Clinical trial NCT00448747: Investigation of a New, Oral Growth Hormone Secretagogue, AEZS-130 as a Growth Hormone Stimulation Test.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diagnosis of Adult Growth Hormone Deficiency (AGDH)
Keywords: Ghrelin mimetic, growth hormone secretagogue
Lead sponsor: AEterna Zentaris
Sponsor class: INDUSTRY
First posted: 2007-03-19
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Receiver Operating Characteristic (ROC) Analysis on Peak GH (Growth Hormon) Concentrations
timeFrame: GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose
Secondary outcomes:
measure: Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment
timeFrame: 15 min. before macimorelin administration and at 150 min after macimorelin administration
measure: Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration
timeFrame: GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose
measure: Number of Participants With Drug Related Adverse Events (AEs)
timeFrame: 14 days
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Radiant Research Inc.
state: Illinois
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Lincoln
country: United States
facility: Celerion
state: Nebraska
city: Neptune
country: United States
facility: Celerion
state: New Jersey
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: Cetero Research
state: Texas
city: Tacoma
country: United States
facility: VA Puget Sound HCS University of Washington
state: Washington
Study officials:
affiliation: Massachusetts General Hospital, Boston
name: Beverly MK Biller, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.