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. 

MCID (Minimum Clinical Important Difference) for 6MWD - how low can we go?

I went back to watch the FDA CRDAC (Cardiovascular and Renal Drugs Advisory Committee) meeting to discuss Alnylam's drug Patisiran for the treatment of ATTR-CM (Transthyretin Amyloidosis) - a rare form of heart disease. The meeting discussion was centered on the clinical meaningfulness of the efficacy measures in the primary efficacy endpoint of 6MWD (how many meters patients can walk in 6 minutes) and the secondary endpoint of KCCQ - a patient-reported quality of life measure. 

The sponsor, Alnylam, conducted a phase III study called "APOLLO-B: A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)". The study results showed statistically significant differences in 6MWD and in KCCQ total score. However, the magnitude of the treatment differences was very small: 14.7 meters in 6MWD and 3.7 points in KCCQ at month 12.

To judge if the treatment difference is clinically meaningful, people will compare the magnitude of the treatment differences from the study with the MCID (minimal clinically important difference). MCID. MCID is the smallest change in a treatment outcome that individual patients would identify as important and which would indicate a change in the patients' management.  The MCID is a patient-centered concept that captures both the magnitude of the improvement and the value patients place on the change.  In other words, the MCID is the smallest amount of change in the score of a scale recognized by the patient without considering the side effects and cost. 

In FDA's briefing book for CRADAC meeting, FDA casted doubts about the Patisiram's efficacy: 

The 6MWT, a performance outcome (PerfO), is a practical simple test that measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated responses of all the systems involved during exercise. The results of the APOLLO-B trial showed a statistically significant but small treatment effect for the primary efficacy endpoint. Subjects treated with patisiran experienced an average decrease in their 6MWD of 13 m at Month 12 from an average 6MWD of 361 m at baseline, while subjects in the placebo arm experienced an average decrease in their 6MWD of 31 m at Month 12 from an average 6MWD of 375 m at baseline. The change from baseline at Month 12 in 6MWT (Hodges-Lehmann [HL] estimate of median difference) for patisiran vs. placebo was 14.7 m (95% confidence interval [CI] 0.7, 28.7; p-value 0.04). Literature has reported a range of meaningful differences (22 to 90 m) reflective of the heterogeneity in cardiomyopathy patients (Mathai et al. 2012; Shoemaker et al. 2012).

 The KCCQ, a patient-reported outcome (PRO) and a disease-specific measure for HF, is a 23-item self-administered questionnaire developed to measure the patient’s perception of their health status, which includes heart failure symptoms, impact on physical and social function, and how heart failure impacts their quality of life (QOL) within a 2-week recall period. The KCCQ-OSS has a 0-100 transformed score range where higher scores reflect better health status (based on the Physical Limitation, Symptom Frequency, Symptom Burden, Quality of Life and Social Limitations Domain Scores). In the APOLLO-B trial,the treatment effect for the first secondary efficacy endpoint, change from baseline at Month 12 in KCCQ-OSS was small (3.7 points on a 0 to 100 transformed score range; 95% CI 0.2, 7.2; p-value 0.04). On average, subjects treated with patisiran had an increase in KCCQ-OSS of 0.3 points at Month 12 from the average baseline score of 69.8 points, while subjects in the placebo arm had a decrease in KCCQ-OSS of 3.4 points at Month 12 from the average baseline score of 70.3 points.  

Sponsor, Alnyam's briefing book and presentation spent a lot of effort to defend that the small, but statistically significant treatment differences are clinically meaningful. 

Sponsor attempted to derive an MCID using KCCQ category as an anchor based on the data from the study itself (APOLLO-B study). 

Not surprisingly, the MCID they generated were much smaller (MCID in the range of 7 - 8 meters) than the MCIDs reported in the literature. If the MCID is indeed in the range of 7 - 8 meters, the 14.7 meters (treatment difference observed in Apollo-B study) would be clinically meaningful. 

During the FDA advisory committee meeting, most of the members were not convinced by sponsor's presentation to defend the clinical meaningfulness of  small treatment difference in 6MWD (about 14 meter). However, majority of them (9-3) still voted in favor of the Patisiran's efficacy and the benefit-risk profile. 

FDA panel endorses Alnylam's heart drug - after picking apart its supporting data 

Expert Perspective: FDA CRDAC Vote on Patisiran for ATTR-CM, with Ahmad Masri, MD

Pfizer's tafamidis is the only approved drug for the treatment of ATTR-CM. According to the product label, the treatment difference in 6MWD was much larger - 76 meters with 95% confidence interval 58, 94 meters at month 30. 

For the same 6MWD, the MCID may be different depending on the treating diseases, different patient population, whether patients receiving the background therapies,... However, a treatment difference of 14 meters is still not a convincing number to be clinical meaningful. Putting on the relative scale, the 14 meters in patients with baseline 6MWD 361 meter is less than 5%. It is difficult to convince people a treatment difference less than 5% is clinically meaningful. 

I am particularlly interested in the MCID of 6MWD in lung diseases (especially the pulmonary arterial hypertension). 

Anne E. Holland (2014) "An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease" stated

“Available evidence suggests a minimal important difference (MID) of 30 m for the 6MWD in adults with chronic respiratory disease.”

Jude Moutchia (2023) "Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension" found:

The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27–38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29–43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class.

Here is a table containing some literatures with estimated MCID. The MCID was found to be in the range of 20 - 54 meters depending on the indication/disease. 

Study/Article	Indication/Disease	MCID Range	MCID Midpoint
Chan (2015)	ARF	20 – 30	25
du Bois (2011)	IPF	24 – 45	35
Gilbert (2009)	PAH	41	41
Granger (2015)	Lung Cancer	22 – 42	32
Holland (2009)	DPLD/IPF	29 – 34	32
Holland (2010)	COPD	25	25
Mathai (2012)	PAH	33	33
Nathan (2015)	IPF	22 – 37	30
Polkey (2013)	COPD	30	30
Puhan (2008)	COPD	35	35
Puhan (2011)	COPD	24 – 28	26
Redelmeier (1997)	CLD	54	54
Swigris (2010)	IPF	28	28

Latest update: 

In the end, the FDA did not approve Patisiran for the treatment of ATTR-CM  because the treatment difference in 6MWD was too small (way below the MCID)  and not clinically meaningful even though the FDA advisory committee voted in favor of the Patisiran's benefit and there was no issue with the safety and the manufacturing. 

Alnylam Announces Receipt of Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Patisiran for the Treatment of the Cardiomyopathy of ATTR Amyloidosis

FDA blocks Alnylam’s bid to expand Onpattro label - PharmaLive

 "In its Complete Response Letter (CRL), the regulator said that Alnylam had not provided enough evidence of the therapy’s benefit in the proposed indication. At the same time, the FDA did not flag any problems with patisiran’s clinical safety, drug quality, manufacturing processes or study conduct.

“The CRL indicated that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established,” according to the company’s announcement. In light of the rejection, Alnylam will no long work toward an expanded label for Onpattro in the U.S."