Clinical Trials Register

Summary
EudraCT Number:	2015-002337-22
Sponsor's Protocol Code Number:	AEZS-130-052
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-28
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

UK - MHRA

A.2

EudraCT number

2015-002337-22

A.3

Full title of the trial

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)

A.3.1

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

Comparison of the substance macimorelin (drinking solution) with insulin (injection) to confirm that it works as diagnostic test for lacking growth hormone in adults

A.3.2

Name or abbreviated title of the trial where available

Validation of macimorelin as a test for Adult Growth Hormone Deficiency

A.4.1

Sponsor's protocol code number

AEZS-130-052

A.5.4

Other Identifiers

Name:

IND number

Number:

073196

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

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	Aeterna Zentaris GmbH
B.5.2	Functional name of contact point	Clinical trial information desk
B.5.3	Address:
B.5.3.1	Street Address	Weismuellerstraße 50
B.5.3.2	Town/ city	Frankfurt am Main
B.5.3.3	Post code	60314
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4969426023472
B.5.5	Fax number	+4969426023404
B.5.6	E-mail	clinical.trials@aezsinc.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	No
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.3.2	Product code	AEZS-130
D.3.4	Pharmaceutical form	Granules for oral solution
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 acetate
D.3.9.1	CAS number	945212-59-9
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	SUB177751
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	69.9 to 72.3
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	Insulin
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Insulin
D.3.9.1	CAS number	9004-10-8
D.3.9.2	Current sponsor code	Insulin
D.3.9.3	Other descriptive name	INSULIN
D.3.9.4	EV Substance Code	SUB02689MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.10 to 0.20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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 Adult Growth Hormone Deficiency (AGHD)

E.1.1.1

Medical condition in easily understood language

Diagnosis of lacking growth hormone in adults

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 validate the use of single dose oral macimorelin for the dagnosis of AGHD ('macimorelin GHST'), using the Insulin Tolerance Test (ITT) as comparator (non-reference standard) GHST.

E.2.2

Secondary objectives of the trial

To characterize the safety profile of single dose oral macimorelin in suspected AGHD subjects

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged between 18 and 65 years.
2. 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).
OR (recruitment at dedicated trial sites only)
3. Group D: Healthy* control
Subject matching a Group A subject by
- sex, age (+/- 5 years), BMI (+/- 2 kg/m2), and estrogen status** (women only);
* ‘healthy’ comprising:
- history of normal growth and development,
- serum prolactin concentration within normal range limits,
- history of regular, age-appropriate menses in females
- serum testosterone concentration within normal range limits for males.
** matching for ‘estrogen status’:
- Group A subjects below 50 years and on oral estrogen therapy will be matched to control subjects who are also taking estrogen (as an oral contraceptive or for replacement); the route of estrogen administration (e.g. oral vs transdermal) must also be matched.
- Group A subjects 50 years or older and with untreated estrogen deficiency will be matched to female control subjects who are not receiving estrogen.

E.4

Principal exclusion criteria

Lack of suitability for the trial:
1. GH therapy within 1 month prior to anticipated first GHST within this trial (within 3 months in case of long-acting GH formulation).
Note: A patient with ongoing GH therapy will not be a candidate for this trial, if a corresponding treatment-free interval is not medically justifiable.
2. GHST within 7 days prior to the anticipated first test day within the trial.
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 first test day within the trial
4. Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial.
Note: Postmenopausal status will not be considered as an exclusion.
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. Medical history of ongoing clinically symptomatic severe psychiatric disorders.
8. Parkinson’s disease.
9. Cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial.
10. Type 1 diabetes or untreated or poorly controlled Type 2 diabetes, as defined by HbA1c > 8%.
11. Body mass index (BMI) ≥ 40.0 kg/m2.
12. Participation in a trial with any investigational drug within 30 days prior to trial entry.
13. Vigorous physical exercise within 24 hours prior to each GHST within this trial.

Safety concerns:
14. Known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation.
15. Clinically significant cardiovascular or cerebrovascular disease.
16. Prolonged ECG QT interval, defined as QTc > 500 msec.
17. 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 (registration required),a copy of which is included in the Investigator’s File) a copy of which is included in the Investigator’s File).
Note: A patient who receives such treatment will not be a candidate for this trial, 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.
18. Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (ASAT, ALAT,GGT > 2.5 x ULN; , creatinine, or bilirubin > 1.5x ULN).
19. Medical history of seizure disorders.
20. Known immunosuppression.
21. Current active malignancy other than non-melanoma skin cancer.
22. Breastfeeding or positive urine pregnancy test (for women of childbearing potential only).
23. 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).

Administrative reasons:
24. Lack of ability or willingness to give informed consent.
25. Anticipated non-availability for trial visits/procedures.

E.5 End points

E.5.1

Primary end point(s)

Co-Primary efficacy variables will be 'Percent Negative Agreement' and 'Percent Positive Agreement' when using predefined cut-points of both GHSTs.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation of the Primary endpoints will be performed at two timepoints (i.e. during two separate visits per Growth Hormone Stimulation Test): For Test 1 on Day 1, for Test 2 on D8-28 (i.e. on one day within a time period from Day8 to Day28)

E.5.2

Secondary end point(s)

Secondary efficacy criteria will be 'Percent Overall Agreement' and estimated sensitivity and specificity of both GHSTs when using predefined cut-points of both GHSTs.

Safety:
Adverse events, clinical laboratory and 12-lead ECG.

Other:
Test acceptance/Preference by Trial subjects and investigators.
Preliminary PK: Tmax and Cmax of macimorelin Plasma concentrations in the sampling period.
Preliminary PK/PD: Tmax for macimorelin vs Tmax for GH; Cmax for macimorelin vs Cmax for GH.

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation of the secondary endpoints will be:
- efficacy related at two timepoints (i.e. during two separate visits per Growth Hormone Stimulation Test), as mentioned in Section E.5.1.1: For Test 1 on Day 1, for Test 2 on D8-28 (i.e. on one day within a time period from Day8 to Day28)
- safety related at four timepoints, i.e. at all four visits of this Trial (Screening visit, Test 1, Test 2, End-of-Trial visit)

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

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

Austria

France

Germany

Italy

Poland

Serbia

Spain

United Kingdom

United States

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

110

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

Yes

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

110

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)

The trial is being performed within the diagnostic work-up of subjects suspected to have AGHD, by applying the experimental assay in addition to the diagnostic standard. The acutal conclusion on the AGHD diagnosis and the implementation of treatment, if needed, is not subject of this trial.

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

2015-12-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-11-29

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