Abstract: LB SUN 59
Validation of Macimorelin As a Diagnostic Test for Adult Growth Hormone Deficiency (AGHD): A Phase 3 Study in Comparison with the Insulin Tolerance Test (ITT)
Presenter: Jose Garcia
INTRODUCTION: The diagnosis of adult GH deficiency (AGHD) is challenging. Since GH is secreted in pulses, random measurements of GH levels will not reliably distinguish GH-deficient from GH-sufficient subjects. Accordingly, the diagnosis of AGHD often depends on GH stimulation tests (GHST) using agents known to provoke GH release above a certain level in healthy people to determine the maximum GH level in patients suspected of having the disorder. view more
INTRODUCTION: The diagnosis of adult GH deficiency (AGHD) is challenging. Since GH is secreted in pulses, random measurements of GH levels will not reliably distinguish GH-deficient from GH-sufficient subjects. Accordingly, the diagnosis of AGHD often depends on GH stimulation tests (GHST) using agents known to provoke GH release above a certain level in healthy people to determine the maximum GH level in patients suspected of having the disorder. Currently, the insulin tolerance test (ITT) is considered the non-reference standard GHST and the glucagon stimulation test an alternative. Other GHSTs are either not available in the US or considered to have low accuracy. Macimorelin, a potent orally active GH secretagogue (GHS), could be used to assess for AGHD by measuring the stimulated GH levels after an oral dose.
METHODS: This multicenter, international, open-label, randomized, 2-way crossover trial was designed to validate the use of single-dose oral macimorelin for the diagnosis of AGHD, using the ITT as the comparator test. A second objective was to characterize the safety profile of macimorelin in this setting. Subjects with high (n=38), intermediate (n=37), and low (n=40) likelihood for AGHD and healthy, matched controls (n=25) were enrolled in the study. The cut-off values for stimulated GH levels measured by the IDS-Isys hGH assay were 2.8 ng/mL for macimorelin test and 5.1 ng/mL for the ITT based on previously published data1,2. In addition, a subset of patients (n=34) underwent the macimorelin test twice to evaluate the reproducibility of this test.
RESULTS: A total of 157 subjects were enrolled in the study: 93 (59%) males, 64 (41%) females, 135 (86%) whites, with a median age of 41 years (18–66 years) and a median BMI of 27.5 kg/m2 (17 – 40 kg/m2). After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Negative agreement was 93.94% (confidence interval [CI] 85.20% - 98.32%) and positive agreement was 74.32% (CI 62.84% - 83.78%) between macimorelin and the ITT. Sensitivity was 87% (CI 72-96%), specificity was 96% (CI 80-100%) and reproducibility was 94% for macimorelin. Posthoc analyses showed that a cut-off point for macimorelin between 4.6 ng/mL and 8.2 ng/mL would have resulted in optimal negative and positive agreement with the ITT and in optimal sensitivity and specificity for the macimorelin test. No serious adverse events (SAE) were reported for macimorelin, one case of a broken arm was reported after an ITT. Other non-SAE were more common and of greater severity during ITT than macimorelin.
CONCLUSIONS: GH stimulation with the oral ghrelin mimetic macimorelin is a simple, well-tolerated, reproducible and safe diagnostic test for AGHD, with comparable accuracy to that of the ITT. Increasing the cut-off point for the macimorelin test above its pre-specified value may be justified by the more potent GH stimulatory effect of macimorelin compared to the ITT.