Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

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.