An Open-label Phase 4 Study to Explore Immunogenicity of the Liquid Formulation of Saizen® in Subjects With Adult Growth Hormone Deficiency (AGHD)

Study Overview
=================
Brief Summary
-----------------
This is an open-label, single-arm, multicenter, Phase 4 study to explore the immunogenicity of the liquid formulation of Saizen® in subjects with Adult Growth Hormone Deficiency (AGHD), who are growth hormone (GH) treatment-naïve or who had prior GH treatment for GHD which was stopped at least 1 month prior to Screening and have no contraindication to the use of GH.

Official 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)

Conditions
-----------------
Adult Growth Hormone Deficiency

Intervention / Treatment
-----------------
* Drug: Saizen® solution for injection (referred as Saizen®)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects, 18-65 years of age, inclusive, at the time of signature of informed consent 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 AGHD, or in the Saizen® label, whichever is more stringent, or by confirming the presence of at least 3 pituitary hormone deficiencies and an IGF-1 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 less than 3 nanogram per milliliter (ng/mL); GH-releasing hormone (GHRH) plus arginine test, peak GH depends on body mass index (BMI): BMI less than 25 kilogram per square meter (kg/m^2) indicates a peak GH less than 11 ng/mL microgram per liter [mcg/L]). BMI 25-30 kg/m^2 indicates a peak GH less than 8 ng/mL (mcgg/L). BMI greater than 30 kg/m^2 indicates a peak GH less than 4 ng/mL (mcg/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 less than 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 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 Negative BAbs from the Screening visit sample Body mass index (BMI, Weight in kilograms / Height in square meters) measured at Screening visit as less than or equal to 35 kilogram per square meter (kg/m^2) Negative serum pregnancy test at the Screening for women of childbearing potential and subject is not lactating Understanding and willingness of the subject to comply with the procedures of the study Informed Consent form signed prior to the performance of any trial-related activities Exclusion Criteria: Hypersensitivity to the active substance or to any of the Saizen® excipients 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 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. Proliferative or pre-proliferative diabetic retinopathy 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 Severe hepatic or renal failure that could compromise the interpretation of IGF-1, that is: Alanine transaminase [ALT] or aspartate transaminase [AST] greater than 3 * upper limit of the normal range; Glomerular filtration rate (GFR) less than 30 milliliter per minute (mL/min) Note: GFR will be calculated by the laboratory according to the Modification of Diet in Renal Disease (MDRD) equation History of anti-GH antibodies 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 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 (greater than 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 Diabetes mellitus (per American Diabetes Association 2010 guidelines): either i) standard diabetes symptoms and a random glucose greater than or equal to 200 milligram per deciliter (mg/dL) (11.1 millimolar per liter [mmol/L]); ii) a fasting plasma glucose greater than 126 mg/dL (6.99 mmol/L); iii) a 2-hour plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT); or iv) an glycosylated hemoglobin (HbA1c) greater than or equal to 6.5 percent Concomitant or prior participation in an interventional trial within 30 days prior to the Screening visit Known alcohol or drug addiction/dependency Has a legal incapacity or limited legal capacity 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 Has received substitutive therapy with glucocorticosteroids, thyroid replacement, vasopressin, or sex hormones for less than 3 months or substitutive therapy has not been stable (that is, dose was not generally constant or medical condition was not controlled) for 3 months prior to Screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saizen®<br> | Drug: Saizen® solution for injection (referred as Saizen®)<br>* Saizen® solution for injection will be administered subcutaneously daily for 39 weeks according to locally approved product labeling for the currently marketed formulation of Saizen®.<br>* Other names: Recombinant human growth hormone (r-hGH);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Developing Binding Antibodies (BAbs) to Saizen® | Percentage of subjects developing BAbs = (Number of BAb positive subjects / Total number of subjects) x 100. | Baseline up to Week 39 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Binding Antibodies (BAbs) Who Became Positive for Neutralizing Antibodies (NAbs) | Percentage of subjects with BAbs who become positive for NAbs = (Number of NAb positive subjects / Number of BAbs positive subjects) x 100 | Baseline up to Week 39 | 
| Insulin-like Growth Factor-I (IGF-I) Levels | Growth Hormone (GH) biomarker levels were summarized by GH treatment status at study entry (that is subjects were classified as GH treatment-naïve subjects or subjects with prior GH treatment for adult growth hormone deficiency [AGHD]). | Baseline, Week 2, 8, 16, 29, 39 and 41 | 
| Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels | Growth Hormone (GH) biomarker levels were summarized by GH treatment status at study entry (that is subjects were classified as GH treatment-naïve subjects or subjects with prior GH treatment for adult growth hormone deficiency [AGHD]) | Baseline, Week 2, 8, 16, 29, 39 and 41 | 
| Insulin-like Growth Factor-I Standard Deviation Score (IGF-I SDS) | Insulin-like Growth Factor-1 SDS was calculated based on the actual value of IGF-1 minus reference value of IGF-1 divided by reference standard deviation of IGF-1. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a subject's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated that the IGF-I value was lower compared to the reference population. | Baseline, Week 2, 8, 16, 29, 39 and 41 | 
| Treatment Adherence Rate as Documented Using EasypodTM Connect | Treatment adherence rate was measured by: (total dose received divided by total dose prescribed) multiplied by 100. Saizen solution for injection was administered using the easypod device and treatment adherence information was obtained from the device using the easypod connect software. | Week 2, 8, 16, 29 and 39 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adult Growth hormone deficiency, Saizen®, Recombinant human growth hormone (r-hGH), Somatropin