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PRIMA

Privigen Impact on Mobility and Autonomy: Efficacy and safety of Privigen in patients with chronic inflammatory demyelinating polyneuropathy

Year of Publication: 2013

Authors: Jean-Marc Léger, Jan L. De Bleecker, Claudia Sommer, ..., Ingemar S. J. Merkies; on behalf of the PRIMA study investigators

Journal: Journal of the Peripheral Nervous System

Citation: J Peripher Nerv Syst 2013;18:130-140

Link: https://doi.org/10.1111/jns5.12017

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Is Privigen (10% liquid human IVIG stabilized with L-proline) efficacious and safe for induction and maintenance treatment in patients with CIDP?

Bottom Line

Privigen demonstrated efficacy in CIDP with a 60.7% responder rate based on adjusted INCAT score improvement, exceeding the predefined success threshold. IVIG-pretreated patients showed higher response rates than IVIG-naïve patients. Treatment was generally well-tolerated, though two cases of hemolysis during induction led to discontinuation.

        Major Points
        Single-arm, open-label Phase III study using historical control comparison to ICE study placebo arm
Primary endpoint met: 60.7% responder rate (95% CI: 42.4-76.4%) exceeded the predefined threshold of >35%
IVIG-pretreated patients had higher responder rate (76.9%) than IVIG-naïve patients (46.7%)
Half of responders (9/18) showed response after induction dose at Week 4; all but one responded by Week 10
Median time to first INCAT response: 3 weeks for IVIG-pretreated vs. 18 weeks for IVIG-naïve patients
Consistent improvements across all secondary endpoints: INCAT score, grip strength, and MRC sum score
MRC-based responder rate was 82.1% (23/28 patients)
Two serious adverse events of hemolysis during induction phase in patients with non-O blood groups
Both hemolysis cases resolved after treatment discontinuation without need for transfusion
Study suggests patients not responding by 6 weeks may still respond with continued treatment

      

Design

Study Type: Prospective, multicenter, single-arm, open-label Phase III study

Randomization:

Blinding: None (open-label)

Enrollment Period: December 2010 to November 2011

Follow-up Duration: 25 weeks (induction plus up to 7 maintenance doses at 3-week intervals)

Centers: 13

Countries: Germany, Belgium, Poland, France, Finland

Sample Size: 28

Analysis: Intention-to-treat (ITT) based on full analysis set; per-protocol (PP) analysis on valid cases set; Wilson-Score confidence intervals; Hodges-Lehmann estimators; Kaplan-Meier for time-to-response

Inclusion Criteria

Age ≥18 years
Definite or probable CIDP as defined by EFNS/PNS guidelines
IVIG-naïve patients: newly diagnosed CIDP developed over ≥2 months OR treatment interrupted ≥1 year with progressive disease deteriorating in last 2 months
IVIG-pretreated patients: stable IVIG dose (±20%) at constant 2-6 week intervals for ≥6 months prior to screening
IVIG-pretreated patients required ≥1 point adjusted INCAT deterioration during washout period (up to 10 weeks)

Exclusion Criteria

Multifocal motor neuropathy with conduction block
MGUS associated with anti-MAG IgM antibodies
Distal acquired demyelinating symmetric neuropathy (DADS)
Any disease causing similar symptoms or interfering with treatment/assessments
Creatinine >1.5× ULN
LDH >1.5× ULN
CRP >60 mg/dL
Hemoglobin <10 g/dL
Plasma exchange within 3 months prior to enrollment
Immunomodulatory agents other than corticosteroids, methotrexate, or azathioprine within 6 months
Rituximab within 12 months before enrollment

Baseline Characteristics

Overall Cohort (n=28):

Male: 18 (64.3%)
Female: 10 (35.7%)
Age - median (range): 58 (22-79) years
Race - Caucasian: 28 (100%)
Body weight - median (range): 83 (50-118) kg
BMI - median (range): 27.9 (18-36) kg/m²
Height - median (range): 172 (158-195) cm
Duration of CIDP ≤1 year: 9 (32.1%)
Duration of CIDP >1 to ≤2 years: 4 (14.3%)
Duration of CIDP >2 to ≤10 years: 12 (42.9%)
Duration of CIDP >10 years: 3 (10.7%)
IVIG-pretreated: 13 (46.4%)
IVIG-naïve: 15 (53.6%)
INCAT score - median (IQR): 3.5 (3.0-4.5)
Maximum grip strength - mean (SD): 66.7 (37.24) kPa
MRC sum score - median (IQR): 67.0 (61.5-72.0)
Serum IgG level - mean (SD): 1259.5 (377.47) mg/dL
Concomitant corticosteroids: 5 (17.9%)
Concomitant azathioprine: 2 (7.1%)

Arms

Field	Privigen
Intervention	Privigen (10% liquid human IVIG, L-proline stabilized): Induction dose 2 g/kg body weight over 2-5 days, followed by up to 7 maintenance doses of 1 g/kg at 3-week intervals; mean infusion rate 5.89 mg/kg/min (range 1.48-8.36)
Duration	25 weeks total (induction + maintenance phase)

Outcomes

Outcome	Type	Intervention	P-value
Responder rate by adjusted INCAT score at completion; responder defined as ≥1 point improvement; success criterion: lower limit of 95% CI >35% (based on ICE study placebo arm)	Primary		Met success criterion (lower CI 42.4% > 35%)
Change in adjusted INCAT score \| Baseline: 3.5 (3.0-4.5) median (IQR); Completion: 2.5 (1.0-3.0) median (IQR); Hodges-Lehmann estimate: -1.3 points (95% CI: -2.0 to -0.5)	Secondary
Maximum grip strength (dominant hand) \| Baseline: 66.7 (37.24) kPa mean (SD); Completion: 80.9 (31.06) kPa mean (SD); Change: +14.0 kPa (95% CI: 0.79-27.46)	Secondary
MRC sum score \| Baseline: 67.0 (61.5-72.0) median (IQR); Completion: 75.5 (71.5-79.5) median (IQR); Hodges-Lehmann estimate: +6.5 points (95% CI: 4.0-9.5)	Secondary
Time to first adjusted INCAT response \| All patients: 50% responded by Week 4 (after induction); IVIG-pretreated median: 3 weeks; IVIG-naïve median: 18 weeks; Kaplan-Meier response probability: 64.3% (95% CI: 46.5-82.0%)	Secondary
MRC-based responder rate (≥3 point improvement) \| All patients: 82.1% (23/28); IVIG-naïve: 86.7% (13/15); IVIG-pretreated: 76.9% (10/13); Median time to MRC response: 6 weeks (IQR 3-9)	Secondary
Serum IgG levels \| Pre-infusion mean: 1828.4 (547.7) mg/dL; Post-infusion mean: 3363.5 (880.0) mg/dL; Change in responders: 1759.0 (758.8) mg/dL; Change in non-responders: 1342.7 (612.2) mg/dL	Secondary
Overall AE rate	Adverse	Patients with AEs: 22 (78.6%); Total AEs: 108; Rate per infusion: 0.417
Temporally associated AEs (within 72h)	Adverse	Patients: 19 (67.9%); Total AEs: 66; Rate per infusion: 0.255
Treatment-related AEs	Adverse	Patients: 17 (60.7%); Total AEs: 49; Rate per infusion: 0.189
Headache	Adverse	Patients: 9 (32.1%); Events: 20; Rate: 0.077 per infusion
Pain in extremity	Adverse	Patients: 6 (21.4%); Events: 7; Rate: 0.027 per infusion
Hypertension	Adverse	Patients: 4 (14.3%); Events: 6; Rate: 0.023 per infusion
Asthenia	Adverse	Patients: 4 (14.3%); Events: 4; Rate: 0.015 per infusion
Leukopenia	Adverse	Patients: 4 (14.3%); Events: 4; Rate: 0.015 per infusion
Hemolysis (SAE)	Adverse	Patients: 2 (7.1%); Events: 2; Details: Both occurred within 2 days after induction dose; both patients had non-O blood groups (AB and A); both resolved after discontinuation without transfusion

Subgroup Analysis

IVIG-pretreated patients demonstrated higher responder rates (76.9% vs 46.7%) and shorter time to response (median 3 weeks vs 18 weeks) compared to IVIG-naïve patients. Three IVIG-pretreated non-responders included one who did not deteriorate during washout (should not have been enrolled), one with possible insufficient dosing, and one who improved in grip/MRC but not INCAT.

Criticisms

Single-arm design without concurrent control group limits causal inference
Historical control comparison to ICE study placebo arm rather than randomized comparison
Small sample size (n=28) limits generalizability
Open-label design introduces potential bias in outcome assessment
Success criterion based on historical data from different IVIG product
Mixed population of IVIG-pretreated and IVIG-naïve patients complicates interpretation
Washout design for IVIG-pretreated patients may have selected for treatment-dependent patients
Short follow-up (25 weeks) does not assess long-term durability
Higher responder rate in pretreated patients may reflect selection bias
Two hemolysis SAEs highlight safety concerns with high-dose IVIG induction

Funding

CSL Behring AG, Berne, Switzerland

Based on: PRIMA (Journal of the Peripheral Nervous System, 2013)