Post-polio Syndrome
Conditions
Keywords
FORCE, Post-polio syndrome, Flebogamma®, Immune Globulin Intravenous, IVIG
Brief summary
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).
Interventions
BIOLOGICALFlebogamma® 5% DIF
Human plasma-derived immunoglobulin
DRUGPlacebo
Matching placebo
Sponsors
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline to Week 52 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pain Using Visual Analogue Scale (VAS) of Pain | Baseline to Week 52 | 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. |
| 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) | Baseline to Week 52 | 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. |
| Change From Baseline in Endurance Assessed by Six-Minute Walk Distance (6MWD) Test | Baseline to Week 52 | 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. |
Countries
Canada, Czechia, Denmark, Germany, Italy, Netherlands, Poland, Spain, United States
Participant flow
Recruitment details
Participants took part in the study from 23 September 2014 to 24 November 2022.
Pre-assignment details
A total of 238 participants were screened, out of which 191 participants were randomized in the study. Participants with post-polio syndrome (PPS) were randomized to receive Flebogamma® 5% DIF or placebo during Stage 1 or 2 of the study. During Stage 1, 161 participants were screened, of which 126 participants were randomized in the study. During Stage 2, 77 participants were screened, of which 65 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 42 |
| 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. | 42 |
| 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. | 42 |
| 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. | 33 |
| 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. | 32 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 4 | 4 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 1 | 1 | 0 |
| Overall Study | Reason not specified | 0 | 1 | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 2 | 2 | 3 | 4 |
Baseline characteristics
| Characteristic | Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | Stage 1 Arm 3: Placebo | Stage 2 Arm 1: 1 g/kg Flebogamma® 5% DIF | Stage 2 Arm 2: Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 6.24 | 62.3 years STANDARD_DEVIATION 6.88 | 62.2 years STANDARD_DEVIATION 7.22 | 65.1 years STANDARD_DEVIATION 7 | 63.9 years STANDARD_DEVIATION 6.26 | 63.2 years STANDARD_DEVIATION 6.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 6 Participants | 4 Participants | 1 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 36 Participants | 36 Participants | 29 Participants | 31 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 40 Participants | 40 Participants | 40 Participants | 31 Participants | 31 Participants | 182 Participants |
| Sex: Female, Male Female | 23 Participants | 21 Participants | 27 Participants | 22 Participants | 22 Participants | 115 Participants |
| Sex: Female, Male Male | 19 Participants | 21 Participants | 15 Participants | 11 Participants | 10 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 75 | 0 / 74 |
| other Total, other adverse events | 36 / 42 | 71 / 75 | 60 / 74 |
| serious Total, serious adverse events | 3 / 42 | 7 / 75 | 9 / 74 |
Outcome results
Primary
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.
Time frame: Baseline to Week 52
Population: ITT population included all participants who were randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline | 109.03 meters (m) | Standard Deviation 30.564 |
| Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Change from Baseline at Week 52 | 7.50 meters (m) | Standard Deviation 14.666 |
| Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Change from Baseline at Week 52 | 10.89 meters (m) | Standard Deviation 19.067 |
| Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline | 112.55 meters (m) | Standard Deviation 27.987 |
| Stage 1 Arm 3: Placebo | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline | 105.86 meters (m) | Standard Deviation 31.942 |
| Stage 1 Arm 3: Placebo | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Change from Baseline at Week 52 | 3.17 meters (m) | Standard Deviation 11.08 |
| Stage 2 Arm 1: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline | 101.18 meters (m) | Standard Deviation 22.588 |
| Stage 2 Arm 1: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Change from Baseline at Week 52 | 11.31 meters (m) | Standard Deviation 12.108 |
| Stage 2 Arm 2: Placebo | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Change from Baseline at Week 52 | 5.65 meters (m) | Standard Deviation 10.388 |
| Stage 2 Arm 2: Placebo | Change From Baseline in Physical Performance Assessed by Two-Minute Walk Distance (2MWD) Test | Baseline | 107.10 meters (m) | Standard Deviation 30.167 |
p-value: 0.0469Posch and Bauer Method
Secondary
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.
Time frame: Baseline to Week 52
Population: ITT population included all participants who were randomized. As pre-specified in SAP, the analyses was performed over the two stages combined, using the placebo and selected dose of Flebogamma® 5% DIF treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | Change From Baseline in Endurance Assessed by Six-Minute Walk Distance (6MWD) Test | 29.16 meters (m) |
| Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Endurance Assessed by Six-Minute Walk Distance (6MWD) Test | 13.36 meters (m) |
p-value: 0.120595% CI: [-4.19, 35.79]Mixed-effect Model Repeated Measures
Secondary
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.
Time frame: Baseline to Week 52
Population: ITT population included all participants who were randomized. As pre-specified in SAP, the analyses was performed over the two stages combined, using the placebo and selected dose of Flebogamma® 5% DIF treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | 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) | 4.78 Score on a scale |
| Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | 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) | 2.79 Score on a scale |
p-value: 0.161595% CI: [-0.8, 4.8]Mixed-effect Model Repeated Measures
Secondary
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.
Time frame: Baseline to Week 52
Population: ITT population included all participants who were randomized. As pre-specified in SAP, the analyses was performed over the two stages combined, using the placebo and selected dose of Flebogamma® 5% DIF treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Stage 1 Arm 1: 2 g/kg Flebogamma® 5% DIF | Change From Baseline in Pain Using Visual Analogue Scale (VAS) of Pain | -3.2 millimeter (mm) |
| Stage 1 Arm 2: 1 g/kg Flebogamma® 5% DIF | Change From Baseline in Pain Using Visual Analogue Scale (VAS) of Pain | -2.6 millimeter (mm) |
p-value: 0.889795% CI: [-7.7, 6.7]Mixed-effect Model Repeated Measures