLS, median (range), yearsa 5.8 (0–22.8) 3.2. Effectiveness
513.5 (17–7406)

Full analysis set Eligibility


Over the course of the study (Fig. 2), mean CGI-1 scores were
(n = 97) completer comparable for the eligibility completer set and the full analysis set.
set (n = 43) Among the 43 eligible study completers, the mean (standard
CGI-1 score (1–7), mean ± SD 5.2 ± 0.7 5.3 ± 0.7 deviation (SD)) change from baseline to the final visit (Visit 7) was
CGI-1 severity category, n (%) −1.9 ± 1.3, and the median change (Hodges–Lehman estimate [95%
Moderately ill 17 (17.5) 6 (14.0) CI]) was −2.0 (−2.5, −1.5). At the final visit, 37 of the 43 patients had
Markedly ill 46 (47.4) 19 (44.2)
improved by at least one CGI-1 category (27 of the 43 patients
Severely ill 32 (33.0) 17 (39.5)
Among the most extremely ill 2 (2.1) 1 (2.3) improved by two or more categories), with 16 of the 43 patients
IRLS score (0–40), mean ± SD 27.8 ± 6.2 29.2 ± 5.4 classified as CGI-1 responders (≥50% improvement in score). Overall,
IRLS score (0–40), median (range) 28.0 (9–39) 29.0 (18–39) 28 of the 43 patients improved to a category of “borderline” (eight
RLS-6 item scores (0–10), mean ± SD patients) or “mildly ill” (20 patients). At the final visit, numerical
Item 1: Satisfaction with sleep 6.7 ± 2.4 6.9 ± 2.3
improvements were also observed in all RLS-6 item scores (Fig. 3).
Item 2: Symptom severity when falling 5.7 ± 2.8 6.4 ± 2.8
asleep Among patients in the eligibility completer set, mean IRLS score was
Item 3: Symptom severity during night 5.5 ± 2.8 5.8 ± 2.8 reduced from 29.2 ± 5.4 at baseline to 14.3 ± 9.2 at Visit 5 (~7 months)
Item 4: Symptom severity during the day 5.1 ± 2.6 5.4 ± 2.5 (mean change: −14.8 ± 8.6) and 16.6 ± 9.7 at the final visit (mean
when at rest
change: −12.7 ± 7.5) (Fig. 4). Mean change in IRLS score for the full
Item 5: Symptom severity during the day 2.3 ± 2.4 2.3 ± 2.5
when active analysis set was −13.9 ± 9.4 at Visit 5 and −12.4 ± 7.6 at the final visit
Item 6: Daytime sleepiness and tiredness 5.4 ± 2.8 5.9 ± 2.6 (Fig. 4). As defined by the NIH criteria, all patients in the eligibility
SD = standard deviation; RLS = restless legs syndrome; CGI = Clinical Global Im-
completer set were experiencing augmentation at baseline (Table 2).
pression; IRLS = International RLS Study Group Rating Scale. Fig. 5 shows ASRS scores over time. At the final visit, patients had
a Time since diagnosis.
a median ASRS score of 0 (mean ± SD: 1.2 ± 2.7), indicating “no

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006
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A. Eligibility completer set (n = 43) before rotigotine initiation. The nine patients with an “overlap-
7 ping switch” received overlapping treatment for a mean of 25.9 ± 48.6
days (median: six days; range: 1–147 days). In total, 15 patients con-
tinued to receive their existing oral dopaminergic medication at the
6
time of initiation of rotigotine (ie, had an “overlapping switch” or
Mean CGI-1 score (± SD)

ongoing oral dopaminergic treatment). Of the 15, eight were on

Improvement
5 levodopa monotherapy (mean daily dose: 215.6 ± 83.4), six were on
dopamine agonist monotherapy (mean daily levodopa equivalent
4 dose: 102.7 ± 88.6), and one was receiving levodopa in combina-
tion with a dopamine agonist (mean daily levodopa equivalent dose:
3 635.0 mg).
Following titration (~28 days post baseline), the dose of rotigotine
was 1 mg/24 h for 11 (25.6%) patients, 2 mg/24 h for 18 (41.9%), and
2 3 mg/24 h for 12 (27.9%) (two patients in the eligibility completer
set had a dose of 4 mg/24 h, which is out with the dosage range
1 approved by the European Medical Association). Overall, 19 pa-
tients in the eligibility completer set had no further dose changes,
0 22 had at least one dose increase, and two had at least one dose
Baseline Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(~1-7 days) (~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
decrease. Table 4 shows switching and dosing data for the eligibil-
(n = 43) (n = 42) (n = 42) (n = 38) (n = 43) (n = 41) (n = 43) ity completer set and full analysis set.
B. Full analysis set (n = 97)
7 3.4. Safety and tolerability

Adverse events were reported by 68 of the 99 patients, of whom


6
53 experienced an AE that was considered by the investigator to
Mean CGI-1 score (± SD)

be treatment related. AEs reported by ≥5 patients were applica-


Improvement

5 tion site reactions (ASRs) (MedDRA High-Level Term: application


and instillation site reactions; 33 patients), nausea (13 patients),
4 fatigue (nine patients), and headache (six patients). Overall, 33 of
the 99 patients experienced a total of 48 skin reactions, none of
3 which were considered to be serious. The most common skin
reactions were erythema (15), ASRs (nine), and pruritus (eight). In
total, 30 of the 99 patients reported an AE that led to their discon-
2
tinuation. AEs reported as a reason for discontinuation by ≥2 patients
were ASRs (19 patients), nausea (three), RLS (three), fatigue (two),
1 malaise (two), and peripheral edema (two). ASRs leading to
discontinuation most commonly began during the first month of
0 treatment (time of onset; ≤ 1 month: five patients; > 1– ≤ 2 months:
Baseline Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(~1-7 days) (~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
two patients; > 2– ≤ 3 months: three patients; > 3–≤ 4 months: three
(n = 97) (n = 89) (n = 77) (n = 58) (n = 52) (n = 45) (n = 46) patients; > 4– ≤ 11 months: 0–2 patients per month).
A total of 23 serious AEs were reported by nine patients. Serious
Fig. 2. CGI-1 scores over the course of the study. CGI, Clinical Global Impression; AEs occurring in more than one patient (MedDRA system organ class)
SD, standard deviation.
were musculoskeletal and connective tissue disorders (two
patients: rotator cuff syndrome, osteoarthritis), neoplasms (two
patients; colon cancer, malignant melanoma), and psychiatric
worsening/occurrence of augmentation” (median ASRS score for full
disorders (two patients: depression, personality change, acute stress
analysis set: 0 (mean ± SD: 1.2 ± 2.6)). A post hoc analysis of ASRS
disorder, abnormal thinking). Two patients experienced serious AEs
item 1 for the eligibility completer set showed a shift in mean time
that were considered to be drug related: one patient reported a
(24-h clock) of symptom onset from 12:38 at baseline to 18:25 at
change of personality, depression, abnormal thinking, and irrita-
the final visit (Table 3).
bility; and one patient reported micturition urgency. One patient
died during the study due to intestinal necrosis following a nearly
3.3. Switching practice assessed up to 28 days after entering
complete bowel resection due to colon cancer. The treating physi-
the study
cian considered this death to be unrelated to rotigotine.
Among the 43 patients included in the eligibility completer set,
previous dopaminergic medications to be switched for rotigotine 4. Discussion
were levodopa (benserazide/levodopa (19 patients), carbidopa (two
patients), levodopa preparation (one patient), pramipexole (19 pa- This study provides a long-term observation of the manage-
tients), and ropinirole (seven patients) (Table 4). Five patients ment of preexisting augmentation in patients with RLS. Switching
switched to rotigotine after >1-day drug holiday (intake of previ- of augmented patients from oral dopaminergic treatment to the
ous dopaminergic medication stopped before the initiation of rotigotine transdermal patch (continuous 24-h dopaminergic
rotigotine intake), 23 patients switched overnight (ie, within one stimulation) was performed in accordance with routine clinical prac-
day), nine patients had an overlapping switch, and six patients tice, with no restrictions in terms of how RLS treatment was
received ongoing oral dopaminergics with rotigotine throughout the conducted. Among patients who remained on rotigotine therapy for
study. Patients with a drug holiday (n = 5) stopped their previous 13 months, improvements in RLS symptom severity, and there-
dopaminergic medication for a median of 1 day (range: 1–2 days) fore reduction of augmentation, were observed.

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
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A. Eligibility completer set (n = 43)


8
Mean ± SD change at final visit
7 Item 1: Satisfaction with sleep -3.5 ± 3.3
Item 2: Symptom severity when falling asleep -3.8 ± 3.4

Improvement
6 Item 3: Symptom severity during the night -3.6 ± 4.1
Item 4: Symptom severity during the day when at rest -3.7 ± 2.8
Mean RlS-6 item score

5 Item 5: Symptom severity during the day when active -1.4 ± 2.2
Item 6: Daytime sleepiness/tiredness -2.7 ± 2.9
4

0
Baseline Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(n = 43) Visit 2 (~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
(~1-7 days) (n = 42) (n = 38) (n = 43) (n = 41) (n = 43)
(n = 42)

B. Full analysis set (n = 97)


8 Mean ± SD change at final visit

Item 1: Satisfaction with sleep -3.5 ± 3.2


7 Item 2: Symptom severity when falling asleep -3.9 ± 3.4
Item 3: Symptom severity during the night -3.5 ± 4.0

Improvement
6 Item 4: Symptom severity during the day when at rest -3.6 ± 2.8
Item 5: Symptom severity during the day when active -1.3 ± 2.2
Mean RlS-6 item score

5 Item 6: Daytime sleepiness/tiredness -2.5 ± 3.1

0
Baseline Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(n = 97) Visit 2 (~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
(~1-7 days) (n = 76) (n = 56) (n = 52) (n = 45) (n = 46)
(n = 89)

Fig. 3. RLS-6 item scores over the course of the study. RLS, restless legs syndrome; SD, standard deviation.

Patients had severe RLS at baseline (median IRLS score of 29), indicating that patients were severely affected by RLS despite their
with 40% classified as “severely ill” according to the CGI-1. As no existing therapies. Overall, 45% of patients completed the 13-
washout of previous RLS therapies was mandatory, baseline scores month observational period, with withdrawal of rotigotine therapy
likely represent RLS symptoms while under previous treatment, documented in 44% of patients and 8% lost to follow-up. It should

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006
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A. Eligibility completer set (n = 43) A. Eligibility completer set (n = 43)


40 5

Mean ASRS score (± SD)


Mean IRLS score (± SD)

30

Improvement
3
20

10
1

0
Baseline Visit 5 Final visit 0
(~7 mths) Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(~13 mths) Visit 2
(~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
(n = 43) (n = 43) (n = 42) (~1-7 days)
(n = 41) (n = 36) (n = 35) (n = 37) (n = 35) (n = 42)

B. Full analysis set (n = 97)


B. Full analysis set (n = 97)
40
5
Mean IRLS score (± SD)

30 4
Mean ASRS score (± SD)
Improvement

3
20

2
10

0
Baseline Visit 5 Final visit
(~7 mths) (~13 mths) 0
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Final visit
(n = 97) (n = 52) (n = 45) (~1-7 days) (~1 mth) (~4 mths) (~7 mths) (~10 mths) (~13 mths)
(n = 86) (n = 67) (n = 50) (n = 45) (n = 39) (n = 45)
Fig. 4. IRLS scores. IRLS, International Restless Legs Syndrome Study Group Rating
Scale; SD, standard deviation. Fig. 5. ASRS scores. ASRS, Augmentation Severity Rating Scale; SD, standard deviation.

Table 2
Characteristics of augmentation at baseline.

Full analysis Eligibility completer


set (n = 97) set (n = 43)

NIH criterion, n (%)


1. Symptoms start earlier (at least by 2 h) compared with initial therapeutic response at the beginning of RLS treatment. 91 (93.8) 43 (100)
2. Symptoms increase when daily dose is increased. 74 (76.3) 38 (88.4)
3. Symptoms are reduced when daily dose is reduced. 34 (35.1) 17 (39.5)
4. Shorter latency until RLS symptoms occur at rest compared with initial therapeutic response at the beginning of RLS 88 (90.7) 41 (95.3)
treatment or before the treatment was instituted.
5. Extension of symptoms to previously unaffected parts of the body. 58 (59.8) 30 (69.8)
6. Decrease of initial duration of therapeutic response. 85 (87.6) 40 (93.0)
7. Periodic limb movements while awake either occur for the first time or are worse than with initial therapeutic response or 68 (70.1) 37 (86.0)
before the treatment was instituted.
Patients with augmentation per NIH criteriaa 93 (95.9) 43 (100)

NIH = National Institutes of Health; RLS = restless legs syndrome.


a
A diagnosis of augmentation requires (A) criteria 1 to be met; or (B) criteria 2 or 3 to be met in addition to criteria 4, 5, 6, or 7; or (C) two criteria out of 4, 5, 6, and 7
to be met.

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
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Table 3 results for the IRLS were consistent with those of the other sever-
ASRS item 1. During the past week, at what time did RLS symptoms usually start? ity scales, with a marked improvement in RLS symptoms from severe
(eligibility completer set).
(29.2 ± 5.4) to moderate (16.6 ± 9.7) at the end of treatment. As noted
Mean time of symptom onset previously, baseline IRLS values likely represent symptom severi-
(24-h clock)
ty while under previous treatment. For completeness, data were also
Baseline (n = 43) 12:38 reported for the full analysis set (all patients who received rotigotine
Visit 2 (Day 1–7) (n = 41) 15:50 and had evaluable data for the primary outcome). Comparable results
Visit 3 (up to 1 month) (n = 36) 16:18
Visit 4 (~4 months) (n = 35) 16:31
were obtained for both analysis sets. It should be noted that the el-
Visit 5 (~7 months) (n = 38) 15:39 igibility completer set was a subset of the full analysis set, consisting
Visit 6 (~10 months) (n = 37) 17:38 of patients who completed the study. Final visit data were re-
Final visit (13 months) (n = 42) 18:25 ported for 46 patients in the full analysis set, of whom 43 were also
ASRS = Augmentation Severity Rating Scale; RLS = restless legs syndrome. included in the eligibility completer set. The results of the present
study are consistent with those of a structured case series in which
improvements in IRLS and ASRS scores were observed among 28
be noted that severely augmented patients are very difficult to treat patients with severe RLS and augmentation switched to rotigotine
and may require frequent medication adjustments. Rapid interven- monotherapy [19].
tion may be warranted to compensate for loss of efficacy of patient’s Augmentation was assessed using the ASRS. This scale was de-
existing dopaminergic medications. In this study, the most common signed to prospectively assess changes in augmentation severity over
reasons for withdrawal of rotigotine were AEs (25%) and lack of time, with an initial baseline assessment performed prior to the ini-
efficacy (14%). Application site reactions were the most common tiation of dopaminergic therapy and potential development of
AEs, reported by a third of patients, and were also the AEs most augmentation. This was not possible in the present study as all pa-
frequently leading to discontinuation of rotigotine. The AE profile tients had preexisting augmentation and received dopaminergic
was consistent with dopaminergic stimulation, and the use of a trans- treatment; however, the ASRS was the only validated augmentation-
dermal patch, and comparable to that observed in interventional specific rating scale available. Therefore, patient’s RLS symptoms
studies of rotigotine in RLS [14,31,32]. were rated in comparison to the baseline visit. At the final visit,
In order to evaluate RLS severity and augmentation over time patients had a median ASRS of “0,” the best possible score, indi-
in patients who tolerated rotigotine, analyses of effectiveness were cating the possibility of reversing augmentation. In order to
performed on eligible study completers. Improvements in RLS investigate the circadian rhythm of RLS over 1 year of rotigotine treat-
symptom severity, as assessed by CGI-1, were apparent during the ment, an analysis of mean time of symptom onset (ASRS item 1)
first month of rotigotine therapy and sustained over the 13- was also carried out. Earlier symptom onset in comparison to initial
month study period. Patients had a median improvement of around therapeutic response is a key feature of augmentation, and it was
two points in the seven-point CGI-1 scale, with 37% classed as reported at baseline by all patients analyzed for effectiveness. ASRS
responders and 65% moving to a “mild” or “borderline” severity cat- item 1 data showed an ~6-h shift in symptom onset from noon to
egory. Furthermore, reductions in RLS-6 item scores indicated that early evening, suggesting a reduction in augmentation with rotigotine
continuous therapy with rotigotine was effective in improving both and a normalization of the characteristic circadian rhythm of the
daytime and nighttime symptoms in patients with severe RLS. The syndrome [33,34].
Our data indicate that augmented patients receiving oral
dopaminergics can be rapidly switched to rotigotine, with around
Table 4 50% switching to the patch overnight. One month after the
Switching practice and rotigotine dosing. decision to switch, only six patients were continuing to receive their
Previous dopaminergic RLS Full analysis Eligibility completer preexisting RLS therapy (identified as the RLS medication to be
medication to be switcheda set (n = 97) set (n = 43) switched) with rotigotine. As this was an observational study,
Pramipexole 45 19
physicians were free to decide on the most suitable treatment regi-
Benserazide/levodopa 31 19 mens for their patients. These regimens could be adjusted throughout
Ropinirole 14 7 the observational period, as deemed appropriate by the physician
Carbidopa 6 2 or patient. In the 12-month period following titration, 51% of
Levodopa preparations 3 1
patients in the eligibility completer set had at least one increase in
Cabergoline 1 -
Dopadura 1 - rotigotine dose. Some patients may have required dose increases
Pergolide 1 - in response to increasing RLS symptom severity, which could
Regimen for switching Full analysis Eligibility completer
potentially indicate a gradual return to augmentation. However, this
set (n = 97) set (n = 43) cannot be determined from the available data. The reasons for the
observed rotigotine dose adjustments are unknown, and clinical
>1-day drug holiday 5 5
Overnight switch (i.e., within 1 day) 43 23 experience indicates that RLS patients often require continuous
Overlapping switch 24 9 changes to their treatment over time.
No switch 20 6 Our study has several inherent limitations. Patients were treated
Rotigotine dose following titration Full analysis Eligibility completer according to routine clinical practice in Germany [2]. No washout
(~28 days post-baseline) set (n = 97)b set (n = 43) of previous dopaminergic medications was required; thus, the effects
1 mg/24 h 18 11 of previous dopamine treatment were not eliminated. Many
2 mg/24 h 35 18 patients (58%) received concomitant RLS therapies at least once
3 mg/24 h 24 12 during the observational period, in addition to rotigotine and/or their
4 mg/24 h 5 2
dopaminergic medications to be switched. The most common con-
5 mg/24 h 1 -
Missing data 13 -
comitant therapies were levodopa and pramipexole. The use of
concomitant medications may have had both positive and
RLS = restless legs syndrome.
a Patients could have >1 previous medication to be switched. negative effects on the effectiveness and safety outcomes. As such,
b
A dose of “0 mg/24 h” rotigotine was documented for one patient in the full anal- the observed treatment effects cannot be fully attributed to the
ysis set. Dosages >3 mg/24 h are not approved for the treatment of RLS. rotigotine patch. Given the observational study design and the

Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006
ARTICLE IN PRESS
8 C. Trenkwalder et al. / Sleep Medicine ■■ (2015) ■■–■■

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Please cite this article in press as: Claudia Trenkwalder, et al., Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study, Sleep Medicine
(2015), doi: 10.1016/j.sleep.2015.10.006