Embed Size (px)
Citation preview
Cognitive Behavioral Therapy positively affects fatigue in patients with Multiple Sclerosis:
Results of a randomized controlled trial
Lizanne Eva van den AkkerHeleen Beckerman
Emma Hubertine ColletteJos Twisk
Gijs Bleijenberg Joost Dekker
Hans KnoopVincent de Groot
TREFAMS-ACE Study Group*
* The complete TREFAMS-ACE Study Group is provided in Appendix 1
Submitted for publication
7
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
156
Abstract
Background Fatigue is a common symptom in Multiple Sclerosis (MS) and often restricts societal participation. Cognitive Behavioural Therapy (CBT) may alleviate MS-related fatigue, but evidence in literature is inconclusive.
Objective Evaluate the effectiveness of CBT in improving MS-related fatigue and participation.
Methods In a multicentre, assessor-masked, randomized controlled trial, participants with severe MS-related fatigue were assigned to CBT or control treatment. CBT consisted of twelve individual sessions with a psychologist trained in CBT, the control treatment consisted of three consultations with a MS nurse, both delivered over 16 weeks. Assessments were at baseline, 8, 16 (i.e. post-intervention), 26 and 52 weeks post-baseline. Primary outcomes were the Checklist Individual Strength-fatigue subscale (CIS20r fatigue) and the Impact on Participation and Autonomy questionnaire (IPA). Data were analysed with intention-to-treat, using Mixed Model Analysis.
Results Between December 2011 and August 2014, 91 patients were randomized (CBT: n=44; control: n=47). Between-group analysis showed a positive post-intervention effect for CBT on CIS20r fatigue (T16: -6.7 [95% CI, -10.7 to -2.7] points) that diminished during follow-up T52: 0.5 [95% CI, -3.6 to 4.4]). No clinically relevant effects were found on societal participation.
Conclusion Severe MS-related fatigue can be reduced effectively with CBT in the short-term. More research is needed on how to maintain this effect over the long-term.
157
7
Introduction
Patients with Multiple Sclerosis (MS) frequently report fatigue as one of their most troublesome symptoms.1-3 It negatively affects societal participation and health-related quality of life,4,5 but remains poorly understood.2 Current approaches to decrease MS-related fatigue include pharmacological and non-pharmacological treatments or a combination of these approaches.
A recent review concluded that non-pharmacological interventions (both exercise and psychological/educational interventions) appear to reduce fatigue more than commonly prescribed pharmacological treatments.6,7 Furthermore, it appears that psychological interventions can be a clinically feasible and cost-effective treatment for MS-related fatigue.7 To provide a starting point for the treatment of MS-related fatigue, van Kessel et al. (2006)8 developed a cognitive-behavioral model to explain the persistence of MS-related fatigue. This model encompasses both disease-related factors and psychological factors identified in literature. According to this model, disease-related factors trigger fatigue in MS, and cognitive, emotional and behavioral factors then determine the extent to which fatigue influences daily life.8 In addition, this theoretical model suggests that the combination of these factors may perpetuate or worsen MS-related fatigue. This basic understanding is of interest when considering the effectiveness of non-pharmacological treatments. Cognitive Behavioral Therapy (CBT) for MS-related fatigue aims to influence the dysfunctional cognitions, behaviors and emotions that perpetuate fatigue. It has been suggested that MS-related fatigue can be treated and decreased instead of managed and accepted.9 Therapists will challenge the meaning of dysfunctional cognitions and aim to change the behavior of patients with MS-related fatigue and emphasize more realistic cognitions, emotions and behaviors.8 Together these changes can break the vicious circle of fatigue.8
A recent meta-analysis concluded that CBT has a moderately positive short-term effect on MS-related fatigue.10 However, this effect decreases with cessation of treatment. When the TREFAMS-CBT study began, the only available randomized controlled trial (RCT) was that of Kessel et al. (2008).11 While this study served as an example for the TREFAMS-CBT study, it had one major limitation: the same therapist provided both the CBT and the control treatments.11 This made the generalizability of the reported findings problematic.
We aimed to assess the effectiveness of CBT in decreasing fatigue and improving societal participation in patients with MS, compared to 3 MS nurse consultations. The
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
158
CBT therapists were certified psychologists and CBT was compared to a control treatment provided by MS nurses.12 Furthermore, the study included an extended 1-year post-randomization follow-up and only patients with severe MS-related fatigue were included.
Methods
Study design and participants
The TREFAMS-CBT study is part of a multi-trial research program (TREFAMS-ACE) designed to study the effectiveness of Aerobic Training, Cognitive Behavioral Therapy, and Energy Conservation Management in the treatment of MS-related fatigue. The design of the 3 individual trials is identical and has been outlined previously.12 The TREFAMS-ACE study12 was approved by the Medical Ethics Committee of the VU University Medical Center. Fonds NutsOhra (grant number ZonMw 89000005) funded the program. The Consolidated Standards of Reporting Trials guidelines for non-pharmacological trials (CONSORT statement) was used to standardize reporting.13
Participants were recruited in three Dutch centers (VU University Medical Center in Amsterdam, the Radboud University Medical Centre and the St. Maartenskliniek in Nijmegen), via referral from physicians at regional centers, personal invitation letters, advertisement via internet and posters/pamphlets. Interested patients were invited for an intake interview to provide additional information about the trial and to test for eligibility. The intake consisted of a structured medical history taking, a structured physical examination, questionnaires and a blood draw. Main eligibility criteria were: a) definitive diagnosis of MS; b) experience of severe fatigue (CIS20r- fatigue ≥35); c) be ambulatory (Expanded Disability Status Scale [EDSS] score ≤6); d) no signs of exacerbation; e) no clinical depression (Hospital Anxiety and Depression Scale [HADS-depression] score >11. Full inclusion criteria are published.12 Prior to inclusion, written informed consent was obtained from all participants.
Randomization and masking
Randomization was performed using concealed computerized block wise randomization, stratified by treatment center. The block size of 8 was disclosed after finishing all follow-up measurements. An independent investigator, not the assessors, carried out the
159
7
randomization and informed the patient and therapist about the therapy allocation. The assessors were blinded for the treatment, and patients and therapists were instructed not to unblind the assessors. The analyses were performed blinded to participant treatment allocation.
Procedures
The treatment procedure began in December 2011 and ended in December 2014; a comprehensive overview (TIDieR checklist) of the CBT intervention is available in Appendix 2.
The patients randomly allocated to the CBT received 12 sessions of individual face-to-face therapy spread over a 4-month period (8 sessions in the first 2 months, 4 sessions in the last 2 months). The CBT protocol consists of 10 modules: formulating goals, regulating sleep/wake pattern, changing beliefs regarding MS, changing beliefs regarding fatigue, reduce the focus on fatigue, regulation of physical, social and mental activity, addressing the role of the environment and handling pain (more information about the modules is available in Appendix 3). The intervention was patient-tailored: questionnaires with predefined cut-off scores and information from the intake session with the psychologist were used to determine which modules were indicated for the patient. After an intake session in which information was provided on the cognitive-behavioral model of MS-related fatigue and CBT, patients started by formulating their treatment goals. The following sessions addressed the fatigue-maintaining cognitions and behaviors and were aimed at realizing the set treatment goals. The final therapy sessions focused on integrating the obtained skills into daily life and on how patients should handle relapses of fatigue. All CBT therapists were state-certified healthcare psychologists who received a 3-day course on how to deliver CBT according to the TREFAMS-CBT protocol. Furthermore, the CBT therapists received supervision every other week from an experienced CBT psychologist.
The control intervention consisted of a protocolized treatment by an experienced MS nurse that included 3 consultations of 45 minutes over a 4-month period. The treatment protocol did not allow the MS nurses to refer patients to a psychologist or other healthcare professionals for the treatment of fatigue. During the consultations, the patient received written and oral information about MS-related fatigue, and patients discussed their personal experiences in coping with fatigue and other fatigue-related issues. A more detailed description of the CBT intervention and the MS nurse consultations is available elsewhere (Appendix 2 and Appendix 3).12
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
160
Outcomes
Outcome measures were completed at baseline, 8 weeks (T8), 16 weeks (T16; i.e. post-intervention), 26 weeks (T26) and 52 weeks (T52) follow-up. Baseline and T52 measurements included socio-demographic and disease characteristics. The primary outcome measures were the CIS20r fatigue and the IPA.14,15 Secondary outcomes for fatigue were: Fatigue Severity Scale (FSS),16 Modified Fatigue Impact Scale (MFIS)17 and the CIS20r subscales physical activity, concentration and motivation.14 Secondary outcomes for participation were the Medical Outcome Study Short Form 3618 (SF36) and the Rehabilitation Activities Profile (RAP).19
The CIS20r subscale fatigue14 was used to measure MS-related fatigue. It consists of 8 statements that are rated on a 7-point scale; the score ranges from 8 to 56 points. All participants needed a score of 35 or higher on the CIS20r fatigue before enrolment in the TREFAMS study. A higher score means greater reduction and worse problems. The CIS20r focuses on the previous two weeks, and is considered reliable and valid for measuring fatigue in a clinical setting in patients with MS.20
The IPA15 was used to measure societal participation. This self-report questionnaire measures a person’s current perception of the ability of how to live his/her life. The questionnaire includes items such as carrying out domestic activities when one wants, and cooking the way one prefers.15 The questionnaire consists of 32 questions. Five subscales are distinguished: 1. Autonomy indoors (5 items), 2. Family role (7 items), 3. Autonomy outdoors (7 items), 4. Social life and relations (7 items), 5. Work and education (6 items). The score on each IPA domain is the average score on the items of the domain and ranges from 0 to 4, with lower scores indicating better societal participation and autonomy. The IPA is a valid and reliable instrument for assessing autonomy and societal participation in chronic medical disorders.21
The FSS is a measure of fatigue severity and comprises 9 statements that are scored from 1 to 7 (1 = completely disagree; 7 = completely agree). The final score is the mean of the item scores.16 The MFIS is a 21-item shortened version of the Fatigue Impact Scale; 3 subscales are distinguished - physical, cognitive, and psychosocial functioning.17 Higher scores mean a greater impact of fatigue on functioning in the specified domain.
The outcomes of the RAP and the results of the SF36 to describe patients’ daily functioning and participation are also reported. The patients’ treatment adherence was determined by assessing the number of sessions each participant attended.
161
7
Power analysis
The sample size calculation was based on a clinically relevant between-group difference of ≥8 points on the CIS20r fatigue scale.22 In total, 90 patients (45 per treatment group) were needed to detect this clinically relevant difference with an SD of 12.7,23 a power of 80%, an alpha of 0.05 and a maximum attrition rate of 20%.
Statistical analysis
Statistical analyses were pre-specified and performed with SPSS for Windows statistical software package (Version 22; SPSS, Inc, Chicago, IL). Primary analyses were performed according to the intention-to-treat principle and consisted of all participants (analyzed as randomized).
We used mixed linear models to study the effectiveness of CBT. Mixed model analysis takes into account the dependency of the repeated observations within the patient. In total, 3 models were analyzed: 1) a crude model, only adjusted for the baseline value of the particular outcome, 2) a model adjusted for center, since the randomization per center was stratified and therefore scores of patients who belong to the same center are correlated,24 3) a model adjusted for covariates that were likely to have a prognostic influence to improve precision.25 The covariates were determined a priori: gender, disease severity (Expanded Disability Status Scale [EDSS]), general self-efficacy (General Self-Efficacy scale [GSES]), anxiety (Hospital Anxiety and Depression Scale [HADS], subscale anxiety) and comorbidities (Cumulative Illness Rating Scale [CIRS]) at baseline. For all models, both an overall effect of CBT and the effects of CBT at the different measurement points were estimated. For the latter, time and interaction between group and time were added to the model. Time was thereby treated as a categorical variable represented by dummy variables.
Furthermore, we calculated the Absolute Risk Reduction (ARR), the number needed to treat (NNT) and the 95% confidence interval (CI) for patients that showed an improvement of ≥8 points on the CIS20r fatigue scale and for patients who scored <35 on the post-treatment measurement (T16). The NNT is the average number of patients who need to be treated for one patient to benefit in comparison to the control group (in this case an improvement of ≥8 points or a score <35 points).26
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
162
Results
Participants
The flow chart is displayed in Figure 7.1. Between November 2011 and July 2014, 91 patients were randomized, of whom 44 were allocated to CBT and 47 to the MS nurse.
Baseline demographic and disease characteristics are displayed in Table 7.1.
Table 7.1 Baseline demographic and disease characteristics
PatientsCBT
(n=44)MS nurse
(n=47)
Age (years) 50.6 (8.3) 46.4 (11.6)
Gender Male 13 (29.5) 8 (17.0)Female 31 (70.5) 39 (83.0)
Time since diagnosis (years) 8.2 (2.9–14.2) 5.2 (2.1–11.5)
EDSS 3.0 (2.8; 3.6) 2.5 (2.3; 3.0)
Disease courseRR 32 (72.7) 35 (74.5)PP 6 (13.6) 4 (8.5)SP 5 (11.4) 7 (14.9)Other 1 (2.3) 0Unknown 0 1 (2.1)
Civil statusLiving with partner 34 (77.3) 33 (70.2)Living without partner 10 (22.7) 13 (27.7)
Employment status Full-time 4 (9.1) 4 (8.5)Part-time 16 (36.4) 18 (38.3)
Disability pension 9 (65.3) 9 (50.0)Unemployed 20 (45.5) 19 (40.4)
Disability pension 17 (85.0) 15 (75.0)Retirement 1 (2.3) 3 (6.4)Study 1 (2.3) 2 (4.3)Unknown 2 (4.6) 1 (2.1)
CIRS 3.6 (2.4) 3·7 (2.2)
HADS anxiety 6.7 (3.7) 6·1 (3.3)
GSES 28.7 (5.6) 30·8 (4.5)
Data are mean (SD), or median (IQR), or n (%).CIRS, Cumulative Illness Rating Scale; EDSS, Expanded Disability Status Scale; GSES, General Self-Efficacy Scale; HADS, Hospital Anxiety and Depression Scale; RR, Relapsing Remitting; SP, Secondary Progressive; PP, Primary Progressive.
163
7
1
46 analyzed intention-to-treat
Measurement T52 (39/44) Non-responder (n=2) No extra drop-outs
Measurement T16 (39/44) post-treatment Non-responder (n=2) No extra drop-outs
Measurement T26 (39/44) Non-responder (n=2) No extra drop-outs
Measurement T16 (35/47) post-treatment Non-responder (n=6) Drop-outs (n=6) Too fatigued (n=1)
Measurement T26 (36/47) Non-responder (n=3) Drop-outs (n=8) Impossible to make an appointment (n=2)
139 patients assessed for eligibility 48 excluded 23 CIS20r <35 7 HADS >11 4 No definite MS diagnosis 3 EDSS >6.0 3 Treatment fatigue <3 months 1 Relapse <3 months 1 Steroid treatment < 3 months 1 Comorbidity 1 Blood parameters deviations 1 Unable to read questionnaires 1 Declined to participate 1 No transportation 1 Would quit if allocated to MS nurse
3 centers performing MS nurse consultations; 3 MS nurses 36 VU University Medical Center 11 Radboud University Medical Centre/St. Maartenskliniek
44 patients allocated to CBT Missing baseline measures (n=0)
2 centers performing CBT; 6 CBT therapists 32 VU University Medical Center 12 Expert Centre for Chronic Fatigue Nijmegen
47 patients allocated to MS nurse consultations Missing baseline measures (n=1)
Randomized (n=91)
44 analyzed intention-to-treat
Measurement T8 (38/44) Non-responder (n=3) Drop-outs (n=3) Not willing to participate (n=1) Financial issues (n=1) No transportation (n=1)
Measurement T52 (35/47) Non-responder (n=4) No extra drop-outs
Measurement T8 (38/47) Non-responder (n=4) Drop-outs (n=5) Overburdened (n=1) Comorbidities (n=1) Impossible to make an appointment (n=1) Not willing to participate (n=2)
Figure 7.1 Flow chart, number of drop-outs is cumulative.
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
164
Three patients (7%) in the CBT study group and 8 (17%) in the control study group dropped out during the study. In total 28 (64%) patients in the CBT study group completed ≥10 sessions, with a median of 10.5 sessions (interquartile [ICQ1–3] 8.8–11.0). In the control study group, 37 (79%) completed all three MS nurse consultations, with a median 3.0 of sessions (ICQ1–3 3.0–3.0). The demographics of the drop-outs are available in Supplemental Table S4.1.
During the treatment period, 1 serious adverse event (MS relapse confirmed by a neurologist, followed by inpatient treatment) was reported in the CBT study group, and 2 (1 MS relapse and 1 gall bladder surgery) were reported in the control study group. During the long-term follow-up period, 3 serious adverse events (2 MS relapses and 1 surgery) were reported in the CBT study group and 1 (MS relapse) was reported in the control study group. These events were reported to, and judged by the Medical Ethics Committee not to be directly associated with the interventions.
Effect on fatigue and societal participation
The mean scores (SD) of the fatigue and participation outcomes at baseline and follow-up are presented in Table 7.2.
The between-group effects of the second model (i.e. adjusted for center) of CBT on fatigue, societal participation and on the secondary fatigue outcomes are displayed in Table 7.3. The results of the other models are provided in Supplemental Table S4.2.
Post-treatment CIS20r fatigue scores showed a positive treatment effect for CBT compared to the MS nurse intervention (β=-6.7 [95% CI, -10.7 to -2.7]) (Figure 7.2) that gradually wore off during the subsequent 8 months (T52: β=0.5 [95% CI, -3.5 to 4.5]). IPA domain scores did not show between-group differences at any time point, except for a significant between-group effect on the IPA work and education domain at T26 (β=-0.3 [95% CI, -0.7 to -0.0]). In addition to the CIS20r fatigue results, the secondary fatigue measures showed comparable scoring patterns during the one-year study (significant results FSS on T8, T16 and overall; MFIS on T8, SF36-vitality on T8, T16 and overall, see Table 7.3).
The number of participants that showed a clinically relevant change of 8 points or more immediate post-intervention (T16) in the CBT-study group was 22 out of 39 patients, and in the control group 9 out of 35. A score below the cut-off of 35 points on the CIS20r fatigue appeared in 21 out of 39 patients in the CBT-study group, and in 7 out of 35 in the control study group. The ARR of reporting a clinically relevant change
165
7
Tabl
e 7.
2 M
ean
scor
es (S
D) o
f the
prim
ary
and
seco
ndar
y ou
tcom
e m
easu
res
at e
ach
mea
sure
men
t mom
ent
Base
line
T8T1
6T2
6T5
2
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
n
Prim
ary
outc
omes
CIS2
0r fa
tigue
(8–5
6)†
CBT
42.9
(8.5
)44
33.5
(10.
4)38
34.0
(11.
2)39
36.9
(12.
1)39
38.9
(9.7
)39
Cont
rol
44.2
(6.0
)46
41.0
(8.3
)38
40.3
(8.2
)35
40.9
(7.8
)36
39.5
(9.0
)35
IPA
indo
ors
(0–4
)†CB
T0.
9 (0
.5)
440.
7 (0
.5)
380.
7 (0
.6)
380.
9 (0
.5)
390.
8 (0
.5)
39Co
ntro
l 0.
7 (0
.6)
460.
7 (0
.6)
380.
8 (0
.6)
360.
8 (0
.6)
350.
7 (0
.6)
36
IPA
fam
ily ro
le (0
–4)†
CBT
1.4
(0.7
)44
1.3
(0.5
)38
1.3
(0.7
)38
1.3
(0.6
)39
1.3
(0.6
)39
Cont
rol
1.5
(0.7
)46
1.4
(0.7
)38
1.4
(0.7
)36
1.5
(0.7
)35
1.5
(0.7
)36
IPA
out
door
s (0
–4)†
CBT
1.8
(0.6
)44
1.5
(0.5
)38
1.4
(0.6
) 38
1.4
(0.6
)39
1.5
(0.6
)39
Cont
rol
1.7
(0.7
)46
1.6
(0.6
)38
1.5
(0.5
)35
1.6
(0.6
)35
1.5
(0.6
)36
IPA
soc
ial r
elat
ions
(0–4
)†CB
T1.
1 (0
.6)
441.
1 (0
.5)
381.
1 (0
.5)
381.
1 (0
.5)
391.
0 (0
.5)
39Co
ntro
l 1.
0 (0
.6)
461.
0 (0
.5)
380.
9 (0
.5)
361.
0 (0
.5)
351.
0 (0
.5)
36
IPA
wor
k an
d ed
ucat
ion
(0–4
)†CB
T2.
2 (0
.8)
371.
8 (0
.9)
352.
0 (0
.8)
341.
8 (0
.7)
341.
9 (0
.9)
35Co
ntro
l 1.
9 (0
.8)
421.
9 (0
.8)
341.
9 (0
.9)
342.
0 (0
.8)
311.
9 (0
.8)
30
Seco
ndar
y ou
tcom
esFS
S (1
–7)†
CBT
5.4
(0.7
)44
4.7
(0.9
)38
4.5
(1.1
)38
4.9
(1.0
)39
5.0
(0.9
)39
Cont
rol
5.5
(0.8
)46
5.3
(0.9
)37
5.2
(0.7
)36
5.3
(0.7
)34
5.1
(0.9
)37
MFI
S to
tal (
0–84
)†CB
T47
.3 (1
2.5)
4438
.3 (1
5.0)
3838
.7 (1
6.4)
3840
.9 (1
6.5)
3942
.5 (1
2.2)
39Co
ntro
l 47
.7 (9
.6)
4644
.3 (1
4.2)
3641
.2 (1
1.9)
3641
.7 (1
3.5)
3439
.1 (1
3.8)
37
MFI
S ph
ysic
al (0
–36)
†CB
T21
.6 (5
.7)
4417
.4 (6
.4)
3817
.8 (7
.3)
3819
.5 (8
.1)
3920
.3 (6
.1)
39Co
ntro
l 22
.5 (5
.0)
4620
.8 (6
.2)
3619
.6 (6
.3)
3619
.4 (6
.3)
3418
.1 (6
.8)
37
MFI
S co
gniti
ve (0
–40)
†CB
T21
.5 (7
.8)
4417
.6 (8
.7)
3817
.4 (8
.8)
3817
.7 (8
.5)
3918
.6 (7
.3)
39Co
ntro
l 20
.8 (6
.2)
4619
.6 (8
.5)
3618
.1 (7
.3)
3618
.7 (7
.6)
3417
.6 (7
.4)
37
Tabl
e 7.
2 co
ntin
ues o
n ne
xt p
age
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
166
Tabl
e 7.
2 Co
ntin
ued
Base
line
T8T1
6T2
6T5
2
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
n
MFI
S ps
ycho
soci
al (0
–8)†
CBT
4.3
(1.6
)44
3.3
(1.9
)38
3.4
(1.8
)38
3.7
(1.9
)39
3.6
(1.6
)39
Cont
rol
4.3
(1.4
)46
4.0
(1.8
)36
3.4
(1.3
)36
3.6
(1.5
)34
3.4
(1.6
)37
CIS2
0r to
tal (
20–1
40)†
CBT
94.4
(19.
4)44
77.0
(23.
3)38
78.5
(24.
6)39
84.2
(24.
8)39
87.5
(20.
8)39
Cont
rol
94.6
(13.
8)46
90.0
(16.
4)38
83.6
(22.
9)36
88.1
(19.
0)36
86.3
(21.
2)35
CIS2
0r c
once
ntra
tion
(5–3
5)†
CBT
22.7
(8.5
)44
20.0
(8.1
)38
20.1
(7.6
)39
20.8
(7.4
)39
20.8
(7.0
)39
Cont
rol
22.1
(6.6
)46
21.3
(6.2
)38
21.3
(7.3
)36
20.0
(6.5
)36
20.4
(8.0
)35
CIS2
0r m
otiv
atio
n (4
–28)
†CB
T15
.5 (6
.3)
4413
.2 (5
.8)
3813
.9 (6
.4)
3914
.9 (6
.3)
3914
.8 (6
.1)
39Co
ntro
l 15
.1 (4
.9)
4615
.2 (5
.1)
3815
.1 (5
.0)
3615
.6 (5
.8)
3614
.2 (5
.1)
35
CIS2
0r p
hysi
cal a
ctiv
ity (3
–21)
†CB
T13
.4 (5
.6)
4410
.3 (4
.9)
3810
.5 (5
.3)
3911
.6 (4
.7)
3912
.9 (5
.0)
39Co
ntro
l 13
.2 (3
.6)
4612
.4 (3
.6)
3812
.4 (4
.3)
3611
.6 (4
.6)
3612
.1 (4
.4)
35
SF36
vita
lity
(0–1
00)
CBT
42.3
(13.
4)44
54.2
(16.
6)38
53.2
(17.
2)37
50.9
(19.
0)39
46.9
(16.
6)39
Cont
rol
40.4
(14.
7)46
43.7
(14.
4)38
45.4
(12.
3)36
45.6
(13.
5)36
46.2
(17.
1)37
SF36
phy
sica
l fun
ctio
ning
(0–1
00)
CBT
55.8
(22.
1)44
58.8
(21.
5)38
58.2
(24.
8)37
55.8
(23.
7)39
55.9
(22.
3)39
Cont
rol
62.2
(20.
4)46
57.0
(23.
3)38
61.3
(20.
1)35
58.1
(21.
7)36
60.3
(22.
0)37
SF36
bod
ily p
ain
(0–1
00)
CBT
68.8
(17.
5)44
74.2
(17.
6)38
73.3
(19.
7)37
67.6
(20.
5)39
70.4
(20.
7)39
Cont
rol
66.7
(20.
2)46
69.9
(20.
5038
68.6
(21.
3)36
67.2
(22.
9)36
70.5
(24.
6)37
SF36
gen
eral
hea
lth (0
–100
)CB
T49
.5 (1
2.6)
4446
.1 (1
3.6)
3846
.5 (1
6.2)
3748
.6 (1
3.1)
3948
.6 (1
5.3)
39Co
ntro
l 53
.8 (1
4.5)
4651
.3 (1
3.6)
3848
.2 (1
3.4)
3649
.2 (1
4.5)
3650
.3 (1
5.3)
37SF
36 p
hysi
cal r
ole
func
tioni
ng (0
–100
)CB
T20
.5 (3
1.6)
4449
.3 (4
0.9)
3848
.0 (4
0.1)
3742
.9 (4
6.2)
3928
.8 (3
7.4)
39Co
ntro
l 16
.3 (2
8.5)
4623
.7 (3
2.9)
3832
.4 (3
5.5)
3627
.8 (3
8.2)
3638
.5 (3
9.4)
37
Tabl
e 7.
2 co
ntin
ues o
n ne
xt p
age
167
7
Tabl
e 7.
2 Co
ntin
ued
Base
line
T8T1
6T2
6T5
2
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
nM
ean
(SD
)n
Mea
n (S
D)
n
SF36
em
otio
nal r
ole
func
tioni
ng (0
–100
)CB
T60
.6 (4
1.5)
4482
.5 (3
2.6)
3874
.8 (3
6.3)
3776
.1 (4
0.4)
3971
.8 (3
6.3)
39Co
ntro
l 67
.4 (4
1.9)
4671
.1 (4
2.6)
3872
.2 (3
9.4)
3673
.1 (3
9.7)
3671
.2 (4
2.4)
37
SF36
soc
ial f
unct
ioni
ng (0
–100
)CB
T61
.1 (1
8.5)
4470
.7 (1
8.7)
3868
.9 (2
1.0)
3770
.8 (2
2.1)
3967
.7 (1
9.0)
39Co
ntro
l 61
.7 (1
8.9)
4669
.1 (1
8.1)
3874
.3 (1
6.8)
3571
.9 (1
7.5)
3673
.6 (2
0.6)
37
SF36
men
tal h
ealth
(0–1
00)
CBT
64.5
(13.
5)44
73.8
(12.
1)38
71.7
(12.
4)37
72.9
(13.
7)39
68.3
(15.
4)39
Cont
rol
68.8
(12.
6)46
71.4
(13.
6)38
71.7
(13.
9)36
71.0
(16.
8)36
71.1
(16.
1)37
RAP
com
mun
icat
ion
(0–4
)†CB
T2.
9 (0
.9)
432.
8 (1
.0)
412.
9 (0
.7)
412.
9 (0
.9)
402.
7 (0
.7)
39Co
ntro
l 2.
7 (0
.8)
452.
5 (0
.8)
422.
5 (0
.6)
422.
6 (0
.8)
382.
7 (0
.9)
39
RAP
mob
ility
(0–1
5)†
CBT
10.9
(2.9
)41
10.2
(2.8
)40
10.7
(2.9
)41
10.7
(3.0
)39
11.5
(3.0
)39
Cont
rol
10.1
(2.7
)45
10.0
(2.5
)40
10.5
(3.2
)42
10.6
(2.5
)38
10.7
(2.9
)38
RAP
self-
care
(0–1
0)†
CBT
10.1
(2.8
)42
9.3
(2.1
)41
9.8
(2.3
)39
10.3
(4.2
)38
10.3
(2.8
)39
Cont
rol
9.4
(2.3
)45
9.8
(2.4
)42
9.3
(2.5
)41
9.9
(2.6
)38
10.4
(2.4
)38
RAP
occu
patio
nal (
0–14
)†CB
T7.
3 (1
.9)
426.
4 (2
.0)
406.
7 (4
.0)
416.
4 (2
.3)
387.
2 (2
.1)
38Co
ntro
l 6.
9 (2
.0)
447.
4 (2
.6)
426.
7 (2
.2)
417.
2 (2
.0)
357.
1 (2
.0)
39
RAP
rela
tions
hips
(0–9
)†CB
T5.
0 (2
.1)
444.
0 (1
.9)
413.
7 (1
.6)
413.
7 (1
.7)
404.
2 (1
.9)
37Co
ntro
l4.
2 (1
.9)
453.
7 (1
.5)
423.
5 (1
.3)
423.
5 (1
.3)
373.
7 (1
.4)
39† L
ower
is b
ette
r. CI
S20r
, Che
cklis
t Ind
ivid
ual S
tren
gth;
IPA
, Im
pact
on
Part
icip
atio
n an
d Au
tono
my;
FSS
, Fat
igue
Sev
erity
Sca
le; M
FIS,
Mod
ified
Fat
igue
Impa
ct S
cale
; SF,
Shor
t For
m; R
AP,
Reha
bilit
atio
n Ac
tivity
Pro
file;
SD
, sta
ndar
d de
viat
ion.
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
168
Tabl
e 7.
3 Be
twee
n-gr
oup
effec
t of C
BT v
ersu
s M
S nu
rse
cons
ulta
tions
, cor
rect
ed fo
r bas
elin
e va
lue
and
cent
er
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
Prim
ary
outc
omes
CIS2
0r_f
atig
ue (8
–56)
†-4
.22
(-7.
11; -
1.33
)-7
.19
(-11
.13;
-3.2
5)-6
.67
(-10
.68;
-2.7
0)-3
.46
(-7.4
3; 0
.51)
0.48
(-3
.51;
4.4
7)
IPA
indo
ors
(0–4
)†-0
.05
(-0.2
1; 0
.11)
-0.0
9 (-0
.29;
0.1
1)-0
.13
(-0.3
3; 0
.07)
-0.0
1 (-0
.21;
0.1
9)0.
02
(-0.1
8; 0
.22)
IPA
fam
ily ro
le (0
–4)†
-0.0
5 (-0
.25;
0.1
5)0.
06
(-0.1
9; 0
.31)
-0.1
1 (-
0.37
; 0.1
4)-0
.11
(-0.3
6; 0
.14)
-0.0
4 (-0
.29;
0.2
1)
IPA
out
door
s (0
–4)†
-0.1
4 (-0
.32;
0.0
5)
-0.1
9 (-0
.43;
0.0
5)-0
.16
(-0.4
0; 0
.08)
-0.2
2 (-0
.46;
0.0
2)0.
03
(-0.2
1; 0
.26)
IPA
soc
ial r
elat
ions
(0–4
)†0.
05
(-0.1
0; 0
.21)
0.04
(-0
.15;
0.2
2)0.
08
(-0.1
1; 0
.27)
0.11
(-0
.08;
0.3
0)-0
.02
(-0.
20; 0
.17)
IPA
wor
k an
d ed
ucat
ion
(0–4
)†-0
.15
(-0.3
5; 0
.06)
-0.1
2 (-0
.43;
0.1
9)-0
.09
(-0.4
1; 0
.22)
-0.3
4 (-
0.66
; -0.
03)
-0.0
4 (-0
.36;
0.2
7)
Seco
ndar
y ou
tcom
esFS
S (1
–7)†
-0.3
9 (-
0.67
; -0.
12)
-0.4
6 (-
0.83
; -0.
10)
-0.7
1 (-
1.07
; -0.
34)
-0.3
8 (-
0.75
; -0.
01)
-0.0
4 (-0
.41;
0.3
2)
MFI
S to
tal (
0–84
)†-1
.65
(-5.7
0; 2
.40)
-5.4
5 (-
10.7
0; -0
.20)
-3.9
4 (-9
.19;
1.3
1)-1
.29
(-6.5
8; 4
.00)
4.02
(-1
.19;
9.2
3)
MFI
S ph
ysic
al (0
–36)
†-0
.26
(-2.3
0; 1
.79)
-2.7
2 (-
5.32
; -0.
12)
-1.8
0 (-4
.39;
0.8
0)0.
12
(-2.4
8; 2
.72)
3.20
(0
.62;
5.7
8)
MFI
S co
gniti
ve (0
–40)
†-1
.49
(-3.5
3; 0
.54)
-2.4
7 (-5
.15;
0.2
1)-2
.28
(-4.9
8; 0
.42)
-1.4
8 (-4
.18;
1.2
2)0.
25
(-2.4
2; 2
.93)
Tabl
e 7.
3 co
ntin
ues o
n ne
xt p
age
169
7
Tabl
e 7.
3 Co
ntin
ued
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
MFI
S ps
ycho
soci
al (0
–8)†
-0.0
1 (-0
.56;
0.5
3)-0
.66
(-1.3
9; 0
.07)
0.01
(-0
.72;
0.7
4)0.
24
(-0.5
0; 0
.97)
0.35
(-0
.37;
1.0
8)
CIS2
0r to
tal (
20–1
40)†
-8.1
6 (-
14.5
5; -1
.77)
-13.
91
(-22
.31;
-5.5
2)-1
4.35
(-
22.8
4; -5
.86)
-5.4
9 (-1
3.95
; 2.9
6)1.
18 (-
7.32
; 9.6
7)
CIS2
0r c
once
ntra
tion
(5–3
5)†
-0.9
5 (-3
.30;
1.4
0)-1
.30
(-4.1
8; 1
.58)
-2.4
4 (-
5.34
; 0.4
7)0.
15
(-2.7
6; 3
.06)
-0.1
1 (-3
.03;
2.8
1)
CIS2
0r m
otiv
atio
n (4
–28)
†-1
.20
(-3.1
0; 0
.70)
-1.9
9 (-4
.36;
0.3
9)-2
.16
(-4.5
5; 0
.24)
-1.0
9 (-3
.49;
1.3
0)0.
52
(-1.8
8; 2
.93)
CIS2
0r p
hysi
cal a
ctiv
ity (3
–21)
†-1
.08
(-2.6
4; 0
.48)
-2.1
3 (-
4.14
; -0.
11)
-2.4
6 (-
4.49
; -0.
43)
-0.4
1 (-2
.44;
1.6
2)0.
78
(-1.2
6; 2
.82)
SF36
vita
lity
(0–1
00)
5.55
(0
.52;
10.
58)
9.56
(3
.10;
16.
01)
8.39
(1
.85;
14.
93)
5.12
(-1
.37;
11.
61)
-0.6
8 (-7
.15;
5.7
8)
SF36
phy
sica
l fun
ctio
ning
(0–1
00)
0.76
(-3.
51; 5
.03)
4.63
(-0
.86;
10.
12)
1.32
(-4
.28;
6.9
2)0.
22
(-5.3
1; 5
.75)
-3.1
2 (-8
.61;
2.3
8)
SF36
bod
ily p
ain
(0–1
00)
-0.0
1 (-5
.89;
5.8
6)2.
75
(-5.0
3; 1
0.53
)2.
24
(-5.6
7; 1
0.14
)-1
.47
(-9.3
1; 6
.36)
-3.3
0 (-1
1.10
; 4.4
9)
SF36
gen
eral
hea
lth (0
–100
)-1
.51
( -5.
30; 2
.27)
-3.7
1(-9
.01;
1.5
8)-1
.44
(-6.8
1; 3
.93)
-0.4
2 (-5
.74;
4.9
0)-0
.47
(-5.7
6; 4
.82)
SF36
phy
sica
l rol
e fu
nctio
ning
(0–1
00)
10.2
1 (-1
.4; 2
1.46
)24
.49
(7.6
6; 4
1.32
)14
.58
(-2.5
5; 3
1.71
)13
.63
(-3.3
2; 3
0.58
)-1
1.60
(-2
8.44
; 5.2
5)
SF36
em
otio
nal r
ole
func
tioni
ng (0
–100
)5.
70
(-5.7
6; 1
7.15
)12
.91
(-3.8
6; 2
9.69
)5.
65
(-11.
42; 2
2.72
)4.
37
(-12.
53; 2
1.26
)0.
02 (-
16.7
5; 1
6.79
)
Tabl
e 7.
3 co
ntin
ues o
n ne
xt p
age
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
170
Tabl
e 7.
3 Co
ntin
ued
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
SF36
soc
ial f
unct
ioni
ng (0
–100
)-1
.56
(-7.6
1; 4
.49)
2.31
(-5
.79;
10.
42)
-3.3
3 (-1
1.60
; 4.9
4)0.
49
(-7.6
6; 8
.65)
-5.8
9 (-1
3.99
; 2.2
2)
SF36
men
tal h
ealth
(0–1
00)
1.91
(-2
.73;
6.5
5)2.
26 (-
3.76
; 8.2
9)2.
45
(-3.6
6; 8
.56)
3.62
(-2
.44;
9.6
9)-0
.52
(-6.5
4; 5
.50)
RAP
com
mun
icat
ion
(0–4
)†0.
09
(-0.1
2; 0
.31)
0.12
(-0
.26;
0.4
9)0.
27
(-0.1
1;0.
64)
0.09
(-0
.30;
0.4
8)-0
.12
(-0.5
0; 0
.27)
RAP
mob
ility
(0–1
5)†
0.26
(-0
.48;
1.0
1)0.
07
(-0.9
2; 1
.07)
0.08
(-1
.06;
0.91
)0.
25
(-0.7
6; 1
.26)
0.85
(-0
.17;
1.8
6)
RAP
self-
care
(0–1
0)†
0.03
(-0
.88;
0.9
4)-0
.75
(-2.0
5; 0
.54)
0.42
(-0
.90;
1.74
)0.
50
(-0.8
5; 1
.85)
-0.0
0 (-1
.34;
1.3
4)
RAP
occu
patio
n (0
–14)
†-0
.59
(-1.3
9; 0
.21)
-1.0
8 (-2
.39;
0.2
3)-0
.14
(-1.4
5;1.
17)
-0.9
8 (-2
.36;
0.4
0)-0
.15
(-1.5
0; 1
.20)
RAP
rela
tions
hips
(0–9
)†0.
14
(-0.3
9; 0
.67)
0.18
(-0
.50;
0.8
6)0.
06
(-0.6
2;0.
74)
0.07
(-0
.62;
0.7
7)0.
28 (-
0.42
; 0.9
8)† L
ower
is b
ette
r; si
gnifi
cant
bet
wee
n-gr
oup
diffe
renc
es a
re p
rese
nted
in b
old.
CIS
20r,
Chec
klis
t Ind
ivid
ual S
tren
gth;
IPA
, Im
pact
on
Part
icip
atio
n an
d Au
tono
my;
FSS
, Fa
tigue
Sev
erity
Sca
le; M
FIS,
Mod
ified
Fat
igue
Impa
ct S
cale
; SF,
Shor
t For
m; R
AP,
Reha
bilit
atio
n Ac
tivity
Pro
file;
se,
sta
ndar
d er
ror;
β, b
eta
for b
etw
een-
grou
p eff
ect,
i.e.
the
betw
een-
grou
p di
ffere
nce
at th
at ti
me
poin
t.
171
7
of 8 or more points on the CIS20r fatigue scale in the CBT study group compared to the control study group was: 0.31 (95% CI, 0.09 to 0.52), with a NNT of 3.3 (95% CI, 1.9 to 10.6). The ARR for patients to score below the cut-off of 35 points was 0.34 (95% CI, 0.13 to 0.54), with a NNT of 3.0 (95% CI, 1.8 to 7.5).
Discussion
This study found a significant beneficial effect of Cognitive Behavioral Therapy (CBT) on MS-related fatigue directly following treatment. The significant 6.7 point difference on the CIS20r fatigue found after the 16 week intervention period approached the a priori defined clinically relevant change of 8 points or more. Furthermore, patients scored below the cut-off point of 35 for extreme fatigue, and the secondary fatigue questionnaires show similarly positive and significant results. In addition to these positive effects, the number needed to treat (NNT) was low at 3.3. The follow-up measurements showed that the positive effects gradually wore off after treatment cessation. Summarizing the results, the study found positive short-term effects of CBT on MS-related fatigue compared to the MS nurse consultations.
The results regarding societal participation were not as positive. Except for one positive and significant result on IPA work and education at T26, we found no significant effect of CBT compared to the MS nurse control condition. The participants did not show
Figure 7.2 Observed results on the primary outcome CIS20r fatigue (Mean, SD, at each measurement moment).
1
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
172
substantial limitations on the IPA at baseline, which could be interpreted as a ceiling effect; there was little room for improvement. Furthermore, a note of caution about the interpretation of the IPA is due here; it might not be the most suitable tool to measure societal participation. However, the secondary participation measures, SF36 and RAP, also failed to show significant between-group differences, with the exception of SF36 physical role functioning at T8. This leads us to conclude that CBT for MS-related fatigue did not influence participation in this study.
Some strengths of this study need to be highlighted. First of all, we had a follow-up period of one year. Only three studies have provided long term (8–12 months) follow-up data.10,27,28 A second (methodological) strength of the current study was that we excluded patients with fatigue potentially caused by other factors (e.g. depression, primary sleep disorders). This led to the inclusion of patients with primary MS-related fatigue and the results can therefore be generalized to any ambulant population with primary MS-related fatigue. A third strength of the current study was that the therapy was only provided by certified psychologists with CBT training. Finally, this is the first study in which CBT was tailored to the fatigue-maintaining factors that are relevant for patients.
Some limitations should be considered when interpreting the results. First, recruitment bias might have occurred towards patients who were highly motivated to start with CBT and who were willing to be treated by a psychologist.29 The fast drop-out of 5 persons in the MS nurse study group is likely related to patient preferences and the disappointment about treatment allocation.
The present study makes several noteworthy contributions to the field of CBT treatment of MS-related fatigue. The current results seem to be consistent with the theoretical model proposed by van Kessel et al.,8 and support the supposition that cognitive, emotional and behavioral factors can perpetuate or worsen fatigue.
Based on the current results some recommendations can be given. Future research into the factors related to the process of change during CBT may improve CBT for MS-related fatigue. Furthermore, insight into factors related to the diminishing post-treatment effects might aid the improvement of the current CBT program, or the development of interventions that are able to sustain a positive short-term effect over the long-term (e.g. CBT booster sessions). The evidence provided by this study supports a clinical practice recommendation to start CBT in patients with severe MS-related fatigue.
173
7
Conclusion
The TREFAMS-CBT trial showed a significant and beneficial short-term effect of individually-tailored CBT provided by certified psychologists compared to the control intervention on MS-related fatigue. Future research should focus on identifying the mechanisms of change to provide a basis for maintaining positive effects over the long-term.
Acknowledgements
We gratefully acknowledge the participants, CBT therapists and the specialized MS nurses that contributed to this trial. We would also like to thank the rehabilitation physicians for their help during the recruitment phase, and would like to acknowledge the support provided by the national and regional patient organizations MSVN and everybody involved with the TREFAMS-CBT trial in the participating centers.
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
174
References1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17.
2. Giovannoni G. Multiple sclerosis related fatigue. J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):2-3.
3. Fox RJ, Bacon TE, Chamot E, Salter AR, Cutter GR, Kalina JT, Kister I. Prevalence of multiple sclerosis symptoms across lifespan: data from the NARCOMS Registry. Neurodegener Dis Manag. 2015;5(6 Suppl):3-10. doi: 10.2217/nmt.15.55. Erratum in: Neurodegener Dis Manag. 2016;6(2):178.
4. Metz L. Multiple sclerosis: symptomatic therapies. Semin Neurol. 1998;18(3):389-95.
5. Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C. Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess. 2000;4(27):1-61.
6. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. 2014;2014:798285.
7. Khan F, Amatya B, Galea M. Management of Fatigue in Persons with Multiple Sclerosis. Front Neurol. 2014;5:177.
8. van Kessel K, Moss-Morris R. Understanding multiple sclerosis fatigue: a synthesis of biological and psychological factors. J Psychosom Res. 2006 Nov;61(5):583-5.
9. Knoop H, Bleijenberg G, Gielissen MF, van der Meer JW, White PD. Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom. 2007;76(3):171-6.
10. van den Akker LE, Beckerman H, Collette EH, Eijssen IC, Dekker J, de Groot V. Effectiveness of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. J Psychosom Res. 2016 Nov; 90:33-42.
11. van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008 Feb;70(2):205-13.
12. Beckerman H, Blikman LJ, Heine M, Malekzadeh A, Teunissen CE, Bussmann JB, Kwakkel G, van Meeteren J, de Groot V; TREFAMS-ACE study group. The effectiveness of aerobic training, cognitive behavioural therapy, and energy conservation management in treating MS-related fatigue: the design of the TREFAMS-ACE programme. Trials. 2013 Aug 12;14: 250.
13. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P; CONSORT Group.. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment:explanation and elaboration. Ann Intern Med. 2008 Feb 19;148(4):295-309.
14. Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res. 1994 Jul;38(5):383-92.
175
7
15. Cardol M, de Haan RJ, van den Bos GA, de Jong BA, de Groot IJ. The development of a handicap assessment questionnaire: the Impact on Participation and Autonomy (IPA). Clin Rehabil. 1999 Oct;13(5):411-9.
16. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3.
17. Kos D, Kerckhofs E, Nagels G, D’Hooghe BD, Duquet W, Duportail M, Ketelaer P. Assessing fatigue in multiple sclerosis: Dutch modified fatigue impact scale. Acta Neurol Belg. 2003 Dec;103(4):185-91.
18. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, Sprangers MA, te Velde A, Verrips E. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998 Nov;51(11):1055-68.
19. van Bennekom CA, Jelles F, Lankhorst GJ, Bouter LM. The Rehabilitation Activities Profile: a validation study of its use as a disability index with stroke patients. Arch Phys Med Rehabil. 1995 Jun;76(6):501-7.
20. Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G. Prognosis in chronic fatigue syndrome: a prospective study on the natural course. J Neurol Neurosurg Psychiatry. 1996 May;60(5):489-94.
21. Cardol M, Beelen A, van den Bos GA, de Jong BA, de Groot IJ, de Haan RJ. Responsiveness of the Impact on Participation and Autonomy questionnaire. Arch Phys Med Rehabil. 2002 Nov;83(11):1524-9.
22. van der Werf SP, Jongen PJ, Lycklama à Nijeholt GJ, Barkhof F, Hommes OR, Bleijenberg G. Fatigue in multiple sclerosis: interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability. J Neurol Sci. 1998 Oct 8;160(2):164-70.
23. Gielissen MF, Verhagen S, Witjes F, Bleijenberg G. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol. 2006 Oct 20;24(30):4882-7.
24. Vierron E, Giraudeau B. Design effect in multicenter studies: gain or loss of power? BMC Med Res Methodol. 2009 Jun 18;9:39.
25. Yu LM, Chan AW, Hopewell S, Deeks JJ, Altman DG. Reporting on covariate adjustment in randomised controlled trials before and after revision of the 2001 CONSORT statement: a literature review. Trials. 2010 May 18;11:59.
26. Sedgwick P. Measuring the benefit of treatment: number needed to treat. BMJ. 2015 Apr 27;350:h2206.
27. Thomas S, Thomas PW, Kersten P, Jones R, Green C, Nock A, Slingsby V, Smith AD, Baker R, Galvin KT, Hillier C. A pragmatic parallel arm multi-centre randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based fatigue management programme (FACETS) for people with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1092-9.
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
176
28. Ehde DM, Elzea JL, Verrall AM, Gibbons LE, Smith AE, Amtmann D. Efficacy of a Telephone-Delivered Self-Management Intervention for Persons With Multiple Sclerosis: A Randomized Controlled Trial With a One-Year Follow-Up. Arch Phys Med Rehabil. 2015 Nov;96(11):1945-58.
29. Duquin JA, Parmenter BA, Benedict RH. Influence of recruitment and participation bias in neuropsychological research among MS patients. J Int Neuropsychol Soc. 2008 May; 14(3):494-8.
177
7
Supplemental Table S7.1 Demographics of the immediate drop-outs
PatientsCBT(n=41)
Drop-out(n=3 )
MS nurse(n=42)
Drop-out(n=5)
Age (years) 50.6 (8.5) 49.7 (5.4) 47.6 (11.5) 36.1 (7.0)
GenderMale 13 (32) 0 8 (19) 0Female 28 (68) 3 (100) 34 (81) 5 (100)
Time since diagnosis (years) 9.3 (2.8–13.8) 15.8 (11.1–18.1) 8.0 (0.6–11.9) 3.2 (0.6–6.6)
EDSS 3.3 (2.5–4.0) 2.5 (2.0–2.75) 2.7 (2.0–3.1) 2.0 (1.5–2.5)
Disease courseRR 29 (71) 3 (100) 31 (74) 4 (80)PP 6 (15) 0 4 (10) 0SP 5 (12) 0 7 (17) 0Other 0 0 0 0Unknown 1 (2) 0 0 1 (20)
Relapse(s) in previous 12 monthsYes 12 (29) 3 (100) 13 (31) 0No 26 (63) 0 22 (52) 4 (80)Do not know 3 (7) 0 7 (17) 1 (20)
Disease modifying drugsYes 19 (46) 1 (33) 20 (48) 2 (40)No 22 (54) 2 (67) 22 (52) 2 (40)Unknown 0 0 0 1 (20)
Civil statusLiving with partner 32 (78) 2 (67) 30 (70) 3 (60)Living without partner 9 (22) 1 (33) 12 (28) 1 (20)Unknown 0 0 0 1 (20)
Employment status Full-time 4 (10) 0 4 (9)Part-time 16 (39) 0 15 (36) 3 (60)
Disability pension 9 (56) 0 9 (60) 0Unemployed 17 (19) 3 (100) 18 (43) 1 (20)
Disability pension 15 (88) 2 (67) 15 (73) 0Retirement 1 (2) 0 3 (6) 0Study 1 (2) 0 2 (4) 0Unknown 2 (5) 0 0 1 (20)
CIRS 3.4 (2.4) 3.8 (2.1) 3.6 (1.9) 3.4 (2.2)
HADS anxiety 6.8 (3.8) 5.7 (3.3) 5.9 (3.4) 8.5 (2.4)
GSES 28.4 (5.6) 33.0 (3.6) 31.0 (4.6) 29.3 (3.9)
Data are mean (SD), or median (IQR), or n (%).CIRS, Cumulative Illness Rating Scale; EDSS, Expanded Disability Status Scale; GSES, General Self-Efficacy Scale; HADS, Hospital Anxiety and Depression Scale; RR, Relapsing Remitting; SP, Secondary Progressive; PP, Primary Progressive.
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
178
Supp
lem
enta
l Tab
le S
7.2
Resu
lts o
f the
bet
wee
n-gr
oup
diffe
renc
es o
f CBT
ver
sus
MS
nurs
e co
nsul
tatio
ns, u
nadj
uste
d (m
odel
1),
adju
sted
for c
entr
e (m
odel
1),
ad-
ditio
nal a
djus
tmen
t for
pro
gnos
tic c
ovar
iate
s (m
odel
3)
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
Prim
ary
outc
ome
mea
sure
s
CIS2
0r fa
tigue
(8–5
6)†
1. U
nadj
uste
d-4
.22
(-7.1
2; -1
.33)
-7.1
7 (-1
1.12
; -3.
22)
-6.7
0 (-1
0.69
; - 2
.70)
-3.4
6 (-7
.44;
0.5
1)0.
43 (-
3.56
; 4.4
3)
2. A
djus
ted
(cen
tre)
-4.2
2 (-7
.11;
-1.3
3)-7
.19
(-11.
13; -
3.25
)-6
.67
(-10.
68; -
2.70
)-3
.46
(-7.4
3; 0
.51)
0.48
(-3.
51; 4
.47)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-4.2
3 (-7
.35;
-1.1
0)-6
.88
(-10.
98; -
2.79
)-6
.54
(-10.
70; -
2.38
)-3
.46
(-7.6
2; 0
.71)
0.67
(-4.
16; 4
.17)
IPA
aut
onom
y in
door
s (0–
4)†
1. U
nadj
uste
d-0
.05
(-0.2
1; 0
.11)
-0.0
9 (-0
.29;
0.1
2)-0
.13
(-0.3
4; 0
.07)
-0.0
1 (-0
.22;
0.1
9)0.
01 (-
0.19
; 0.2
2)
2. A
djus
ted
(cen
tre)
-0.0
5 (-0
.21;
0.1
1)-0
.09
(-0.2
9; 0
.11)
-0.1
3 (-0
.33;
0.0
7)-0
.01
(-0.2
1; 0
.19)
0.02
(-0.
18; 0
.22)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.0
4 (-0
.20;
0.1
3)-0
.08
(-0.2
9; 0
.13)
-0.1
2 (-0
.33;
0.0
9)0.
01 (-
0.20
; 0.2
2)0.
03 (-
0.18
; 0.2
4)
IPA
fam
ily ro
le (0
–4)†
1. U
nadj
uste
d-0
.05
(-0.2
5; 0
.15)
0.06
(-0.
19; 0
.31)
-0.1
1 (-0
.37;
0.1
4)-0
.11
(-0.3
6; 0
.14)
-0.0
4 (-0
.29;
0.2
1)
2. A
djus
ted
(cen
tre)
-0.0
5 (-0
.25;
0.1
5)0.
06 (-
0.19
; 0.3
1)-0
.11
(-0.3
7; 0
.14)
-0.1
1 (-0
.36;
0.1
4)-0
.04
(-0.2
9; 0
.21)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.0
8 (-0
.29;
0.1
3)0.
02 (-
0.23
; 0.2
8)-0
.12
(-0.3
8; 0
.13)
-0.1
3 (-0
.39;
0.1
2)-0
.10
(-0.3
6; 0
.16)
IPA
aut
onom
y ou
tdoo
rs (0
–4)†
1. U
nadj
uste
d-0
.14
(-0.3
3; 0
.05)
-0.1
9 (-0
.43;
0.0
5)-0
.16
(-0.4
0; 0
.08)
-0.2
2 (-0
.46;
0.0
2)0.
02 (-
0.22
; 0.2
6)
2. A
djus
ted
(cen
tre)
-0.1
4 (-0
.32;
0.0
5)
-0.1
9 (-0
.43;
0.0
5)-0
.16
(-0.4
0; 0
.08)
-0.2
2 (-0
.46;
0.0
2)0.
03 (-
0.21
; 0.2
6)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.1
5 (-0
.34;
0.0
3)-0
.21
(-0.4
5; 0
.02)
-0.1
5 (-0
.39;
0.0
8)-0
.23
(-0.4
7; 0
.00)
-0.0
0 (-0
.24;
0.2
3)
IPA
soci
al re
latio
ns (0
–4)†
1. U
nadj
uste
d0.
05 (-
0.10
; 0.2
0)0.
04 (-
0.15
; 0.2
2)0.
07 (-
0.11
; 0.2
6)0.
11 (-
0.08
; 0.3
0)-0
.02
(-0.2
1; 0
.17)
2. A
djus
ted
(cen
tre)
0.05
(-0.
10; 0
.21)
0.04
(-0.
15; 0
.22)
0.08
(-0.
11; 0
.27)
0.11
(-0.
08; 0
.30)
-0.0
2 (-0
.20;
0.1
7)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.05
(-0.
10; 0
.20)
0.03
(-0.
16; 0
.22)
0.09
(-0.
10; 0
.28)
0.11
(-0.
08; 0
.30)
-0.0
3 (-0
.21;
0.1
6)
IPA
wor
k/ed
ucat
ion
(0–4
)†1.
Una
djus
ted
-0.1
4 (-0
.35;
0.0
7)-0
.12
(-0.4
3; 0
.19)
-0.0
8 (-0
.39;
0.2
3)-0
.34
(-0.6
6; -0
.02)
-0.0
3 (-0
.35;
0.2
9)
2. A
djus
ted
(cen
tre)
-0.1
5 (-0
.35;
0.0
6)-0
.12
(-0.4
3; 0
.19)
-0.0
9 (-0
.41;
0.2
2)-0
.34
(-0.6
6; -0
.03)
-0.0
4 (-0
.36;
0.2
7)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.1
7 (-0
.38;
0.0
5)-0
.11
(-0.4
3; 0
.20)
-0.1
4 (-0
.45;
0.1
8)-0
.33
(-0.6
5; -0
.01)
-0.0
8 (-0
.40;
0.2
4)
Supp
lem
enta
l Tab
le S
7.2
cont
inue
s on
next
pag
e
179
7
Supp
lem
enta
l Tab
le S
7.2
Cont
inue
d
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
Seco
ndar
y ou
tcom
e m
easu
res
FSS
(1–7
)†1.
Una
djus
ted
-0.3
9 (-0
.67;
-0.1
2)-0
.46
(-0.8
3; -0
.10)
-0.7
1 (-1
.07;
-0.3
4)-0
.38
(-0.7
5; -0
.01)
-0.0
5 (-0
.41;
0.3
2)
2. A
djus
ted
(cen
tre)
-0.3
9 (-0
.67;
-0.1
2)-0
.46
(-0.8
3; -0
.10)
-0.7
1 (-1
.07;
-0.3
4)-0
.38
(-0.7
5; -0
.01)
-0.0
4 (-0
.41;
0.3
2)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.3
9 (-0
.68;
-0.1
1)-0
.45
(-0.8
3; -0
.08)
-0.6
9 (-1
.07;
-0.3
1)-0
.38
(-0.7
6; -0
.00)
-0.0
7 (-0
.45;
0.3
1)
MFI
S to
tal (
0–84
)†1.
Una
djus
ted
-1.6
5 (-5
.70;
2.4
0)-5
.46
(-10.
72; -
0.19
)-3
.99
(-9.2
6; 1
.27)
-1.3
3 (-6
.63;
3.9
7)3.
92 (-
1.30
; 9.1
4)
2. A
djus
ted
(cen
tre)
-1.6
5 (-5
.70;
2.4
0)-5
.45
(-10.
70; -
0.20
)-3
.94
(-9.1
9; 1
.31)
-1.2
9 (-6
.58;
4.0
0)4.
02 (-
1.19
; 9.2
3)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-1.6
5 (-5
.82;
2.5
1)-5
.61
(-10.
91; -
0.31
)-3
.68
(-8.9
8; 1
.61)
-0.9
5 (-6
.28;
4.3
7)3.
48 (-
1.81
; 8.7
6)
MFI
S ph
ysic
al (0
–36)
†1.
Una
djus
ted
-0.2
8 (-2
.37;
1.8
0)-2
.71
(-5.3
5; -0
.08)
-1.8
3 (-4
.46;
0.8
0)0.
10 (-
2.54
; 2.7
4)3
.14
(0.5
3; 5
.76)
2. A
djus
ted
(cen
tre)
-0.2
6 (-2
.30;
1.7
9)-2
.72
(-5.3
2; -0
.12)
-1.8
0 (-4
.39;
0.8
0)0.
12 (-
2.48
; 2.7
2)3.
20 (0
.62;
5.7
8)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.4
1 (-2
.52;
1.7
0)-2
.98
(-5.6
2; -0
.34)
-1.7
8 (-4
.42;
0.8
6)0.
08 (-
2.56
; 2.7
2)2.
92 (0
.29;
5.5
5)
MFI
S co
gniti
ve (0
–40)
†1.
Una
djus
ted
-1.4
9 (-3
.52;
0.5
3)-2
.46
(-5.1
3; 0
.22)
-2.2
8 (-4
.97;
0.4
2)-1
.47
(-4.1
7; 1
.22)
0.24
(-2.
43; 2
.91)
2. A
djus
ted
(cen
tre)
-1.4
9 (-3
.53;
0.5
4)-2
.47
(-5.1
5; 0
.21)
-2.2
8 (-4
.98;
0.4
2)-1
.48
(-4.1
8; 1
.22)
0.25
(-2.
42; 2
.93)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-1.6
1 (-3
.71;
0.4
9)-2
.50
(-5.2
1; 0
.22)
-2.3
0 (-5
.03;
0.4
2)-1
.33
(-4.0
6; 1
.40)
-0.2
9 (-3
.01;
2.4
3)
MFI
S ps
ycho
soci
al (0
–8)†
1. U
nadj
uste
d-0
.02
(-0.5
5; 0
.52)
-0.6
6 (-1
.38;
0.0
7)0.
01 (-
0.72
; 0.7
4)0.
24 (-
0.50
; 0.9
7)0.
35 (-
0.38
; 1.0
7)
2. A
djus
ted
(cen
tre)
-0.0
1 (-0
.56;
0.5
3)-0
.66
(-1.3
9; 0
.07)
0.01
(-0.
72; 0
.74)
0.24
(-0.
50; 0
.97)
0.35
(-0.
37; 1
.08)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.02
(-0.
56; 0
.59)
-0.7
5 (-1
.49;
-0.0
1)0.
08 (-
0.66
; 0.8
2)0.
27 (-
0.47
; 1.0
2)0.
44 (-
0.30
; 1.1
8)
CIS2
0r to
tal (
20–1
40)†
1. U
nadj
uste
d-8
.19
(-14.
59; -
1.80
)-1
3.91
(-22
.31;
-5.5
0)-1
4.38
(-22
.87;
-5.8
8)-5
.52
(-13.
98; 2
.94)
1.06
(-7.
44; 9
.56)
2. A
djus
ted
(cen
tre)
-8.1
6 (-1
4.55
; -1.
77)
-13.
91 (-
22.3
1; -5
.52)
-14.
35 (-
22.8
4; -5
.86)
-5.4
9 (-1
3.95
; 2.9
6)1.
18 (-
7.32
; 9.6
7)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-8.2
1 (-1
5.07
; -1.
35)
-13.
44 (-
22.1
0; -4
.78)
-14.
00 (-
22.7
8; -5
.23)
-5.5
2 (-1
4.31
; 3.2
6)0.
34 (-
8.44
; 9.1
3)
CIS2
0r c
once
ntra
tion
(5–3
5)†
1. U
nadj
uste
d-0
.96
(-3.2
9; 1
.38)
-1.3
1 (-4
.17;
1.5
6)-2
.44
(-5.3
4; 0
.45)
0.14
(-2.
76; 3
.03)
-0.1
2 (-3
.02;
2.7
9)
2. A
djus
ted
(cen
tre)
-0.9
5 (-3
.30;
1.4
0)-1
.30
(-4.1
8; 1
.58)
-2.4
4 (-5
.34;
0.4
7)0.
15 (-
2.76
; 3.0
6)-0
.11
(-3.0
3; 2
.81)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-1.5
1 (-4
.00;
0.9
7)-1
.78
(-4.7
6; 1
.20)
-2.9
4 (-5
.95;
0.0
8)-0
.33
(-3.3
6; 2
.70)
-0.8
6 (-3
.88;
2.1
7)
Supp
lem
enta
l Tab
le S
7.2
cont
inue
s on
next
pag
e
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
180
Supp
lem
enta
l Tab
le S
7.2
Cont
inue
d
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
CIS2
0r m
otiv
atio
n (4
–28)
†1.
Una
djus
ted
-1.2
1 (-3
.10;
0.6
8)-1
.99
(-4.3
6; 0
.38)
-2.1
6 (-4
.55;
0.2
3)-1
.10
(-3.4
9; 1
.29)
0.51
(-1.
89; 2
.91)
2. A
djus
ted
(cen
tre)
-1.2
0 (-3
.10;
0.7
0)-1
.99
(-4.3
6; 0
.39)
-2.1
6 (-4
.55;
0.2
4)-1
.09
(-3.4
9; 1
.30)
0.52
(-1.
88; 2
.93)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-1.3
3 (-3
.35;
0.7
0)-2
.06
(-4.5
2; 0
.39)
-2.0
6 (-4
.53;
0.4
2)-1
.38
(-3.8
7; 1
.11)
0.29
(-2.
20; 2
.78)
CIS2
0r p
hysi
cal a
ctiv
ity (3
–21)
†1.
Una
djus
ted
-1.0
9 (-2
.65;
0.4
8)-2
.13
(-4.1
4; ;-
0.11
)-2
.46
(-4.4
9; -0
.43)
-0.4
2 (-2
.45;
1.6
2)0.
76 (-
1.28
; 2.8
0)
2. A
djus
ted
(cen
tre)
-1.0
8 (-2
.64;
0.4
8)-2
.13
(-4.1
4; -0
.11)
-2.4
6 (-4
.49;
-0.4
3)-0
.41
(-2.4
4; 1
.62)
0.78
(-1.
26; 2
.82)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-1.6
8 (-3
.15;
-0.2
0)-2
.64
(-4.5
7; -0
.71)
-3.0
4 (-5
.00;
-1.0
8)-1
.01(
-2.9
8; 0
.96)
0.02
(-1.
94; 1
.99)
SF36
vita
lity
(0–1
00)
1. U
nadj
uste
d5.
60 (0
.57;
10.
63)
9.56
(3.1
1; 1
6.02
)8.
43 (1
.90;
14.
97)
5.18
(-1.
31; 1
1.67
)-0
.59
(-7.0
5; 5
.87)
2. A
djus
ted
(cen
tre)
5.55
(0.5
2; 1
0.58
)9.
56 (3
.10;
16.
01)
8.39
(1.8
5; 1
4.93
)5.
12 (-
1.37
; 11.
61)
-0.6
8 (-7
.15;
5.7
8)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
6.76
(1.6
3; 1
1.89
)10
.36
(3.9
0; 1
6.82
)8.
90 (2
.38;
15.
42)
6.29
(-0.
24; 1
2.81
)1.
49 (-
8.00
; 5.0
2)
SF36
phy
sica
l fun
ctio
ning
(0–1
00)
1. U
nadj
uste
d0.
91 (-
3.38
; 5.2
0)4.
72 (-
0.80
; 10.
23)
1.49
(-4.
13; 7
.11)
0.38
(-5.
17; 5
.93)
-2.9
2 (-8
.44;
2.6
0)
2. A
djus
ted
(cen
tre)
0.76
(-3.
51; 5
.03)
4.63
(-0.
86; 1
0.12
)1.
32 (-
4.28
; 6.9
2)0.
22 (-
5.31
; 5.7
5)-3
.12
(-8.6
1; 2
.38)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.4
9 (-4
.92;
3.9
3)3.
45 (-
2.15
; 9.0
5)-0
.31
(-6.0
0; 5
.37)
-0.9
9 (-6
.65;
4.6
7)4.
15 (-
9.79
; 1.4
8)
SF36
bod
ily p
ain
(0–1
00)
1. U
nadj
uste
d-0
.03
(-5.9
1; 5
.85)
2.67
(-5.
11; 1
0.46
)2.
21 (-
5.70
; 10.
12)
-1.4
7 (-9
.32;
6.3
7)-3
.26
(-11.
06; 4
.54)
2. A
djus
ted
(cen
tre)
-0.0
1 (-5
.89;
5.8
6)2.
75 (-
5.03
; 10.
53)
2.24
(-5.
67; 1
0.14
)-1
.47
(-9.3
1; 6
.36)
-3.3
0 (-1
1.10
; 4.4
9)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.8
3 (-7
.06;
5.4
0)1.
56 (-
6.54
; 9.6
6)1.
09 (-
7.10
; 9.2
8)-2
.32
(-10.
51; 5
.87)
-3.4
2 (-1
1.58
; 4.7
5)
SF36
gen
eral
hea
lth (0
–100
)1.
Una
djus
ted
-1.5
3 (-5
.33;
2.2
7)-3
.65
(-8.9
6; 1
.65)
-1.4
6 (-6
.84;
3.9
3)-0
.47
(-5.8
0; 4
.86)
-0.5
5 (-5
.86;
4.7
5)
2. A
djus
ted
(cen
tre)
-1.5
1( -5
.30;
2.2
7)-3
.71(
-9.0
1; 1
.58)
-1.4
4 (-6
.81;
3.9
3)-0
.42
(-5.7
4; 4
.90)
-0.4
7 (-5
.76;
4.8
2)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-2.1
9 (-6
.11;
1.7
4)-4
.03
(-9.3
9; 1
.34)
-2.3
6 (-7
.76;
3.0
4)-1
.46
(-6.8
6; 3
.94)
-0.9
6 (-6
.34;
4.4
3)
SF36
phy
sica
l rol
e fu
nctio
ning
(0–1
00)
1. U
nadj
uste
d10
.43
(-0.9
8; 2
1.84
)24
.42
(7.4
6; 4
1.39
)14
.78
(-2.4
8; 3
2.04
)13
.92
(-3.1
6; 3
1.00
)-1
1.07
(-28
.04;
5.9
0)
2. A
djus
ted
(cen
tre)
10.2
1 (-1
.40;
21.
46)
24.4
9 (7
.66;
41.
32)
14.5
8 (-2
.55;
31.
71)
13.6
3 (-3
.32;
30.
58)
-11.
60 (-
28.4
4; 5
.25)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
14.0
3 (2
.20;
25.
86)
27.3
8 (1
0.18
; 44.
58)
18.6
2 (1
.19;
36.
05)
15.4
6 (-1
.96;
32.
89)
-5.1
5 (-2
2.50
; 12.
19)
Supp
lem
enta
l Tab
le S
7.2
cont
inue
s on
next
pag
e
181
7
Supp
lem
enta
l Tab
le S
7.2
Cont
inue
d
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
SF36
em
otio
nal r
ole
func
tioni
ng (0
–100
)1.
Una
djus
ted
5.75
(-5.
65; 1
7.14
)12
.85
(-3.8
9; 2
9.59
)5.
67 (-
11.3
7; 2
2.71
)4.
44 (-
12.4
2; 2
1.30
)0.
19 (-
16.5
4; 1
6.93
)
2. A
djus
ted
(cen
tre)
5.70
(-5.
76; 1
7.15
)12
.91
(-3.8
6; 2
9.69
)5.
65 (-
11.4
2; 2
2.72
)4.
37 (-
12.5
3; 2
1.26
)0.
02 (-
16.7
5; 1
6.79
)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
8.43
(-1.
29; 1
8.15
)14
.26
(-0.9
8; 2
9.51
)7.
50 (-
7.96
; 22.
97)
6.29
(-9.
16; 2
1.74
)5.
50 (-
9.86
; 20.
86)
SF36
soci
al fu
nctio
ning
(0–1
00)
1. U
nadj
uste
d-1
.42
(-7.5
6; 4
.72)
2.33
(-5.
85; 1
0.50
)-3
.18
(-11.
52; 5
.16)
0.67
(-7.
57; 8
.90)
-5.6
4 (-1
3.82
; 2.5
3)
2. A
djus
ted
(cen
tre)
-1.5
6 (-7
.61;
4.4
9)2.
31 (-
5.79
; 10.
42)
-3.3
3 (-1
1.60
; 4.9
4)0.
49 (-
7.66
; 8.6
5)-5
.89
(-13.
99; 2
.22)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-2.2
2 (-8
.20;
3.7
5)1.
48 (-
6.54
; 9.4
9)-4
.87
(-13.
03; 3
.28)
-0.4
3 (-8
.54;
7.6
9)-5
.34
(-13.
42; 2
.74)
SF36
men
tal h
ealth
(0–1
00)
1. U
nadj
uste
d1.
87 (-
2.74
; 6.4
9)2.
21 (-
3.79
; 8.2
1)2.
41 (-
3.68
; 8.4
9)3.
60 (-
2.45
; 9.6
4)-0
.53
(-6.5
3; 5
.47)
2. A
djus
ted
(cen
tre)
1.91
(-2.
73; 6
.55)
2.26
(-3.
76; 8
.29)
2.45
(-3.
66; 8
.56)
3.62
(-2.
44; 9
.69)
-0.5
2 (-6
.54;
5.5
0)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.23
(-3.
80; 3
.34)
0.81
(-5.
64; 4
.01)
0.65
(-5.
52; 4
.23)
1.27
(-3.
60; 6
.14)
-0.7
8 (-5
.61;
4.0
5)
RAP
com
mun
icat
ion
(0–4
)†1.
Una
djus
ted
0.09
(-0.
12; 0
.30)
0.11
(-0.
26; 0
.49)
0.27
(-0.
11; 0
.64)
0.09
(-0.
30; 0
.47)
-0.1
2 (-0
.51;
0.2
7)
2. A
djus
ted
(cen
tre)
0.09
(-0.
12; 0
.31)
0.12
(-0.
26; 0
.49)
0.27
(-0.
11; 0
.64)
0.09
(-0.
30; 0
.48)
-0.1
2 (-0
.50;
0.2
7)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.13
(-0.
12; 0
.38)
0.12
(-0.
29; 0
.54)
0.39
(-0.
03; 0
.81)
0.14
(-0.
28; 0
.56)
-0.1
3 (-0
.55;
0.2
9)
RAP
mob
ility
(0–1
5)†
1. U
nadj
uste
d0.
26 (-
0.48
; 1.0
0)0.
07 (-
0.93
; 1.0
6)0.
08 (-
1.07
;0.9
0)0.
24 (-
0.77
; 1.2
5)0.
84 (-
0.17
; 1.8
5)
2. A
djus
ted
(cen
tre)
0.26
(-0.
48; 1
.01)
0.07
(-0.
92; 1
.07)
0.08
(-1.
06;0
.91)
0.25
(-0.
76; 1
.26)
0.85
(-0.
17; 1
.86)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.35
(-0.
42; 1
.11)
0.16
(-0.
87; 1
.19)
0.07
(-1.
11;0
.97)
0.46
(-0.
58; 1
.50)
0.73
(-0.
30; 1
.76)
RAP
self-
care
(0–1
0)†
1. U
nadj
uste
d-0
.01
(-0.9
3; 0
.92)
-0.7
8 (-2
.09;
0.5
3)0.
38 (-
0.95
;1.7
1)0.
44 (-
0.92
; 1.8
0)-0
.05
(-1.4
0; 1
.30)
2. A
djus
ted
(cen
tre)
0.03
(-0.
88; 0
.94)
-0.7
5 (-2
.05;
0.5
4)0.
42 (-
0.90
;1.7
4)0.
50 (-
0.85
; 1.8
5)-0
.00
(-1.3
4; 1
.34)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
0.31
(-0.
48; 1
.10)
-0.1
3 (-0
.96;
1.2
2)0.
49 (-
0.63
;1.6
1)0.
67 (-
0.44
; 1.7
9)-0
.15
(-1.2
5; 0
.96)
RAP
occu
patio
n (0
–14)
†1.
Una
djus
ted
-0.6
0 (-1
.39;
0.1
9)-1
.09
(-2.3
9; 0
.22)
-0.1
5 (-1
.46;
1.16
)-0
.99
(-2.3
7; 0
.38)
-0.1
7 (-1
.52;
1.1
7)
2. A
djus
ted
(cen
tre)
-0.5
9 (-1
.39;
0.2
1)-1
.08
(-2.3
9; 0
.23)
-0.1
4 (-1
.45;
1.17
)-0
.98
(-2.3
6; 0
.40)
-0.1
5 (-1
.50;
1.2
0)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.7
1 (-1
.46;
0.0
3)-0
.96
(-2.2
7; 0
.34)
-0.5
5 (-1
.88;
0.77
)-1
.06
(-2.4
3; 0
.30)
-0.3
0 (-1
.62;
1.0
2)
Supp
lem
enta
l Tab
le S
7.2
cont
inue
s on
next
pag
e
Effectiveness of CBT on MS-related fatigue: Results of a RCT Chapter 7
182
Supp
lem
enta
l Tab
le S
7.2
Cont
inue
d
Mix
ed L
inea
r Mod
el; β
(95%
Con
fiden
ce In
terv
al)
Betw
een-
grou
p eff
ect
Ove
rall
T8T1
6T2
6T5
2
RAP
rela
tions
hips
(0–9
)†1.
Una
djus
ted
0.14
(-0.
39; 0
.66)
0.18
(-0.
50; 0
.85)
0.06
(-0.
62;0
.73)
0.07
(-0.
63; 0
.77)
0.27
(-0.
43; 0
.97)
2. A
djus
ted
(cen
tre)
0.14
(-0.
39; 0
.67)
0.18
(-0.
50; 0
.86)
0.06
(-0.
62;0
.74)
0.07
(-0.
62; 0
.77)
0.28
(-0.
42; 0
.98)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
-0.0
2 (-0
.60;
0.5
6)-0
.04
(-0.7
8; 0
.70)
0.06
(-0.
69;0
.81)
-0.1
0 (-0
.85;
0.6
6)0.
02 (-
0.74
; 0.7
7)
HA
DS
anxi
ety
(0–2
1)†
1. U
nadj
uste
d-0
.32
(-1.1
5; 0
.51)
0.70
(-1.
85; 0
.46)
-0.5
3 (-1
.71;
0.6
5)-0
.42
(-1.5
9; 0
.76)
0.30
(-0.
87; 1
.46)
2. A
djus
ted
(cen
tre)
-0.3
2 (-1
.16;
0.5
2)0.
70 (-
1.86
; 0.4
6)-0
.53
(-1.7
1; 0
.65)
-0.4
1 (-1
.59;
0.7
6)0.
30 (-
0.87
; 1.4
7)
3. A
djus
ted
(cen
tre
+ co
varia
tes)
*-0
.14
(-1.0
4; 0
.75)
-0.6
1 (-1
.82;
0.6
0)-0
.33
(-1.5
5; 0
.89)
-0.2
2 (-1
.45;
1.0
0)-0
.52
(-1.7
4; 0
.70)
† A lo
wer
sco
re re
pres
ents
a b
ette
r out
com
e.
* A
ll co
varia
tes
exce
pt H
AD
S an
xiet
y.Ab
brev
iatio
ns: C
IS, C
heck
list
Indi
vidu
al S
tren
gth;
FSS
, Fat
igue
Sev
erity
Sca
le; H
AD
S, H
ospi
tal A
nxie
ty a
nd D
epre
ssio
n Sc
ale;
IPA
, Im
pact
on
Part
icip
atio
n an
d Au
tono
my
ques
tionn
aire
; MFI
S,
Mod
ified
Fat
igue
Impa
ct S
cale
; RA
P, Re
habi
litat
ion
Activ
ity P
rofil
e; S
F36,
Sho
rt F
orm
Hea
lth S
urve
y.
183
7
