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

NCT04786873 | Completed Phase 3 FDA Drug

• 3 other identifiers: AEZS-130-P022018-001989-42U1111-1248-5075
• Study Type: interventional
• Target: 101
• Locations: 10 countries
• Sites: 42

Brief Summary

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).

Conditions

Growth Hormone Deficiency

Keywords

childhood-onset growth hormone deficiency; diagnosis of growth hormone deficiency; diagnosis of childhood-onset growth hormone deficiency; diagnostic test for growth hormone deficiency

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Sensitivity for the macimorelin GHST

  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

  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

  Visit 4 (between day 11 and day 58)

Study Arms (2)

standard GHST order randomized: arginine - clonidine

ACTIVE COMPARATOR

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; Diagnostic Test: Arginine; Diagnostic Test: Clonidine

standard GHST order randomized: clonidine - arginine

ACTIVE COMPARATOR

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; Diagnostic Test: Arginine; Diagnostic Test: Clonidine

Interventions

Macimorelin DRUG

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.

Also known as: Macrilen, AEZS-130, Macimorelin GHST, Macimorelin test, Macrilen GHST, Macrilen test

standard GHST order randomized: arginine - clonidine; standard GHST order randomized: clonidine - arginine

Arginine DIAGNOSTIC_TEST

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.

Also known as: R-Gene 10, arginine test, arginine GHST

standard GHST order randomized: arginine - clonidine; standard GHST order randomized: clonidine - arginine

Clonidine DIAGNOSTIC_TEST

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.

Also known as: Catapressan 75, Clonidine test, Clonidine GHST

standard GHST order randomized: arginine - clonidine; standard GHST order randomized: clonidine - arginine

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• Male and female pediatric subjects from 2 to less than 18 years of age at the time of signing informed consent.
• Indication for the performance of growth hormone stimulation test.
• Presence of a height measurement minimum 6 and maximum 18 months prior to screening.

You may not qualify if:

• 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.).
• Ongoing growth hormone therapy.
• Presence of hypothyroidism and/or adrenal insufficiency without adequate and stable replacement therapy treatment for at least 30 days prior to first GHST.
• 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).
• Medical history of ongoing clinically symptomatic psychiatric disorders.
• nd 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.
• Previous participation in this trial. Participation is defined as signed informed consent.
• Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening.
• Known or suspected hypersensitivity to trial product(s) or related products;
• Any disorder, which in the investigator's opinion might jeopardize subject's safety or compliance with the protocol.
• 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;
• 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);
• Current active malignancy other than non-melanoma skin cancer;
• Female of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
• 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).

Sponsors & Collaborators

• AEterna Zentaris: lead

Study Sites (45)

Angel Wing Clinic For Children With Diabetes

Tucson, Arizona, 85724, United States

Location

Pediatric Endocrine Associates, p.c.

Greenwood Village, Colorado, 80111, United States

Location

John Hopkins All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

Emory Healthcare-Children's Center

Atlanta, Georgia, 30329, United States

Location

St. Luke's Children's Endocrinology

Boise, Idaho, 83712, United States

Location

University of Minnesota, Masonic Children's Hospital

Minneapolis, Minnesota, 55454, United States

Location

The Children's Mercy Hospital - Broadway

Kansas City, Missouri, 64108, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10129, United States

Location

Children's Hospital at Montefiore

The Bronx, New York, 10709, United States

Location

UNC Hospitals

Chapel Hill, North Carolina, 27599, United States

Location

Alchemi Research Center

Rosharon, Texas, 77583, United States

Location

Multicare Health System

Tacoma, Washington, 98405, United States

Location

Yerevan State Medical University after Mkhitar Heraci

Yerevan, 0024, Armenia

Location

JSC Maritime Hospital

Batumi, 0179, Georgia

Location

National Institute of Endocrinology

Tbilisi, 0159, Georgia

Location

TSMU Givi Jvania Pediatric Academic Clinik

Tbilisi, 0159, Georgia

Location

Evangelisches Klinikum Bethel

Bielefeld, 33617, Germany

Location

Ospedale Pediatrico G. Salesi

Ancona, 60126, Italy

Location

Azienda Ospedaliero-Universitaria Anna Meyer

Florence, 50139, Italy

Location

Osp. dei Bambini V. Buzzi, ASST Fatebenefratelli Sacco

Milan, 20154, Italy

Location

Azienda Ospedaliero-Universitaria di Parma Ospedale dei Bambini Pietro Barilla, Clinica Pediatrica

Parma, 43100, Italy

Location

IRCCS Ospedale Pediatrico Bambino Gesù

Roma, 00165, Italy

Location

MED-POLONIA Sp.z o.o.

Poznan, 60-693, Poland

Location

Kliniczny Szpital Wojewodzki nr 2 im. Sw. Jadwigi Krolowej w Rzeszowie

Rzeszów, 35-301, Poland

Location

SPSK Nr 1 im. prof. Tadeusza Sokolowskiego PUM

Szczecin, 71252, Poland

Location

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu

Wroclaw, 50368, Poland

Location

Cen Med de Diagn si Trat Amb NEOMED

Brasov, 500283, Romania

Location

Sana Monitoring

Bucharest, 011025, Romania

Location

Medicover Hospitals

Bucharest, 013982, Romania

Location

Institutul de Endocrinologie "C.I. Parhon"

Bucharest, 10587, Romania

Location

Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Constanta

Constanța, 900591, Romania

Location

Spitalul Clinic Judetean de Urgenta "Sf. Spiridon" Iasi

Iași, 700111, Romania

Location

Spitalul Clinic Judetean Mures

Târgu Mureş, 540072, Romania

Location

Spitalul Cl. de Urgenta pentru Copii Louis Turcanu Timisoara

Timișoara, 300011, Romania

Location

University children's clinic Belgrade - Department of Endocrinology

Belgrade, 11000, Serbia

Location

Clinical Center Nis - Clinic for Children's Internal Medicine

Niš, 18000, Serbia

Location

Institute for Child and Youth Health Care of Vojvodina - Endocrinology

Novi Sad, 21000, Serbia

Location

National Institute of Children's Diseases

Bratislava, 83340, Slovakia

Location

Children's University Hospital Kosice

Košice, 4011, Slovakia

Location

National Institute of Endocrinology and Diabetology

Ľubochňa, 03491, Slovakia

Location

Univerzitetni Klinicni Center Ljubljana - Pediatrics

Ljubljana, 1000, Slovenia

Location

Ankara University, Faculty of Medicine

Ankara, 6100, Turkey (Türkiye)

Location

Antalya Training and Research Hospital

Antalya, 7050, Turkey (Türkiye)

Location

Kocaeli University Faculty of Medicine

Kocaeli, 41380, Turkey (Türkiye)

Location

Karadeniz Technical University

Ortahisar, 61080, Turkey (Türkiye)

Location

MeSH Terms

Conditions

Dwarfism, Pituitary

Interventions

macimorelin; Citrullination

Condition Hierarchy (Ancestors)

Dwarfism; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Bone Diseases, Endocrine; Hypopituitarism; Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Protein Processing, Post-Translational; Protein Modification, Translational; Protein Biosynthesis; Peptide Biosynthesis; Biochemical Phenomena; Chemical Phenomena; Metabolism; Gene Expression Regulation; Genetic Phenomena

Study Officials

• Nicola K Ammer, MD

  AEterna Zentaris

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: This study is open label. Masking is performed with regard to the GHST results (i.e. growth hormone (GH) values). GH values from all GHSTs will be assessed centrally by a central lab: GH values following the two standard GHSTs at V3 and V4 will not be disclosed to the trial site prior to the end of V5 (i.e., the second macimorelin GHST). To avoid bias in the final diagnostic assessments by the investigators, macimorelin pharmacodynamic (PD) data will remain blinded to the trial sites, clinical research associates (CRAs), and trial management at contract research organization (CRO) and Sponsor until trial closure. An Independent Adjudication Committee (IAC) is established to perform ongoing blinded adjudication of subjects' growth hormone deficiency status. The IAC will adjudicate in a consistent manner by use of pre-defined definitions and guidelines.
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is an open label, single-dose trial to determine the diagnostic efficacy and safety of macimorelin in pediatric subjects aged 2 to less than 18 years of age in whom, based on auxological and clinical criteria, growth hormone stimulation test (GHST) is indicated due to suspected growth hormone deficiency. Four GHSTs will be conducted during the trial: the macimorelin GHST will be performed twice, and arginine and clonidine standard GHSTs will be performed once each. The macimorelin GHST will be administered at the beginning of the trial and after serial performance of the two different standard GHSTs. The macimorelin GHSTs will be performed twice to show repeatability of the macimorelin GHST. All subjects will be randomized 1:1 to the order of the arginine and clonidine GHSTs, and in a crossover manner all subjects will receive both these GHSTs.

Study Record Dates

• First Submitted: March 3, 2021
• First Posted: March 8, 2021
• Study Start: November 16, 2021
• Primary Completion: June 13, 2024
• Study Completion: June 13, 2024
• Last Updated: August 12, 2024

Record last verified: 2024-08

Locations

RO (8); DE (1); GE (3); AR (1); US (12); SE (3); PL (4); SL (1); TU (4); IT (5)