MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: A multicenter, randomized, placebo-controlled phase IIb study
Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y, Liu N, Papanicolaou DA
Archives of Gerontology and Geriatrics (2011) · n=123
IGF-1 rose, gait speed improved modestly (p=0.011), most functional measures did not differentiate — and the trial was terminated early on a congestive heart failure signal (4 of 62 active-arm versus 1 of 61 placebo-arm patients). The MK-677 sarcopenia-adjacent reading that reproduced the Nass mass-without-function pattern with a safety signal attached.
The Adunsky 2011 trial is the second of the two large MK-677 (ibutamoren mesylate) trials with bearing on age-related muscle loss — the first being Nass et al. 2008 in healthy older adults. Where Nass tested whether two years of daily MK-677 reproduced young-adult IGF-1 levels and produced body-composition change in adults free of acute illness, Adunsky tested MK-677 in a frail, post-acute-event population: elderly patients in the recovery window after hip fracture, where rehabilitation outcomes are heavily constrained by muscle wasting, weakness, and protein-catabolic state during hospitalization and immediate post-discharge.
The design was a multicenter, randomized, double-blind, placebo-controlled Phase IIb trial. One hundred and twenty-three elderly patients recovering from hip fracture were randomized to oral MK-0677 25 mg daily (n=62) or matching placebo (n=61) for 24 weeks. Primary endpoints were a pre-specified rank-analysis composite of objective functional performance measures and change in serum IGF-1. The functional composite was constructed to capture rehabilitation-relevant outcomes — gait speed, chair-rise, balance, and stair-climb measurements — that translate into independence and fall-risk.
The IGF-1 axis result was robust. Serum IGF-1 rose by 51.4 ng/mL versus placebo over the treatment period, reproducing the GH-secretagogue mechanism characterized in the Nass trial and in the broader MK-677 preclinical literature. The body-composition direction was consistent with mechanism: lean tissue rose on active treatment, in a magnitude smaller than the longer-duration Nass result but qualitatively the same. Gait speed showed a statistically significant improvement (mean difference 0.7 score units, 95% CI 0.17–1.28, p=0.011) — the one functional measure that differentiated cleanly from placebo. Fall incidence was numerically lower in the treatment group, though the trial was not adequately powered for that endpoint as a primary outcome. Most other functional measures did not differentiate from placebo.
The trial was terminated early on a safety signal. Congestive heart failure was observed in 4 of 62 patients in the MK-0677 arm versus 1 of 61 in the placebo arm. The absolute event count is small, the population was frail post-fracture elderly with high baseline cardiovascular risk, and the trial was not designed as a cardiovascular outcomes study — but the directional consistency and the underlying mechanistic plausibility (GH-axis stimulation, fluid retention, sodium retention as known GH-secretagogue effects) led the data and safety monitoring board to recommend stoppage. The published interpretation by the authors was that MK-0677 "has an unfavorable safety profile in this patient population," language that became the operative regulatory consensus for the indication. The pharmaceutical development of MK-677 in elderly populations with frailty or post-acute rehabilitation needs effectively ended with this trial.
For sarcopenia-and-peptides, Adunsky is the second instance of the mass-without-strength pattern that runs through the GH-secretagogue literature, alongside Nass et al. 2008 and Temel et al. 2016. Three trials, two molecules (both GHSR-1a agonists), three populations, one consistent finding: mass moves more than function. The safety signal in Adunsky adds the dimension the other two trials did not develop — that the population most clinically in need of muscle-mass restoration may also be the population least able to tolerate sustained GH-secretagogue exposure. For the MK-677 peptide page and the MK-677 long-cycle taper playbook, Adunsky is the load-bearing reference for the cardiac-safety conversation.
The trial population was frail elderly hip-fracture patients with high baseline cardiovascular comorbidity load — generalizability to healthy younger adults using MK-677 in elective contexts is limited. The safety signal is based on a small absolute event count (4 versus 1) and a sample size that did not power cardiac-outcomes detection; the signal is real but its precision is limited. The 24-week treatment duration is shorter than the two-year Nass trial, which did not report the cardiac safety signal Adunsky identified, suggesting either population specificity (the frail post-fracture cohort was at higher baseline risk) or duration-specificity. Industry sponsorship by Merck is disclosed; the MK-677 development program was discontinued in the early 2000s and the trial was conducted as part of that wind-down. The functional-composite design as primary endpoint is unusual and produces results less directly comparable to subsequent EWGSOP2-anchored sarcopenia trials. The interaction between the underlying hip-fracture rehabilitation, the standard-of-care physical therapy applied to both arms, and the MK-0677 effect on muscle tissue is not characterizable from the trial alone — strength gains in this population are heavily dependent on the rehabilitation intensity, which was not separately controlled.
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