Multiple Sclerosis Journal - October 2017 - 1519

M Heine, O Verschuren et al.
trained single-blinded assessor (M.H.) and performed
at the hospital-based outpatient clinic through which
the patient was recruited on separate days from those
in which the experimental and control condition were
provided to maintain blinding. The primary outcomes
of the TREFAMS-AT trial were MS-related fatigue
measured with the Checklist Individual Strength
(CIS20r) fatigue subscale, and societal participation
measured with the Impact on Participation and
Autonomy (IPA) questionnaire.14,15
The CIS20r fatigue subscale entails eight items on a
7-point Likert scale leading to a sum score between
8 and 56 points and details perceived fatigue (e.g. 'I
feel tired') over the previous 2 weeks.14 A change of
eight points was considered to be a clinically relevant difference.12 The IPA is a generic questionnaire
that addresses perceived problems of participation
and autonomy, reflected in 32 items assigned to five
domains including autonomy indoors, autonomy
outdoors, family role, social relations, work and
education.15 A score of 0-4 is calculated for each
domain, and a higher score indicates greater perceived restrictions in that respective domain. A
responsiveness study in a heterogeneous outpatient
rehabilitation setting showed that the IPA questionnaire has a moderate ability to detect within-patient
changes over time.15
Safety was assessed in terms of the number of selfreported as well as (steroid) treated MS relapses during each visit window and defined as new or a
worsening of reoccurring symptoms for a duration
longer than 24 hours, in the absence of fever or secondary inflammation (e.g. infection).
The secondary outcome measures were related to the
primary working mechanism (i.e. physical fitness) as
well as complementary fatigue measures. Participants
performed a CPET including gas exchange measurement on an electromagnetically braked cycle ergometer to determine peak exercise capacity at each
measurement visit. Following a 3-minute rest phase,
participants cycled at 25+10 W/min (women) or
15 W/min (men) until voluntary exhaustion. The following CPET parameters were used in this study:
peak oxygen consumption (VO2peak, VO2peak corrected for body weight and %predicted-VO2peak16),
peak power output (W) and the anaerobic threshold
(%predicted-VO2peak).
In addition to the CIS20r fatigue subscale, we also
included the CIS20r subscales for concentration,
motivation and activity, the Modified Fatigue Impact
Scale (MFIS)17 which entails a physical, cognitive
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and psychosocial subscale and the Fatigue Severity
Scale (FSS) which assesses the impact of fatigue.18
Therapy adherence
Therapy adherence was assessed by (1) the number of
therapy sessions adhered to and (2) the percentage
work performed within the aerobic training group
relative to the work prescribed. Next to the aerobic
training or MS nurse consultation, the number of
additional medical and allied healthcare consultations
was documented at each visit.
Statistical analysis
The sample size calculation was based on the CIS20r
fatigue subscale. A total of 45 patients per arm, and 90
patients in total, were needed to detect a clinically relevant difference of eight points on the CIS20r fatigue
subscale in an MS population with a standard deviation (SD) of 12.7, with a power of 80%, an alpha of
0.05 and a drop-out rate of 20%.19,20 Successful blinding of the assessor (M.H.) for treatment allocation
was tested by comparing the assessors' guesses with
actual treatment allocation using a Cohen's Kappa
statistic following completion of the data collection
and analysis (i.e. successful blinding when Kappa statistic <0.20).21 An independent two-sample t-test or
chi-square test was used to compare differences
between the two groups at baseline.
Longitudinal mixed-model analyses were performed
on an intention-to-treat basis. The primary analysis
was the change in the CIS20r fatigue subscale score in
the aerobic training group compared with the control
intervention. Study centre, baseline value of the
dependent variable, time, study group and time-bystudy group were included as independent variables.
In addition, adjusted analyses were performed by adding gender and EDSS at baseline as fixed covariates
on the basis of their association with aerobic capacity.22
These analyses were repeated for the IPA subdomains
and secondary outcomes related to physical fitness
and MS-related fatigue. We calculated (adjusted for
disease severity) both the odds of reporting an MS
relapse and having received steroid treatment under
the hypothesis that the latter would be indicative of a
significant relapse requiring treatment as confirmed
by a neurologist. The proportion of patients that
showed a clinically meaningful difference (⩾8 points)
in the aerobic training group against those in the control intervention was calculated. Based on the absolute risk reduction (ARR) between the intervention
and control condition, the number needed to treat
(NNT) was estimated. All analyses were performed
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Table of Contents for the Digital Edition of Multiple Sclerosis Journal - October 2017
