Diagnosis of Adult Growth Hormone Deficiency (AGDH)
Conditions
Keywords
Ghrelin mimetic, growth hormone secretagogue
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.
Interventions
DRUGAEZS-130 (formerly ARD-07)
A single oral administration of AEZS-130 as Growth Hormone Stimulation Test
DRUGL-ARG+GHRH
A single administration of L-ARG+GHRH (iv bolus) followed by a 30min infusion of L-ARG as Growth Hormone Stimulation Test
Sponsors
AEterna Zentaris
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Receiver Operating Characteristic (ROC) Analysis on Peak GH (Growth Hormon) Concentrations | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose | The primary endpoint for each individual is the peak GH concentration following AEZS-130 (macimorelin) administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | 15 min. before macimorelin administration and at 150 min after macimorelin administration | Descriptive summaries for IGF-1 and correlation with GH concentrations based on macimorelin treatment. Mean IGF-1 values taken pre- and post- macimorelin administration. |
| Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose | 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. |
| Number of Participants With Drug Related Adverse Events (AEs) | 14 days | Total number of participants with drug related AEs, following macimorelin administration of L-Arginine (ARG) - Growth Hormone Releasing Hormone (GHRH) administration. |
Countries
United States
Participant flow
Recruitment details
Overall, 53 AGHD patients and 48 matched control subjects were enrolled at 11 centers across the United States, and all subjects, with the exception of 1 AGHD patient, received macimorelin and completed the study. In Amendment No. 4, the objective of the study was changed to delete the comparison with L-ARG + GHRH.
Participants by arm
| Arm | Count |
|---|---|
| AGHD Patients (= Cases) All AGHD patients enrolled in the study. | 53 |
| Matched Controls (= Controls) All matched control subjects enrolled in the study. | 48 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | collapsed veins | 1 | 0 |
Baseline characteristics
| Characteristic | AGHD Patients (= Cases) | Total | Matched Controls (= Controls) |
|---|---|---|---|
| Age, Customized < 50 years | 27 Participants | 46 Participants | 19 Participants |
| Age, Customized >= 50 years | 26 Participants | 55 Participants | 29 Participants |
| Body Mass Index (kg/m^2) Lean (<25) | 7 Participants | 14 Participants | 7 Participants |
| Body Mass Index (kg/m^2) Obese (>=30) | 31 Participants | 59 Participants | 28 Participants |
| Body Mass Index (kg/m^2) Overweight (>=25 and <30) | 15 Participants | 28 Participants | 13 Participants |
| Etiology of AGHD CNS tumors | 8 participants | 8 participants | 0 participants |
| Etiology of AGHD Others | 18 participants | 18 participants | 0 participants |
| Etiology of AGHD Pituitary Adenoma | 34 participants | 34 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 20 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 49 Participants | 78 Participants | 29 Participants |
| Region of Enrollment United States | 53 Participants | 101 Participants | 48 Participants |
| Sex: Female, Male Female | 31 Participants | 61 Participants | 30 Participants |
| Sex: Female, Male Male | 22 Participants | 40 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 48 | 0 / 43 | 0 / 10 |
| other Total, other adverse events | 19 / 52 | 10 / 48 | 26 / 43 | 3 / 10 |
| serious Total, serious adverse events | 0 / 52 | 1 / 48 | 0 / 43 | 0 / 10 |
Outcome results
Primary
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.
Time frame: GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose
Population: PPS = per protocol set: this was considered to be the most appropriate for determination of the diagnostic utility of macimorelin
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cases/AEZS-130 Administered | Receiver Operating Characteristic (ROC) Analysis on Peak GH (Growth Hormon) Concentrations | 2.36 ng/mL | Standard Deviation 5.69 |
| Control/AEZS-130 Administered | Receiver Operating Characteristic (ROC) Analysis on Peak GH (Growth Hormon) Concentrations | 17.71 ng/mL | Standard Deviation 19.11 |
Comparison: Summary of ROC Analyses following macimorelin administration.
Comparison: ROC analysis on peak GH concentrations in response to macimorelin: GH cut point of 2.7 ng/mL.
Comparison: ROC analysis on peak GH concentrations in response to macimorelin: GH cut point of 2.7 ng/mL.
Comparison: ROC analysis on peak GH concentrations in response to macimorelin: GH cut point of 2.7 ng/mL.
Secondary
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.
Time frame: GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose
Population: PPS = per protocol set. Decision tree for sex abandoned. Following Amendment No. 4, no comparison with L-ARG + GHRH was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cases/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Misclassification | 13.3 percentage of participants |
| Cases/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Specificity | 91.7 percentage of participants |
| Cases/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Sensitivity | 82.0 percentage of participants |
| Control/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Misclassification | 11.2 percentage of participants |
| Control/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Specificity | 85.4 percentage of participants |
| Control/AEZS-130 Administered | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Sensitivity | 92.0 percentage of participants |
| Peak GH & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Sensitivity | 90.0 percentage of participants |
| Peak GH & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Misclassification | 10.2 percentage of participants |
| Peak GH & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Specificity | 89.6 percentage of participants |
| Peak GH & BMI & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Misclassification | 9.2 percentage of participants |
| Peak GH & BMI & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Specificity | 95.8 percentage of participants |
| Peak GH & BMI & Age | Classification and Regression Tree (CART) Analysis of Peak Growth Hormone (GH) Following Macimorelin Administration | Sensitivity | 86.0 percentage of participants |
Secondary
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.
Time frame: 14 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cases/AEZS-130 Administered | Number of Participants With Drug Related Adverse Events (AEs) | following AEZS-130 administration | 10 Participants |
| Cases/AEZS-130 Administered | Number of Participants With Drug Related Adverse Events (AEs) | following L-ARG+GHRH administration | 19 Participants |
| Control/AEZS-130 Administered | Number of Participants With Drug Related Adverse Events (AEs) | following AEZS-130 administration | 6 Participants |
| Control/AEZS-130 Administered | Number of Participants With Drug Related Adverse Events (AEs) | following L-ARG+GHRH administration | 3 Participants |
Secondary
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.
Time frame: 15 min. before macimorelin administration and at 150 min after macimorelin administration
Population: Modified Intent-to-treat analysis set used for analysis of mean IGF-1 values taken pre- and post-macimorelin administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cases/AEZS-130 Administered | Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | 15 min before AEZS-130 | 58.1 ng/mL | Standard Deviation 37.29 |
| Cases/AEZS-130 Administered | Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | 150 min after AEZS-130 | 53.0 ng/mL | Standard Deviation 34.57 |
| Control/AEZS-130 Administered | Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | 15 min before AEZS-130 | 128.1 ng/mL | Standard Deviation 52.47 |
| Control/AEZS-130 Administered | Peak Insulin-Like Growth Factor (IGF)-1 Concentration Following Treatment | 150 min after AEZS-130 | 125.9 ng/mL | Standard Deviation 54.26 |
Comparison: Summary of IGF-1 before and after AEZS-130 administration: post - pre differences