Back to resultsValidation of Macimorelin as a Test for Adult Growth Hormone Deficiency
Primary Purpose
Growth Hormone Deficiency With Pituitary Anomalies
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Macimorelin
Insulin
Sponsored by
About this trial
This is an interventional diagnostic trial for Growth Hormone Deficiency With Pituitary Anomalies focused on measuring Adult Growth Hormone Deficiency
Eligibility Criteria
Inclusion Criteria:
Suspected growth hormone deficiency (GHD), based on either of the following:
- structural hypothalamic or pituitary disease, or
- surgery or irradiation in these areas, or
- head trauma as an adult, or
- evidence of other pituitary hormone deficiencies, or
- idiopathic childhood onset GHD (without known hypothalamic or pituitary lesion or injury).
- Healthy* control subjects, matching a 'high likelihood GHD' subjects
Exclusion Criteria:
- GH therapy within 1 month prior to anticipated first GHST within this trial (within 3 months in case of long-acting GH formulation).
- GHST within 7 days prior to the anticipated first test day within the trial.
- Subjects with a medical history and clinical signs of a not adequately treated thyroid dysfunction or subjects who had a change in thyroid therapy within 30 days prior to anticipated first test day within the trial.
- Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial.
- Treatment with drugs directly affecting the pituitary secretion of somatotropin (e.g. somatostatin analogues, clonidine, levodopa, and dopamine agonists) or provoking the release of somatostatin; antimuscarinic agents (atropine).
- Concomitant use of a CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort).
- Medical history of ongoing clinically symptomatic severe psychiatric disorders.
- Parkinson's disease.
- Cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial.
- Type 1 diabetes or untreated or poorly controlled Type 2 diabetes, as defined by HbA1c > 8%.
- Body mass index (BMI) ≥ 40.0 kg/m2.
- Participation in a trial with any investigational drug within 30 days prior to trial entry.
- Vigorous physical exercise within 24 hours prior to each GHST within this trial.
- Known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation.
- Clinically significant cardiovascular or cerebrovascular disease.
- Prolonged ECG QT interval, defined as corrected QT interval (QTc) > 500 msec.
- Concomitant treatment with any drugs that might prolong QT/QTc.
- Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (aspartate amino transferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transpeptidase (GGT)> 2.5 x ULN; ), creatinine, or bilirubin > 1.5x ULN).
- Medical history of seizure disorders.
- Known immunosuppression.
- Current active malignancy other than non-melanoma skin cancer.
- Breastfeeding or positive urine pregnancy test (for women of childbearing potential only).
- Women of childbearing age without contraception, such as hormonal contraception or use of condom and spermicides or use of diaphragm and spermicides or Intra Uterine Device (IUD).
- Lack of ability or willingness to give informed consent.
- Anticipated non-availability for trial visits/procedures.
Sites / Locations
- Harbor UCLA Medical Center
- Texas Diabetes and Endocrinology
- Baylor College of Medicine-Endocrinology
- VA Puget Sound Health Care System
- Swedish Medical Center - Cherry Hill
- Krankenanstalt Rudolfstiftung
- Medical University & General Hospital of Vienna, AKH,
- CHU de Lyon HCL-GH Est
- GHU Paris-Sud - Hôpital de Bicêtre
- Hôpital Haut-Lévêque
- Klinikum der LMU München
- Max Planck Institut
- University Hospital Marburg
- RWTH Aachen University Hospital
- Klinik für Endokrinologie, Diabetes und Ernährungsmedizin der Charité
- San Luca Hospital
- Centrum Kliniczno-Badawcze
- Centrum Medyczne Angelius Provita
- Phase I - MTZ Clinical Research Sp. z o.o.
- Wromedica
- Clinical Centre of Serbia
- Clinical Centre of Vojvodina
- Hospital de Sant Pau
- Hospital Universitari Vall d' Hebron
- Hospital de Conxo
- St Bartholomew's Hospital
- The Christie NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
GHST Sequence A
GHST Sequence B
Arm Description
1st Macimorelin-GHST, 2nd Insulin Tolerance Test
1st Insulin Tolerance Test, 2nd Macimorelin-GHST
Outcomes
Primary Outcome Measures
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT
In the primary efficacy analysis, the estimated percentages of the agreements and the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) of the percent agreement based on Clopper-Pearson are presented. The probability for a "Negative Agreement" equals the sum of the probability of both tests being correct (negative test results for both tests for subjects with "true non-AGHD") and the probability of both tests being wrong (negative test results for both tests for subjects with "true AGHD").
The performance of the GHST with Macimorelin was considered to be acceptable if the lower bound of the two-sided 95% confidence interval (or lower bound of the one-sided 97.5% confidence interval) for the primary efficacy variables was 75% or higher for 'percent negative agreement', and 70% or higher for the 'percent positive agreement'.
The following cut-off values for stimulated GH levels were used: - MAC: GH: 2.8 ng/mL, - ITT: GH: 5.1 ng/mL.
Secondary Outcome Measures
Overall Agreements (Positive/ Negative) for MAC and ITT
As part of the secondary efficacy analysis, the percent of overall agreement was analyzed, using the same methodology described for the analyses for the primary efficacy variables.
Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE
GHST ('Test') emergent AEs (TEAEs): AEs occurring or observed from the day of first GHST (administration of an IMP) throughout End-of-Study (EOS) visit or Early Termination, whichever occurred first. TEAEs were analyzed and compared for both GHSTs. Detailed listings are presented in the Adverse Events section. The frequencies presented in this section refer to number of subjects with any TEAE, each subject was counted only once within each category.
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose
During the GHSTs, ECGs were measured at pre-dose (up to 15 min before) and 60 minutes post-dose. Furthermore, ECGs were measured at screening and at End-of-Study (EOS) Visit.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02558829
Brief Title
Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency
Official Title
Confirmatory Validation of Oral Macimorelin as a Growth Hormone (GH) Stimulation Test (ST) for the Diagnosis of Adult Growth Hormone Deficiency (AGHD) in Comparison With the Insulin Tolerance Test (ITT)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2018
Overall Recruitment Status
Completed
Study Start Date
December 3, 2015 (Actual)
Primary Completion Date
November 29, 2016 (Actual)
Study Completion Date
November 29, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AEterna Zentaris
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The Macimorelin Growth Hormone Stimulation Test (GHST) will be compared with the Insulin Tolerance Test (ITT) in an open-label, randomized, 2-way crossover Trial. The trial will include subjects suspected to have adult growth hormone deficiency (AGHD) and a group of healthy control subjects.
Detailed Description
Trial subjects will be assigned to groups of descending likelihood of having AGHD:
Group A, B, C: High, intermediate, and low likelihood of GHD, respectively; Group D: Healthy control subjects matching Group A subjects .
The sequential order of the GHSTs for suspected AGHD subjects (Group A-C) will be determined by stratified randomization; healthy control subjects (Group D) will be tested in the same sequence as the matched Group A subjects.
Serum concentrations of GH will be measured at pre-defined time points before and after GHST with macimorelin or insulin. A peak GH value below the GHST-specific cut-off value will be considered 'test positive'. The ITT will be considered as comparator (non-reference standard) to assess positive and negative agreement of both GHSTs, based on the predefined cut-off values.
The following cut-off values for simulated GH levels were used for both GHST tests to be compared: macimorelin-GHST: GH: 2.8 ng/mL, ITT: GH: 5.1 ng/mL.
Amendment no. 1 (repeatability extension): had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects (planned N=30, 10 per Group) that had completed the core study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Growth Hormone Deficiency With Pituitary Anomalies
Keywords
Adult Growth Hormone Deficiency
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Masking Description
This was an open label trial. No masking with regard to the Growth Hormone Stimulation Tests (GHSTs) performed was done. However, Data Review Committee/Sponsor/Project Management was masked towards the Growth Hormone (GH) values as results fo both tests. GH values were provided to the investigator only after both GHSTs had been performed, to avoid bias.
Allocation
Randomized
Enrollment
157 (Actual)
8. Arms, Groups, and Interventions
Arm Title
GHST Sequence A
Arm Type
Experimental
Arm Description
1st Macimorelin-GHST, 2nd Insulin Tolerance Test
Arm Title
GHST Sequence B
Arm Type
Experimental
Arm Description
1st Insulin Tolerance Test, 2nd Macimorelin-GHST
Intervention Type
Drug
Intervention Name(s)
Macimorelin
Other Intervention Name(s)
Macimorelin-GHST (MAC)
Intervention Description
macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose
Intervention Type
Drug
Intervention Name(s)
Insulin
Other Intervention Name(s)
Insulin Tolerance Test (ITT)
Intervention Description
Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose
Primary Outcome Measure Information:
Title
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT
Description
In the primary efficacy analysis, the estimated percentages of the agreements and the two-sided 95% confidence interval (or one-sided 97.5% confidence interval) of the percent agreement based on Clopper-Pearson are presented. The probability for a "Negative Agreement" equals the sum of the probability of both tests being correct (negative test results for both tests for subjects with "true non-AGHD") and the probability of both tests being wrong (negative test results for both tests for subjects with "true AGHD").
The performance of the GHST with Macimorelin was considered to be acceptable if the lower bound of the two-sided 95% confidence interval (or lower bound of the one-sided 97.5% confidence interval) for the primary efficacy variables was 75% or higher for 'percent negative agreement', and 70% or higher for the 'percent positive agreement'.
The following cut-off values for stimulated GH levels were used: - MAC: GH: 2.8 ng/mL, - ITT: GH: 5.1 ng/mL.
Time Frame
90 minutes
Secondary Outcome Measure Information:
Title
Overall Agreements (Positive/ Negative) for MAC and ITT
Description
As part of the secondary efficacy analysis, the percent of overall agreement was analyzed, using the same methodology described for the analyses for the primary efficacy variables.
Time Frame
90 minutes
Title
Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE
Description
GHST ('Test') emergent AEs (TEAEs): AEs occurring or observed from the day of first GHST (administration of an IMP) throughout End-of-Study (EOS) visit or Early Termination, whichever occurred first. TEAEs were analyzed and compared for both GHSTs. Detailed listings are presented in the Adverse Events section. The frequencies presented in this section refer to number of subjects with any TEAE, each subject was counted only once within each category.
Time Frame
up to 70 days
Title
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose
Description
During the GHSTs, ECGs were measured at pre-dose (up to 15 min before) and 60 minutes post-dose. Furthermore, ECGs were measured at screening and at End-of-Study (EOS) Visit.
Time Frame
60 minutes
Other Pre-specified Outcome Measures:
Title
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL
Description
Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects.
Time Frame
90 minutes
Title
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)
Description
Amendment no 1 (repeatability extension) had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Agreements were calculated with two-sided 95% confidence intervals.
Time Frame
90 minutes
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Suspected growth hormone deficiency (GHD), based on either of the following:
structural hypothalamic or pituitary disease, or
surgery or irradiation in these areas, or
head trauma as an adult, or
evidence of other pituitary hormone deficiencies, or
idiopathic childhood onset GHD (without known hypothalamic or pituitary lesion or injury).
Healthy* control subjects, matching a 'high likelihood GHD' subjects
Exclusion Criteria:
GH therapy within 1 month prior to anticipated first GHST within this trial (within 3 months in case of long-acting GH formulation).
GHST within 7 days prior to the anticipated first test day within the trial.
Subjects with a medical history and clinical signs of a not adequately treated thyroid dysfunction or subjects who had a change in thyroid therapy within 30 days prior to anticipated first test day within the trial.
Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial.
Treatment with drugs directly affecting the pituitary secretion of somatotropin (e.g. somatostatin analogues, clonidine, levodopa, and dopamine agonists) or provoking the release of somatostatin; antimuscarinic agents (atropine).
Concomitant use of a CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort).
Medical history of ongoing clinically symptomatic severe psychiatric disorders.
Parkinson's disease.
Cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial.
Type 1 diabetes or untreated or poorly controlled Type 2 diabetes, as defined by HbA1c > 8%.
Body mass index (BMI) ≥ 40.0 kg/m2.
Participation in a trial with any investigational drug within 30 days prior to trial entry.
Vigorous physical exercise within 24 hours prior to each GHST within this trial.
Known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation.
Clinically significant cardiovascular or cerebrovascular disease.
Prolonged ECG QT interval, defined as corrected QT interval (QTc) > 500 msec.
Concomitant treatment with any drugs that might prolong QT/QTc.
Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (aspartate amino transferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl transpeptidase (GGT)> 2.5 x ULN; ), creatinine, or bilirubin > 1.5x ULN).
Medical history of seizure disorders.
Known immunosuppression.
Current active malignancy other than non-melanoma skin cancer.
Breastfeeding or positive urine pregnancy test (for women of childbearing potential only).
Women of childbearing age without contraception, such as hormonal contraception or use of condom and spermicides or use of diaphragm and spermicides or Intra Uterine Device (IUD).
Lack of ability or willingness to give informed consent.
Anticipated non-availability for trial visits/procedures.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jose M Garcia, MD PhD
Organizational Affiliation
Baylor College of Medicine, Houston, TX, U.S.
Official's Role
Study Chair
Facility Information:
Facility Name
Harbor UCLA Medical Center
City
Torrance
State/Province
California
ZIP/Postal Code
90509
Country
United States
Facility Name
Texas Diabetes and Endocrinology
City
Austin
State/Province
Texas
ZIP/Postal Code
78731
Country
United States
Facility Name
Baylor College of Medicine-Endocrinology
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
VA Puget Sound Health Care System
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108
Country
United States
Facility Name
Swedish Medical Center - Cherry Hill
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States
Facility Name
Krankenanstalt Rudolfstiftung
City
Vienna
ZIP/Postal Code
1030
Country
Austria
Facility Name
Medical University & General Hospital of Vienna, AKH,
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
CHU de Lyon HCL-GH Est
City
Bron Cedex
ZIP/Postal Code
69677
Country
France
Facility Name
GHU Paris-Sud - Hôpital de Bicêtre
City
Le Kremlin-Bicêtre
ZIP/Postal Code
94270
Country
France
Facility Name
Hôpital Haut-Lévêque
City
Pessac
ZIP/Postal Code
33600
Country
France
Facility Name
Klinikum der LMU München
City
Muenchen
State/Province
Bayern
ZIP/Postal Code
80336
Country
Germany
Facility Name
Max Planck Institut
City
Muenchen
State/Province
Bayern
ZIP/Postal Code
80804
Country
Germany
Facility Name
University Hospital Marburg
City
Marburg
State/Province
Hessen
ZIP/Postal Code
35033
Country
Germany
Facility Name
RWTH Aachen University Hospital
City
Aachen
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
52074
Country
Germany
Facility Name
Klinik für Endokrinologie, Diabetes und Ernährungsmedizin der Charité
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
San Luca Hospital
City
Milano
ZIP/Postal Code
20149
Country
Italy
Facility Name
Centrum Kliniczno-Badawcze
City
Elblag
ZIP/Postal Code
82-300
Country
Poland
Facility Name
Centrum Medyczne Angelius Provita
City
Katowice
ZIP/Postal Code
40-611
Country
Poland
Facility Name
Phase I - MTZ Clinical Research Sp. z o.o.
City
Warszawa
ZIP/Postal Code
02-106
Country
Poland
Facility Name
Wromedica
City
Wrocław
ZIP/Postal Code
51-685
Country
Poland
Facility Name
Clinical Centre of Serbia
City
Belgrad
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinical Centre of Vojvodina
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia
Facility Name
Hospital de Sant Pau
City
Barcelona
ZIP/Postal Code
08026
Country
Spain
Facility Name
Hospital Universitari Vall d' Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital de Conxo
City
Santiago de Compostela
ZIP/Postal Code
15706
Country
Spain
Facility Name
St Bartholomew's Hospital
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Name
The Christie NHS Foundation Trust
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
29860473
Citation
Garcia JM, Biller BMK, Korbonits M, Popovic V, Luger A, Strasburger CJ, Chanson P, Medic-Stojanoska M, Schopohl J, Zakrzewska A, Pekic S, Bolanowski M, Swerdloff R, Wang C, Blevins T, Marcelli M, Ammer N, Sachse R, Yuen KCJ. Macimorelin as a Diagnostic Test for Adult GH Deficiency. J Clin Endocrinol Metab. 2018 Aug 1;103(8):3083-3093. doi: 10.1210/jc.2018-00665.
Results Reference
derived
Learn more about this trial
Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency
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