Exploration if Saizen marketed solution for injection induces an immunogenic reaction

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2012-004263-47-GB
• Date of registration: 08/01/2013
• Prospective Registration: Yes
• Primary sponsor: Merck KGaA
• Public title: Exploration if Saizen marketed solution for injection induces an immunogenic reaction
• Scientific title: 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) of adult onset - Saizen, Phase 4 study in Growth Hormone Deficiency
• Date of first enrolment: 01/03/2013
• Target sample size: 77
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004263-47
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Australia, Czech Republic, Germany, Sweden, United Kingdom

Contacts

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female subjects, 18-65 years of age, inclusive, at the time of signature of informed consent.

2. Documented AO-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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
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 substi

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Adult Growth Hormone Deficiency
MedDRA version: 17.1 Level: PT Classification code 10056438 Term: Growth hormone deficiency System Organ Class: 10014698 - Endocrine disorders

Intervention(s)

Trade Name: SAIZEN
Pharmaceutical Form: Solution for injection

Primary Outcome(s)

Main Objective: 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).

Primary end point(s): The primary endpoint of the trial is the proportion of subjects developing BAbs to Saizen

Secondary Objective: 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.

Timepoint(s) of evaluation of this end point: Any time during the 39-week course of treatment.

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: Any time during the 39-week course of treatment.

Secondary ID(s)

EMR200104-011

Source(s) of Monetary Support

Merck KGaA

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 03/03/2017
• Date Completed: 21/03/2016
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004263-47/results