Investigation of a New, Oral Growth Hormone Secretagogue, AEZS-130 as a Growth Hormone Stimulation Test.

Study Overview
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Brief Summary
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The diagnosis of growth hormone deficiency (GHD) in adults is established by laboratory testing in patients with an appropriate clinical history of hypothalamic pituitary disease. Two tests that are considered to be gold standard tests for the diagnosis of GHD are the insulin tolerance test (ITT) and growth hormone releasing hormone (GHRH) combined with L-arginine (L-ARG). However, these tests are either bothersome (given intravenously) to the patient or are linked with side effects. Therefore, an orally available compound like AEZS-130 (formerly ARD-07), if demonstrated to be safe and providing adequate sensitivity and specificity could be a welcome alternative and/or complement to the current available tests. The intent was to recruit 40 adult GHD (AGHD) patients and 40 healthy control subjects into this trial, but the original sponsor (Ardana Biosciences Ltd.) discontinued the study for financial reasons before this was completed. At the time of withdrawal of GHRH from the market in 2008, 42 AGHD patients and 10 normal controls had completed the study at 9 US sites. This study reactivated to complete the remaining 30 matched control subjects. Additionally upon agreement with the FDA in a Special Protocol Assessment (SPA), 10 additional adult growth hormone deficient and their matched control were planned to be enrolled into this trial for a total treated population of approximatively 100 subjects.

Detailed Description
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Thirty control subjects (i.e., without AGHD) were matched to the 30 AGHD patients who were not previously matched. Matching was based upon gender, age, BMI, and estrogen status for females. They received one oral dose of AEZS-130 followed by serial blood draws for growth hormone (GH), insulin-like growth factor 1 (IGF-1) and pharmacokinetic (PK) determinations. There was no cross over due to the unavailability of GHRH (Geref) in the United States. Under Amendment #4 to this protocol, 10 additional AGHD subjects were to be enrolled and matched as described above. Furthermore, the objective of the study was changed to delete comparison with L-ARG + GHRH.

Official Title
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A Multi-center, Study Investigating a New, Oral Growth Hormone Secretagogue (GHS)(AEZS 130, Formerly Ardana (ARD)-07) as a Growth Hormone (GH) Stimulation Test in Terms of Safety and Efficacy

Conditions
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Diagnosis of Adult Growth Hormone Deficiency (AGDH)

Intervention / Treatment
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* Drug: AEZS-130 (formerly ARD-07)
* Drug: L-ARG+GHRH


Participation Criteria
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Eligibility Criteria
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Inclusion for Matched Control Subjects: Undergone normal growth and development Normal serum prolactin (PRL) concentrations Females should have a history of regular, age-appropriate menses Males should have normal serum testosterone concentrations Matched GHD subject already enrolled in study; matched in terms of sex, age, BMI and Estrogen status (women only) Exclusion Criteria for Matched Control Subjects: Inability or unwillingness to comply with study medication Pregnancy or lactation Clinically relevant ECG abnormalities (including QT/QTc interval > 450 ms) at any time prior to dosing at Visit 2 Treatment with any drugs that might prolong QT/QTc Inclusion criteria dor Adult GHD Subjects: Confirmed GH deficiency with a low IGF-1 3 months of stable treatment for those requiring hormone replacement therapy for hormones deficiencies other than GHD subjects with hypogonadism must be treated with sex steroid therapy, excluding women over 50 yr of age women on estrogen therapy, for whatever reason, must be on stable treatment for ar least 3 months prior to study Exclusion criteria for Adult GHD Subjects: Untreated hypothyroidism Known hypersensitivity to any excipient in study medication Inability or unwillingness to comply with study procedures Intracranial lesions stable for less than 12 months GH therapy within one month of study entry Clinically significant cardiovascular, or cerebrovascular disease Current active malignancy other than non-melanoma skin cancer Renal or hepatic dysfunction (> 3 x ULN liver function enzymes (LFEs) - aspartate amino transferase (ASAT); alanine amino transferase (ALAT); gamma-glutamyltransferase (GGT) or creatinine > 2x ULN) Pregnancy or lactation Active Cushing's disease Clinically relevant ECG abnormalities (including QT/heart rate corrected QT interval (QTc) interval > 450 ms) at any time prior to dosing at Visit 2 Treatment with any drugs that might prolong QT/QTc

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Multi-center, randomized, open-label, cross-over trial to compare AEZS-130 to an established GH stimulation test, L-ARG+GHRH, in the diagnosis of GH deficiency and in terms of safety. Following Amendment no. 3 (version 27 May 2010) , no cross-over was performed anymore due to unavailability of L-ARG+GHRH with resulting single arm testing of AEZS-130. Thus, two treatment arms were applicable only as long as GHRH as substance was available.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AEZS-130 ( formerly ARD-07)<br>A single oral administration of AEZS-130 (0.5 mg/kg po) as Growth Hormone Stimulation Test | Drug: AEZS-130 (formerly ARD-07)<br>* A single oral administration of AEZS-130 as Growth Hormone Stimulation Test<br>* Other names: Macimorelin;|
| Active Comparator: L-ARG+GHRH<br>This trial was set up as a multi-center, randomized, cross-over study investigating AEZS-130 as a Growth Hormone Stimulation Tests in terms of safety and efficacy compared to L-ARG+GHRH. When GHRH became unavailable on the US market, this comparator arm was no longer available, which was addressed by Amendment No. 3 (version 27-March-2010). Control subject enrolled under Amendment No. 3 were not randomized as there was no cross-over due to unavailability of L-ARG+GHRH. These control subjects received only AEZS-130 | Drug: L-ARG+GHRH<br>* A single administration of L-ARG+GHRH (iv bolus) followed by a 30min infusion of L-ARG as Growth Hormone Stimulation Test<br>* Other names: Test Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Receiver Operating Characteristic (ROC) Analysis on Peak GH (Growth Hormon) Concentrations | The primary endpoint for each individual is the peak GH concentration following AEZS-130 (macimorelin) administration. | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | Descriptive summaries for IGF-1 and correlation with GH concentrations based on macimorelin treatment. Mean IGF-1 values taken pre- and post- macimorelin administration. | 15 min. before macimorelin administration and at 150 min after macimorelin administration | 
| Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | The CART Analysis for macimorelin estimated: a) a macimorelin cut-point that minimized the misclassification of AGHD patients and healthy control subjects; b) an optimal decision tree for macimorelin that incorporated age, sex and BMI. Sensitivity (correct identification of AGHD cases) and specificity (correct identification of control subjects) for macimorelin was summarized for age, gender, BMI and estrogen status subgroups containing n > 10. At least 8 of the 10 newly enrolled AGHD patients should have been correctly classified for a protocol pre-specified threshold of Peak GH concentration which was 8.5 (ng/ml). Software CART Version 6.0 was used. | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose | 
| Number of Participants With Drug Related Adverse Events (AEs) | Total number of participants with drug related AEs, following macimorelin administration of L-Arginine (ARG) - Growth Hormone Releasing Hormone (GHRH) administration. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ghrelin mimetic, growth hormone secretagogue