Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

Confirmatory Validation of Oral Macimorelin as a Growth Hormone (GH) Stimulation Test (ST) for the Diagnosis of Adult Growth Hormone Deficiency (AGHD) in Comparison With the Insulin Tolerance Test (ITT)

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.

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.