| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This is GH replacement therapy in adult subjects with documented Growth Hormone Deficiency (GHD) either idiopathic or acquired and childhood- or adult-onset |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056438 |
| E.1.2 | Term | Growth hormone deficiency |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the immunogenicity of the r-hGH liquid multidose formulation (SaizenÒ solution for injection) by measuring the proportion of subjects who become positive for binding antibodies (BAbs+) during a 6-month (26-week) course of daily GH replacement therapy in adult subjects with documented GHD (either idiopathic or acquired and childhood- or adult-onset). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the proportion of adult subjects with GHD who become positive for neutralizing antibodies (NAbs+), only if those same samples were already determined to have been positive for binding antibodies (BAbs+).
To assess the effect of Saizen solution for injection on GH biomarkers (IGF-I and IGFBP-3).
To assess the safety profile of Saizen solution for injection, via TEAEs, vital signs, physical examinations, and laboratory results, including GH biomarkers. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult male and female subjects, 18-60 years of age, inclusive, at the time the Informed Consent is signed.
2. Subject satisfies any of the following conditions in relation to GH deficiency:
a. Is GH treatment-naïve
b. Had received Saizen (freeze-dried formulation) for PGHD
c. Has or had received Saizen (freeze-dried formulation) for AGHD and either:
i. Had discontinued Saizen for reasons other than safety, tolerability, or efficacy; or
ii. Is currently being treated with Saizen for at least 3 consecutive months prior to Screening.
3. For GH treatment-naïve subjects or subjects previously treated with Saizen (freeze-dried formulation) for PGHD and not currently on Saizen for AGHD, subjects, must have confirmed AGHD before initiating study treatment (Saizen solution for injection), as documented by GH provocative testing described below. The peak GH level needs to be less than the pre-determined cutoff value in one of the following GH provocative/stimulation tests (per the GH Research Society’s 2007 guidelines for the diagnosis and treatment of adult GHD). (30) Note: If more than 2 tests are performed, all peak GH levels should be less than the following, predetermined cutoff values:
· <3 ng/mL for a peak GH level if an Insulin Tolerance Test (ITT) or a glucagons stimulation test is performed.
· If a GHRH + arginine test is performed, the following cutoff levels have been validated:
· 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).
4. Subjects who had previously undergone or are currently undergoing treatment for adult GHD with Saizen® freeze-dried formulation prestudy must have shown evidence of treatment responsiveness and compliance by either (i) an IGF-I SDS >0.0 during treatment, or (ii) an increase of at least 1 SD in IGF-I levels, relative to what those levels were prior to initiating Saizen® freeze-dried treatment. Note: The Sponsor will make every effort to provide each site with appropriate, normative IGF-I SDS tables/standards.
5. All subjects, i.e., both GH treatment-naïve and those who had been receiving or are currently receiving Saizen® freeze-dried formulation for adult GHD must undergo a blood sampling for binding antibodies (BAbs) to GH and must be binding antibody-negative (BAbs-) for the Screening visit sample. NOTE: Study sites should make every effort to obtain at least samples for antibody testing within a window of 21-28 days prior to the anticipated start of study treatment on Day 1 in order to ensure that the antibody results will be available from the central laboratory(ies) prior to the planned initiation of treatment.
6. No evidence of concomitant disease, intercurrent illness, or resultant therapy that would interfere with subject compliance, the evaluation of study results, or compromise the safety of the subject.
7. Has no history of GH antibodies, autoimmune disease, or GH1 gene defect.
8. Euthyroid with or without therapy at Screening.
9. Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit (and at each scheduled visit during the study). NOTE: To qualify for entry into the study, women must be either surgically sterile or post-menopausal or, if capable of conceiving, use appropriate contraceptive measures from at least 2 months prior to the Screening visit through Study Day 1 and during the entire 6 months (26 weeks) of study treatment and for the 4 weeks off-treatment, until the 1-month, post-treatment, follow-up clinic visit is completed. See also Sections 6.5.1.1, and 7.4.2.
10. Willingness of the subject to comply with the procedures of the study; and
11. Willingness of the subject to sign an IEC/IRB-approved Informed Consent form. |
|
| E.4 | Principal exclusion criteria |
1. Is currently receiving or has previously received treatment for adult GHD or any other indication, including PGHD, with a commercial GH product other than Saizen freeze-dried formuation.
2. Had a chronic underlying disease within 6 months prior to Screening or concomitant medication(s) that in the opinion of the Investigator would exclude the subject from the trial (i.e., could interfere with the safety of the subject, evaluation of study data, etc.).
3. Has chronic liver disease documented in medical history.
4. Has alanine transaminase [ALT] or aspartate transaminase [AST] > 2.5 x upper limit of the normal range, unless permitted by sponsor medical responsible.
5. Has significant renal impairment, as indicated by a glomerular filtration rate (GFR) <60 mL/min.
6. Has diabetes mellitus (per American Diabetes Association 2010 guidelines): either (i) standard diabetes symptoms and a random glucose ³ 200 mg/dL (11.1 mmol/L); (ii) a fasting plasma glucose > 126 mg/dL (6.99 mmol/L); (iii) a plasma glucose ³ 200 mg/dL (11.1 mmol/L) during an OGTT); or (iv) an HbA1c ≥ 6.5%.
7. Has a current malignancy or a history of any malignancy (excluding fully-treated basal cell carcinoma).
8. Has craniopharyngioma or another intracranial benign neoplasm in remission for less than one year.
9. Has participated in another study and received an investigational drug within 30 days prior to Screening visit.
10. Is positive for HIV, hepatitis B surface antigen, or hepatitis C at Screening or by documentation from within 3 months prior to Screening.
11. Is immunosuppressed or receiving immunosuppressive therapy.
12. Has a known alcohol or drug addiction/dependency.
13. Has active Cushing’s disease, Prader Willi syndrome, benign intracranial hypertension (or a history of that condition), a history of acromegaly, or signs and symptoms suggestive of transmissible spongiform encephalopathy.
14. Has a serious psychiatric illness or inability to understand the study, i.e., the subject must fully understand the study and the importance of attending scheduled clinic visits.
15. Has a legal incapacity or limited legal capacity.
16. Has received anabolic steroids (except for gonadal steroid replacement therapy) or systemic corticosteroids (except for replacement doses) within 3 months prior to Screening.
17. Has a clinically significant abnormal laboratory value(s) at Screening or Day 1, per the Investigator’s or Sponsor’s Medical Responsible (or qualified designate’s) clinical judgment.
18. Has a known hypersensitivity or allergy to exogenous human growth hormone or any of the excipients or phenol, the bacteriostatic agent in the SaizenÒ solution for injection cartridges to be used in this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint in this study will be the proportion of adult subjects with GHD who develop binding antibodies (BAbs+) to Saizen solution for injection at any time during a 26-week (6-month) course of single daily SC injections. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| All enrolled subjects who have received at least one dose of study drug have completed all scheduled visits (including all prematurely discontinued subjects who should undergo at least the Week 26/End of Treatment (+ one-month post-treatment follow-up visits if the subject is willing to do so). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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