Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

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)

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.

Study Overview

• Status: Completed
• Conditions: Growth Hormone Deficiency With Pituitary Anomalies
• Intervention / Treatment: Drug: Macimorelin; Drug: Insulin

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: Interventional
• Enrollment (Actual): 157
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1030
    • Krankenanstalt Rudolfstiftung
  • Vienna, Austria, 1090
    • Medical University & General Hospital of Vienna, AKH,
• France
  • Bron Cedex, France, 69677
    • CHU de Lyon HCL-GH Est
  • Le Kremlin-Bicêtre, France, 94270
    • GHU Paris-Sud - Hôpital de Bicêtre
  • Pessac, France, 33600
    • Hôpital Haut-Lévèque
• Germany
  • Berlin, Germany, 10117
    • Klinik für Endokrinologie, Diabetes und Ernährungsmedizin der Charité
  • Bayern
    • Muenchen, Bayern, Germany, 80336
      • Klinikum der LMU München
    • Muenchen, Bayern, Germany, 80804
      • Max Planck Institut
  • Hessen
    • Marburg, Hessen, Germany, 35033
      • University Hospital Marburg
  • Nordrhein-Westfalen
    • Aachen, Nordrhein-Westfalen, Germany, 52074
      • RWTH Aachen University Hospital
• Italy
  • Milano, Italy, 20149
    • San Luca Hospital
• Poland
  • Elblag, Poland, 82-300
    • Centrum Kliniczno-Badawcze
  • Katowice, Poland, 40-611
    • Centrum Medyczne Angelius Provita
  • Warszawa, Poland, 02-106
    • Phase I - MTZ Clinical Research Sp. z o.o.
  • Wrocław, Poland, 51-685
    • Wromedica
• Serbia
  • Belgrad, Serbia, 11000
    • Clinical Centre of Serbia
  • Novi Sad, Serbia, 21000
    • Clinical Centre of Vojvodina
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d' Hebron
  • Barcelona, Spain, 08026
    • Hospital de Sant Pau
  • Santiago de Compostela, Spain, 15706
    • Hospital de Conxo
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • St Bartholomew's Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
• United States
  • California
    • Torrance, California, United States, 90509
      • Harbor Ucla Medical Center
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Diabetes and Endocrinology
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine-Endocrinology
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center - Cherry Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GHST Sequence A; 1st Macimorelin-GHST, 2nd Insulin Tolerance Test	Drug: Macimorelin; macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose; Other Names: Macimorelin-GHST (MAC); Drug: Insulin; Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose; Other Names: Insulin Tolerance Test (ITT)
Experimental: GHST Sequence B; 1st Insulin Tolerance Test, 2nd Macimorelin-GHST	Drug: Macimorelin; macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose; Other Names: Macimorelin-GHST (MAC); Drug: Insulin; Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose; Other Names: Insulin Tolerance Test (ITT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	90 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	90 minutes
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.	up to 70 days
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.	60 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL	Exploratory evaluation of sensitivity and specificity of the MAC as performance characteristic, based on test outcome in Group A and Group D subjects.	90 minutes
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)	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.	90 minutes

Collaborators and Investigators

• Sponsor: AEterna Zentaris
• Investigators: Study Chair: Jose M Garcia, MD PhD, Baylor College of Medicine, Houston, TX, U.S.

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2015
• Primary Completion (Actual): November 29, 2016
• Study Completion (Actual): November 29, 2016

Study Registration Dates

• First Submitted: September 21, 2015
• First Submitted That Met QC Criteria: September 22, 2015
• First Posted (Estimate): September 24, 2015

Study Record Updates

• Last Update Posted (Actual): April 10, 2018
• Last Update Submitted That Met QC Criteria: March 13, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Adult Growth Hormone Deficiency
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Pituitary Diseases; Dwarfism; Bone Diseases, Developmental; Hypopituitarism; Dwarfism, Pituitary; Endocrine System Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: AEZS-130-052; 2015-002337-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided