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

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.

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