Clinical trial NCT02558829: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Growth Hormone Deficiency With Pituitary Anomalies
Keywords: Adult Growth Hormone Deficiency
Lead sponsor: AEterna Zentaris
Sponsor class: INDUSTRY
First posted: 2015-09-24
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

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.

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.

Primary outcomes:
measure: Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT
timeFrame: 90 minutes
Secondary outcomes:
measure: Overall Agreements (Positive/ Negative) for MAC and ITT
timeFrame: 90 minutes
measure: Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE
timeFrame: up to 70 days
measure: ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose
timeFrame: 60 minutes
Other outcomes:
measure: Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL
timeFrame: 90 minutes
measure: Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)
timeFrame: 90 minutes
Locations:
city: Torrance
country: United States
facility: Harbor UCLA Medical Center
state: California
city: Austin
country: United States
facility: Texas Diabetes and Endocrinology
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine-Endocrinology
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center - Cherry Hill
state: Washington
city: Vienna
country: Austria
facility: Krankenanstalt Rudolfstiftung
city: Vienna
country: Austria
facility: Medical University & General Hospital of Vienna, AKH,
city: Bron Cedex
country: France
facility: CHU de Lyon HCL-GH Est
city: Le Kremlin-Bicêtre
country: France
facility: GHU Paris-Sud - Hôpital de Bicêtre
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
city: Muenchen
country: Germany
facility: Klinikum der LMU München
state: Bayern
city: Muenchen
country: Germany
facility: Max Planck Institut
state: Bayern
city: Marburg
country: Germany
facility: University Hospital Marburg
state: Hessen
city: Aachen
country: Germany
facility: RWTH Aachen University Hospital
state: Nordrhein-Westfalen
city: Berlin
country: Germany
facility: Klinik für Endokrinologie, Diabetes und Ernährungsmedizin der Charité
city: Milano
country: Italy
facility: San Luca Hospital
city: Elblag
country: Poland
facility: Centrum Kliniczno-Badawcze
city: Katowice
country: Poland
facility: Centrum Medyczne Angelius Provita
city: Warszawa
country: Poland
facility: Phase I - MTZ Clinical Research Sp. z o.o.
city: Wrocław
country: Poland
facility: Wromedica
city: Belgrad
country: Serbia
facility: Clinical Centre of Serbia
city: Novi Sad
country: Serbia
facility: Clinical Centre of Vojvodina
city: Barcelona
country: Spain
facility: Hospital de Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d' Hebron
city: Santiago de Compostela
country: Spain
facility: Hospital de Conxo
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Baylor College of Medicine, Houston, TX, U.S.
name: Jose M Garcia, MD PhD
role: STUDY_CHAIR
References:
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.