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ICE

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

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Year of Publication: 2008

Authors: Richard A C Hughes, Peter Donofrio, Vera Bril, ..., on behalf of the ICE Study Group

Journal: Lancet Neurology

Citation: Lancet Neurol 2008; 7: 136-44

Link: https://doi.org/10.1016/S1474-4422(07)70329-0

Clinical Question

Does IGIV-C (10% caprylate-chromatography purified immune globulin) provide short-term and long-term benefit compared to placebo in patients with CIDP?

Bottom Line

IGIV-C significantly improved disability in CIDP patients compared to placebo at 24 weeks (54% vs 21% responders), with benefits maintained during extension phase where continued IGIV-C treatment prevented relapse significantly longer than placebo withdrawal.

Major Points

  • 54% of IGIV-C patients vs 21% placebo maintained >=1 point INCAT improvement through week 24 (treatment difference 33.5%, p=0.0002)
  • Grip strength improved significantly in both hands with IGIV-C treatment
  • Results validated in crossover period: 58% vs 22% response rates for IGIV-C vs placebo
  • Extension phase showed 13% relapse with continued IGIV-C vs 45% with placebo withdrawal (HR 0.19, p=0.011)
  • MRC sum score and ISS score also improved significantly with IGIV-C
  • Compound muscle action potential amplitude did not differ significantly between groups
  • IGIV-C was well tolerated with similar serious adverse event rates to placebo (0.8% vs 1.9% per infusion)
  • This was the largest reported trial of any CIDP treatment at the time

Design

Study Type: Randomized, double-blind, placebo-controlled, response-conditional crossover trial with extension phase

Randomization: 1

Blinding: Double-blind: computer-generated randomization codes prepared by independent group within sponsor hierarchy. Unblinded pharmacist at each site prepared medication. All other study team members blinded throughout study

Enrollment Period: April 2004 to June 2005

Follow-up Duration: Up to 72 weeks (24-week first period + 24-week crossover + 24-week extension)

Centers: 33

Countries: USA, Canada, UK, Germany, Netherlands, Italy, Poland, Czech Republic, Serbia, Israel, Argentina

Sample Size: 117

Analysis: Intention-to-treat. Primary outcome by chi-square test (alpha=0.05, two-sided). Secondary outcomes by ANCOVA adjusted for geographic region and baseline. Kaplan-Meier and log-rank test for time to relapse. SAS version 8.2.

Inclusion Criteria

  • Age >=18 years
  • Diagnosis of CIDP
  • Progressive or relapsing motor and sensory dysfunction of at least one limb over >=2 months before study entry
  • INCAT disability score of 2-9 (score of 2 required to be exclusively from leg disability)

Exclusion Criteria

  • Treatment with steroids (>10 mg/day prednisolone equivalent), IVIg, or plasma exchange in 3 months before study entry
  • Fish-oil supplements in previous month
  • Immunomodulatory/immunosuppressive agents (interferon, azathioprine) in previous 6 months
  • Myelopathy or evidence of central demyelination
  • Persistent neurological deficits from stroke, CNS trauma, or peripheral neuropathy from other causes
  • Motor syndrome fulfilling criteria for multifocal motor neuropathy with conduction block
  • Evidence of systemic disease that might cause neuropathy

Arms

FieldControlIGIV-C
Intervention0.1% albumin IV, loading dose over 2-4 days then maintenance infusion over 1-2 days every 3 weeks for up to 24 weeksIGIV-C (Gamunex) 2 g/kg loading dose over 2-4 days, then 1 g/kg maintenance infusion over 1-2 days every 3 weeks for up to 24 weeks
Duration24 weeks (first period)24 weeks (first period)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Percentage of patients who maintained improvement from baseline of >=1 point in adjusted INCAT disability score through week 24Primary12/58 (21%)32/59 (54%)33.55%0.0002
Change from baseline in grip strength - dominant hand (kPa)Secondary1.513.20.0008
Change from baseline in grip strength - non-dominant hand (kPa)Secondary4.313.30.005
Change from baseline in CMAP amplitude (mV)Secondary0.470.690.542
Time to relapse in extension phaseSecondary45% relapse probability13% relapse probabilityHR 0.19 (95% CI 0.05-0.70)0.011
Change in adjusted INCAT disability score (first period)Secondary-0.3-1.10.010
Change in MRC sum score (first period)Secondary0.23.30.001
Change in ISS score (first period)Secondary0.2-1.20.021
Crossover period respondersSecondary5/23 (22%)26/45 (58%)0.005
Any adverse eventAdverse45 (47%)85 (75%)
HeadacheAdverse8 (8%)36 (32%)
PyrexiaAdverse015 (13%)
HypertensionAdverse4 (4%)10 (9%)
Serious adverse events per infusionAdverse11/575 (1.9%)9/1096 (0.8%)
DeathsAdverse1 (fatal sepsis after study exit)0

Subgroup Analysis

Previous IVIg exposure did not bias response: 60% of IGIV-C patients with prior IVIg vs 0% placebo were responders (p=0.0006); 51% vs 26% in IVIg-naive patients (p=0.024). Treatment outcome not affected by sex (p=0.977), time to CIDP diagnosis (p=0.379), or CMAP amplitude (p=0.536).

Criticisms

  • Imbalance in sex distribution between groups (53% vs 79% male)
  • Previous IVIg treatment differed between groups (34% vs 21%)
  • Response-conditional crossover design may complicate interpretation
  • Extension phase had unequal group sizes due to differential response rates
  • No significant improvement in compound muscle action potential amplitude
  • Albumin placebo may not be completely inert
  • Short loading-dose infusion schedule (2-4 days) differs from common clinical practice (5 days)

Funding

Talecris Biotherapeutics

Based on: ICE (Lancet Neurology, 2008)

Authors: Richard A C Hughes, Peter Donofrio, Vera Bril, ..., on behalf of the ICE Study Group

Citation: Lancet Neurol 2008; 7: 136-44

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