Supplementary Appendix

Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a
randomized controlled trial

Table of Contents Page

Supplementary table S1
Overview of CBT (Fit after COVID) treatment modules 2

Supplementary table S2
Details on delivery of CBT 3

Supplementary table S3 A-D

Sensitivity analyses 4

Supplementary table S4
Care use during CBT and in CAU 6

Supplementary table S5
Adverse events 7

References 8

1
Supplementary table S1. Overview of CBT (Fit after COVID) treatment modules

Module name Instrument and Brief description of module content

cut-off score*
1. Goal setting † Not applicable - Psychoeducation regarding the cognitive-behavioral model of post-infectious
fatigue following COVID-19.
- Patients set treatment goals in concrete activities which will be performed when
the fatigue is alleviated.
2. Sleep-wake Sleep diary - Targets a disrupted sleep-wake pattern.
pattern † ISI ≥ 10 - Patients establish a regular sleep-wake pattern and follow sleep-hygiene
practices.
- Patients are encouraged to stop sleeping or lying down at daytime.
3. Helpful J-FCS ≥ 16 - Targets unhelpful cognitions regarding fatigue.
thinking † IMQ ≥ 30 - Patients learn to identify unhelpful thoughts and replace them with helpful
SES ≤ 19 thoughts and increase their self-efficacy.
- Patients learn to redirect their attention away from fatigue.
4. Social SSL-I ≥ 14 - Targets low perceived social support and negative interactions.
support ‡ SSL-D ≥ 50 - Patients learn how to communicate with significant others about their fatigue,
be assertive and adapt expectations about their environment.
5. Graded Activity pattern - Targets a low or fluctuating physical activity pattern.
activity † (actigraph), - Patients with low activity pattern start with a gradual increase of their daily
relatively active physical activity.
vs. low active - Patients with a relative active activity pattern learn first to evenly distribute their
activities during the day and then subsequently gradually increase their daily
activity.
6. Processing IES subscales - Targets emotional problems of patients who did not process COVID-19.
COVID-19 ‡ intrusion and/or - Patients are helped to process negative experiences of their illness.
avoidance ≥ 10
7. Fears and COWS ≥ 10 - Targets excessive fears and worries regarding COVID-19.
worries - Patients record what the content of their fears and worries are regarding COVID-
regarding 19.
COVID-19 ‡ - Patients learn to formulate helpful thoughts and to distance themselves from
their anxious thoughts.
8. Coping with SF-36, pain - Targets unhelpful cognitions with respect to pain.
pain ‡ subscale ≤ 40 - Patients are helped to deal with pain in such a way that it does not limit them
during the gradual increase of activities.
9. Realizing Not applicable - Patients make an action plan to realize their treatment goals, like increasing
goals † social and mental activities.
- Patients learn about the difference between severe fatigue and normal fatigue.
- Patients learn to let go of the regular sleep-wake pattern and even distribution of
activities.
- Patients evaluate their progress.
* The intervention is personalized in two ways: First, content of the graded activity module is adapted based on the
patient’s scores on the baseline assessment (T0) and based on data provided with an actigraph, a device worn at the wrist
to assess physical activity and discerning a low active and relative active pattern. Second, of the optional modules only
those are selected that apply to the patient, based on T0 scores as well as information collected by the therapist during the
intake session.
† Standard module. ‡ Optional module. ISI Insomnia Severity Index[1] , J-FCS Jacobsen - Fatigue Catastrophizing Scale[2],
IMQ Illness Management Questionnaire[3], SES Self-Efficacy Scale[4], SSL-I Van Sonderen Social Support Inventory[5],
subscale negative interactions, SSL-D Van Sonderen Social Support Inventory[5], subscale discrepancy, IES Impact of Event
Scale[6], CWS COVID-19 Worry Scale (adapted from the Cancer Worry Scale (CWS)[7]), SF-36 Short Form Health Survey (SF-
36)[8].

2
Supplementary table S2: Details on delivery of CBT*

n = 56†
Modules followed‡
1. Goal setting 56 (100%)
2. Sleep-wake pattern 55 (98%)
3. Helpful thinking 53 (95%)
4. Social support 20 (36%)
5. Graded activity 53 (95%)
6. Processing COVID-19 12 (21%)
7. Fears and worries regarding COVID-19 19 (34%)
8. Coping with pain 6 (11%)
9. Realizing goals 51 (91%)

Number of interactions between therapist Mean (SD)

and patient
Face-to-face consult 2.9 (3.0)
Video consult 4.0 (3.8)
Telephone consult 0.3 (0.7)
Contact via email 4.6 (4.2)
Total 11.8 (3.5)

Duration
Treatment duration (weeks) 18.7 (2.3)
Duration between randomization and T1 § 21.1 (2.7)
CBT Cognitive behavioral therapy.
Presented data are mean (SD) or n (%).
† One patient did not start CBT.
‡ On the basis of log data of the online platform and/or indicated by the therapist.
§ Duration between randomization and T1 in the CAU group was 20.1 (1.8) weeks.

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Supplementary table S3A: Sensitivity Analyses 1*

Outcome measure Operationalization of n Overall P value overall Cohen’s d

CBT completion between- group between-group
(CBT vs. CAU) (CBT vs. CAU)
difference difference
Mean (95% CI)
Primary outcome
Fatigue Operationalization a† 53 -9.3 (-12.4 to -6.3) <0.001 0.77
(CIS-fatigue) Operationalization b‡ 52 -8.9 (-12.0 to -5.9) <0.001 0.74
Secondary continuous outcomes
Physical functioning
(SF-36) Operationalization a 53 7.3 (3.2 to 11.4) 0.001 0.36
Operationalization b 52 7.0 (2.9 to 11.1) 0.001 0.35
Social functioning
(WSAS) Operationalization a 53 -7.1 (-9.5 to -4.8) <0.001 0.66
Operationalization b 52 -6.9 (-9.2 to -4.5) <0.001 0.63
Somatic symptoms
(PHQ-15) Operationalization a 53 -2.0 (-3.0 to -1.1) <0.001 0.46
Operationalization b 52 -2.0 (-3.0 to -1.1) <0.001 0.45
Problems concentrating
(CIS-con) Operationalization a 53 -5.3 (-7.0 to -3.5) < 0.001 0.68
Operationalization b 52 -5.2 (-7.0 to -3.4) < 0.001 0.68

Secondary dichotomous outcomes n n (%) Relative Risk (95% CI) P value

CIS-fatigue T1 < 35 Operationalization a 53 33 (62%) 2.37 (1.46 to 3.83) <0.001
Operationalization b 52 32 (62%) 2.34 (1.44 to 3.80) <0.001

CIS-fatigue T1 < 35 Operationalization a 53 33 (62%) 2.37 (1.46 to 3.83) <0.001

& reliable change Operationalization b 52 32 (62%) 2.34 (1.44 to 3.80) <0.001

Not chronically, Operationalization a 53 36 (68%) 2.24 (1.44 to 3.47) <0.001

fatigued at T1 Operationalization b 52 35 (67%) 2.22 (1.43 to 3.44) <0.001

CIS-fatigue T2 < 35 Operationalization a 53 33 (64%) 2.40 (1.47 to 3.94) <0.001

Operationalization b 52 32 (63%) 2.38 (1.45 to 3.90) <0.001

CIS-fatigue T2 < 35 Operationalization a 53 33 (64%) 2.59 (1.55 to 4.33) <0.001

& reliable change Operationalization b 52 32 (63%) 2.56 (1.53 to 4.29) <0.001

Not chronically, Operationalization a 53 38 (73%) 2.33 (1.50 to 3.61) <0.001

fatigued at T2 Operationalization b 52 37 (73%) 2.31 (1.49 to 3.59) <0.001

CAU Care as usual, CBT Cognitive behavioral therapy, CI Confidence interval.

* Per protocol analysis with 2 operationalizations of treatment completion.
† Operationalization a: Per protocol analysis. Intervention completion was operationalized as participants who have filled
out the treatment goals and opened the 5 standard modules of the intervention (portal log data) or who attended at least
three sessions (therapist registration) face-to-face or via video consult.
‡ Operationalization b: Per protocol analyses. Treatment completion was operationalized as having completed the
intervention according to the therapist.
CIS Checklist Individual Strength[9], SF-36 Short Form Health Survey[8], WSAS Work and Social Adjustment Scale[10], PHQ-
15 Patient Health Questionnaire[11].

4
Supplementary table S3B: Sensitivity Analyses 2*

Outcome CBT CAU Mean difference (95% Cohen’s d P value

(n = 57) (n = 57) CI) between CBT and effect size
CAU
Primary outcome at T1
Fatigue severity (CIS-fatigue), mean 30.5 (1.4) 40.0 (1.4) -9.5 (-13.5 to -5.6) 0.76 <0.001
(SD)
Primary outcome at T2
Fatigue severity (CIS-fatigue), mean 31.6 (1.7) 39.8 (1.7) -8.3 (-12.9 to -3.6) 0.64 0.001
(SE)
* One-way analyses of covariance (ANCOVA) for T1 and T2 separately with group allocation as a fixed factor, baseline CIS-
fatigue score as covariate and either the CIS-fatigue scores at T1 or T2 as dependent variable.

Supplementary table S3C: Sensitivity analyses 3*

Covariate P-value
Dyspnea at T0 (yes versus no) 0.86
Hospitalized for COVID-19 (yes versus no) 0.25
Age (years) 0.96
Days since diagnosis of COVID-19 or hospital discharge 0.54
Sex (male versus female) 0.02†
* Association of covariates with the primary outcome. These analyses were conducted by including these variables and
their interaction-terms with condition as covariates in the mixed linear models.
† The mean fatigue severity score of males is larger compared to the mean fatigue severity scores of females. When
controlling for sex in the analysis of the primary outcome, the mean difference between CBT and CAU increases from -8.8 to
-9.0.
Previous hospitalization for COVID-19, dyspnea at T0, age and time since COVID-19 were not associated with the primary
outcome.

Supplementary table S3D: Sensitivity analyses 4*

Outcomes CBT CAU Mean difference (95% Cohen’s d P value

(n = 57) (n = 57) CI) between CBT and effect size
CAU
Primary outcome at T1
Fatigue severity (CIS-fatigue), mean 30.8 (1.4) 40.0 (1.4) -9.2 (-13.1 to -5.3) 0.73 <0.001
(SE)
Primary outcome at T2
Fatigue severity (CIS-fatigue), mean 31.7 (1.6) 39.2 (1.7) -7.5 (-12.0 to -2.9) 0.58 0.001
(SE)
* One-way analyses of covariance (ANCOVA) for T1 and T2 separately with group allocation as a fixed factor, baseline CIS-
fatigue score as covariate and either the CIS-fatigue scores at T1 or T2 as dependent variable, replacing missing values with
multiple imputation using chained equations. The imputation model included baseline sociodemographic and clinical
characteristics assessed at baseline and follow-up measurements. A total of five data sets was imputed and pooled
according to Rubin’s rule.

5
Supplementary table S4: Care use during CBT and in CAU

Care use characteristics CBT CAU

n = 55* n = 56*
Healthcare provider †
General practitioner 19 (35%) 34 (61%)
Physician at an outpatient clinic 8 (15%) 21 (38%)
Physical therapist 21 (38%) 36 (64%)
Guided Exercise ‡ 17 (31%) § 22 (39%)
Aerobe training 15 (27%) 19 (34%)
Muscle / strength training 11 (20%) 15 (27%)
Massage 3 (5%) 8 (14%)
Other 2 (4%) 6 (11%)
Unknown 2 (4%) 2 (4%)
Occupational therapist 0 (0%) 22 (39%)
Pacing of activity on the basis of fatigue levels 0 (0%) 19 (34%)
Other 0 (0%) 3 (5%)

Psychologist 4 (7%) 6 (11%)

Psychiatrist 0 (0%) 1 (2%)
Social worker 1 (2%) 1 (2%)
Other 6 (11%) 14 (25%)
Frequency and intensity of treatment
Frequency of visits to physical therapist
Once every two weeks or less frequent 2 (4) 2 (4)
Once a week 6 (11) 6 (11)
Twice a week or more frequent 7 (13) 19 (34)
Duration treatment by physical therapist
4 weeks or less 1 (2%) 2 (4%)
4 to 17 weeks 2 (4%) 7 (13%)
More than 17 weeks 15 (27%) 24 (43%)
Frequency of visits to occupational therapist
Once every two weeks or less frequent 1 (2%) 13 (23%)
Once a week 0 (0%) 3 (5%)
Twice a week or more frequent 0 (0%) 2 (4%)
Duration treatment occupational therapist
4 weeks or less 0 (0%) 1 (2%)
4 to 17 weeks 0 (0%) 12 (21%)
More than 17 weeks 1 (2%) 7 (13%)
Number of healthcare providers consulted - no. (%)
None 15 (27%) 5 (9%)
1 healthcare provider 25 (45%) 14 (25%)
2 healthcare providers 11 (20%) 10 (18%)
3 or more healthcare providers 4 (7%) 27 (48%)
Mean number of healthcare providers consulted (±SD) 1.1 (1.0) 2.4 (1.6)
CAU Care as usual, CBT Cognitive behavioral therapy.
Presented values are mean (SD) or n (%).
* Data of 3 patients are missing.
† Percentages do not add up to 100% as some patients consulted several healthcare providers. All percentages are the
proportion of all patients in the treatment condition.
‡ Guided exercise entails aerobe training and/or muscle / strength training.
§ In case of guided exercise during CBT, the CBT therapist contacted the physical therapist at the start of CBT to ensure the
increase of activity is graded.

6
Supplementary table S5. Adverse Events

Type of event* CBT CAU

n = 57 n = 57
Any AE – no. of patients (%) 7 (12%) 14 (25%)
Symptoms developed between T0 and T1 - no. of patients (%) 6 (11%) 13 (23%)
Increase of symptoms present at T0 - no. of patients (%) 2 (4%) 3 (5%)
Discontinued treatment due to AE - no of patients (%) 0 (0%) not applicable
Any SAE – no. of patients (%) 0 (0%) 0 (0%)
No. AE – no. patients (%)
1 6 (14%) 11 (19%)
2 1 (2%) 1 (2%)
3 - 1 (2)
4 - 1 (2)
Relation with CBT † – no. AEs (%)
No relation with CBT 2 (25%) -
Possible relation with CBT 6 (75%) ‡ -
Category of AE – no. AEs (%)
Musculoskeletal 4 (50%) 5 (25%)
Gastrointestinal - 3 (15%)
Neurological 1 (13%) 4 (20%)
Pulmonic - 3 (15%)
Ear, Nose, Throat - 1 (5%)
Psychological - 2 (10%)
Biochemical - 1 (5%)
Cardinal (tachycardia) 1 (13%) -
Increase of fatigue 2 (25%) 1 (5%)
AE Adverse event, CAU Care as usual, CBT Cognitive behavioral therapy, SAE Serious adverse event.
* AEs as self-reported by the patient at the T1 assessment. Patients could have multiple AEs. No additional AEs were
recorded by therapists or the research assistant.
† As independently judged by 2 physicians.
‡ Musculoskeletal (3x), cardinal, neurological, increase of fatigue

7
References

1. Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric
indicators to detect insomnia cases and evaluate treatment response. Sleep 2011; 34(5): 601-8.
2. Jacobsen PB, Andrykowski MA, Thors CL. Relationship of Catastrophizing to Fatigue among
Women Receiving Treatment for Breast Cancer. Journal of Consulting and Clinical
Psychology 2004; 72(2): 355-61.
3. Ray C, Weir W, Stewart D, Miller P, Hyde G. Ways of coping with Chronic Fatigue
Syndrome: Development of an illness management questionnaire. Social Science and
Medicine 1993; 37(3): 385-91.
4. Heins MJ, Knoop H, Burk WJ, Bleijenberg G. The process of cognitive behaviour therapy for
chronic fatigue syndrome: Which changes in perpetuating cognitions and behaviour are
related to a reduction in fatigue? Journal of Psychosomatic Research 2013; 75(3): 235-41.
5. Bridges KR, Sanderman R, Van Sonderen E. An English language version of the social
support list: Preliminary reliability. Psychological Reports 2002; 90(3 PART 1): 1055-8.
6. van der Ploeg E, Mooren TTM, Kleber RJ, van der Velden PG, Brom D. Construct Validation
of the Dutch Version of the Impact of Event Scale. Psychological Assessment 2004; 16(1).
7. Custers JAE, van den Berg SW, van Laarhoven HWM, Bleiker EMA, Gielissen MFM, Prins
JB. The Cancer Worry Scale. Cancer Nursing 2014; 37(1): E44-E50.
8. Aaronson NK, Muller M, Cohen PDA, et al. Translation, Validation, and Norming of the
Dutch Language Version of the SF-36 Health Survey in Community and Chronic Disease
Populations. Journal of Clinical Epidemiology 1998; 51(11): 1055-68.
9. Worm-Smeitink M, Gielissen M, Bloot L, et al. The assessment of fatigue: Psychometric
qualities and norms for the Checklist individual strength. Journal of Psychosomatic Research
2017; 98: 40-6.
10. Mundt JC, Marks IM, Shear MK, Greist JH. The Work and Social Adjustment Scale: a simple
measure of impairment in functioning. British Joural of Psychiatry 2002; 180: 461-4.
11. Kroenke K, Spitzer RL, Williams JBW. The PHQ-15: Validity of a New Measure for
Evaluating the Severity of Somatic Symptoms. Psychosom Med 2002; 64: 258–66.