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

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

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.

Study Overview

• Status: Completed
• Conditions: Diagnosis of Adult Growth Hormone Deficiency (AGDH)
• Intervention / Treatment: Drug: AEZS-130 (formerly ARD-07); Drug: L-ARG+GHRH

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Celerion
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Torrance, California, United States, 90502
      • Harbor-UCLA Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60654
      • Radiant Research Inc.
    • Chicago, Illinois, United States, 60611-3008
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • Celerion
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Celerion
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229-4801
      • Cetero Research
  • Washington
    • Tacoma, Washington, United States, 98493
      • VA Puget Sound HCS University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AEZS-130 ( formerly ARD-07); A single oral administration of AEZS-130 (0.5 mg/kg po) as Growth Hormone Stimulation Test	Drug: AEZS-130 (formerly ARD-07); A single oral administration of AEZS-130 as Growth Hormone Stimulation Test; Other Names: Test 1; Macimorelin
ACTIVE_COMPARATOR: L-ARG+GHRH; 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; A single administration of L-ARG+GHRH (iv bolus) followed by a 30min infusion of L-ARG as Growth Hormone Stimulation Test; Other Names: Test Control

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AEterna Zentaris
• Investigators: Principal Investigator: Beverly MK Biller, MD, Massachusetts General Hospital, Boston

Publications and helpful links

General Publications

• Garcia JM, Swerdloff R, Wang C, Kyle M, Kipnes M, Biller BM, Cook D, Yuen KC, Bonert V, Dobs A, Molitch ME, Merriam GR. Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2013 Jun;98(6):2422-9. doi: 10.1210/jc.2013-1157. Epub 2013 Apr 4.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (ACTUAL): July 1, 2011
• Study Completion (ACTUAL): July 1, 2011

Study Registration Dates

• First Submitted: March 16, 2007
• First Submitted That Met QC Criteria: March 16, 2007
• First Posted (ESTIMATE): March 19, 2007

Study Record Updates

• Last Update Posted (ACTUAL): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 3, 2019
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Ghrelin mimetic, growth hormone secretagogue
• Other Study ID Numbers: AEZS 130 047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: To share IPD is not planned as subjects were not informed about this possibility and thus, no related patient consent is available (data protection issue).