validation of macimorelin as a test for adult growth hormone deficiency

Conditions: Growth Hormone Deficiency With Pituitary Anomalies

Summary: the macimorelin growth hormone stimulation test (ghst) will be compared with the insulin tolerance test (itt) in an open-label, randomized, 2-way crossover trial. the trial will include subjects suspected to have adult growth hormone deficiency (aghd) and a group of healthy control subjects.

trial subjects will be assigned to groups of descending likelihood of having aghd: group a, b, c: high, intermediate, and low likelihood of ghd, respectively; group d: healthy control subjects matching group a subjects . the sequential order of the ghsts for suspected aghd subjects (group a-c) will be determined by stratified randomization; healthy control subjects (group d) will be tested in the same sequence as the matched group a subjects. serum concentrations of gh will be measured at pre-defined time points before and after ghst with macimorelin or insulin. a peak gh value below the ghst-specific cut-off value will be considered 'test positive'. the itt will be considered as comparator (non-reference standard) to assess positive and negative agreement of both ghsts, based on the predefined cut-off values. the following cut-off values for simulated gh levels were used for both ghst tests to be compared: macimorelin-ghst: gh: 2.8 ng/ml, itt: gh: 5.1 ng/ml. amendment no. 1 (repeatability extension): had been issued for selected sites in europe to obtain exploratory data on the repeatability of the mac in a subset of subjects (planned n=30, 10 per group) that had completed the core study.

Eligibility criteria:
inclusion criteria: * suspected growth hormone deficiency (ghd), based on either of the following: * structural hypothalamic or pituitary disease, or * surgery or irradiation in these areas, or * head trauma as an adult, or * evidence of other pituitary hormone deficiencies, or * idiopathic childhood onset ghd (without known hypothalamic or pituitary lesion or injury). * healthy\* control subjects, matching a 'high likelihood ghd' subjects exclusion criteria: * gh therapy within 1 month prior to anticipated first ghst within this trial (within 3 months in case of long-acting gh formulation). * ghst within 7 days prior to the anticipated first test day within the trial. * subjects with a medical history and clinical signs of a not adequately treated thyroid dysfunction or subjects who had a change in thyroid therapy within 30 days prior to anticipated first test day within the trial. * untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial. * treatment with drugs directly affecting the pituitary secretion of somatotropin (e.g. somatostatin analogues, clonidine, levodopa, and dopamine agonists) or provoking the release of somatostatin; antimuscarinic agents (atropine). * concomitant use of a cyp3a4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, st. john's wort). * medical history of ongoing clinically symptomatic severe psychiatric disorders. * parkinson's disease. * cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial. * type 1 diabetes or untreated or poorly controlled type 2 diabetes, as defined by hba1c \> 8%. * body mass index (bmi) ≥ 40.0 kg/m2. * participation in a trial with any investigational drug within 30 days prior to trial entry. * vigorous physical exercise within 24 hours prior to each ghst within this trial. * known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation. * clinically significant cardiovascular or cerebrovascular disease. * prolonged ecg qt interval, defined as corrected qt interval (qtc) \> 500 msec. * concomitant treatment with any drugs that might prolong qt/qtc. * elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (aspartate amino transferase (asat), alanine aminotransferase (alat), gamma-glutamyl transpeptidase (ggt)\> 2.5 x uln; ), creatinine, or bilirubin \> 1.5x uln). * medical history of seizure disorders. * known immunosuppression. * current active malignancy other than non-melanoma skin cancer. * breastfeeding or positive urine pregnancy test (for women of childbearing potential only). * women of childbearing age without contraception, such as hormonal contraception or use of condom and spermicides or use of diaphragm and spermicides or intra uterine device (iud). * lack of ability or willingness to give informed consent. * anticipated non-availability for trial visits/procedures.

Keywords: adult growth hormone deficiency