Study of the Efficacy and Safety of Immune Globulin Intravenous (Human) Flebogamma® 5% Dual Inactivation and Filtration (DIF) in Participants With Post-polio Syndrome (FORCE)

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 Participants With Post-Polio Syndrome

This was a multicenter, prospective, randomized, placebo-controlled, double-blind, parallel group clinical trial with adaptive dose selection in participants with post-polio syndrome (PPS).

The main purpose of this study was 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 consisted 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).

Study Overview

• Status: Terminated
• Conditions: Post-polio Syndrome
• Intervention / Treatment: Drug: Placebo; Biological: Flebogamma® 5% DIF

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 191
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute Clinical Research Unit, McGill University
• Czechia
  • Prague, Czechia, 4
    • Thomayerova nemocnice, Klinicko-farmakologická jednotka
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus Universitets Hospital-Neurologisk Forskning
  • København Ø, Denmark, 2100
    • Rigshospitalet
• Germany
  • Berlin, Germany, 10117
    • Charite Campus Mitte
  • Hanover, Germany, 30625
    • Hannover Medical School
  • Jena, Germany, 07747
    • Universitatsklinikum Jena
  • Koblenz, Germany, 56073
    • Klinik für konservative Orthopädie und des Poliozentrums
  • Münster, Germany, 48149
    • Westfälische Wilhelms-Universität Münster
• Italy
  • Verona, Italy, 37124
    • Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma)
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum Amsterdam UMC, Locatie AMC
• Poland
  • Krakow, Poland, 31-436
    • MedTrials
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie
  • Poznan, Poland, 60-848
    • Clinical Research Center Sp. z o.o.
  • Warsaw, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczny
• Spain
  • Badalona, Spain, 08916
    • Institut Guttman
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3596
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants with Body Mass Index less than 35 kg/m^2.
• Participants who meet the clinical criteria for diagnosis of PPS as set by March-of-Dimes.
• Participants who are ambulatory or are able to walk with a cane or other aids or use a wheelchair (but they are not wheelchair-bound).
• Participants 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 a 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.
• Participants 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.
• Participants who are able to walk a 2MWD of at least 50 meters at the SV and Enrollment Visit/Infusion Visit 1 (EV/IV1)
• Participants 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:

• Participants who have received human normal immune globulin treatment given by intravenous, subcutaneous, or intramuscular route within the last 3 years.
• Participants who are not ambulatory (wheelchair-bound individuals).
• Participants with poor venous access.
• Participants with intractable pain requiring narcotics or other psychotropic drugs.
• Participants with a history of anaphylactic reactions or severe reactions to any blood-derived product.
• Participants with a history of intolerance to any component of the investigational products, such as sorbitol.
• Participants receiving corticosteroids, except for those who are taking inhaled corticosteroids for asthma.
• Participants with a documented diagnosis of hyper viscosity or hypercoagulable state or thrombotic complications to polyclonal intravenous immunoglobulin (IVIG) therapy in the past.
• Participants with a history of recent (within the last year) myocardial infarction, stroke, or uncontrolled hypertension.
• Participants who suffer from congestive heart failure, embolism, or electrocardiogram changes indicative of unstable angina or atrial fibrillation.
• Participants with a history of chronic alcoholism or illicit drug abuse (addiction) in the preceding 12 months prior to the SV.
• Participants with active psychiatric illness that interferes with compliance or communication with health care personnel.
• Participants 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.
• Participants 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.
• Participants currently receiving, or have received within 3 months prior to the SV, any investigational medicinal product or device.
• Participants 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.
• Participants with known selective Immune globulin A class (IgA) deficiency and serum antibodies anti-IgA.
• Participants 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).
• Participants with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding more than 2.5 times the ULN.
• Participants 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.
• Participants with known seropositive to Hepatitis C virus (HCV), Human immunodeficiency virus-1 (HIV-1) and/or Human immunodeficiency virus-2 (HIV-2).
• Participants with a history of intolerance to fructose.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF; Participants received Flebogamma® 5% DIF 2 g/kg of body weight administered via intravenous (IV) infusion over 2 consecutive days (Flebogamma® 5% DIF 1 g/kg infused on Day 1, followed by Flebogamma® 5% DIF 1 g/kg infused on Day 2) every 4 weeks for 52 weeks.	Biological: Flebogamma® 5% DIF; Human plasma-derived immunoglobulin; Other Names: immune globulin intravenous (human)
Experimental: Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF; Participants received Flebogamma® 5% DIF 1 g/kg of body weight administered via IV infusion on Day 1, followed by 20 mL/kg of matching placebo 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 Flebogamma® 5% DIF or matching placebo was randomly determined for each participant and was the same for the participant for all infusion visits during the treatment period.	Drug: Placebo; Matching placebo; Biological: Flebogamma® 5% DIF; Human plasma-derived immunoglobulin; Other Names: immune globulin intravenous (human)
Placebo Comparator: Stage 1 Arm 3: Placebo; Participants received matching placebo at a total dose of 40 mL/kg of body weight administered via IV infusion over 2 consecutive days. On Day 1, a dose of 20 mL/kg of matching placebo was given, followed by the second dose of 20 mL/kg of matching placebo on Day 2, administered every 4 weeks for 52 weeks.	Drug: Placebo; Matching placebo
Experimental: Stage 2 Arm 1: 1 g/kg Flebogamma® 5% DIF; Participants received Flebogamma® 5% DIF 1 g/kg of body weight administered via IV infusion on Day 1, followed by 20 mL/kg of matching placebo 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 Flebogamma® 5% DIF or matching placebo was randomly determined for each participant and was the same for the participant for all infusion visits during the treatment period.	Drug: Placebo; Matching placebo; Biological: Flebogamma® 5% DIF; Human plasma-derived immunoglobulin; Other Names: immune globulin intravenous (human)
Placebo Comparator: Stage 2 Arm 2: Placebo; Participants received matching placebo at a total dose of 40 mL/kg of body weight administered via IV infusion over 2 consecutive days. On Day 1, a dose of 20 mL/kg of matching placebo was given, followed by the second dose of 20 mL/kg of matching placebo on Day 2, administered every 4 weeks for 52 weeks.	Drug: Placebo; Matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test	The 2MWD was used to assess physical performance by measuring the distance that a participant can quickly walk at a self-preferred speed on an indoor flat, hard surface 30 m (100-ft) hallway in a period of 2 minutes. A positive change from baseline indicates improvement (i.e. a patient can walk farther). Increase in distance walked (in meters) indicates improvement.	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	VAS is a participant self-reported pain scale used to evaluate the pain level in a 24 hours period. The scale consists of a 100 millimeters (mm) scale where 100 mm stands for the worst imaginable pain and zero stands for no pain. Higher scores indicate severe pain. A negative change from baseline indicates improvement. LS mean and 95% (CI) were based on MMRM method.	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 (SF-36) Physical Component Summary (PCS)	HRQoL SF-36 is participant self-reported survey.It yields 8-scale profile of functional health and well-being as well as physical and mental health summary measures. It consists of the subscales:physical functioning,limitations due to physical health,body pain,general health,vitality,social functioning,emotional problems, and mental health. Each domain score ranges from 0(worst) to 100(best),higher scores reflect better functional status.PCS is a subscale score & give broader metric of physical HRQoL.PCS score ranges from 0 to 100 and is computed such that mean score of 50 corresponds to the general US population.Based on norm-based scoring,scores above 50 is better-than-average health & below 50 is below-average health.Higher scores represents better physical health.Positive change from baseline indicates improvement.LS mean and 95% CI were based on MMRM.	Baseline to Week 52
Change From Baseline in Endurance Assessed by Six-Minute Walk Distance (6MWD) Test	The 6MWD was used to assess physical performance by measuring the distance that a patient can quickly walk at maximal speed on a flat, hard surface 30 m (100-ft) hallway in a period of 6 minutes. A positive change from baseline indicates improvement (i.e., a patient can walk farther). Increase from baseline in distance walked (in meters) indicated improvement. LS mean and 95% CI were based on MMRM method.	Baseline to Week 52

Collaborators and Investigators

• Sponsor: Instituto Grifols, S.A.
• Investigators: Principal Investigator: Marinos Dalakas, MD, Coordinating Investigator

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2014
• Primary Completion (Actual): November 24, 2022
• Study Completion (Actual): November 24, 2022

Study Registration Dates

• First Submitted: June 25, 2014
• First Submitted That Met QC Criteria: June 25, 2014
• First Posted (Estimated): June 27, 2014

Study Record Updates

• Last Update Posted (Estimated): December 5, 2025
• Last Update Submitted That Met QC Criteria: November 21, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: IVIG; Post-polio syndrome; FORCE; Immune Globulin Intravenous; Flebogamma®
• Additional Relevant MeSH Terms: Neuroinflammatory Diseases; Musculoskeletal Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Infections; RNA Virus Infections; Virus Diseases; Neurodegenerative Diseases; Enterovirus Infections; Picornaviridae Infections; Muscular Disorders, Atrophic; Spinal Cord Diseases; Central Nervous System Infections; Myelitis; Poliomyelitis; Postpoliomyelitis Syndrome; Amino Acids, Peptides, and Proteins; Proteins; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Immunoglobulin G; Immunoglobulins, Intravenous; gamma-Globulins
• Other Study ID Numbers: IG1104; 2013-004503-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No