Clinical Trials Register

Summary
EudraCT Number:	2018-001988-23
Sponsor's Protocol Code Number:	AEZS-130-P01
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-09-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-001988-23

A.3

Full title of the trial

Open label, group comparison, dose escalation trial to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of macimorelin acetate after single oral dosing of 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg in pediatric patients with suspected growth hormone deficiency (GHD)

Nyílt elrendezésű, összehasonlító csoportos, dózisemeléses vizsgálat a macimorelin-acetát biztonságosságának, tolerálhatóságának, farmakokinetikájának és farmakodinámiájának vizsgálatára 0,25 mg/kg-os, 0,5 mg/kg-os, és 1 mg/kg-os egyszeri orális adagolást követően a feltételezett növekedési hormon hiányban szenvedő gyermekek esetén (GHD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study with macimorelin acetate comparing three doses in their safety and tolerability in children with suspected growth hormone deficiency (GHD)

A.4.1

Sponsor's protocol code number

AEZS-130-P01

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/105/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Aeterna Zentaris GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Aeterna Zentaris GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Accelsiors CRO and Consultancy Services Ltd
B.5.2	Functional name of contact point	Regulatory Unit
B.5.3	Address:
B.5.3.1	Street Address	50 Miskolci Str
B.5.3.2	Town/ city	Budapest
B.5.3.3	Post code	1147
B.5.3.4	Country	Hungary
B.5.4	Telephone number	+3612990091
B.5.5	Fax number	+3612990096
B.5.6	E-mail	regulatory@accelsiors.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Macrilen
D.2.1.1.2	Name of the Marketing Authorisation holder	Stongbridge Ireland Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	macimorelin
D.3.4	Pharmaceutical form	Granules for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	macimorelin
D.3.9.1	CAS number	381231-18-1
D.3.9.2	Current sponsor code	AEZS-130
D.3.9.3	Other descriptive name	MACIMORELIN ACETATE
D.3.9.4	EV Substance Code	SUB190334
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	63.6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diagnosis of Growth Hormone Deficiency

E.1.1.1

Medical condition in easily understood language

Diagnosis of lack of growth hormone in the body

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10073227
E.1.2	Term	Growth hormone stimulation test
E.1.2	System Organ Class	100000004848

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To investigate the safety and tolerability of macimorelin acetate after ascending single oral doses of macimorelin in pediatric patients with suspected GHD.

E.2.2

Secondary objectives of the trial

- To investigate the pharmacokinetics (PK) of macimorelin acetate in pediatric subjects with suspected GHD;
-To investigate the pharmacodynamics (PD) of macimorelin acetate as measured by growth hormone (GH) release in pediatric subjects with suspected GHD;
- To explore the PK/PD relationship following single oral dose administration of macimorelin acetate in pediatric subjects with suspected GHD

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female pediatric patients from 2 to less than 18 years of age;
2. Suspected GHD based on auxological and clinical criteria;
3. Indication for the performance of provocative GHST
4. A subject with sex steroid priming prior to GHSTs that are part of the standard diagnostic procedures must also have sex steroid priming for the macimorelin GHST.

E.4

Principal exclusion criteria

Lack of suitability for the trial:
1. Established diagnosis of a disease that is sufficient to explain growth deficiency or metabolic disorders that are also associated with GHD (e.g. Turner syndrome, skeletal dysplasias, malnutrition, etc.);
2. Ongoing GH therapy;
3. 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 macimorelin test day;
4. Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to the anticipated macimorelin test day;
5. 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);
6. Concomitant use of a CYP3A4 inducer (e.g. carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort);
7. Concomitant use of a CYP3A4 inhibitor;
8. Medical history of ongoing clinically symptomatic psychiatric disorders;
9. Cushing disease or subjects on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated macimorelin test day;
10. Participation in a trial with any investigational drug within 30 days prior to trial entry;
11. Vigorous physical exercise within 24 hours prior to the macimorelin test dose.
Safety concerns:
12. Known hypersensitivity to any of the constituents of the macimorelin preparation;
13. Prolonged ECG QT interval, defined as QTc > 500 msec;
14. Concomitant treatment with any drugs that might prolong QT/QTc (see list of drugs at http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm
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;
15. Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (AST, ALT, GGT > 2.5 x ULN; creatinine or bilirubin > 1.5x ULN);
16. Current active malignancy other than non-melanoma skin cancer;
17. Girls of childbearing age without effective contraception, defined as hormonal contraception or use of condom (male or female) and spermicides or use of diaphragm and spermicides or Intra Uterine Device (IUD).
Administrative reasons:
18. Lack of ability or willingness to give informed consent by the subject and/or his/her legal representative;
19. Anticipated non-availability for trial visits/procedures.

E.5 End points

E.5.1

Primary end point(s)

SAFETY AND TOLERABILITY
- Subjective tolerability (including acceptability of taste and impact on sleep, appetite, and gastrointestinal symptoms), adverse events (AEs);
- Determination of changes in laboratory parameters which are relevant to safety;
- Influence on vital parameters (pulse rate, blood pressure, electrocardiogram [ECG]).
PHARMACOKINETICS
- Concentration-time profiles of macimorelin;
- Target parameters: AUC, Cmax, Tmax, T1/2.
PHARMACODYNAMICS
- Concentration-time profiles of GH;
- Target parameters: Cmax, Tmax;
- Preliminary PK/PD: Tmax for macimorelin vs. Tmax for GH; Cmax for macimorelin vs. Cmax for GH
OTHER
- Establishment of a recommended dose for diagnostic purposes in pediatric subjects with suspected GHD;
- Exploration of a suitable GH cut-off point for a subsequent testing to establish the diagnosis of GHD in pediatric subjects.

E.5.1.1

Timepoint(s) of evaluation of this end point

SAFETY AND TOLERABILITY - D1, D7+, D14+, D21+
PHARMACOKINETICS - Blood sampling for macimorelin plasma concentrations: pre-dose (sampling time window: +/- 15 minutes, then 15, 30, 45, 60, 90, 120 (sampling time window: +/- 5 minutes) and 360 minutes (sampling time window: +/- 10 minutes) after the oral administration of the macimorelin dose.
PHARMACODYNAMICS: - Blood sampling for GH serum concentrations: pre-dose (sampling time window: +/- 15 minutes, then 15, 30, 45, 60, 90, 120 (sampling time window: +/- 5 minutes) and 360 minutes (sampling time window: +/- 10 minutes) after the oral administration of the macimorelin dose;

E.5.2

Secondary end point(s)

Not applicable.

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

open label, group-comparison, single dose, dose-escalation trial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Hungary

Poland

Russian Federation

Serbia

Ukraine

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

All subjects with confirmed GHD will receive appropriate medical care per Investigators' discretion and local practice.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-01-24

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IMP with orphan designation in the indication
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