Clinical Trials Register

Summary
EudraCT Number:	2012-004263-47
Sponsor's Protocol Code Number:	EMR200104-011
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-02-25
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

Germany - BfArM

A.2

EudraCT number

2012-004263-47

A.3

Full title of the trial

Open-label, single-arm, phase IV, multicenter trial to explore the immunogenicity of the liquid formulation of Saizen® in subjects with adult growth hormone deficiency (AGHD)

A.3.1

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

Exploration if Saizen marketed solution for injection induces an immunogenic reaction

A.3.2

Name or abbreviated title of the trial where available

Saizen, Phase 4 study in Growth Hormone Deficiency

A.4.1

Sponsor's protocol code number

EMR200104-011

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	Merck KGaA
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	Merck KGaA
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	Merck KGaA
B.5.2	Functional name of contact point	Communication Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496151725200
B.5.5	Fax number	+496151722000
B.5.6	E-mail	service@merck.de

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	SAIZEN
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Serono Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Somatropin
D.3.9.1	CAS number	12629-01-5
D.3.9.3	Other descriptive name	SOMATROPIN
D.3.9.4	EV Substance Code	SUB10584MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5.83
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	Yes
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

Adult Growth Hormone Deficiency

E.1.1.1

Medical condition in easily understood language

Adult Growth Hormone Deficiency

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10056438
E.1.2	Term	Growth hormone deficiency
E.1.2	System Organ Class	10014698 - Endocrine disorders

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 determine whether the marketed Saizen solution for injection, administered according to the approved label for 9 months (39 weeks) in adults with GHD, induces the development of binding antibodies (BAbs).

E.2.2

Secondary objectives of the trial

Determine the proportion of subjects having developed BAbs who also developed neutralizing antibodies (NAbs).

Assess the overall pharmacodynamic profile (insulin-like growth factor type I [IGF-I]; insulin-like growth factor binding protein type 3 [IGFBP-3]; IGF-I standard deviation score [SDS]) in subjects with or without antibodies.

Assess the safety of Saizen® solution for injection through the evaluation of treatment-emergent adverse events (TEAEs), physical examination, weight, blood pressure (BP), and heart rate (HR) changes, and changes in laboratory parameters.

Calculate treatment adherence using the easypod™ connect software application.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female subjects, 18-65 years of age, inclusive, at the time of signature of informed consent.
2. Documented AGHD, i.e. childhood onset (CO) or adult onset (AO), either by a stimulation test as described in the GH Research Society’s 2007 guidelines for the diagnosis and treatment of adult GHD, or in the Saizen® label, whichever is more stringent, or by confirming the presence of at least 3 pituitary hormone deficiencies and an IGF-I level below the reference range of the laboratory where testing is performed.
Stimulation test as described in the 2007 GH Research Society guidelines and applicable to all subjects who underwent or will undergo a stimulation test:
Insulin Tolerance Test (ITT) or glucagon stimulation test: peak GH < 3 ng/mL;
GHRH + arginine test, peak GH depends on BMI:
· BMI < 25 kg/m2 à a peak GH <11 ng/mL (mg/L);
· BMI 25–30 kg/m2 à a peak GH < 8 ng/mL (mg/L);
· BMI > 30 kg/m2 à a peak GH < 4 ng/mL (mg/L).
Clonidine, l-dopa, and arginine alone are not acceptable as stimulation tests for determining eligibility in this trial.
Stimulation tests remain under the Investigator’s or the subject’s physician’s responsibility, including the selection of the GH assay.
Saizen® label: in Europe, only one single test is required; in Australia, 2 stimulation tests showing a peak GH < 2.5 ng/mL are required. The inclusion criteria were chosen based on the approved label for Saizen® in the countries where the trial is being implemented, as well as in respect of the most current international guidelines for AGHD. There is no limit in time prior to the Screening visit for the stimulation test(s), as long as documentation is available and the stimulation tests comply with the GH Research Society 2007 guidelines, and as such, there is no need to repeat the test for subjects having stopped their GH therapy prior to the Screening visit.
No stimulation test is required for subjects with 3 or more pituitary hormone deficiencies.
3. GH treatment-naïve or prior GH treatment for AGHD stopped at least 1 month prior to Screening visit.
Whereas any prior use of GH is permitted, providing an adequate wash-out period is respected to secure the interpretation of the biomarkers, the reason for stopping the GH therapy should neither be safety- nor efficacy-related, and documentation should be present in the source information.
4. Negative BAbs from the Screening visit sample.
5. Body mass index (BMI) measured at the Screening visit (Weight in kilograms / [Height in meters]2) ≤ 40 kg/m2.
6. Negative serum pregnancy test at the Screening visit for women of childbearing potential and subject is not lactating.
7. Understanding and willingness of the subject to comply with the procedures of the study.
8. Informed Consent form signed prior to the performance of any trial-related activities.

E.4

Principal exclusion criteria

Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Hypersensitivity to the active substance or to any of the Saizen® excipients.
2. Evidence of growing intracranial tumor including pituitary tumor, or affecting the optic chiasm, or requiring treatment (surgery or radiation) within the 6 months prior to and the 12 months after the Screening visit.
3. Presence of active malignancy, neoplasia or any evidence of
progression or recurrence of an underlying tumor. In case of a history of
neoplasia or any pre-existing malignancy, the tumor must be inactive
and anti-tumor therapy completed prior to starting trial on active Saizen
therapy.
4. Proliferative or preproliferative diabetic retinopathy.
5. Evidence of chronic underlying disease within 6 months prior to the Screening visit or concomitant medication that would interfere with subject compliance, the evaluation of trial results, or compromise the safety of the subject.
6. Severe hepatic or renal failure that could compromise the interpretation of IGF-I, i.e.:
· Alanine transaminase [ALT] or aspartate transaminase [AST] > 3 x upper limit of the normal range;
· Glomerular filtration rate (GFR) < 30 mL/min.
Note: GFR will be calculated by the laboratory according to the Modification of Diet in Renal Disease (MDRD) equation
7. History of anti-GH antibodies,
8. History or presence of an autoimmune disease, such as Hashimoto’s disease or Systemic Lupus Erythematosus (SLE), immunosuppression regardless of etiology, or GH1 gene defect.
9. Absence of effective contraception in place at the Screening visit in women of childbearing potential.
Acceptable forms of effective contraception include: established use of oral (> 2 months), injected, or implanted hormonal methods of contraception, intrauterine devices (IUD), or barrier methods of contraception, specifically, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
10. Diabetes mellitus (per American Diabetes Association 2010 uidelines): either i) standard diabetes symptoms and a random glucose
≥200 mg/dL (11.1 mmol/L); ii) a fasting plasma glucose > 126 mg/dL (6.99 mmol/L); iii) a 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT); or iv) an glycosylated hemoglobin (HbA1c) ≥ 6.5%.
11. Concomitant or prior participation in an interventional trial within 30 days prior to the Screening visit.
12. Known alcohol or drug addiction/dependency.
13. Has a legal incapacity or limited legal capacity.
14. Has received anabolic steroids (except for gonadal steroid replacement therapy) or systemic corticosteroids (except for replacement doses) within 3 months prior to the Screening visit.
15. Has received substitutive therapy with glucocorticosteroids, thyroid replacement, vasopressin, or sex hormones for < 3 months or substitutive therapy has not been stable (i.e., dose was not generally constant or medical condition was not controlled) for the 3 months prior to Screening.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the trial is the proportion of subjects developing BAbs to Saizen

E.5.1.1

Timepoint(s) of evaluation of this end point

Any time during the 39-week course of treatment.

E.5.2

Secondary end point(s)

·proportion of subjects with BAbs who become positive for NAbs,· effects of Saizen® on the GH biomarker IGF-I, IGFBP-3, IGF-I SDS, and
adherence to treatment using easypod connect.
Safety endpoints include TEAEs, physical examination, weight, BP, HR, and laboratory parameters exploring lipid and glucose metabolism, as well as thyroid function.

E.5.2.1

Timepoint(s) of evaluation of this end point

Any time during the 39-week course of treatment.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

Australia

Czech Republic

Germany

Sweden

United Kingdom

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

This trial will be considered as completed at the date of the last visit of the last participant or the completion of any follow-up monitoring and data collection described in the protocol, whichever is the later date.

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

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:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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)

None

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

2013-03-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-03-21

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