Clinical trial NCT01806298: An Open-label Phase 4 Study to Explore Immunogenicity of the Liquid Formulation of Saizen® in Subjects With Adult Growth Hormone Deficiency (AGHD)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Adult Growth Hormone Deficiency
Keywords: Adult Growth hormone deficiency
Saizen®
Recombinant human growth hormone (r-hGH)
Somatropin
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2013-03-07
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Percentage of Subjects Developing Binding Antibodies (BAbs) to Saizen®
timeFrame: Baseline up to Week 39
Secondary outcomes:
measure: Percentage of Subjects With Binding Antibodies (BAbs) Who Became Positive for Neutralizing Antibodies (NAbs)
timeFrame: Baseline up to Week 39
measure: Insulin-like Growth Factor-I (IGF-I) Levels
timeFrame: Baseline, Week 2, 8, 16, 29, 39 and 41
measure: Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Levels
timeFrame: Baseline, Week 2, 8, 16, 29, 39 and 41
measure: Insulin-like Growth Factor-I Standard Deviation Score (IGF-I SDS)
timeFrame: Baseline, Week 2, 8, 16, 29, 39 and 41
measure: Treatment Adherence Rate as Documented Using EasypodTM Connect
timeFrame: Week 2, 8, 16, 29 and 39
Other outcomes:
measure: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation
timeFrame: Baseline up to Week 41
Locations:
city: Adelaide
country: Australia
facility: Research site
state: South Australia
city: Perth
country: Australia
facility: Research site
state: Western Australia
city: Clayton
country: Australia
facility: Research site
city: Darlinghurst
country: Australia
facility: Research site
city: Fitzroy
country: Australia
facility: Research site
city: Berlin
country: Germany
facility: Research site
city: Oldenburg
country: Germany
facility: Research site
city: Würzburg
country: Germany
facility: Research site
city: Goteborg
country: Sweden
facility: Research site
city: Stockholm
country: Sweden
facility: Research site
city: Birmingham
country: United Kingdom
facility: Research site
city: Cleveland
country: United Kingdom
facility: Research site
city: Guildford
country: United Kingdom
facility: Research site
city: Liverpool
country: United Kingdom
facility: Research site
city: Manchester
country: United Kingdom
facility: Research site
city: Manchester
country: United Kingdom
facility: Research site
city: Norfolk
country: United Kingdom
facility: Research site
city: Oxford
country: United Kingdom
facility: Research site
city: Truro
country: United Kingdom
facility: Research site
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical Director
role: STUDY_DIRECTOR
References: