Oral macimorelin safe diagnostic test for adult GH deficiency
Among adults with suspected growth hormone deficiency, the oral ghrelin agonist macimorelin is a safe and effective alternative GH stimulation agent vs. the more invasive and potentially risky insulin tolerance test, according to findings from an open-label, two-way crossover trial.
“Growth hormone therapy offers clinical benefits in individuals with adult GH deficiency,” Jose M. Garcia, MD, PhD, associate professor in the department of medicine at University of Washington in Seattle, and colleagues wrote. “However, diagnosing this condition is often challenging and remains a barrier to initiating GH treatment.”
The insulin tolerance test, considered the gold standard GH stimulation test, is also labor-intensive, can be unpleasant for patients and has potential risks, including severe hypoglycemia, according to the researchers, whereas other alternative tests, such as arginine plus GH-releasing hormone or glucagon stimulation tests, are not available in the U.S. or have limitations.
Garcia and colleagues analyzed data from adults with suspected GH deficiency based on either structural hypothalamic or pituitary disease, surgery or irradiation, head trauma as an adult, evidence of other pituitary hormone deficiencies or idiopathic childhood-onset GH deficiency. Participants were stratified as low (n = 39), intermediate (n = 37) and high likelihood (n = 38) for adult GH deficiency based on symptom presentation. Researchers randomly assigned participants to a sequence of two tests, including the macimorelin (Macrilen, Aeterna Zentaris) GH stimulation test (oral solution, dose of 0.5 mg/kg of body weight administered within 30 minutes) and the insulin tolerance test (regular human insulin administered at 0.1 U/kg), performed 7 to 30 days apart and while fasting 8 hours prior to and throughout the tests. Cutoff values determined a priori for the tests were 2.8 ng/mL for the macimorelin test and 5.1 ng/mL for the insulin tolerance test, with tests classified as “positive” for GH deficiency when the peak GH value was below the cutoff point. Researchers also included a group of 25 healthy matched controls in the efficacy analysis.
With the prespecified cutoff points, negative agreement between the macimorelin GH stimulation test and the insulin tolerance test was 95.38% (95% CI, 87.1-99.04) and positive agreement was 74.32% (95% CI, 62.84-83.78). In post hoc analyses using a cutoff point of 5.1 ng/mL for both tests, negative agreement was 93.85% (95% CI, 84.99-98.3) and positive agreement was 82.43% (95% CI, 71.83-90.3).
The researchers noted that due to the lack of a “standard of truth” to determine true adult GH deficiency status for each participant, sensitivity and specificity for both tests could only be estimated from test outcomes in a subset of the efficacy population. When using the cutoff point of 2.8 ng/mL for macimorelin, sensitivity was 87% and specificity was 96%; increasing the GH cutoff point for macimorelin between 2.8 ng/mL and approximately 8 ng/mL will increase sensitivity with a minimal effect on specificity, according to researchers. With a cutoff of 5.1 ng/mL, sensitivity and specificity of the macimorelin test was 92% and 96%, respectively. Reproducibility of the macimorelin test was 94%.
“GH stimulation with oral macimorelin is a simple, well-tolerated, reproducible and safe diagnostic test for [adult GH deficiency], with comparable accuracy to that of the [insulin tolerance test],” the researchers wrote. “Evaluating the test at the same GH cutoff of 5.1 ng/mL as used for the [insulin tolerance test] limits the risk of a false-positive diagnosis while maintaining a high detection rate of affected patients based on the more potent GH stimulatory effect of macimorelin compared to the [insulin tolerance test].”
The FDA approved macimorelin in December. – by Regina Schaffer
Disclosures: Aeterna Zentaris funded this study and all authors have received research support from the company. Garcia reports he has received research support from Novo Nordisk and Pfizer. Please see the study for the other authors’ relevant financial disclosures.