A Research Study of How Well Macimorelin Works to Find Out if Children Have a Lack of Growth Hormone and How Safe it is (DETECT)

Multicenter, Open Label Trial to Investigate the Efficacy and Safety of a Single Oral Dose of 1.0 mg/kg Macimorelin Acetate as Growth Hormone Stimulation Test (GHST) in Pediatric Patients With Suspected Growth Hormone Deficiency (GHD)

This research study will find out if a new growth hormone stimulation test is safe and works as well as other tests to diagnose growth hormone deficiency (GHD) in children. The stimulation test will use a new growth hormone stimulating substance called macimorelin. By now, only adults in the USA can get this new stimulation test. The results of this study are expected to help children and teenagers with suspected GHD to get the macimorelin stimulation test.

The macimorelin test will be compared to a clonidine and an arginine test. Both are known standard stimulation tests. Altogether two macimorelin tests are planned to be performed in the study, to show how repeatable macimorelin tests results are (under a set of similar conditions).

Study Overview

• Status: Completed
• Conditions: Growth Hormone Deficiency
• Intervention / Treatment: Drug: Macimorelin; Diagnostic test: Arginine; Diagnostic test: Clonidine

Detailed Description

Each study participant (patient) will have 5 to 6 visits in total with the study doctor.

The study will last for about 1 to 4 months, dependent on how close the visits are done. At the visits 2, 3, 4 and 5, the patient will get a stimulation test done and blood samples will be taken. At those 4 visits, the patient will have either to drink a macimorelin drink, take some clonidine tablets or get an arginine infusion. In total, the patient will get 2 macimorelin, 1 clonidine and 1 arginine test done. The level of growth hormone (GH) will be measured 4 times during the clonidine and during the arginine test and 5 times during the macimorelin test. After the test, questions on the test tolerability will be captured from patients and parents. After the arginine test, a urine dipstick test is to be done by the patient at home.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

Study Locations

• Armenia
  • Yerevan, Armenia, 0024
    • Yerevan State Medical University after Mkhitar Heraci
• Georgia
  • Batumi, Georgia, 0179
    • JSC Maritime Hospital
  • Tbilisi, Georgia, 0159
    • National Institute of Endocrinology
  • Tbilisi, Georgia, 0159
    • TSMU Givi Jvania Pediatric Academic Clinik
• Germany
  • Bielefeld, Germany, 33617
    • Evangelisches Klinikum Bethel
• Italy
  • Ancona, Italy, 60126
    • Ospedale Pediatrico G. Salesi
  • Firenze, Italy, 50139
    • Azienda Ospedaliero-Universitaria Anna Meyer
  • Milano, Italy, 20154
    • Osp. dei Bambini V. Buzzi, ASST Fatebenefratelli Sacco
  • Parma, Italy, 43100
    • Azienda Ospedaliero-Universitaria di Parma Ospedale dei Bambini Pietro Barilla, Clinica Pediatrica
  • Roma, Italy, 00165
    • IRCCS Ospedale Pediatrico Bambino Gesu
• Poland
  • Poznań, Poland, 60-693
    • MED-POLONIA Sp.z o.o.
  • Rzeszów, Poland, 35-301
    • Kliniczny Szpital Wojewodzki nr 2 im. Sw. Jadwigi Krolowej w Rzeszowie
  • Szczecin, Poland, 71252
    • SPSK Nr 1 im. prof. Tadeusza Sokolowskiego PUM
  • Wrocław, Poland, 50368
    • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
• Romania
  • Braşov, Romania, 500283
    • Cen Med de Diagn si Trat Amb NEOMED
  • Bucharest, Romania, 10587
    • Institutul de Endocrinologie "C.I. Parhon"
  • Bucuresti, Romania, 011025
    • Sana Monitoring
  • Bucuresti, Romania, 013982
    • Medicover Hospitals
  • Constanţa, Romania, 900591
    • Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Constanta
  • Iaşi, Romania, 700111
    • Spitalul Clinic Judetean de Urgenta "Sf. Spiridon" Iasi
  • Timişoara, Romania, 300011
    • Spitalul Cl. de Urgenta pentru Copii Louis Turcanu Timisoara
  • Târgu-Mureş, Romania, 540072
    • Spitalul Clinic Judetean Mures
• Serbia
  • Belgrade, Serbia, 11000
    • University children's clinic Belgrade - Department of Endocrinology
  • Niš, Serbia, 18000
    • Clinical Center Nis - Clinic for Children's Internal Medicine
  • Novi Sad, Serbia, 21000
    • Institute for Child and Youth Health Care of Vojvodina - Endocrinology
• Slovakia
  • Bratislava, Slovakia, 83340
    • National Institute of Children's Diseases
  • Košice, Slovakia, 4011
    • Children's University Hospital Košice
  • Ľubochňa, Slovakia, 03491
    • National Institute of Endocrinology and Diabetology
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Univerzitetni Klinicni Center Ljubljana - Pediatrics
• Turkey
  • Ankara, Turkey, 6100
    • Ankara University, Faculty of Medicine
  • Antalya, Turkey, 7050
    • Antalya Training And Research Hospital
  • Kocaeli, Turkey, 41380
    • Kocaeli University Faculty of Medicine
  • Ortahisar, Turkey, 61080
    • Karadeniz Technical University
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Angel Wing Clinic For Children With Diabetes
  • Colorado
    • Greenwood Village, Colorado, United States, 80111
      • Pediatric Endocrine Associates, p.c.
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • John Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory Healthcare-Children's Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Children's Endocrinology
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota, Masonic Children's Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital - Broadway
  • New York
    • Bronx, New York, United States, 10709
      • Children's Hospital at Montefiore
    • New York, New York, United States, 10129
      • ICAHN School of Medicine at Mount Sinai
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Hospitals
  • Texas
    • Rosharon, Texas, United States, 77583
      • Alchemi Research Center
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Informed consent of subject, parent(s) or legally acceptable representative (LAR) of subject and child assent, if appropriate, must be obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
2. Male and female pediatric subjects from 2 to less than 18 years of age at the time of signing informed consent.
3. Indication for the performance of growth hormone stimulation test.
4. Presence of a height measurement minimum 6 and maximum 18 months prior to screening.

Exclusion Criteria:

1. Established diagnosis of a disease that is sufficient to explain growth deficiency or metabolic disorders that are also associated with short stature (e.g., Turner syndrome, skeletal dysplasia's, celiac disease, etc.).
2. Ongoing growth hormone therapy.
3. Presence of hypothyroidism and/or adrenal insufficiency without adequate and stable replacement therapy treatment for at least 30 days prior to first GHST.
4. 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 e.g., atropine).
5. Medical history of ongoing clinically symptomatic psychiatric disorders.
6. 2nd or 3rd degree atrioventricular-block, prolongation of the QRS complex over 120 milliseconds, prolongation of the QTc interval over 450 milliseconds, or any other clinically significant abnormal electrocardiogram results at the V2 pre-dose electrocardiogram (ECG) as judged by the investigator.
7. Previous participation in this trial. Participation is defined as signed informed consent.
8. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening.
9. Known or suspected hypersensitivity to trial product(s) or related products;
10. Any disorder, which in the investigator's opinion might jeopardize subject's safety or compliance with the protocol.
11. Concomitant treatment with any drugs that might prolong QT/QTc Note: A subject who receives such treatment will not be a candidate for this study, if his/her condition does not allow for a treatment-free period of at least 5 elimination half-lives of the drug that might prolong QT/QTc before the GHST;
12. Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (aspartate amino transferase (AST), alkaline phosphatase (ALT), gamma-glutamyl transferase (GGT) > 2.5 x upper limit of normal (ULN); creatinine or bilirubin > 1.5x ULN);
13. Current active malignancy other than non-melanoma skin cancer;
14. Female of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
15. Male of reproductive age who or whose partner(s) is not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
16. Lack of ability or willingness to give informed consent by the subject and/or his/her legal representative;
17. 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: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: standard GHST order randomized: arginine - clonidine; At visit 2 (V2), all subjects will perform the macimorelin GHST and will be randomized 1:1 to the order of the clonidine and arginine GHSTs at visit 3 (V3) and visit 4 (V4). In this arm, those subjects will be presented which will have been randomized to the arginine GHST at V3 and the clonidine GHST at V4. At visit 5 (V5) all subjects will perform the macimorelin GHST.	Drug: Macimorelin; Dosage form: granules for oral solution, Dosage: 1.0 mg/kg body weight, Frequency and duration: single oral dose administration. Macimorelin will be supplied in single-use aluminum pouches (synonymous: sachets) each containing 63.6 mg macimorelin as acetate, which provide 0.5 mg/mL of macimorelin when dissolved in 120 mL of water. The excess amount of 3.6 mg represents an overfill, which is needed to obtain the target concentration.; Other Names: Macrilen; AEZS-130; Macimorelin GHST; Macimorelin test; Macrilen GHST; Macrilen test; Diagnostic test: Arginine; For the arginine GHST, R-Gene® 10 from Pfizer will be provided as labelled investigational medicinal product (IMP). After an overnight fast, soluble arginine hydrochloride (0.5 g/kg) will be given i.v. as an infusion with an infusion duration of 30 min.; Other Names: R-Gene 10; arginine test; arginine GHST; Diagnostic test: Clonidine; For the clonidine GHST, CATAPRESAN® 75 tablets (Boehringer Ingelheim) will be provided as labelled IMP. Each tablet contains 75 ug clonidine hydrochloride. The tablets will be provided in boxes containing 10 tablets. The target dose is 0.15 mg/m2 body surface with a dose range of 0.08 - 0.15 mg/m2. Maximum dose will be 0.25 mg. After an overnight fast, clonidine (0.15 mg/m2 body surface) will be given orally.; Other Names: Catapressan 75; Clonidine test; Clonidine GHST
Active Comparator: standard GHST order randomized: clonidine - arginine; At V2, all subjects will perform the macimorelin GHST and will be randomized 1:1 to the order of the clonidine and arginine GHSTs at V3 and V4. In this arm, those subjects will be presented which will have been randomized to the clonidine GHST at V3 and to the arginine GHST at V4. At V5 all subjects will perform the macimorelin GHST.	Drug: Macimorelin; Dosage form: granules for oral solution, Dosage: 1.0 mg/kg body weight, Frequency and duration: single oral dose administration. Macimorelin will be supplied in single-use aluminum pouches (synonymous: sachets) each containing 63.6 mg macimorelin as acetate, which provide 0.5 mg/mL of macimorelin when dissolved in 120 mL of water. The excess amount of 3.6 mg represents an overfill, which is needed to obtain the target concentration.; Other Names: Macrilen; AEZS-130; Macimorelin GHST; Macimorelin test; Macrilen GHST; Macrilen test; Diagnostic test: Arginine; For the arginine GHST, R-Gene® 10 from Pfizer will be provided as labelled investigational medicinal product (IMP). After an overnight fast, soluble arginine hydrochloride (0.5 g/kg) will be given i.v. as an infusion with an infusion duration of 30 min.; Other Names: R-Gene 10; arginine test; arginine GHST; Diagnostic test: Clonidine; For the clonidine GHST, CATAPRESAN® 75 tablets (Boehringer Ingelheim) will be provided as labelled IMP. Each tablet contains 75 ug clonidine hydrochloride. The tablets will be provided in boxes containing 10 tablets. The target dose is 0.15 mg/m2 body surface with a dose range of 0.08 - 0.15 mg/m2. Maximum dose will be 0.25 mg. After an overnight fast, clonidine (0.15 mg/m2 body surface) will be given orally.; Other Names: Catapressan 75; Clonidine test; Clonidine GHST

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the Receiver Operator Characteristic curve (ROC AUC) based on GH concentration during GHST following macimorelin administration	Assuming the outcome of GHD status adjudication final clinical diagnosis as the "true" GHD status, the diagnostic efficacy (estimated sensitivity, specificity, misclassification) of the macimorelin GHST will be based on the area under the receiver operating characteristic curve (ROC AUC).	Derived from Cmax GH measurements collected in the time frame from 0 to 90 minutes after initial macimorelin GHST (visit 2 (day 0)) and GH adjudication status performed by the adjudication committee after visit 4 (between day 11 and day 58)).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity for the macimorelin GHST	Sensitivity (confirmatory secondary endpoint) will be derived from the empirical ROC plot using this GH cut-off point.	Derived from Cmax GH measurements collected in the time frame from 0 to 90 minutes after initial macimorelin GHST (visit 2 (day 0)) and GH adjudication status performed by the adjudication committee after visit 4 (between day 11 and day 58)).
Specificity for the macimorelin GHST	Specificity (confirmatory secondary endpoint) will be derived from the empirical ROC plot using this GH cut-off point.	Derived from Cmax GH measurements collected in the time frame from 0 to 90 minutes after initial macimorelin GHST (visit 2 (day 0)) and GH adjudication status performed by the adjudication committee after visit 4 (between day 11 and day 58)).
Overall agreement between the outcome of the macimorelin GHST and the combined outcome from the 2 standard GHSTs	Agreement between the outcome of macimorelin and the combined outcome of the 2 standard GHSTs will be evaluated by 'percent overall agreement'.	Visit 4 (between day 11 and day 58)

Collaborators and Investigators

• Sponsor: AEterna Zentaris
• Collaborators: Novo Nordisk A/S
• Investigators: Study Director: Nicola K Ammer, MD, AEterna Zentaris

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2021
• Primary Completion (Actual): June 13, 2024
• Study Completion (Actual): June 13, 2024

Study Registration Dates

• First Submitted: March 3, 2021
• First Submitted That Met QC Criteria: March 3, 2021
• First Posted (Actual): March 8, 2021

Study Record Updates

• Last Update Posted (Actual): August 12, 2024
• Last Update Submitted That Met QC Criteria: August 9, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: childhood-onset growth hormone deficiency; diagnosis of growth hormone deficiency; diagnosis of childhood-onset growth hormone deficiency; diagnostic test for 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; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympatholytics; Clonidine
• Other Study ID Numbers: AEZS-130-P02; 2018-001989-42 (EudraCT Number); U1111-1248-5075 (Other Identifier: Universal Trial Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No