A Randomized, Double-Blind, Placebo Controlled, Cross-over Study of the Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Multifocal Motor Neuropathy
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 50
- Locations
- 17
- Primary Endpoint
- Co-Primary Endpoint: Guy's Neurologic Disability Scale (GNDS) for Upper Limbs
Study Overview
Brief Summary
The purpose of the study is to evaluate the efficacy (effect on grip strength and disability) and safety/tolerability of IGIV, 10% in subjects with Multifocal Motor Neuropathy.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Written informed consent obtained from the participant prior to any study-related procedures and study product administration
- •Diagnosis of definite or probable MMN based on the criteria of the American Association of Electrodiagnostic Medicine (AAEM) (Olney et al., 2003, see Section 15.1 for the full length publication). Conduction block can be identified by a drop in amplitude. Diagnosis can be based on chart records a) Hand grip (finger flexor) weakness of Medical Research Council (MRC) grade 4 or less at disease onset or appearing prior to screening; b) No upper motor signs c) No bulbar or cranial signs or symptoms; d) No clinically identifiable sensory abnormalities
- •Must be on a stable regimen of IGIV for at least 3 months prior to first study product administration
- •Treatment interval with IGIV of 2 to 5 weeks (+/- 3 days)
- •Dose of IGIV to be 0.4 to 2.0 g per kg BW and infusion cycle
- •Participants are adults, male or female, at least 18 years of age
- •If female and capable of bearing children - have a negative urine pregnancy test result at enrollment and agree to employ adequate birth control measures for the duration of the study
- •Ability and willingness to travel to the study site for infusions and assessments if required by the protocol
Exclusion Criteria
- •Any clinical or electrophysiological evidence of coexisting neuropathy which may interfere with outcome assessments, such as diabetic neuropathy, toxic neuropathy, or neuropathy due to systemic lupus erythematosus
- •Treatment with other immunosuppressive agents besides IGIV, which has demonstrated efficacy in MMN such as cyclophosphamide during the 3 months prior to enrollment (or treatment with Rituximab during the 12 months prior to enrollment). Pre-study treatment with mycophenolate mofetil or azathioprine is permitted if the dose has been stable for 3 months prior to enrollment.
- •Cerebrospinal fluid protein > 100 mg/dL (if done as part of a previous evaluation)
- •Participants positive at enrollment for one or more of the following: Hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for Hepatitis C (HCV), PCR for human immunodeficiency virus (HIV) Type 1
- •Participants with levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal for the testing laboratory
- •Participants with neutropenia (defined as an absolute neutrophil count [ANC]≤1000/mm^3)
- •Participants with serum creatinine levels greater than 1.5 times the upper limit of normal for age and gender
- •Participants with malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- •Participants with a history of thrombotic episodes (deep vein thrombosis, myocardial infarction, cerebrovascular accident)
- •Participants who received any blood or blood product exposure other than an IGIV, subcutaneous immunoglobulin, immune serum globulin (ISG) preparation, or albumin within the 6 months prior to enrollment
- •Participants with an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IGIV or human albumin
- •Participants with immunoglobulin A (IgA) deficiency and known anti IgA antibodies
- •Participants using another investigational product or device within 30 days prior to enrollment
- •Participants who are unable or unwilling to meet all the requirements of this study
- •If female, is pregnant or lactating at time of enrollment
Arms & Interventions
IGIV, 10% Then Placebo
STUDY PART 1: Open-label stabilization on IGIV, 10% (Stabilization Phase 1) all participants. STUDY PART 2: IGIV, 10% (double-blind treatment Cross-Over Period 1). STUDY PART 3: Between the two double-blind treatment cross-over periods, participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 2). STUDY PART 4: Placebo (0.25% human albumin: BUMINATE 25% Albumin (Human)(Baxter Healthcare Corporation) used where licensed; otherwise Human Albumin 200 g/L Baxter Solution for Infusion was used) (double-blind treatment cross-over period 2). STUDY PART 5: Participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 3).
Each study part was 12 weeks in length. Participants received IGIV, 10% at the same equivalent dose per week administered prior to the study (0.4 to 2.0 g per kg body weight (BW) per infusion cycle).
Intervention: Immune Globulin Intravenous (human), 10% (Biological)
IGIV, 10% Then Placebo
STUDY PART 1: Open-label stabilization on IGIV, 10% (Stabilization Phase 1) all participants. STUDY PART 2: IGIV, 10% (double-blind treatment Cross-Over Period 1). STUDY PART 3: Between the two double-blind treatment cross-over periods, participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 2). STUDY PART 4: Placebo (0.25% human albumin: BUMINATE 25% Albumin (Human)(Baxter Healthcare Corporation) used where licensed; otherwise Human Albumin 200 g/L Baxter Solution for Infusion was used) (double-blind treatment cross-over period 2). STUDY PART 5: Participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 3).
Each study part was 12 weeks in length. Participants received IGIV, 10% at the same equivalent dose per week administered prior to the study (0.4 to 2.0 g per kg body weight (BW) per infusion cycle).
Intervention: 0.25% human albumin solution (Placebo) (Biological)
Placebo Then IGIV, 10%
STUDY PART 1: Open-label stabilization on IGIV, 10% (Stabilization Phase 1) all participants. STUDY PART 2: Placebo (0.25% human albumin: BUMINATE 25% Albumin (Human) (Baxter Healthcare Corporation) used where licensed; otherwise Human Albumin 200 g/L Baxter Solution for Infusion was used) (double-blind treatment Cross-Over Period 1). STUDY PART 3: Between the two double-blind treatment cross-over periods, participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 2). STUDY PART 4: IGIV, 10% (double-blind treatment cross-over period 2). STUDY PART 5: Participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 3).
Each study part was 12 weeks in length. Participants received IGIV, 10% at the same equivalent dose per week administered prior to the study (0.4 to 2.0 g per kg BW per infusion cycle)
Intervention: Immune Globulin Intravenous (human), 10% (Biological)
Placebo Then IGIV, 10%
STUDY PART 1: Open-label stabilization on IGIV, 10% (Stabilization Phase 1) all participants. STUDY PART 2: Placebo (0.25% human albumin: BUMINATE 25% Albumin (Human) (Baxter Healthcare Corporation) used where licensed; otherwise Human Albumin 200 g/L Baxter Solution for Infusion was used) (double-blind treatment Cross-Over Period 1). STUDY PART 3: Between the two double-blind treatment cross-over periods, participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 2). STUDY PART 4: IGIV, 10% (double-blind treatment cross-over period 2). STUDY PART 5: Participants received open-label treatment/stabilization with IGIV, 10% (Stabilization Phase 3).
Each study part was 12 weeks in length. Participants received IGIV, 10% at the same equivalent dose per week administered prior to the study (0.4 to 2.0 g per kg BW per infusion cycle)
Intervention: 0.25% human albumin solution (Placebo) (Biological)
Outcomes
Primary Outcomes
Co-Primary Endpoint: Guy's Neurologic Disability Scale (GNDS) for Upper Limbs
Time Frame: Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit
GNDS (based on Sharrack and Hughes, 1999) for the upper limbs were integers 0 to 5, with 0 indicating no impairment.
Co-Primary Endpoint: Proportion of Participants With Deterioration in Guy's Neurological Disability Score (GNDS)
Time Frame: Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4)
GNDS (based on Sharrack and Hughes, 1999) for the upper limbs were integers 0 to 5, with 0 indicating no impairment.
Mean Relative Change in Grip Strength in the More Affected Hand
Time Frame: Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4)
Relative Change is defined as 100 \* (End of the Cross-Over Period - baseline of Cross-Over Period) divided by baseline of Cross-Over Period. The grip strength was measured using a DynEx digital dynamometer. The result of grip strength was recorded to a resolution of 0.1 kg. For statistical analysis, the mean of (usually three) trials for cross-over sessions 1 and 2 was computed and the mean of the sessions was used in the analysis as the result of the grip strength measurement. Only if no grip strength testing could be performed the results were considered as missing.
The Percentage of Participants for Whom the Infusion Rate of Any Infusion Was Reduced and/or the Infusion Was Interrupted or Stopped for Any Reason
Time Frame: Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4)
The Percentage of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped for Any Reason
Time Frame: Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4)
The Percentage of Participants Reporting One or More Moderate or Severe AEs That Began During Infusion or Within 72 Hours of Completion of an Infusion
Time Frame: Within 72 hours of completion of an infusion during the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4)
Grip Strength in the More Affected Hand
Time Frame: Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit
The grip strength was measured using a DynEx digital dynamometer. The result of grip strength was recorded to a resolution of 0.1 kg. Each grip strength test consisted of 3 maximal repeated contractions (trials). Each participant will perform 2 sessions of grip strength testing. After a 10-minute break, the testing session will be repeated for a total of 6 grip repetitions per hand.
Rate of Temporally Associated Adverse Events (AEs) Per Infusion
Time Frame: Within 72 hours of completion of an infusion during the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4)
The total number of all AEs which begin during or within 72 hours of completion of an infusion, irrespective of being related or not related to the study product (IGIV, 10% or Placebo), divided by the total number of infusions, and multiplied by 100.
Secondary Outcomes
- Rate of Related AEs Per Infusion(Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- The Proportion of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped for Tolerability Concerns/AEs(Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- The Proportion of Infusions Associated With One or More AEs Related to the Study Product(Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- Percentage of Participants With at Least a 30% Decline in Relative Grip Strength in the More Affected Hand (Measured Using a DynEx Digital Dynamometer)(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))
- Patient Global Impression of Change(Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Overall Disability Sum Score(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Overall Disability Sum Score - Standardized(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Time Required by Participants to Complete the 9 Hole Peg Board Test (9-HPT) With the Non-Dominant Hand(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Grip Strength in the Less Affected Hand(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Proportion of Participants That Were Accelerated Forward Into the Next Stabilization Phase (ie Switched to Open-Label IGIV, 10%)(During the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- Participants' Assessment of Physical Functioning on a Visual Analog Scale (VAS)(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Rate of Related SAEs Per Infusion(Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- The Proportion of Participants for Whom the Infusion Rate of Any Infusion Was Reduced and/or the Infusion Was Interrupted or Stopped for Tolerability Concerns/AEs(Throughout the two study cross-over periods, approximately weeks 13-24 and weeks 37-48 (i.e. Study Parts 2 and 4))
- Mean Relative Change in Grip Strength in the Less Affected Hand(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))
- Mean Relative Change in Overall Disability Sum Score(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))
- Mean Relative Change in Time Required by Participants to Complete the 9 Hole Peg Board Test (9-HPT) With the Dominant Hand(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))
- Time Required by Participants to Complete the 9 Hole Peg Board Test (9-HPT) With the Dominant Hand(Week 0, then at Last infusion cycle for each study part (Day 8 of last treatment cycle for 2-week interval or Day 15 of last treatment cycle for 3 or 4 -week interval), then at the end of study visit)
- Mean Relative Change in Participants' Assessment of Physical Functioning on a Visual Analog Scale (VAS)(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))
- Mean Relative Change in Time Required by Participants to Complete the 9 Hole Peg Board Test (9-HPT) With the Non-Dominant Hand(Baseline and last infusion cycle during the two study cross-over periods, approximately weeks 13 and 24; and weeks 37 and 48 (i.e. baseline and end of Study Parts 2 and 4))