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CompletedNCT02558829Updated Apr 10, 2018Results posted

Validation of Macimorelin as a Test for Adult Growth Hormone Deficiency

A Phase 3 interventional study of Macimorelin and Insulin in Growth Hormone Deficiency With Pituitary Anomalies, sponsored by AEterna Zentaris. Completed at 27 sites in 9 countries. Open to participants aged 18 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-04-10.

Sponsored by AEterna Zentaris · Phase 3, Interventional, and Diagnostic

Phase
Phase 3
Study type
Interventional
Enrollment
157
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Growth Hormone Deficiency With Pituitary Anomalies

Keywords

  • Adult Growth Hormone Deficiency
03

In context

Dwarfism, Pituitary

164 studies on the registry are indexed under Dwarfism, Pituitary; 25 are open to participants now.

This study's enrollment of 157 is above the median of 72 across 122 interventional studies indexed under Dwarfism, Pituitary.

Browse Dwarfism, Pituitary studies →

Lead sponsor

AEterna Zentaris is the lead sponsor of 34 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

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

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.
05

Study design

Phase
Phase 3
Primary purpose
Diagnostic
Allocation
Randomized
Intervention model
Crossover assignment
Masking
None (open label)
Enrollment
157 participants (actual)

Study arms

  • Experimental
    GHST Sequence A

    1st Macimorelin-GHST, 2nd Insulin Tolerance Test

    Drug: Macimorelin · Drug: Insulin

  • Experimental
    GHST Sequence B

    1st Insulin Tolerance Test, 2nd Macimorelin-GHST

    Drug: Macimorelin · Drug: Insulin

Interventions

  • DrugMacimorelin

    macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose

    Also known as: Macimorelin-GHST (MAC)

  • DrugInsulin

    Insulin, 0.10 U/kg (0.15 U/kg if BMI \> 30 kg/m2), intravenous injection, single dose

    Also known as: Insulin Tolerance Test (ITT)

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 90 minutes

Secondary outcomes

  1. 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.

    Time frame: 90 minutes

  2. 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.

    Time frame: up to 70 days

  3. 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.

    Time frame: 60 minutes

Other outcomes

  1. 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.

    Time frame: 90 minutes

  2. 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.

    Time frame: 90 minutes

07

Results

Posted Feb 9, 2018

Participant flow

Study centers: 30 sites in 9 countries had been initiated,i.e. 25 sites in Europe (Austria, Germany, Spain, France, Italy, Poland, Serbia, and UK) with 21 of them becoming active, and 5 sites in the USA. Study period: first subject screened: 01-Oct-2015, first subject randomized (= enrolled): 03-Dec-2015, Last subject completed: 29-Nov-2016.

Participant flow — Overall Study
MilestoneGroup A Test Sequence MAC-ITTGroup A Test Sequence ITT-MACGroup B Test Sequence MAC-ITTGroup B Test Sequence ITT- MACGroup C Test Sequence MAC-ITTGroup C Test Sequence ITT-MACGroup D Test Sequence MAC-ITTGroup D Test Sequence ITT-MAC
Started2121241818261811
Completed201821161624178
Not completed13322213

Outcome measures

PrimaryCo-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.

Time frame:
90 minutes
Reported as:
Count of participants · Participants
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT
ParticipantsPositive MAC, Positive ITTPositive MAC, Negative ITTNegative MAC, Positive ITTNegative MAC, Negative ITT
Co-primary Efficacy Variables: Percent Positive and Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT5541962
Statistical analysis
  • Positive MAC, Positive ITT vs Negative MAC, Positive ITT · Ci (clopper pearson): positive agreement: 74.32 · 95% CI 62.84 to 83.78
  • Positive MAC, Negative ITT vs Negative MAC, Negative ITT · Ci (clopper pearson): negative agreement: 93.94 · 95% CI 85.20 to 98.32
SecondaryOverall 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.

Time frame:
90 minutes
Reported as:
Count of participants · Participants
Overall Agreements (Positive/ Negative) for MAC and ITT
ParticipantsPositive MAC, Positive ITTPositive MAC, Negative ITTNegative MAC, Positive ITTNegative MAC, Negative ITT
Overall Agreements (Positive/ Negative) for MAC and ITT5541962
Statistical analysis
  • Positive MAC, Positive ITT vs Positive MAC, Negative ITT vs Negative MAC, Positive ITT vs Negative MAC, Negative ITT · Overall agreement: 83.57 · 95% CI 76.38 to 89.29
SecondaryNumber 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.

Time frame:
up to 70 days
Reported as:
Count of participants · Participants
Number of Participants With Any Test Emergent Adverse Event (TEAE), With Any TEAE Likely or Possibly Related, and With Any Test Emergent Severe AE
ParticipantsInsulin Tolerance Test (ITT), All Groups, SAF PopulationMacimorelin GHST (MAC), All Groups, SAF Population
Any TEAE (any relation)15139
Any TEAE (likely or possible related)14922
Any test emergent severe AE111
SecondaryECG: 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.

Time frame:
60 minutes
Reported as:
Mean · beats per minute
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose
beats per minuteMAC, Heart Rate at Pre-doseMAC, HR at Post-doseITT, HR at Pre-doseITT, HR at Post-dose
ECG: Change in Heart Rate From Baseline at 60 Minutes Post-dose63.4 ± 10.3560.5 ± 9.4763.7 ± 10.7065.6 ± 10.90
Statistical analysis
  • MAC, Heart Rate at Pre-dose vs MAC, HR at Post-dose · Mean difference (final values): -2.9
  • ITT, HR at Pre-dose vs ITT, HR at Post-dose · Mean difference (final values): 1.8
Other pre-specifiedSensitivity 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.

Time frame:
90 minutes
Reported as:
Count of participants · Participants
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL
ParticipantsPositive MAC, Group APositive MAC, Group DNegative MAC, Group ANegative MAC, Group D
Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL331524
Statistical analysis
  • Positive MAC, Group A vs Negative MAC, Group A · Ci (clopper pearson): 0.87 · 95% CI 0.72 to 0.96
  • Positive MAC, Group D vs Negative MAC, Group D · Ci (clopper pearson): 0.96 · 95% CI 0.80 to 1.00
Other pre-specifiedAgreement (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.

Time frame:
90 minutes
Reported as:
Count of participants · Participants
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)
ParticipantsPositive MAC Core, Positive MAC RepeatabilityPositive MAC Core, Negative MAC RepeatabilityNegative MAC Core, Negative MAC RepeatabilityNegative MAC Core, Positive MAC Repeatability
Agreement (Positive/Negative) for MAC Core Study Part and MAC Repeatability Extension (Amendment 1)162160
Statistical analysis
  • Positive MAC Core, Positive MAC Repeatability vs Positive MAC Core, Negative MAC Repeatability · Ci (clopper pearson): positive agreement: 88.89 · 95% CI 65.29 to 98.62
  • Negative MAC Core, Negative MAC Repeatability vs Negative MAC Core, Positive MAC Repeatability · Ci (clopper pearson): negative agreement: 100.00 · 95% CI 79.41 to 100.00

Adverse events

Collected over Throughout the trial, i.e. over a period of ca. 15 months, the subjects were questioned and/or examined by the Investigators or his/her designee for evidence of adverse events (AEs). Per subject, the time frame for collection of such data was up to 70 days.. Non-serious events are listed at a 2% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Macimorelin GHST (MAC), SAF Population0/154 (0%)1/154 (0.6%)39/154 (25.3%)
Insulin Tolerance Test (ITT), SAF Population0/157 (0%)1/157 (0.6%)151/157 (96.2%)
Most frequent serious events
Most frequent serious events
EventMacimorelin GHST (MAC), SAF PopulationInsulin Tolerance Test (ITT), SAF Population
Upper limp fractureInjury, poisoning and procedural complications1/1541/157
Most frequent other events
Showing 10 of 15
Most frequent other events
EventMacimorelin GHST (MAC), SAF PopulationInsulin Tolerance Test (ITT), SAF Population
HyperhidrosisSkin and subcutaneous tissue disorders2/154105/157
SomnolenceNervous system disorders1/15457/157
HungerGeneral disorders5/15446/157
Feeling hotGeneral disorders2/15444/157
DizzinessNervous system disorders6/15443/157
FatigueGeneral disorders6/15443/157
AstheniaGeneral disorders1/15430/157
TremorNervous system disorders1/15425/157
NauseaGastrointestinal disorders5/15421/157
PalpitationsCardiac disorders1/15417/157

Baseline characteristics

Baseline participants = safety analysis set (SAF, N=157). Efficacy analysis is based on the modified Intention-to-Treat (mITT, N=140): all randomized subjects in whom both GHSTs of the cross-over are evaluable. (In the EU only: 34 patients from the mITT underwent a repeated MAC (repeatability extension, Amendment 1).)

Age, Continuous
Age, Continuous(years)Group AGroup BGroup CGroup DTotal
Mean42.3 ± 15.045.8 ± 11.834.9 ± 10.540.0 ± 12.440.7 ± 13.1
Sex: Female, Male
Sex: Female, Male(Participants)Group AGroup BGroup CGroup DTotal
Female172491464
Male2518351593
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Group AGroup BGroup CGroup DTotal
Hispanic or Latino492015
Not Hispanic or Latino34293629128
Unknown or Not Reported446014
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Group AGroup BGroup CGroup DTotal
American Indian or Alaska Native00000
Asian21205
Native Hawaiian or Other Pacific Islander00101
Black or African American01203
White36363429135
More than one race00000
Unknown or Not Reported445013
Region of Enrollment
Region of Enrollment(Participants)Group AGroup BGroup CGroup DTotal
Austria43007
United States61318037
Poland24142949
United Kingdom01001
Italy01001
France354012
Serbia1227021
Germany8121021
Spain71008
Body Mass Index (kg/m^2)
Body Mass Index (kg/m^2)(kg/m^2)Group AGroup BGroup CGroup DTotal
Mean27.6 ± 4.629.8 ± 4.527.9 ± 5.726.1 ± 3.228.0 ± 4.8
08

Study locations

27 sites
  • Harbor UCLA Medical Center
    Torrance, California 90509, United States
  • Texas Diabetes and Endocrinology
    Austin, Texas 78731, United States
  • Baylor College of Medicine-Endocrinology
    Houston, Texas 77030, United States
  • VA Puget Sound Health Care System
    Seattle, Washington 98108, United States
  • Swedish Medical Center - Cherry Hill
    Seattle, Washington 98122, United States
  • Krankenanstalt Rudolfstiftung
    Vienna, 1030, Austria
  • Medical University & General Hospital of Vienna, AKH,
    Vienna, 1090, Austria
  • CHU de Lyon HCL-GH Est
    Bron Cedex, 69677, France
  • GHU Paris-Sud - Hôpital de Bicêtre
    Le Kremlin-Bicêtre, 94270, France
  • Hôpital Haut-Lévêque
    Pessac, 33600, France
  • Klinikum der LMU München
    Muenchen, Bayern 80336, Germany
  • Max Planck Institut
    Muenchen, Bayern 80804, Germany
  • University Hospital Marburg
    Marburg, Hessen 35033, Germany
  • RWTH Aachen University Hospital
    Aachen, Nordrhein-Westfalen 52074, Germany
  • Klinik für Endokrinologie, Diabetes und Ernährungsmedizin der Charité
    Berlin, 10117, Germany
  • San Luca Hospital
    Milano, 20149, Italy
  • Centrum Kliniczno-Badawcze
    Elblag, 82-300, Poland
  • Centrum Medyczne Angelius Provita
    Katowice, 40-611, Poland
  • Phase I - MTZ Clinical Research Sp. z o.o.
    Warszawa, 02-106, Poland
  • Wromedica
    Wrocław, 51-685, Poland
  • Clinical Centre of Serbia
    Belgrad, 11000, Serbia
  • Clinical Centre of Vojvodina
    Novi Sad, 21000, Serbia
  • Hospital de Sant Pau
    Barcelona, 08026, Spain
  • Hospital Universitari Vall d' Hebron
    Barcelona, 08035, Spain
  • Hospital de Conxo
    Santiago de Compostela, 15706, Spain
  • St Bartholomew's Hospital
    London, EC1A 7BE, United Kingdom
  • The Christie NHS Foundation Trust
    Manchester, M20 4BX, United Kingdom
09

References and documents

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. PubMed 29860473 ↗

Individual participant data

Plan to share: Undecided

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Apr 10, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02558829
Lead sponsor
AEterna Zentaris
Responsible party
Sponsor
First posted
Sep 24, 2015
Start date
Dec 3, 2015
Primary completion
Nov 29, 2016
Completion
Nov 29, 2016
Results posted
Feb 9, 2018
Last update
Apr 10, 2018

Study contacts

Jose M Garcia, MD PhD
study chair · Baylor College of Medicine, Houston, TX, U.S.

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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