Walk Distance versus Timed Walk - endpoints for measuring patients' function in clinical trials

Drug development is now moved to the patient-focused era. Patient-focused drug development (PFDD) is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation. With PFDD, the endpoint or outcome measure needs to be meaningful, it should reflect or describe how the patient feels, functions, and survives.

Various tools can be used to measure functions. The most commonly used functional measure may be the measure of the walk distance or the walking speed.

Measuring the walk distance by fixing the time: six-minute walk test (6MWT) to measure the distance the patient can walk in six minutes (6MWD), two-minute walk test (2MWT) to measure the distance the patient can walk in two minutes (2MWD). 6MWD and 2MWD can provide a functional, therapeutic response and prognostic data that is valuable in the care of patients with respiratory, cardiac, and neurological diseases. It can also be used as the endpoint for clinical trials to evaluate the treatment differences.

There is also a 10-minute walk test to measure fatigability and walking economy, but it is not commonly used as primary efficacy endpoint in clinical trials. 

Measuring the time/speed by fixing the distance: The 10-meter Walk Test is a performance measure used to assess walking speed in meters per second over a short distance. It can be employed to determine functional mobility, gait, and vestibular function. Timed 25 Foot Walk (T25FW) is a quantitative mobility and leg function performance test based on a timed 25-walk. The time to complete 25-foot walk can be used to calculate the walk speed (ft/s). 

Examples/applications:

6MWT/6MWD

The 6MWT is a sub-maximal exercise test used to assess exercise capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. There is a specific guideline developed by ATS (American Thoracic Society): Guidelines for the Six-Minute Walk Test.

6MWT/6MWD was the primary efficacy outcome measure in pivotal studies in pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD).

Bridgebio had a pivotal study to assess the efficacy and safety of the acoramidis in treatment of
ATTRibute-CM (a heart disease) with two parts: 6MWD was the primary efficacy endpoint for part 1 of the study and

Part 1 of the study failed to demonstrate the treatment difference in 6MWD

Part 2 of the study successfully demonstrate the treatment difference in win ratio in clinical events (deaths and cardiovascular related hospitalization)

Alnylam's pivotal study (APOLLO-B study) demonstrated the statistical significant difference in primary efficacy endpoint of 6MWD at week 52. However, the magnitude of the treatment difference was merely 14.7 meters. The study results were published in New England Journal of Medicine and had a positive vote in favor of the approval by the Advisory Committee, however, FDA declined the approval. 

6MWT/6MWD may also be used in neurology diseases, for example: The 6-minute walk test and other endpoints in Duchenne Muscular Dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study

2MWT/2MWD:

Both 6MWT and 2MWT are clinical assessments to evaluate a patient's functional capacity and endurance, particularly in individuals with cardiopulmonary or musculoskeletal conditions. Compared to 6MWT/6MWD, 2MWT/2MWD was less commonly used in clinical trials. However, 2MWT is a shorter, more focused test designed to quickly assess walking capacity and is often used in situations where a shorter test is preferred. 2MWT can be conducted in a smaller space, making it more suitable for clinics or confined settings. 2MWT is particularly useful for assessing functional capacity in situations where time constraints or physical limitations may necessitate a shorter test, and offers a quicker assessment of walking capacity and can be used for patients who may have difficulty completing a longer test.

Two- and 6-minute walk tests assess walking capability equally in neuromuscular diseases

Grifols conducted a pivotal study to assess the efficacy of IGIV in the treatment of post-polio syndrome and used 2MWT as the primary efficacy endpoint. The study is still ongoing. 

MedDay Pharmaceuticals SA conducted a phase 3 study "MD1003-AMN MD1003 in Adrenomyeloneuropathy" with 2MWD as primary efficacy endpoint

Adamas Pharmaceuticals conducted a phase 3 study "Safety and Efficacy of ADS-5102 in Multiple Sclerosis Patients With Walking Impairment" where 2MWT used as the secondary endpoint (T25FW used as the primary endpoint)

The 10 Metre Walk Test

Instructions for conducting 10 Meter Walk Test or Core Measure 10 meter walk test

Sarepta Therapeutics recently released their confirmatory study results of gene therapy for the treatment of DMD (Duchenne Muscular Disease) and 10-meter walk test was one of the secondary efficacy endpoints. The 10-meter walk test results are shown here. The treatment differences are expressed in time (seconds). While all treatment differences are statistically significant, the clinical meaningfulness needs to be vetted by the experts and the regulators. 

Timed 25 Foot Walk (T25FW)

The T25FW is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task.

The drug AMPYRA® (dalfampridine) was approved for improving walking in adult patients with multiple sclerosis (MS). The drug label stated that the T25FW was the primary efficacy endpoints:

The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double-blind no treatment visits (four before the double-blind period and one after). 

Acorda Therapeutics conducted phase 3 studies "Study of Fampridine-SR Tablets in Multiple Sclerosis Patients" and "Study of Oral Fampridine-SR in Multiple Sclerosis" where T25FW was used as the primary efficacy measure.

The paper by Cohen et al "A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment" stated the following:

Walking speed ft/s was used for T25FW since walking speed is more normally distributed as compared to walking time, and is therefore a preferred approach. A 20% change in T25FW is considered a meaningful change in patients with MS

FDA medical review document on ocrelizumab for treatment of RMS discussed the missing data imputation for T25FW. 

Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis

The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis

All four measures discussed above (6MWD, 2MWD, 10-meter walk test, T25FW) can be an acceptable endpoint for confirmatory trials. Which measure to use in a specific trial depends on the indication and the study population. The endpoint selection should be discussed with the review division of regulatory agencies such as FDA.