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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AEZS-130 ( formerly ARD-07) | Experimental | A single oral administration of AEZS-130 (0.5 mg/kg po) as Growth Hormone Stimulation Test |
|
| L-ARG+GHRH | Active Comparator | 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 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AEZS-130 (formerly ARD-07) | Drug | A single oral administration of AEZS-130 as Growth Hormone Stimulation Test |
|
| 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 |
| 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 |
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Inclusion for Matched Control Subjects:
Exclusion Criteria for Matched Control Subjects:
Inclusion criteria dor Adult GHD Subjects:
Exclusion criteria for Adult GHD Subjects:
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| Name | Affiliation | Role |
|---|---|---|
| Beverly MK Biller, MD | Massachusetts General Hospital, Boston | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Celerion | Tempe | Arizona | 85283 | United States | ||
| Cedars-Sinai Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23559086 | Result | 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. |
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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).
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | AGHD Patients (= Cases) | All Adult Growth Hormone Deficiency (AGHD) patients enrolled in the study. |
| FG001 | Matched Controls (= Controls) | All matched control subjects enrolled in the study. |
| Title | Milestones | Reasons Not Completed | ||||
|---|---|---|---|---|---|---|
| Overall Study |
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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.
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| L-ARG+GHRH | Drug | A single administration of L-ARG+GHRH (iv bolus) followed by a 30min infusion of L-ARG as Growth Hormone Stimulation Test |
|
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| 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 |
| Los Angeles |
| California |
| 90048 |
| United States |
| Harbor-UCLA Medical Center | Torrance | California | 90502 | United States |
| Northwestern University | Chicago | Illinois | 60611-3008 | United States |
| Radiant Research Inc. | Chicago | Illinois | 60654 | United States |
| John Hopkins University | Baltimore | Maryland | 21287 | United States |
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| Celerion | Lincoln | Nebraska | 68502 | United States |
| Celerion | Neptune City | New Jersey | 07753 | United States |
| Oregon Health & Science University | Portland | Oregon | 97239 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
| Cetero Research | San Antonio | Texas | 78229-4801 | United States |
| VA Puget Sound HCS University of Washington | Tacoma | Washington | 98493 | United States |
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| Received First Drug Administration |
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| Received Second Drug Administration |
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| Received AEZS-130 |
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| Received L-ARG-GHRH |
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| Received L-ARG-GHRH and AEZS-130 |
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| Per Protocol Population (PPS) |
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| COMPLETED | modified Intention-to-treat (mITT) population |
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| NOT COMPLETED |
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Saftey Analysis Set. This is including one case (AGHD patient) who did not receive AEZS-130.
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| ID | Title | Description |
|---|---|---|
| BG000 | AGHD Patients (= Cases) | All AGHD patients enrolled in the study. |
| BG001 | Matched Controls (= Controls) | All matched control subjects enrolled in the study. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Body Mass Index (kg/m^2) | Count of Participants | Participants |
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| Etiology of AGHD | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | PPS = per protocol set: this was considered to be the most appropriate for determination of the diagnostic utility of macimorelin | Posted | Mean | Standard Deviation | ng/mL | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose |
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| 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. | Modified Intent-to-treat analysis set used for analysis of mean IGF-1 values taken pre- and post-macimorelin administration. | Posted | Mean | Standard Deviation | ng/mL | 15 min. before macimorelin administration and at 150 min after macimorelin administration |
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| 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. | PPS = per protocol set. Decision tree for sex abandoned. Following Amendment No. 4, no comparison with L-ARG + GHRH was performed. | Posted | Number | percentage of participants | GH sampling: pre-dose and 30, 45, 60, 75, 90, 120, 150 min post-dose |
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| 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. | Safety Population | Posted | Count of Participants | Participants | 14 days |
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14 days (time window between test visit (V2) and end-of-trial visit (V3)
Only adverse events that occurred after the first dose of study drug (referred to as treatment-emergent adverse events (TEAEs)) were considered in the safety analysis. All treatment-emergent adverse events were summarized in terms of number and percentage of subjects and number and percentage of events within each treatment period by MedDRA system organ class and preferred term. A TEAE was attributed to the treatment that the subject received prior to the adverse event.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AEZS-130: Cases | All AGHD patients (cases) who received AEZS-130 (macimorelin). | 0 | 52 | 0 | 52 | 19 | 52 |
| EG001 | AEZS-130: Controls | All matched control subjects who received AEZS-130 (macimorelin). | 0 | 48 | 1 | 48 | 10 | 48 |
| EG002 | L-ARG+GHRH: Cases | All AGHD patients (cases) who received L-ARG+GHRH. | 0 | 43 | 0 | 43 | 26 | 43 |
| EG003 | L-ARG+GHRH: Controls | All matched control subjects who received L-ARG+GHRH. | 0 | 10 | 0 | 10 | 3 | 10 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ECG QT prolonged | Investigations | 10.0 | Systematic Assessment |
| |
| ECG T wave abnormal | Investigations | 10.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | 10.0 | Systematic Assessment |
| |
| Dysgeusia | Nervous system disorders | 10.0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | 10.0 | Systematic Assessment |
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| ECG QT prolonged | Investigations | 10.0 | Systematic Assessment |
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| ECG T wave abnormal | Investigations | 10.0 | Systematic Assessment |
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| ECG change | Investigations | 10.0 | Systematic Assessment |
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| Heart rate increased | Investigations | 10.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | 10.0 | Systematic Assessment |
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| Headache | Nervous system disorders | 10.0 | Systematic Assessment |
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| Hypoaesthesia oral | Gastrointestinal disorders | 10.0 | Systematic Assessment |
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| Flushing | Vascular disorders | 10.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | 10.0 | Systematic Assessment |
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| Stomach discomfort | Gastrointestinal disorders | 10.0 | Systematic Assessment |
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| Rhinits | Infections and infestations | 10.0 | Systematic Assessment |
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| Oedema peripheral | General disorders | 10.0 | Systematic Assessment |
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| ear infection | Infections and infestations | 10.0 | Systematic Assessment |
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| Paraesthesia oral | Gastrointestinal disorders | 10.0 | Systematic Assessment |
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| Feeling hot | General disorders | 10.0 | Systematic Assessment |
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| Injection site irritation | General disorders | 10.0 | Systematic Assessment |
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| Phlebitis | Vascular disorders | 10.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | 10.0 | Systematic Assessment |
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Study Protocol Section 10.7 Draft versions of abstracts or manuscripts must be made available to the co-authors and to the sponsor before any presentation of results or submission for publication. At least 2 weeks should be allowed for review and comment of an abstract and 4 weeks in the case of a full paper, respectively.
Multiple review cycles are usual for full papers and respective planning must account for this.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nicola Ammer | Aeterna Zentaris | +496942602 | 3472 | nammer@aezsinc.com |
| ID | Term |
|---|---|
| C582727 | macimorelin |
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| Title | Measurements |
|---|---|
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| Male |
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| Black or African American |
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| Asian |
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| Other |
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| Overweight (>=25 and <30) |
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| Obese (>=30) |
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| CNS tumors |
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| Others |
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| sensitivity (percent) |
| 82 |
| 2-Sided |
| Other |
Sensitivity |
| ROC analysis on peak GH concentrations in response to macimorelin: GH cut point of 2.7 ng/mL. | Specificity (percent) | 92 | 2-Sided | Other | Specificity |
| ROC analysis on peak GH concentrations in response to macimorelin: GH cut point of 2.7 ng/mL. | misclassification (percent) | 13 | 2-Sided | Other | Misclassification |
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| OG002 |
| Peak GH & Age |
CART analysis of Peak GH following macimorelin & Age Case Definition: GH ≤ 2.85 or (2.85 <GH ≤7.15 & age ≤47.5) Control Definition: GH > 7.15 or (2.85 <GH ≤7.15 & age >47.5) |
| OG003 | Peak GH & BMI & Age | CART analysis of Peak GH following macimorelin & BMI & Age Case Definition: GH≤0.85 or (0.85<GH≤2.85 and BMI>27.94) or (2.85<GH≤7.15 and age ≤47.5) Control Definition: GH > 7.15 or (0.85 <GH ≤2.85 & BMI ≤27.94) or (2.85<GH≤7.15 and age >47.5) |
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