Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

AEterna Zentaris

Status and phase: Completed; Phase 3

Conditions: Growth Hormone Deficiency With Pituitary Anomalies

Treatments: Drug: Macimorelin; Drug: Insulin

Study type: Interventional

Funder types: Industry

Identifiers

NCT02558829

2015-002337-22 (EudraCT Number)

AEZS-130-052

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 157 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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157 participants in 2 patient groups

GHST Sequence A

Experimental group

Description:

1st Macimorelin-GHST, 2nd Insulin Tolerance Test

Treatment:

Drug: Macimorelin

Drug: Insulin

GHST Sequence B

Experimental group

Description:

1st Insulin Tolerance Test, 2nd Macimorelin-GHST

Treatment:

Drug: Macimorelin

Drug: Insulin