A Randomized Feasibility Study of a 12-Week Community-Based Exercise Program for People With Huntington's Disease : Journal of Neurologic Physical Therapy

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A Randomized Feasibility Study of a 12-Week Community-Based Exercise Program for People With Huntington's Disease

Busse, Monica PhD; Quinn, Lori EdD; Debono, Katy BSc; Jones, Karen MSc; Collett, Johnathan PhD; Playle, Rebecca PhD; Kelly, Mark PhD; Simpson, Sharon PhD; Backx, Karianne PhD; Wasley, David PhD; Dawes, Helen PhD; Rosser, Anne PhD the Members of the COMMET-HD Management Group

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Journal of Neurologic Physical Therapy 37(4):p 149-158, December 2013. | DOI: 10.1097/NPT.0000000000000016



Participation in regular exercise has been shown to offer health and social benefits in healthy adults.1 Exercise interventions improve physical and cognitive function in older adults with and without cognitive impairment, as well as in individuals with Alzheimer's disease and Parkinson's disease,2,3 and may have a protective effect by improving brain perfusion and neurovascular integrity.4

Huntington's disease (HD) is a multimodal, autosomal dominant neurodegenerative condition caused by a mutation of the Huntington gene. Major features include cognitive deficits, behavioral changes, and motor dysfunction.5 Notwithstanding the general health benefits of exercise, evidence in related disease groups, and data from environmental enrichment studies in HD animal models6–9 suggesting that physical activity and exercise may influence symptom onset and progression in people with HD, robust clinical trials are required to definitively demonstrate the value of such programs in persons with HD. One of the first studies of physical interventions in HD was a time series study performed by Zinzi et al10,11 that incorporated objective outcome measures. In this study, the benefits of an inpatient rehabilitation program, which included a specific physical therapy exercise program, were evaluated.10 This study was an important landmark, as it reported significant findings using well-validated outcome measures, follow-up of patients over time, and consultation with caregivers and family members about their opinions.11

Since the report of the trial by Zinzi et al10,11 in 2007, there has been a gradual increase in the reporting of feasibility and positive benefits from both in- and outpatient physical therapy exercise programs.12,13 A recent study evaluated the use of a video gaming platform to improve dynamic balance and mobility in people with HD.14 The study included 20 individuals with early- to middle-stage HD. Those participants who adhered to the video-based exercise program demonstrated significant improvement in a timed test of dynamic balance. Another randomized study of a low- to moderate-intensity home-based exercise intervention found significant differences between the intervention and control groups on a range of motor performance measures.15 The intervention was composed of strengthening and stretching exercises, as well as aerobic components (self-directed walking). Given that the intervention was home-based and mostly self-directed, it was difficult to quantify adherence and any specific aerobic effects that may have been achieved during the intervention. Furthermore, the assessors were not fully blinded for all assessments, introducing potential bias. It is important for future investigations to provide a more structured, supervised approach, and utilize blinded assessment of outcome measures.

For people with HD, physical and cognitive impairments can significantly impact their ability to initiate and adhere to an exercise program. Community gym-based programs can provide appropriate structure and support and provide an alternative to home-based exercises. Considering the potential that exercise has to provide benefit for people with HD, both in terms of general health and in disease modification, research in this area is clearly warranted. To facilitate application of study findings to a range of settings, detailed reporting of protocols, adherence, retention, and adverse events is also required.16 Reporting of adverse events is especially important, given the evidence for impaired mitochondrial function in muscle cells in HD, and suggestions that excessive exercise may be a potential concern in this population.17 In addition to impaired mitochondrial function, adverse reporting is important in terms of monitoring whether exercise exacerbates weight loss, which can be problematic in people with HD.18

In this mixed methodology, phase 2 randomized feasibility study, we proposed to determine whether provision of a supported, community-based exercise program was feasible (adherence and retention rates), safe (falls and weight loss), acceptable (subjective reports of tolerability and physiological measures recorded during the gym sessions), and of benefit to people with early- and middle-stage HD.


This phase 2 randomized feasibility study (ISRCTN 59910670) was conducted and reported in line with the CONSORT guidelines for randomized controlled trials.19 Estimates of effect size were calculated to inform future planned studies.


Thirty-one sequential eligible people with HD were recruited from the specialist HD clinics in Cardiff, the United Kingdom, and Oxford, the United Kingdom, between March 2011 and November 2011. Inclusion criteria were (1) diagnosis of HD, confirmed by genetic testing and neurological examination, (2) ability to walk independently as primary means of mobility, (3) willing to travel to the exercise center for the intervention, (4) capacity to give informed consent, (5) Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS)20 and Total Functional Capacity (TFC)21 of at least 5/124 and 5/13, respectively, from last clinic visit, and (6) maintenance of a stable medical regimen for 4 weeks prior to initiation of study and considered by the recruiting clinician as able to maintain a stable regimen for the course of the study. Participants were not eligible if they (1) had a history of additional prior major neurological condition such as stroke, (2) had an orthopedic condition that limited mobility, (3) demonstrated uncontrolled psychiatric symptoms, (4) were pregnant, (5) demonstrated any contraindication to exercise, or (6) were involved in any interventional trial or within 3 months of completing an interventional trial. All participants gave their written informed consent. The study was conducted in accordance with the recommendations for physicians involved in research on human participants adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions and was approved by the South East Wales NHS Research Ethics Committee (NHS REC). All participant identification and referral procedures as well as procedures for data storage, processing, and management complied with the Data Protection Act 1998.

Assessments and Randomization

Participants were assessed at baseline (assessment 1), 12 weeks later (assessment 2), and 24 weeks later (assessment 3). Independent random allocation to treatment group was performed to ensure allocation concealment. A minimization program for randomization (MINIM)22 was used to balance the groups on gender, physical activity levels, and disease burden score (DBS).23 Disease burden score is a score based on an individual's age and the length of the Huntington mutation, where higher scores indicate a greater level of impairment.

Participants were asked to continue their typical routine between assessments 1 and 2. This baseline period was incorporated in the study design for several reasons: (1) to enable collection of the data required for the minimization protocol, (2) to facilitate safety assessment prior to initiation of the exercise intervention, (3) to familiarize participants with the testing procedures, and (4) to ensure a stable baseline period.


The exercise intervention was delivered for 12 weeks between assessments 2 and 3. Participants exercised weekly with support from a trained exercise physiologist or physical therapist in a gym. In addition, participants were asked to undertake self-directed walking sessions twice weekly for the duration of the intervention. To inform protocol development, we referred to the American College of Sports Medicine Position Stand for Exercise Prescription in Apparently Healthy Individuals1 and the Joint Position Statement: Recommendations for Cardiovascular Screening, Staffing, and Emergency Policies at Fitness Facilities.24

The gym intervention included both aerobic and anaerobic components. Aerobic training was performed on a stationary cycle. Each participant was instructed to exercise so that heart rate (HR) was maintained in an aerobic training zone (55%-75% of age-predicted maximal HR). The Borg CR10 Rating of Perceived Exertion (RPE)25 was used to ensure that participants maintained moderate to hard levels of exertion (Borg RPE 4-6). Once 20-minute continuous exercise duration was attained, exercise duration was gradually increased up to 30 minutes. Resistance was adjusted to maintain work rate.25,26 Following the aerobic training, anaerobic strength was trained using a range of exercises (including leg press, leg extension, lateral pull down, hamstring curl, and calf raises) performed on a standard multi-gym. These exercises were performed at an initial resistance level at which 10 repetitions could be performed. Repetitions were progressed until 2 full sets of 8 to 12 repetitions could be performed at 60% to 70% of the subject's 1 repetition maximum, with a 2-minute rest between sets.

The independent home walking program was developed in consultation with the exercise physiologist or physical therapist in the first 2 gym-based sessions. Participants were asked to start walking for 10 minutes per day, twice per week. Level of exertion was self-monitored using the Borg CR10 RPE.25 Participants were instructed to maintain their walking activity at moderate to somewhat hard (3–4 on the Borg CR10 scale). Once the participants were walking comfortably at this rate for 10 minutes per day, they were asked to increase walking time at that rate by 5-minute increments, up to a maximum of 30 minutes. Walking diaries were reviewed each week before the gymnasium sessions, and target times were modified accordingly.

The costs of the weekly gym session as well as gym membership fees were paid. Travel costs were reimbursed or taxis provided if necessary. Those in the control group were asked to continue as normal and were offered the intervention at the end of the study.



Feasibility of the intervention was determined by retention and adherence rates. The retention rate was defined as the percentage of individuals who completed the intervention. Adherence was defined as the percentage of gymnasium and walking sessions recorded by those who completed the intervention. Adherence to the gymnasium-based program was recorded using gymnasium-attendance records. Adherence to the home-based exercise program was documented using participant-recorded exercise diaries.


At the outset of this study, potential adverse events were defined in a standard operating procedure as falls, weight loss of greater than 5% of body mass (for participants classified as underweight [body mass index, BMI, < 18.5) at study enrollment),27 muscle soreness that did not resolve spontaneously, and unmanageable self-reported fatigue. Any observed adverse events were recorded in a standard format. One of the key features of our intervention was the supervised exercise in the gym to ensure appropriate use of equipment and correct execution of exercises.


Participants’ subjective reports of tolerability and physiological measures recorded during the gym sessions were the basis for assessing acceptability. Each participant's response to the gym intervention was carefully monitored by recording resting and steady state HR during the cycling sessions. Resting blood pressure (BP) was also recorded before beginning exercise and the end of each session. Participants were asked to sit quietly for 5 minutes before any measure of resting BP was taken. Response to the walking program was self-recorded in the walking diaries and reviewed each week prior to the start of the gym sessions. At the end of the study, participants were asked whether they intended to continue to exercise.


A team of assessors (physical therapists with experience in HD who were blinded to other aspects of the study) conducted all data collection. The assessors were specifically trained in the data collection protocols to ensure consistency. Participant demographic data of age (years), gender (male/female), and height (meters) were recorded at the first assessment, and weight (kg) was recorded at each of the 3 assessments.

Disease-Specific Clinical Measures

Standard disease-specific clinical measures of disease severity included the Unified Huntington's Disease Rating Scale modified Motor Score (UHDRS mMS), UHDRS Independence, Functional Assessment, and Cognitive scales.20 The DBS and Independence and Functional Assessment Scales were recorded only at the first assessment, whereas the UHDRS mMS and cognitive scales were obtained at all 3 assessments.

The UHDRS mMS measures voluntary motor control, while the UHDRS TMS measures both voluntary and involuntary motor control. Since the study intervention was intended to improve voluntary motor function, and due to the extra time required to complete the TMS, the mMS was chosen as an outcome measure. The UHDRS mMS includes assessment of dysarthria, tongue protrusion, alternating hand movement, finger tapping, luria 3-step test (where the patient is asked to imitate 3 hand motions performed by the examiner and then repeat the movements unguided by the examiner), gait, tandem walking, and reactive balance. The cognitive scales included word recall, color naming, stroop interference, symbol digit, and verbal fluency.

Measures of Motor Control and Fitness

Gait: Participants were asked to walk a 10-m distance at comfortable and then fast walking speeds.28Strength, coordination, and balance: Lower limb muscle strength was assessed during the performance of the 30-second chair stand test.29 Standing balance was assessed using the Romberg test.30Physical fitness: A submaximal exercise test31 was administered to each participant over a 9-minute period. Participants had a 3-minute warmup with no load, followed by a 6-minute submaximal test, in which resistance was gradually added until the participant achieved target HR (80% of 220-age). The aim was for the final 3 minutes of the 9-minute test to be performed at steady state HR. Load was set at the first assessment and kept constant at subsequent assessments. HR and Borg CR10 RPE at rest and at the end of a submaximal exercise test were recorded as measures of fitness and perceived exertion.

General Activity and Quality of Life

Community walking: StepWatch Activity monitors (Orthocare Innovations, Seattle, Washington) were used over a 7-day period, immediately following each assessment, to measure daily step counts and percentage of time a person was sedentary or engaged in physical activity.32,33Self-reported physical activity: Self-report of physical activity was recorded using the 7-Day Physical Activity Recall interview.34Walking endurance: Walking endurance was measured by the 6-Minute Walk Test.35Health-related quality of life: The 36-Item Short Form Health Survey (SF-36) version 136 was used as a measure of quality of life. The scores from the 8 subscales of the SF-36 include (1) physical functioning, (2) role limitations due to physical problems, (3) vitality/energy, (4) bodily pain, (5) social functioning, (6) role limitations due to emotional problems, (7) mental health, and (8) general health perceptions (out of 100 for each subscale with higher scores reflecting better quality of life). The SF-36 Mental Component Summary (MCS) scale consists of role limitations due to emotional problems, social functioning, mental health, and vitality/energy while the SF-36 Physical Component Summary consists of physical functioning, role limitations due to physical problems, bodily pain, and general health perceptions. All scores were included in the analyses.

Statistical Methods

This study was powered for feasibility not efficacy.37 We used complete case intention-to-treat analysis for all data analyses. Analysis of covariance (ANCOVA) was used to analyze changes in outcome measures, by controlling for baseline (visit 2) outcome measure scores, as well as the baseline balancing variables. Standard model checking was used to ensure adequate model fit. Estimates of the treatment effect are summarized using results from the adjusted ANCOVA model along with 95% confidence intervals, P values, and standardized effect sizes. SPSS version 16 (SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.) was used for data storage and descriptive analyses. Graphical and ANCOVA analyses were performed in R (version 2.14.0; http://www.r-project.org/).38


Eighty-three (73%) of the 114 sequential people with HD who were approached during recruitment were excluded. The reasons for ineligibility fell into 3 main categories: (1) not meeting inclusion criteria (n = 46), (2) declined participation (n = 14), or (3) did not respond to the invitation letter (n = 23). Those who did not meet the inclusion criteria were mostly in an advanced stage of disease and would not have managed to attend the gym sessions. The recruitment rate was 46% (31 recruits from 68 eligible participants). Of the 31 participants recruited into the study, (16 male; mean [SD] age: 50.4 [11.4] years; DBS: 438 [129]), 16 were randomly allocated to intervention and 15 to the control group (usual care) (see Table 1). The CONSORT flowchart for this study is provided in Figure 1.39

Figure 1:
Modified CONSORT flowchart for individual randomized controlled trials of nonpharmacologic interventions.
Table 1:
Mean (SD) Demographic Characteristics and Indicators of Disease Severity of the Cohort According to Group Allocation

Twenty-seven participants (87%) attended assessment 2 at 12 weeks (3 participants from the exercise intervention and 1 participant in the control dropped out after the first assessment and before their allocation to group had been advised). Twenty-two participants (71%) completed the study. Five individuals did not receive the allocated intervention (reasons: unable to contact [n = 2], uncontrolled hypertension [n = 2], and severe musculoskeletal pain [n = 1]). Of the 11 who started the intervention, 9 completed the intervention. Of the 15 allocated to the control group, 13 completed the study.

At baseline, mean (SD) Total Functional Capacity scores were 8.4 (2.6) and 8.9 (3.1), and mean (SD) UHDRS TMS were 32.4 (15.5) and 35.2 (20.5) in the intervention and control groups, respectively. Medication use (n [%]) was classified into antipsychotic (2 [6%]), antichoreic (4 [13%]), antidepressant (9 [29%]), antihypertensive/cholesterol (14 [45%]), and other medication (diabetes, 4 [13%]; and pain, 6 [19%]). Nearly half of the participants were in receipt of antihypertensives and one third on antidepressant medication.

The majority of participants adhered well to the intervention (9/11), indicating an adherence rate of 82%. Median gym attendance for those who completed the intervention was 10 sessions. One participant missed 3 exercise sessions early in the program (due to back pain, urinary tract infection, and fatigue [tiredness and aching], respectively). This particular individual was very keen to engage in exercise but struggled with extreme chorea, which highlighted the need for the exercise to be scaled appropriately and for greater emphasis during the gym session to be on awareness of symptoms indicative of overuse. The fatigue and back pain did not reoccur after the initial incident. Three other participants reported either fatigue or some aching, but this did not affect their adherence to the program.

Mean (SD) weekly self-reported walking over 12 weeks was 197 (124) minutes. Seven participants achieved at least 150 minutes of moderate physical activity for each week of the intervention.40 Four of the 11 individuals who started the intervention were able to travel to the sessions independently; the remainder required either a family member or a taxi to drive them. Two individuals did not complete the intervention (both dropped out after 2 sessions). There were no related adverse events. There were no observed falls and no reports of excessive fatigue that did not resolve spontaneously with rest and some modification of the intervention. One individual lost 5% of body weight over the study duration but that person was overweight at the start of the study (BMI = 31.7). Six participants were able to achieve a steady state training HR within the age-predicted range; slightly higher steady state HR values were recorded in 3 participants. However, these participants’ average reported RPE values were within the expected range for the intervention. Blood pressure was within accepted normal values for all participants. Intervention group participant and adherence details are provided in Table 2. Details on safety and tolerability are provided in Table 3.

Table 2:
Participant Details and Program Adherence in the Intervention Group
Table 3:
Safety and Tolerability Data for Each Participant Who Completed the Intervention

There was a significant difference between groups for the MCS score (see Figure 2), wherein the treatment group had a mean score of 7 points higher than the control group at assessment 3 (effect size estimate: 7, 95% CI: 0.4-13.7, P = 0.046). The effect sizes for the social function (0.37) and mental health (0.38) subscales suggest that these domains contributed the most to the significant difference seen in the MCS scale (effect size = 0.53). Unadjusted descriptive statistics, by treatment group, for each outcome at assessments 2 and 3, as well as the Adjusted Treatment Effect from a complete case ANCOVA analysis are given in Tables 4 and 5.

Figure 2:
Differences between groups for the Mental Component Summary scores of the SF-36. a P < 0.05.
Table 4:
Unadjusted Descriptive Statistics Split by Treatment Group for Measures of Motor and Cognitive Function, and Physical Activity at Each Assessment, as well as the Adjusted Treatment Effect From a Complete Case ANCOVA Analysis
Table 5:
Unadjusted Descriptive Statistics Split by Treatment Group for Health-Related Quality of Life at Each Assessment as well as the Adjusted Treatment Effect From a Complete Case ANCOVA Analysis

There was some evidence of a treatment benefit for UHDRS cognitive scores (95% CI: −3.8 to 31.0), the 6-minute walk distance (95% CI: −2.8 to 57.2), the 30-second chair stand test (95% CI: −1.2 to 3.8), and HR at minute 9 of the exercise test (95% CI: −21.9 to 7.8). The effect sizes for the cognitive scores and 6-minute walk were moderate (0.4 and 0.44, respectively).

Total costs for intervention delivery can be estimated on the basis of therapist and participant mileage and staff time (travel and intervention delivery). On average, each participant traveled 33 miles and staff traveled 23 miles for each session of gym attendance. Taxi travel was required for some participants (n = 2) who had no family member or carer who could drive them, which inflated costs. On average, staff hours (including travel time and contact time) were 90 minutes per participant per gym session.


We observed that a community exercise program was safe, feasible, and acceptable. The participants in this study were in the early to middle stages of the disease. They were clearly symptomatic in terms of the movement disorder, with varying levels of cognitive and functional impairment. The retention rate for the intervention group was 81% (9/11 individuals who started the intervention completed it) and 7 out of those 9 attended more than 75% (9/12) of the gym sessions. There were no related adverse events and the intervention was generally well tolerated. The moderate effect sizes in disease, mobility, and quality-of-life measures support the potential benefit of exercise on health, well-being, and disease course in people with HD.

In this study, there were no differences in physical activity (daily step counts or moderate activity) and no differences in sedentary activity between groups over time. Visual observation of the physical activity data suggests that participants in both groups either maintained or slightly increased physical activity between assessments. Mean exercise capacity (6-Minute Walk Test) did show a nonsignificant increase in the intervention group, but it is likely that the overall intensity of the intervention (both supervised and unsupervised) was not sufficient to achieve any clear training effect.

It is important that any exercise program be modified according to the personal needs of the individual. It is possible to achieve health benefits from exercise, particularly if sedentary activity during nonexercise activities can be reduced.1 For persons with mobility disability, a whole-of-day approach to physical activity promotion, with a focus on increasing moderate-intensity physical activity but also reducing sedentary time, may be preferential.41

The implementation of an exercise intervention can be seen from the perspective of the impact it may have on general health. Although this may be an incidental observation, the high rates of hypertension and antidepressant medication in our cohort suggest that exercise may be an important lifestyle intervention in terms of managing both hypertension42 and depression.43 Certainly increased social engagement as a result of participating in the intervention may have contributed to our findings. We noted a significant increase in the MCS scale of the SF-36 related to our intervention. We hypothesize that participants had a positive experience relating to the exercise experiences itself. Although this is supported by the effect sizes in the social function and mental health subscales, it is not prudent to infer clinically meaningful effects based on this small feasibility study. A larger definitive trial that incorporates a social contact comparator arm would be required to identify specific benefits attributable to social interaction.44


This was a feasibility study; the sample size was small and thus statistical inferences are not definitive. It is more appropriate to rely on interpretation of effect sizes presented in this report. The study was also conducted at 2 sites, thus introducing the potential for between-sites differences in intervention delivery that we could not control at this stage. We further relied on self-report for the walking adherence and age-predicted ranges for determining training HRs. We cannot be certain that the reported weekly walking was subject to recall bias or that target training rates were accurate in this population. In future studies, target HR should be determined directly rather than depending on standard training zones.

The importance of using measures that are sensitive and accurately reflect both clinical function and lifestyle physical activity cannot be understated. We used activity monitors to gather measures of daily physical activity, using an established methodology,33 but had a number of cases where accelerometers were lost or returned having been worn incorrectly. This resulted in missing data (see Table 4). Future studies need to consider whether activity monitors are appropriate in this population, or indeed if direct monitoring is perhaps a better option to ensure accurate data.


This study set out to establish the feasibility and safety of implementing an exercise protocol in people with HD. Our exercise intervention was safe and well tolerated, and the change in the MCS of the SF-36 suggests that the exercise program was a positive experience for those involved. Importantly, moderate effect sizes were also observed in cognitive and mobility measures, and given the potential benefit on health and disease course in HD, we suggest that further phase 2 studies of exercise in this challenging disease are warranted. For future trials, a primary outcome measure of mobility, cognition, or health-related quality of life could be justified on the basis of the effect sizes observed in this study; measures of fitness may be best suited to support assessment of intervention fidelity. Interventions should be sustained for longer periods of time, incorporate increased exposure (frequency and intensity), and be closely monitored to ensure a specific training effect from exercise. Studies should also include a follow-up period, to determine if people continued to exercise following the study period and if there was any sustained effect.

To develop a successful exercise intervention that is acceptable to a wide number of people, we believe that it is important to include personal preferences and support to facilitate participant uptake and adherence. A key component of our intervention was the one-to-one instructor support in the gym and assistance with travel and associated costs. Reasons for reduced adherence were mostly related to more general aspects such as conflicting appointments and holidays. The physical dependence and the cognitive challenges in people with HD, which make planning difficult, may result in a cumulative barrier to making time for exercise activities. It is recommended that future studies focus on support systems that not only encompass the physical requirements of exercise but also consider the social support requirements of the person with this challenging health condition. Although consideration of social support requirements may have cost consequences, robust evaluation of the long-term health savings may well be justified.


The study team thanks all of the participants of the study and Dr Mark Wardle, Dr Jonathan Gillard, and Professor Rob Shave for convening the study steering committee. We also thank the clinical studies officers, National Institute for Social Care and Health Research Clinical Research Centre and the Dementias & Neurodegenerative Diseases Research Network staff in England as well as Dr Elizabeth Coulthard, North Bristol NHS Trust, for their assistance with this study. We further thank Mrs Jeannie Wyatt Williams and the staff from the National Exercise Referral Scheme in Wales as well as James Bateman in the CLEAR unit (Oxford Brookes University) for their enthusiasm and support in the community gyms.


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adherence; controlled trial; exercise; feasibility; Huntington's disease; physical activity

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