A multicentre, single-blinded, randomized controlled trial (RCT) with 6 months follow-up will be conducted to evaluate the effects of aerobic exercise therapy (AET) in addition to usual care, or cognitive behavioural therapy (CBT) in addition to usual care, compared to usual care alone, in patients with ALS (figure 1). Participants will first be invited to participate in a longitudinal study including four repeated measurements (first permission phase): at entry (T0), at 4 months (T1), at 7 months (T2), and at 10 months (T3). After randomization to one of the intervention groups, the participants will be informed about the intervention they have been assigned to, and will be asked to participate in this intervention (second permission phase). The interventions will take place between T0 and T1, making T2 a short-term and T3 a long-term follow-up for those who participate in an intervention. The patients in the usual care group will not be asked additional permission. This postponed information model  allows us to inform participants about part of the study only, while the rest of the information will be given to them at the end of the study.
The study protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht (UMCU), and all participating centres have agreed to participate. Informed consent according to the declaration of Helsinki will be obtained from all participants (in both the first and second permission phases).
The FACTS-2-ALS trial is part of the FACTS-2-NMD project, along with the FACTS-2-PPS  and FACTS-2-FSHD  trials. An additional study will analyse qualitative data on patients' and partners' expectations of, and experiences with, the interventions, using a responsive methodology for all 3 trials .
The aim is to include 120 patients with ALS, one month post diagnosis, who meet the inclusion and exclusion criteria (table 1). All patients will be recruited from outpatient clinics of the UMCU, the Academic Medical Centre (AMC) in Amsterdam, the University Medical Centre Nijmegen (UMCN) or het Roessingh Rehabilitation Centre in Enschede. The neurologists will refer eligible patients to a rehabilitation physician, who will check the inclusion and exclusion criteria. If a patient meets all the criteria, the rehabilitation physician will inform them about the four measurements, and will ask permission for them to be contacted by the primary investigator. The primary investigator will invite the patients by telephone to take part in the four measurements (first permission phase), and (for those patients randomized to one of the interventions) to participate in the relevant intervention (second permission phase).
Randomization and blinding
Eligible participants will be randomized to one of three groups: (1) AET + usual care, (2) CBT + usual care, or (3) usual care. Patients who exercise for two or more hours a week will be excluded from the AET intervention, due to the small expected treatment effect, but can be randomized to the CBT or control group. In addition, since CBT is not expected to be necessary for patients who show no anxious or depressive symptoms, patients who score less than 8 on the Hospital Anxiety and Depression Scale (HADS)  will be excluded from the CBT intervention, but can be randomized to the AET or control group. All participating patients will be registered and randomized by one independent person. Randomization of the three trial arms will be implemented by the "minimization" method , a dynamic randomization algorithm that ensures even distribution of patients across strata, even if there are relatively small groups of patients to be divided over multiple strata. In this study, patients will be stratified by (a) study site (Amsterdam, Nijmegen, Enschede, Utrecht); (b) age; (c) the use of lithium; (d) type of ALS (spinal / bulbar); and (e) gender. A biphasic randomization of patients will be used, based on a postponed information model . All outcomes will be assessed by blinded and independent research assistants. At the beginning of each assessment, patients will be instructed not to reveal their intervention to the blinded research assistant.
The patients in the control and intervention groups will receive usual care. In the Netherlands, patients with ALS receive multidisciplinary care from specialized ALS care teams consisting of a rehabilitation physician, a physical therapist, an occupational therapist, a speech pathologist, a dietician, and a social worker. The ALS team works according to the Dutch protocol for rehabilitative management in ALS . Rehabilitation medicine plays an important role in the symptomatic and palliative treatment of patients with ALS. The purpose of the rehabilitation treatment is to reduce the impact of the disabilities, so that patients can fulfil the roles they may wish and need to. Maintaining QoL is the primary objective. Rehabilitation treatment includes instructions on safety in mobility, use of aids and appliances, orthoses, and psychosocial guidance. Patients with ALS often receive physical therapy periodically, whenever new mobility problems arise. This therapy usually comprises compensatory strategies. In later stages of the disease, patients mostly receive physical therapy at home by a physical therapist, including passive mobility exercises, with practical goals to help them function safely at home. If necessary, the rehabilitation physician refers a patient to a social worker for social support. If there is a particular presenting complaint regarding mood disturbances, the patient can be referred to a psychologist.
Patients included in our trial will not be restricted in terms of their treatment options in the context of usual care; co-interventions such as exercise therapy and/or psychotherapy will be monitored throughout the study by means of diaries.
Aerobic Exercise Therapy (AET)
The AET will consist of a 16-week aerobic exercise programme, on 3 days a week, twice a week at home (1) and once a week in an individually guided group session at a hospital (2). The therapy will be supervised by specially trained physiotherapists
(1) The training programme at home will consist of individually tailored aerobic exercises on a cycle ergometer and a stepboard. Patients will receive a Polar RS400 heart rate watch with chest strap, a Kettler X7 cycle ergometer, a Kettler stepboard, a log book with training instructions and a training schedule to be used at home for the duration of the intervention. During each training session, their heart rate will be recorded continuously by a (Polar RS400) heart rate monitor. Furthermore, the patients will use the log book to document the number and duration of training sessions, the training intensity, perceived exertion on the Borg Rated Perceived Exertion (RPE) scale , and possible complaints experienced after the training session. Each session will consist of a cycle ergometer training, followed by a stepboard training. The duration of the cycle ergometer training sessions will be gradually increased from 15 to 30 minutes per session in the first four weeks, after which the duration of training will be maintained at 30 minutes. The duration of the stepboard training session will be gradually increased from 3 minutes (weeks 1 - 5) to 4 minutes (weeks 6 - 10) to 5 minutes (weeks 11 - 16) per session. This training structure is based on expert opinion, since there have been no previous studies on aerobic exercise training in persons with ALS. Training intensity will be gradually increased from 50% of the Heart Rate Reserve (HRR) to 75% HRR, in accordance with the American College of Sports Medicine guidelines  for aerobic training in healthy adults and persons with chronic diseases and disabilities . HRR is the difference between the predicted maximum heart rate (220 - age) and the measured resting heart rate. The HRR is equivalent to the difference between maximal and resting maximal oxygen consumption (VO2max). Each participant will be instructed how to adjust the physical intensity to their prescribed individual heart rate. Warming-up and cooling-down will consist of 5 minutes unloaded cycling.
(2) The supervised group training sessions at the hospital will consist of workstations, including individually tailored aerobic exercises and muscle strengthening exercises. Sessions will be divided into a 5-minute warming-up period, 30 minutes of aerobic exercises (cycle ergometer, stepboard, and treadmill) and 20 minutes of muscle strengthening exercises (quadriceps, biceps, and triceps) and a 5-minute cooling-down period.
Aerobic exercise workstations: training intensity will be gradually increased from 50% of the HRR to 75% HRR. Exercise duration per workstation will remain constant, i.e. cycle ergometer 15 minutes; treadmill 10 minutes; stepboard 3 to 5 minutes. After each aerobic workstation, duration and heart rate (as determined by the heart rate monitor) as well as the perceived exertion on the Borg RPE scale, will be recorded in the log book by the physical therapist.
Muscle strengthening exercises at workstations: the maximum strength (1-RM) of different muscle groups in arms and legs will be determined individually using a submaximal test. Since muscle strength is expected to deteriorate over time in patients with ALS, the physical therapist will determine the maximum strength before the start of the programme, and again after 5 and 10 weeks of training, to ensure that the patients exercise at the correct training intensity. In the first 5 weeks, training intensity will be 40% of 1-RM, with each exercise session consisting of 3 series of 10 repetitions each, with 1 minute of rest between series. Training intensity will be increased to 50% of 1-RM in week 6, and in week 11 the number of repetitions will be increased to 15. After each muscle strengthening exercise, the therapist will record the actual training intensity achieved and the number of series and repetitions in the logbook, as well as the perceived exertion on the Borg RPE scale. This progressive, moderate intensity is in accordance with the intensity of the exercise programme for persons with ALS developed by Dal Bello .
Training duration and intensity of both the home-based training programme and the supervised group training schedules will be determined weekly and checked by the therapist by reading out the heart rate monitors, assessing the Borg RPE scale scores and checking the log books. If necessary, individually tailored adjustments to the training schedules will be made by the therapist.
Cognitive Behavioural Therapy (CBT)
Assuming that living with ALS constitutes stress, we based our CBT approach on a stress-coping model originally proposed by Lazarus & Folkman (figure 2) . The impact of the symptoms of ALS and the lack of a curative treatment require adaptive mechanisms; patients have to adjust their internal needs to new external demands. The cognitive process by which this event is interpreted and evaluated is appraisal. Appraisal leads to adaptive tasks, which require coping skills. The required coping skills include a wide range of strategies aimed at stress reduction. Coping influences health-related outcomes such as activities and participation, and improves QoL.
The CBT intervention in the FACTS-2-ALS trial will aim to reduce stress by training effective coping skills, modifying dysfunctional cognitions, providing the right amount of disease- and support-related information and encouraging patients to seek social support. Therapy will be tailored to each individual patient and their partner, using behavioural and rational-emotive principles and comprising six "modules". These modules have been designed on the basis of interviews with ALS patients and caregivers, and include the six most important areas identified by the patients with ALS and caregivers who were interviewed: (1) coming to terms with the diagnosis of ALS; (2) coping with mood disorders; (3) maintaining autonomy; (4) mobilizing social support; (5) fear of the future; and (6) maintaining activity levels. Modules will be chosen in the first intake session by the therapists, based on patients' and partners' perceived problems. Depending on the problems, sessions will be held individually or together with the partners. Cognitive Behavioural Therapy (CBT) will consist of individual support for patient and partner by trained psychologists with experience in rehabilitation medicine. Depending on the perceived problems, the psychologists will determine, in consultation with the patients, the number of sessions (5 to 10) to be held during the 16-week period, each with a duration of 1 hour.
Compliance and attrition
Compliance will be assessed by recording the number of treatment sessions (AET or CBT) attended. For the patients randomized to AET, the total time spent on aerobic exercise on the cycle ergometer and stepboard at home will also be recorded in a log book. Where applicable, participants will be asked to express their motivation for poor compliance or drop-out.
Outcome measurements (table 2) will be obtained at entry into the study (T0), immediately after the 4-month intervention period (T1), at 3-month follow-up (short-term follow-up; T2), and at 6-month follow-up (long-term follow-up; T3). The primary outcome measure will be QoL, assessed with the ALS Assessment Questionnaire (ALSAQ-40)  and Short Form 36 (SF-36) , and functioning as assessed with the LASA Physical Activity Questionnaire (LAPAQ) , the Impact on Participation and Autonomy questionnaire (IPA) , and the Sickness Impact Profile 68 (SIP 68) . Secondary outcome measures will be categorized in accordance with the International Classification of Functioning (ICF)  for the domains of body functions and environmental and personal factors. Outcome measures for the domain of body functions (disease severity, survival, cardio-respiratory fitness, functional capacity, muscle strength, lung function, fatigue, sleep disturbances, pain, blood pressure, and weight/height) and will be determined at the three University Medical Centres by a trained research assistant blinded for treatment allocation.
Participants will be asked to complete the questionnaires at home. If they are unable to complete the questionnaires themselves, e.g. due to limited hand function, they will be able to get help from the research assistant. The ALS Functional Rating Scale Revised (ALSFRS-R) , Hospital Anxiety and Depression Scale (HADS) , and Caregiver Strain Index (CSI)  (partner) will be administered by a rehabilitation physician at T0 and by a research assistant at T1, T2, and T3.
An adverse event is defined as any undesirable experience or outcome. All adverse events reported spontaneously by the participants or observed by the therapists will be recorded. The adverse events will be followed until they have abated, or until a stable situation has been reached.
Generalized estimated equations analysis will be used to investigate differences in the effects on primary and secondary outcome measures between the two intervention groups and the usual care group and to investigate the influence of possible effect modifiers. Data will be analyzed according the intention-to-treat principle. Missing data will be imputed by carrying the last observation forward.
The sample size is based on power analysis, calculated on the basis of a change in the primary outcome during the period from the baseline to 3 months post intervention. Hardly any useful data for an effective power calculation is available. A recent Cochrane review  showed that only two previous trials have been published [38, 47] both describing results of a strength training programme, whereas our study will use aerobic exercise oriented training. The primary outcome of both studies was the ALS-FRS. Drory  found a significant difference between the intervention and control groups of 6.7 points, with a mean SD of 6.7 (Effect Size (ES) 1.0). Dal Bello  found a difference of 2.4 with a mean SD of 2.4 (ES 0.6). The ALS-FRS is a relevant outcome measure of AET, but less so for the CBT in our trial, and is therefore only a secondary outcome measure in our study. Our primary outcome measure is ALSAQ-40, a measure of QoL which is specifically designed for people with ALS. Based on the ESs of 1.0 and 0.6 found on the ALS-FRS, we expect a difference of 0.8 SD (Alpha 0.05; Beta 0.8), resulting in a minimum required number of 26 participants in each group. Allowing for a 35% drop-out rate, we aim to include 40 persons per group, so 120 people in total.