MOBILITY AND FUNCTIONAL OUTCOMES FOR SARCOPENIA TRIALS.

Major mobility disability (MMD) (1, 2), defined as inability to walk ¼ mile or 400 m, is a relevant definite outcome in clinical trials. MMD is of major public health significance. Ability to walk ¼ mile is measured in the US census (3) and in most epidemiologic surveys (4). The MMD outcome based on the 400 m walk test is a feasible, objective, reliable (5), well-validated and important clinical and public health outcome in older people (1, 2, 6), which has been successfully implemented in the LIFE-Pilot and LIFE (7, 8). We have shown it to be a more efficient outcome for clinical trials than self-reported disability or the Short Physical Performance Battery (SPPB) (9). Public health agencies use ability to walk ¼ mile or 400 m to define need and policy impact of interventions (4). Finally, people reporting the inability to walk 400 m incur higher health care costs of $4,000 per person per year, compared with those not reporting inability to walk 400 m (4, 6, 10-12) MMD is operationalized as the inability to complete a 400 m walk test within 15 min without sitting or help of another person or walker (2). Completing the walk in >15 min would be in an extremely slow pace (<0.45 m/sec), which is of little utility in daily life (13). A higher cut point (30 or 60 min), makes the assessment impractical and does not add to the clinical significance of the outcome. The time to walk 400 meters and the ability to complete the test will provide data to test effects of the interventions resulting from both attenuation of decline and increase in walking speed. Non-completion of this test can be addressed by adjudicating MMD based on objective inability to walk 4 m in < 10 sec, or self-, proxy-, or medical record-reported inability to walk across a room. We have developed a detailed manual of procedures to define specific criteria for meeting this endpoint with great specificity. In LIFE, only 13.8% of MMD cases were determined by these alternative measures. Meaningful change in speed and time to cover 400 m was assessed in LIFE Pilot using anchor and distributional methods: 0.095 m/sec was a substantial change (from 490±57/2 sec, a 57 sec difference), and 0.038 m/sec was a small change (from 490±23/2 sec, a 23 sec difference) (14). Changes were captured symmetrically for decline or improvement. Self-reported mobility was used as anchor, as it represents the participant's perspective of a construct related to lower extremity function, an essential criterion for a valid anchor to estimate meaningful change (15). This maps well on the relationship of walking speed to mortality and disability in Health ABC (6). Change in walking speed and the proportion of participants who change their walking speed by at least a small amount (0.037 m/sec) are also possible outcomes (14). The six min walk test (6MWT) (16-18), is an alternative objectively measured mobility outcome (18-21). The 6MWT asks participants to cover as much ground as possible in 6 min, and it estimates VO2max, an important component of mobility. The 400 m walk and the 6MWT are highly correlated. Those who complete a “fast pace” 6 minute and “fast pace” 400 m test, complete them in approximately the same amount of time/distance (22). Both tests are related to VO2max (22). Both tests have well defined metrics for meaningful change (14, 17). The 6MWT has a number of safety exclusions,16 while there are no exclusions for attempting the 400 m walk at usual pace in people who are ambulatory. In both cases, non-completion will occur. To address non-completion (not attending visit, home bound) a 4 m walk test can be conducted during a home visit and used for MMD adjudication (6, 14). We favor the 400 m walk test for its established relationship to mobility disability as a dichotomous outcome, the public health relevance, the well-developed protocols to adjudicate MMD by committee, which are not available for the 6MWT, and its established metrics for meaningful change. Short Physical Performance Batter (SPPB). A low score on the SPPB based on 4 m walk, balance & chair stands tests is a risk factor for disability, institutionalization, morbidity and mortality in initially non-disabled older persons (1-3). The summary score and components of the SPPB have good reliability (ICCs range from 0.88 to 0.92) (4, 5). Frailty is a state of increased vulnerability to endogenous and exogenous stressors (23, 24). Frailty involves fatigue, weight loss, infections, balance, strength and gait impairment leading to an increased risk of falls, delirium, and disability. Frailty can be practically characterize with the Fried criteria developed by Fried et al. that employ self-reported exhaustion, unintentional weight loss, low energy expenditure, slow gait speed, and weak grip strength (25). Those with >3 of the 5 factors are judged to be frail, those with 1 or 2 factors as pre-frail, and those with no factors as non-frail.