|SCHROEDER, E. TODD|
Submitted to: Clinical Trials
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2007
Publication Date: 10/1/2007
Citation: Schroeder, E., Castaneda-Sceppa, C., Wang, Y., Binder, E.F., Kawakubo, M., Stewart, Y., Stroer, T., Roubenoff, R., Bhasin, S., Yarasheski, K.E., Sattler, F.R., Azen, S.P. 2007. Hormonal regulators of muscle and metabolism in aging (HORMA): Design and conduct of a complex, double-masked, multicenter trial. Clinical Trials. 4:560-571.
Interpretive Summary: This paper describes the challenges encountered during the conduct of a complex randomized, double masked multicenter trial investigating the interaction of testosterone and growth hormone in regulating muscle mass, strength, and physical function in older men at risk for muscle wasting and frailty. The study was funded by the National Institutes of Health and designed to determine the efficacy of testosterone and growth hormone administration in older men. The study involved three clinical sites located in the Western, Midwest, and Eastern United States. We describe the strategies implemented to overcome a number of major impediments that enabled this study to be completed in a timely manner with reliable results generated by the specific aims. Despite the complexity of testing procedures, enormity of data generated, and successes in enrollment, we learned a number of important lessons from the challenges occurring while initiating and conducting this complex metabolic multicenter investigation. Complex multicenter clinical studies such as HORMA require intensive oversight, rapid identification of problems and deviation from standardized procedures, and participation of research team members with expertise in informatics, biometry, statistics, data management as well as investigators with expertise in the respective areas of biomedicine. Rapid implementation of strategies as we did to correct problems encountered in real time allowed this important study to be completed in a timely manner and the specific aims were able to test the hypothesis underlying the study design, and so that results may be expeditiously submitted for publication.
Technical Abstract: BACKGROUND: Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging. METHODS: HORMA is a multicenter, randomized double masked study of 65-90-year-old community dwelling men with testosterone levels of 150-550 ng/dL and IGF-1 < 167 ng/dL. Subjects were randomized to transdermal testosterone (5 or 10 g/day) and rhGH (0, 3, or 5 microg/kg/day) for 16 weeks. Outcome measures included body composition by DEXA, MRI, and (2)H(2)O dilution; muscle performance (strength, power, and fatigability), VO2peak, measures of physical function, synthesis/breakdown of myofibrillar proteins, other measures of metabolism, and quality of life. RESULTS: Major challenges included delay in startup caused by need for 7 institutional contracts, creating a 142-page manual of operations, orientation and training, creating a 121-page CRF; enrollment inefficiencies; scheduling 16 evaluations/ subject; overnight admissions for invasive procedures and isotope infusions; large data and image management and transfer; quality control at multiples sites; staff turnover; and replacement of a clinical testing site. Impediments were largely solved by implementation of a web-based data entry and eligibility verification; electronic scheduling for multiple study visits; availability of research team members to educate and reassure subjects; more frequent site visits to validate all source documents and reliability of data entry; and intensifying quality control in testing and imaging. The study exceeded the target goal of 108 (n = 112) completely evaluable cases. Two interim DSMB meetings confirmed the lack of excessive adverse events, lack of center effects, comparability of subjects, and that distribution of subjects and enrollment will not jeopardize outcomes or generalizability of results. CONCLUSIONS: Flexibility and rapidly solving evolving problems is critical when conducting highly complex multicenter metabolic studies.