Study of the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% DIF in Patients With Post-polio Syndrome

Study Overview
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Brief Summary
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This is a multicenter, prospective, randomized, placebo-controlled, double-blind, parallel group clinical trial with adaptive dose selection in subjects with post-polio syndrome (PPS). The main purpose of this study is to select a dose of Flebogamma 5% DIF and confirm the efficacy of the selected Flebogamma® 5% DIF dose by assessing physical performance, as measured by Two-Minute Walk Distance (2MWD) test. The study will consist of 2 stages, with each stage consisting of a screening period (up to 4 weeks), a treatment period (52 weeks), and a follow-up period (24 weeks).

Detailed Description
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This is a phase II/III multicenter, prospective, randomized, placebo-controlled, double-blind, parallel-group clinical trial with an adaptive design (flexible group sequential design with adaptive dose selection) in subjects with PPS. This study will consist of two stages. The first stage (Stage 1) is for dose selection, and the second stage (Stage 2) is to establish the superiority (efficacy confirmation) of Flebogamma 5% DIF and for overall safety analysis. Stage 1 is a 3-arm evaluation of 2 dose levels of Flebogamma 5% DIF intravenous immunoglobulin (IVIG) 1 g/kg and 2 g/kg of body weight) and placebo randomized in a 1:1:1 ratio. Flebogamma 5% DIF 2 g/kg of body weight will be administered over 2 consecutive days (IVIG 1g/kg on Day 1 and IVIG 1g/kg on Day 2) (IVIG 2 g/kg arm), Flebogamma 5% DIF 1 g/kg of body weight plus the equivalent volume of Normal Saline Solution (20 mL/kg of body weight) (IVIG 1 g/kg arm), or a total dose of 40 mL/kg of body weight Normal Saline Solution (equivalent volume of the 2 g/kg of body weight Flebogamma 5% DIF infusions) (placebo arm) will be administered over 2 consecutive days every 4 weeks during a 52-week treatment period. At the end of Stage 1, an interim analysis will be conducted and 1 of the 2 Flebogamma 5% DIF doses will be selected based on predefined criteria to be used for Stage 2. Stage 2 will consist of 2 treatment arms, the selected dose of Flebogamma 5% DIF from Stage 1 and Normal Saline Solution (40 mL/kg of body weight). Study drug will be administered over 2 consecutive days every 4 weeks during a 52-week treatment period. During Stage 2, the selected dose of Flebogamma 5% DIF and Normal Saline Solution will be administered in the same manner as in Stage 1, including administering the total dose for both treatment arms at a volume equivalent to that for the IVIG 2 g/kg arm, regardless of the selected dose. Primary efficacy endpoint will be: • Physical performance 2MWD from baseline to the end of the treatment period (at End of Treatment Visit -Week 52).

Official Title
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A Multicenter, Prospective, Randomized, Placebo-controlled, Double-blind, Parallel-group Clinical Trial to Assess the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% DIF in Patients With Post-Polio Syndrome

Conditions
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Post-polio Syndrome

Intervention / Treatment
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* Biological: Flebogamma 5% DIF
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with Body Mass Index less than 35 kg/m^2. Subjects who meet the clinical criteria for diagnosis of PPS as set by March-of-Dimes. Subjects who are ambulatory or are able to walk with a cane or other aids or use a wheelchair (but they are not wheelchair-bound). Subjects who have at least 2 newly weakened muscle groups due to PPS (as defined by medical history), with at least 1 of them in a lower extremity, and having an Medical Research Council (MRC) scale score greater than 3 at the Manual Muscle Testing (MMT) performed by the independent assessor at the Screening Visit (SV). Female of child-bearing potential must have a negative test for pregnancy (Human chorionic gonadotropin (HCG)-based assay). Female of child-bearing potential and their sexual partners have agreed to practice contraception using a method of proven reliability (i.e., hormonal methods; barrier methods; intrauterine devices methods) to prevent a pregnancy during the course of the clinical trial. Subjects must be willing to comply with all aspects of the clinical trial protocol, including blood sampling and long-term storage of extra samples for the entire duration of the study. Subjects who are able to walk a 2MWD of at least 50 meters at the SV and Enrollment Visit/Infusion Visit 1 (EV/IV1) Subjects who are able to walk a consistent baseline 2 MWD, that is, the difference in 2MWD between the SV and EV/IV1 is not more than 10%. Exclusion Criteria: Subjects have received human normal immune globulin treatment given by intravenous, subcutaneous, or intramuscular route within the last 3 years. Subjects who are not ambulatory (wheelchair-bound individuals). Subjects with poor venous access. Subjects with intractable pain requiring narcotics or other psychotropic drugs. Subjects with a history of anaphylactic reactions or severe reactions to any blood-derived product. Subjects with a history of intolerance to any component of the investigational products, such as sorbitol. Subjects receiving corticosteroids, except for those who are taking inhaled corticosteroids for asthma. Subjects with a documented diagnosis of hyperviscosity or hypercoagulable state or thrombotic complications to polyclonal intravenous immunoglobulin (IVIG) therapy in the past. Subjects with a history of recent (within the last year) myocardial infarction, stroke, or uncontrolled hypertension. Subjects who suffer from congestive heart failure, embolism, or electrocardiogram changes indicative of unstable angina or atrial fibrillation. Subjects with a history of chronic alcoholism or illicit drug abuse (addiction) in the preceding 12 months prior to the SV. Subjects with active psychiatric illness that interferes with compliance or communication with health care personnel. Subjects with depression with scores >30 as assessed by the Center for Epidemiologic Studies Depression (CESD) validated scale. Females who are pregnant or are nursing an infant child. Subjects with any medical condition which makes clinical trial participation unadvisable or which is likely to interfere with the evaluation of the study treatment and/or the satisfactory conduct of the clinical trial according to the Investigator's judgment. Subjects currently receiving, or have received within 3 months prior to the SV, any investigational medicinal product or device. Subjects who are unlikely to adhere to the protocol requirements, or are likely to be uncooperative, or unable to provide a storage serum/plasma sample prior to the first investigational drug infusion. Subjects with known selective Immune globulin A class (IgA) deficiency and serum antibodies anti-IgA. Subjects with renal impairment (i.e., serum creatinine exceeds more than 1.5 times the upper limit of normal [ULN]) for the expected normal range for the testing laboratory). Subjects with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding more than 2.5 times the ULN. Subjects with hemoglobin levels <10 g/dL, platelets levels <100,000 /mm^3, white blood cells count <3.0 k/µL, and erythrocyte sedimentation rate >50 mm/h or twice above normal. Subjects with known seropositive to Hepatitis C virus (HCV), Human immunodeficiency virus-1 (HIV-1) and/or Human immunodeficiency virus-2 (HIV-2). Subjects with a history of intolerance to fructose.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 Arm 1: 2 g/kg Flebogamma 5% DIF<br>Flebogamma 5% DIF 2 g/kg of body weight administered via intravenous infusion over 2 consecutive days (Flebogamma 5% DIF 1 g/kg infused on Day 1 and Flebogamma 5% DIF 1 g/kg infused on Day 2) every 4 weeks for 52 weeks. | Biological: Flebogamma 5% DIF<br>* Human plasma-derived immunoglobulin<br>* Other names: immune globulin intravenous (human);|
| Experimental: Stage 1 Arm 2: 1 g/kg Flebogamma 5% DIF<br>Flebogamma 5% DIF 1 g/kg of body weight administered via intravenous infusion on Day 1 and 20 mL/kg of body weight of normal saline solution (equivalent volume of 1 g/kg of body weight Flebogamma® 5% DIF infusions) will also be administered on a separate day, for a total dosing period of 2 consecutive days. every 4 weeks for 52 weeks. The order of 1 g/kg of body weight of Flebogamma® 5% DIF or 20 mL/kg of body weight normal saline solution infused on 2 consecutive days will be randomly determined for each participant by the Interactive Web Response System (IWRS), which will remain the same for the participant for all infusion visits during the treatment period. | Biological: Flebogamma 5% DIF<br>* Human plasma-derived immunoglobulin<br>* Other names: immune globulin intravenous (human);Drug: Placebo<br>* Normal saline solution<br>|
| Placebo Comparator: Stage 1 Arm 3: Placebo<br>Normal saline solution total dose of 40 mL/kg of body weight (equivalent volume of 2 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered over 2 consecutive days. On Day 1, a dose of 20 mL/kg of body weight Normal Saline Solution (equivalent volume of 1 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered and on Day 2, the second dose of 20 mL/kg of body weight. Normal saline solution (equivalent volume of 1 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered, every 4 weeks for 52 weeks. | Drug: Placebo<br>* Normal saline solution<br>|
| Experimental: Stage 2 Arm 1: Flebogamma 5% DIF<br>The dose of Flebogamma® 5% DIF selected from Stage 1 will be administered over 2 consecutive days every 4 weeks for 52 weeks. | Biological: Flebogamma 5% DIF<br>* Human plasma-derived immunoglobulin<br>* Other names: immune globulin intravenous (human);|
| Placebo Comparator: Stage 2 Arm 1: Placebo<br>Normal saline solution total dose of 40 mL/kg of body weight (equivalent volume of 2 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered over 2 consecutive days. On Day 1, a dose of 20 mL/kg of body weight normal saline solution (equivalent volume of 1 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered and on Day 2, the second dose of 20 mL/kg of body weight normal saline solution (equivalent volume of 1 g/kg of body weight Flebogamma® 5% DIF infusions) will be administered, every 4 weeks for 52 weeks. | Drug: Placebo<br>* Normal saline solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test |  | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pain Using Visual Analogue Scale (VAS) of Pain | Pain scale consists of a 100 mm scale where 100 mm stands for the worst imaginable pain and zero stands for no pain. | Baseline to Week 52 | 
| Change From Baseline in Health-Related Quality of Life (HRQoL) Assessed by Medical Outcomes Study 36-Item Short-Form Health Survey (SF6) Physical Component Summary (PCS) |  | Baseline to Week 52 | 
| Change From Baseline in Endurance Assessed bv Six-Minute Walk Distance (6MWD) Test |  | Baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FORCE, Post-polio syndrome, Flebogamma, Immune Globulin Intravenous, IVIG