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Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

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ClinicalTrials.gov Identifier: NCT02558829
Recruitment Status : Completed
First Posted : September 24, 2015
Results First Posted : February 9, 2018
Last Update Posted : April 10, 2018
Sponsor:
Information provided by (Responsible Party):
AEterna Zentaris

Tracking Information
First Submitted Date  ICMJE September 21, 2015
First Posted Date  ICMJE September 24, 2015
Results First Submitted Date  ICMJE November 27, 2017
Results First Posted Date  ICMJE February 9, 2018
Last Update Posted Date April 10, 2018
Actual Study Start Date  ICMJE December 3, 2015
Actual Primary Completion Date November 29, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2018)
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT [ Time Frame: 90 minutes ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 22, 2015)
  • Percent positive agreement of Macimorelin-GHST with ITT [ Time Frame: 28 days; upper limit for crossover interval between both GHSTs ]
  • Percent negative agreement of Macimorelin-GHST with ITT [ Time Frame: 28 days ]
    Percent positive and negative agreement are defined as co-primary outcome measures.
Change History Complete list of historical versions of study NCT02558829 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2018)
  • Overall Agreements (Positive/ Negative) for MAC and ITT [ Time Frame: 90 minutes ]
    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 [ Time Frame: up to 70 days ]
    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 [ Time Frame: 60 minutes ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2015)
  • Percent overall agreement of Macimorelin-GHST with ITT [ Time Frame: 28 days ]
  • Adverse events [ Time Frame: up to 28 days ]
    AEs during GHST and follow-up until second GHST or end-of-trial visit
  • ECG [ Time Frame: 60 minutes ]
    Pre/post dose comparison of ECGs for both GHSTs
Current Other Pre-specified Outcome Measures
 (submitted: January 11, 2018)
  • Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL [ Time Frame: 90 minutes ]
    Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects.
  • Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1) [ Time Frame: 90 minutes ]
    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.
Original Other Pre-specified Outcome Measures
 (submitted: September 22, 2015)
  • Estimated sensitivity of Macimorelin-GHST [ Time Frame: 90 minutes ]
    Exploratory evaluation of sensitivity and specificity based on GH Peak Levels in Group A and Group D subjects
  • Estimated specificity of Macimorelin-GHST [ Time Frame: 90 minutes ]
  • Estimated sensitivity of ITT [ Time Frame: 120 minutes ]
  • Estimated specificity of ITT [ Time Frame: 120 minutes ]
 
Descriptive Information
Brief Title  ICMJE Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention 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.
Primary Purpose: Diagnostic
Condition  ICMJE Growth Hormone Deficiency With Pituitary Anomalies
Intervention  ICMJE
  • Drug: Macimorelin
    macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose
    Other Name: Macimorelin-GHST (MAC)
  • Drug: Insulin
    Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose
    Other Name: Insulin Tolerance Test (ITT)
Study Arms  ICMJE
  • Experimental: GHST Sequence A
    1st Macimorelin-GHST, 2nd Insulin Tolerance Test
    Interventions:
    • Drug: Macimorelin
    • Drug: Insulin
  • Experimental: GHST Sequence B
    1st Insulin Tolerance Test, 2nd Macimorelin-GHST
    Interventions:
    • Drug: Macimorelin
    • Drug: Insulin
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 9, 2017)
157
Original Estimated Enrollment  ICMJE
 (submitted: September 22, 2015)
110
Actual Study Completion Date  ICMJE November 29, 2016
Actual Primary Completion Date November 29, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   France,   Germany,   Italy,   Poland,   Serbia,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02558829
Other Study ID Numbers  ICMJE AEZS-130-052
2015-002337-22 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party AEterna Zentaris
Study Sponsor  ICMJE AEterna Zentaris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Jose M Garcia, MD PhD Baylor College of Medicine, Houston, TX, U.S.
PRS Account AEterna Zentaris
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP