Multiple Sclerosis Journal - October 2017 - 1518

Multiple Sclerosis Journal 23(11)
Netherlands; EMGO+
Institute for Health and Care
Research, VU University
Medical Center, Amsterdam,
The Netherlands
Gert Kwakkel
VUmc MS Center
Amsterdam and Department
of Rehabilitation Medicine,
VU University Medical
Center, Amsterdam, The
Netherlands/Department of
Neurorehabilitation, Reade
Center of Rehabilitation and
Rheumatology, Amsterdam,
The Netherlands/Department
of Physical Therapy and
Human Movement Sciences,
Northwestern University,
Chicago, IL, USA

(standardized mean difference (SMD): −0.53, 95%
confidence interval (CI) = −0.73 to −0.33).11 However,
the effectiveness of exercise therapy was not investigated in patients specifically selected for severe levels
of fatigue and were insufficiently powered to study
MS-related fatigue.11
The objective of the 'Treating Fatigue in Multiple
Sclerosis-Aerobic training' (TREFAMS-AT) trial
was to estimate the immediate and 1-year follow-up
effect of 16-week aerobic training, in comparison
with a control intervention, on MS-related fatigue and
societal participation in ambulant patients with severe
MS-related fatigue.
Methods
TREFAMS-AT was a multicentre, single-blinded,
randomized controlled trial with five repeated measurements over the course of 12 months. The
TREFAMS-AT trial was part of a multi-trial programme (TREFAMS-ACE) designed to study the
effects of aerobic training, cognitive behavioural therapy and energy conservation management on
MS-related fatigue in ambulant persons with severe
MS-related fatigue (eSupplement 1).12
Study participants
Recruitment took place between October 2011 and
October 2014 through two hospital-based outpatient
MS centres: St Antonius Hospital, Nieuwegein, The
Netherlands and Jeroen Bosch Hospital, Den Bosch,
The Netherlands. The recruiting rehabilitation physician or neurologist informed potential participants
about the TREFAMS-AT trial. Subsequently, potential participants were evaluated against the inclusion
and exclusion criteria and enrolled if eligible. In short,
inclusion criteria included patients with definite MS,
age ⩾18 and ⩽70 years, ambulant (Expanded
Disability Status Scale (EDSS) ⩽6.0), severe fatigue
(Checklist Individual Strength (CIS20r) fatigue subscale ⩾35) and no signs of an MS exacerbation or
corticosteroid treatment <3 months. Patients were
excluded if having severe mood disorders (Hospital
Anxiety and Depression Scale (HADS) - depression
subscale >11), severe co-morbidity (Cumulative
Illness Rating Scale item scores ⩾3), current pregnancy or given birth <3 months, newly initiated pharmacological (e.g. amantadine) or non-pharmacological
treatment for fatigue (e.g. structured aerobic training)
<3 months. This study was approved by the medical
ethical board of the VU University Medical Center,
Amsterdam and registered under number
ISRCTN69520623 (Controlled-trials.com). All participants provided oral and written informed consent

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in compliance with the declaration of Helsinki and
good clinical practice.
Randomization and therapy allocation
Randomization was performed by an independent
researcher, using an online concealed computer-generated randomization scheme with random variable
block sizes (Julius Center, University Medical Center
Utrecht, Utrecht, The Netherlands).
Procedures
For a comprehensive overview, according to the
TiDiER guidelines,13 of the aerobic training intervention, see eSupplement 2. In short, the aerobic training
programme consisted of aerobic interval training,
three times a week, for the duration of 16 weeks. In
total 12 sessions were given in an outpatient clinic
and supervised by an experienced physiotherapist
whereas the remaining 36 sessions were home-based
using identical equipment as provided by the study
team for the duration of the intervention. The frequency of supervised sessions declined gradually during the intervention phase. Each training session
consisted of 30 minutes of aerobic interval training on
an electro-magnetic cycle ergometer. Each training
session entailed six interval cycles consisting of
3 minutes at 40%, 1 minute at 60% and 1 minute at
80% of peak power. Peak power was determined at
the start of training and re-evaluated after 8 weeks by
means of a cardiopulmonary exercise test (CPET)
until voluntary exhaustion. Participants logged the
date and time of training, the number of minutes completed, the perceived exertion at the end of their training session and any comments or reasons for not
completing the training session.
Participants allocated to the control condition received
three 45-minute consultations with an MS nurse over
the 16-week period (see eSupplement 3). The content
of the consultations led by the MS nurse covered two
important aspects in relation to the experimental
intervention: (1) reliable information on MS-related
fatigue and (2) guidance from the experienced MS
nurse that aimed to reassure the patient that his or her
concerns or questions were being taken seriously. The
MS nurse was not allowed to refer the patient to any
other outpatient or inpatient facilities for the treatment of fatigue.
Outcome measures
All outcomes were assessed serially at baseline, 2, 4
(i.e. post-intervention), 6 and 12 months of follow-up.
Face-to-face measurements were performed by a
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