Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

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.