Background
Methods/design
Primary objective
Secondary and exploratory objectives
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To determine the efficacy, safety, and tolerability of IgPro20, with additional clinical outcome measures
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To determine the safety and efficacy of IVIg IgPro10 restabilization and rescue therapy
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To determine health-related quality of life (HRQL) following treatment with IgPro20
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To explore additional safety and efficacy endpoints, serum IgG levels, and the effect of IgPro20 on nerve conduction
Patients
Inclusion criteria
Exclusion criteria
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Within 3 months before enrollment: plasma exchange
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Within 6 months before enrollment: cyclophosphamide, interferon, tumor necrosis factor–alpha inhibitors, fingolimod, or any other immunosuppressive medications
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Within 12 months before enrollment: rituximab or alemtuzumab
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With a change in treatment within 3 months before enrollment: methotrexate, azathioprine, or mycophenolate; patients on corticosteroids not on a maintenance dose (usually below 20 mg/day prednisone equivalent) and where the dosage is likely to be tapered during the duration of the trial; or patients requiring more than 1.6 g/kg IgG every 4 weeks
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Serum IgA level less than 5 % of the lower limit of normal
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Positive result at screening on any of the following viral markers: human immunodeficiency virus-1 or 2, or hepatitis B or C virus
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Abnormal laboratory parameters: creatinine greater than 1.5 times the upper limit of normal (ULN), blood urea nitrogen greater than three times the ULN if the increase is related to potential kidney disease, or hemoglobin less than 10 g/dL
Study procedures
IgG dependency test period
IVIg restabilization period
SC treatment period
Randomization and masking
Outcome assessment
Primary outcome
Secondary outcomes
Assessment schedule of primary and secondary outcome variables
Safety outcomes
Exploratory outcomes
Statistical analysis
Sample size
General considerations
Period | First visit of period | Reference visit(s) of period | Last visit | |
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IgG dependency | Screening | Prior to AMD3: INCAT. After AMD3: INCAT: day 14 phone call I-RODS / mean grip strength: peak value within first 4 weeks | Week 1 day 1, before start of IVIg infusion | …or last visit before/at withdrawal |
IVIg restabilization | Week 1 day 1 at start of IVIg infusion | Week 1 day 1 at start of IVIg infusion. If not available, last visit of IgG Dependency Period | SC week 1 before start of SC infusion | |
SC treatment | SC week 1 at start of SC infusion | Baseline (week 10/13) | Week 25 visit or first IVIg infusion for rescue before IVIg infusion | |
IVIg rescue | first IVIg infusion for rescue at start of IVIg infusion | First IVIg infusion for rescue at start of IVIg infusion | Completion visit |
Efficacy evaluation primary outcome
Efficacy evaluation secondary outcomes
Period (analysis set) | |||
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IVIg restabilization (PSDS) | SC treatment (ITTS, PPS) | IVIg rescue (RSDS) | |
INCAT | |||
Total | Overall: - Descriptive statistics - Change from reference visit - Time to first improvement on IgPro10: Kaplan-Meier estimates | - By treatment and by treatment and subgroup: - Descriptive statistics - Comparison between treatments of changes from reference visit: exact Jonckheere-Terpstra testa
- Comparisons between each IgPro20 dose group and placebo group, and the comparison between the two IgPro20 dose groups of changes from reference visit: Wilcoxon rank sum testb
- Time to CIDP relapse or withdrawal for any other reason: Kaplan-Meier estimatesc
| Overall: - Descriptive statistics - Change from reference visit - Time to improvement after CIDP relapse with IgPro10 rescue: Kaplan-Meier estimates |
Mean grip strength (Dominant/non-dominant hand), MRC sum score, I-RODS | |||
Overall: - Descriptive statistics - Change from reference visit - Time to first improvement on IgPro10: Kaplan-Meier estimates | By treatment and by treatment and subgroup: - Descriptive statistics - Comparison between treatments of changes from reference visit; exact Jonckheere-Terpstra testa
- Comparisons between each IgPro20 dose group and placebo group, and the comparison between the two IgPro20 dose groups of changes from reference visit; Wilcoxon rank sum testb
| Overall: - Descriptive statistics - Change from reference visit | |
Electrophysiological parameters (average distal latency, average proximal latency, overall average conduction velocity, average conduction block, and average compound muscle action potential amplitude) | |||
By treatment and by treatment and subgroup: - Descriptive statistics - Change from reference visit - Between-treatment comparisons of the changes from baseline: analysis of variance (ANOVA) modeld
| |||
IgG level | |||
Overall: - Descriptive statistics - Change from reference visit | By treatment and by treatment and subgroup: - Descriptive statistics - Change from reference visit | Overall: - Descriptive statistics - Change from reference visit | |
EQ-5D dimensions, TSQM, WPAI-GH | |||
Overall: - Descriptive statistics | By treatment: - Descriptive statistics - Change from reference visit - Comparison between treatments of changes from reference visit; exact Jonckheere-Terpstra testa
- Comparisons between each IgPro20 dose group and placebo group, and the comparison between the two IgPro20 dose groups of changes from reference visit; Wilcoxon rank sum testb
| Overall: - Descriptive statistics | |
Patient preference for treatment questionnaire | |||
By treatment: - Descriptive statistics |
Withdrawal reasons | Assignment of patients in: | ||||
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Primary analysis | Sensitivity analysis | ||||
A | B | C | Da
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The patient experiences a CIDP relapse during the SC treatment period (lack of efficacy) | Relapser | Relapser | Relapser | Relapser | Relapser |
The investigator advises that the patient’s safety or wellbeing could be compromised by further participation in the study (physician decision) | Relapser | Non-relapsers | Relapser | Not used for analysis | Censored |
The patient receives prohibited medication (protocol violation) | Censored | ||||
Other withdrawal reason (other, adverse event, death, lost to follow-up, protocol violation, study termination by sponsor, and withdrawal by patient) | Non-relapsers | Censored | |||
Patient continues to study end | Non-relapsers | Non-relapsers | Non-relapsers | Non-relapsers | Non-relapsers |
Safety evaluation
Sensitivity analyses
Subgroup | Primary efficacy analysis of Relapse rate | INCAT total score | Mean grip strength (dominant/ nondominant hand) | I-RODS | MRC sum score | Time to relapse or withdrawal for any other reason | IgG serum levels |
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Sex (male/female) | X | X | X | X | X | X | |
Age group (≥18 years to ≤ 65 years, and > 65 years) | X | X | X | X | X | X | |
Prestudy IVIg treatment modality (IVIg maintenance therapy, acute IVIg therapy)a
| X | X | X | X | X | X | |
Region (Japan/non-Japan) | X | X | |||||
Relapse status (yes/no) | X | ||||||
IVIg Dependency criterion: I-RODS or grip strength | Xb
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Sensitivity analysis A, withdrawn patients are considered nonrelapsers.
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Sensitivity analysis B, withdrawn patients are considered according to withdrawal reason.
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Sensitivity analysis C, withdrawn patients are not included in the analysis.
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Sensitivity analysis D (exploratory), withdrawn patients will be censored at the date of their last visit. Kaplan-Meier estimates of the probability of having a relapse at 24 weeks will be calculated. Between-treatment comparison will be performed using the log-rank test for trend. When an overall trend is demonstrated, two subsequent one-sided comparisons will be performed using the regular log-rank test.