Long-term trials of interventions to promote physical activity for people with Huntington’s disease are feasible, with a “nested trial” approach that assigns some patients already taking part in an observational study to an activities group while others serve as controls, a study reported.
The yearlong effort was designed as a nested trial, also called a trial-within-cohort study, and its researchers consider this approach a “next critical step in progressing the evidence in support of non-pharmacological life-style interventions in [Huntington’s] disease management.”
The study, “Physical activity and exercise outcomes in Huntington’s disease (PACE-HD): results of a 12-month trial-within-cohort feasibility study of a physical activity intervention in people with Huntington’s disease,” was published in Parkinsonism and Related Disorders. The work was funded by the Jacques and Gloria Gossweiler Foundation.
Exercise trials for Huntington’s often short runs
Physical activity plays major roles in health, and some research has suggested that being more physically active can benefit people with Huntington’s. However, existing research into this area has notable limitations, with most studies being small and short-term.
Still, these “short-term (6–8 weeks) intervention studies provide preliminary support for the benefits of [physical activity] … in terms of motor function as well as patient-reported physical and social benefits,” the researchers wrote.
Huntington’s is a rare, progressive neurological disorder, which imposes a number of logistical hurdles when it comes to running large, long-term studies with a rigorous scientific design. Pragmatic designs like nested trials — or a trial-within-cohort (TWiC) — may help to overcome these hurdles. TWiC, as noted, basically involves recruiting a large group of patients who are already participating in an observational study, with some randomized to be part of an active intervention while others are not.
“This was particularly relevant given the knowledge that participants may alter their behavior simply due to participating in a clinical trial,” the researchers wrote.
An international group of scientists tested whether it would be feasible to conduct a long-term TWiC-based study of physical activity for people with Huntington’s.
“The primary objective of this study was to evaluate the feasibility of a TWiC of a physical-therapy led intervention in terms of recruitment, retention, data completeness, adherence, fidelity and acceptability,” the team wrote.
Nested trial-within-cohort design
Patients at six sites taking part in the ENROLL-HD registry — the world’s largest observational study of Huntington’s disease — were included, with those at half of the sites entered into a randomized and controlled clinical trial of physical activity, while the other half served as an observational control group. All trial participants were instructed to fill out monthly exercise/falls diaries, and underwent assessments every half year.
Half of the trial participants were also assigned to a physical therapy intervention aiming to boost physical activity, with a total of 18 sessions over the course of one year. The intervention, led by a trained physical therapist, was tailored based on an individual’s needs, and aimed to build up a routine of moderate-to-vigorous exercise for 30 minutes three to five times per week.
“This intervention was successfully delivered across three countries with different languages and healthcare contexts,” the researchers wrote, noting that the therapist generally reported high fidelity in identifying patient expectations, exercise adaptation, and positive coach-participant interactions. Slightly less fidelity in communication and in involving family members was noted.
From 2018 to 2019, 274 people were screened, 204 met eligibility criteria, and 116 were enrolled in the study — although four withdrew or were lost to follow-up before the study began. Ultimately, 59 people were assigned to the control group and 53 to the trial. After one year, 51 (86.4%) of control and 45 (84.9%) of trial patients remained in the study.
“This met prespecified feasibility progression criteria of less than 30% dropout for the RCT [randomized controlled trial] group. … The retention rate at 12 months was excellent particularly given that the COVID-19 pandemic adversely affected data completion over the last three months,” the researchers wrote.
Among the 26 trial patients randomized to the intervention, all but three attended more than half of the 18 physical therapy sessions — two patients withdrew, and the third “was reported to be experiencing psychosocial issues that impacted their ability to engage with the intervention,” the researchers said.
Data from standardized assessments conducted at study visits were available for most patients, although there were some COVID-19-related issues at the study’s end. The researchers also noted some incompleteness among the data collected throughout; for example, only about 67% of expected exercise/fall diaries were completed. Recordings of physical activity with wearable sensors showed the lowest level of completeness.
“We can thus conclude that nesting a trial within a cohort such as Enroll-HD is feasible when planning long-term PA [physical activity] evaluation in [Huntington’s]. Low data completeness did, however, impact on the interpretation of some important outcomes. This was particularly evident for the research-grade wearable monitors,” the scientists wrote.
Trial data generally suggested that patients who underwent the intervention had higher rates of self-reported physical activity, and performed better on standard measures of exercise capacity like the six-minute walk test, and oxygen utilization during exercise (predicted VO2 max measures).
“As a feasibility study, this study was not designed to assess efficacy and outcomes should be interpreted with caution,” the researchers noted.
“We have shown that it is possible to deliver and evaluate a long-term physical therapist-led intervention” in people with Huntington’s, the researchers concluded. “We have further demonstrated the feasibility of a nested trial within cohort design, that brings with it potential advantages in efficiency and generalizability, providing study teams carefully consider the complexity and associated challenges.”