PRISMS study

IN PRISMS, REBIF® DEMONSTRATED EFFICACY VS PLACEBO IN RELAPSE REDUCTION, LESION REDUCTION, AND DELAYS IN DISABILITY PROGRESSION1-3

PRISMS study design

Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) was a double-blind, placebo-controlled study conducted over 2 years. Patients were randomly assigned Rebif® 44 mcg (n=184), Rebif® 22 mcg (n=189), or placebo (n=187), given 3 times weekly by subcutaneous injection. Outcomes measured included relapse rate, disability, MRI, safety, and antigenicity. Neurological assessments were conducted every 3 months. The primary endpoint of the study was mean relapse count per patient at 2 years.1

PRISMS TRIAL: INITIATED IN 19941

 

Chart showing the PRISM study design schematic

 

 

Icon for PRISMS information

Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis (PRISMS) was a double-blind, placebo-controlled study conducted over 2 years. Patients were randomly assigned Rebif® 44 mcg (n=184), Rebif® 22 mcg (n=189), or placebo (n=187), given 3 times weekly by subcutaneous injection.

 

Icon for Primary endpoint

Primary endpoint: mean relapse count per patient at 2 years. Secondary endpoints included additional relapse measures, disability progression, safety, and the following MRI outcomes:

  • T2 lesions at 2 years
  • Lesion load at 2 years 
  • T1-Gd+ lesions at 9 months
  • Combined unique active lesions at 9 months

All patients had biannual T2 scans and 205 had monthly T2 and T1-Gd+ scans before and during 9 months of treatment.

Relapses

REBIF® DEMONSTRATED SIGNIFICANT REDUCTIONS IN RELAPSES IN PATIENTS WITH A RANGE OF DISABILITY1-3

Demonstrated reduction in the mean number of relapses vs placebo at 2 years1,2

 

TOTAL
(0 TO 5.0 EDSS) COHORT 

32 percent image

 

HIGHER BASELINE
(>3.5 TO 5.0 EDSS) COHORT  

60 percent image

Rebif® 44 mcg: 1.73 (n=184) vs

placebo: 2.56 (n=187), P<0.0001 

 

HIGHER BASELINE
(>3.5 TO 5.0 EDSS) COHORT  

60 percent image

Rebif® 44 mcg: 1.73 (n=184) vs

placebo: 2.56 (n=187), P<0.0001 

Rebif® 44 mcg: 1.22 (n=31) vs

placebo: 3.07 (n=28), P=0.0002

 

The rate of serious adverse events in patients with EDSS >3.5 to 5.0 (regardless of causality) was 20% vs 11.3% for the total patient cohort (EDSS 0 to 5.0)2

Fewer patients had a relapse at 3 months with Rebif® vs placebo3

TOTAL PATIENT COHORT (BASELINE EDSS 0 TO 5.0)

 

Graph labeled - TOTAL PATIENT COHORT (BASELINE EDSS 0 TO 5.0) and showing a graph of Post hoc analysis: Patients with relapses at 3 months with Rebif at 29% and Placebo at 40%

 

28% 

RELATIVE REDUCTION

IN PROPORTION OF PATIENTS

 

SC: subcutaneous; tiw: 3 times weekly.

Regardless of age, Rebif® demonstrated a reduction in ARR at 2 years1,4,5

ARR AT 2 YEARS IN AGES 18-55 VS PLACEBO (BASELINE EDSS 0 TO 5.0)

 

33 percent image

AGE < 40

Post hoc analysis ages 18-39 (n=129),
HR=0.67 (95% CI: 0.57-0.79), P<0.001

 

33 percent image

AGE ≥ 40

Post hoc analysis ages 40-55 (n=55),
HR=0.67 (95% CI: 0.51-0.87), P<0.003

 

ARR: annualized relapse rate; CI: confidence interval; EDSS: Expanded Disability Status Scale; HR: hazard ratio.

Regardless of gender, Rebif® demonstrated a reduction in relapse at 2 years2

 

Graph showing  MALE - 33% REDUCTION  Placebo (n=46) Rebif® 44 mcg (n=62)

 

Graph showing The chart FEMALE - 32% REDUCTION Placebo (n=141) Rebif® 44 mcg (n=122)

 

 

MRI RESULTS

 

REBIF® DEMONSTRATED A SIGNIFICANT REDUCTION IN MRI LESIONS1-3

Patients on Rebif® showed a 78% reduction in T2-active lesions vs placebo after 2 years1,2

Median number of T2-active lesions per patient per scan was 0.5 for 44 mcg (n=172) vs 2.25 for placebo (n=171); P<0.0001*

Significant CUA lesion reduction seen as early as 2 months and persisted up to 9 months2†‡§

MONTHLY SCANS—MEAN NUMBER OF CUA LESIONS OVER TIME

 

Graph showing - REDUCTION IN PERCENT COMBINED ACTIVE SCANS PER PATIENT; on the left at 2 months - 42% RELATIVE REDUCTION; on the right at 9 months - 62% RELATIVE REDUCTION

 
*Based on comparisons from rank-based ANOVA.2
†From a subgroup of 205 patients who underwent monthly MRI scans for the first 9 months, intent-to-treat population had biannual scans.6
‡Analysis of the subgroup of patients undergoing PD/T2 and T1-Gd+ MRI scans at prestudy day 1, and monthly for the first 9 months of treatment based on ANOVA on the ranks taking center and number of active lesions at baseline into account.2
§Proportion of scans per patient per treatment group with new activity, including new, enlarging, recurrent PD/T2, or enhancing T1 lesions.6

CUA: combined unique active, defined as any lesion that was T1 active or T2 active.
SC: subcutaneous; tiw: 3 times weekly.
Post hoc analysis of a 205-patient subset who received monthly MRI scans in the PRISMS study.

PD/T2 lesion load also decreased significantly compared with placebo1,6

DECREASED PD/T2 LESION LOAD: BIANNUAL SCANS6

 

Graph showing DECREASED PD/T2 LESION LOAD: BIANNUAL SCANS for Placebo, Rebif®22mcg and Rebif®44mcg

 

N values: At 6 months, placebo (n=182), Rebif® 22 mcg (n=182), Rebif® 44 mcg (n=182); at 12 months, placebo (n=179), Rebif® 22 mcg (n=180), Rebif® 44 mcg (n=180); at 18 months, placebo (n=176), Rebif® 22 mcg (n=177), Rebif® 44 mcg (n=172); and at 24 months, placebo (n=172), Rebif® 22 mcg (n=171), Rebif® 44 mcg (n=171).6 Lesion load is defined as the total area of lesions in the brain measured in mm2.6

PD: proton density; SC: subcutaneously; tiw: 3 times weekly.

 

  • Both Rebif® groups exhibited a decrease in T2 lesion load, which was evident by 6 months of observation; at 2 years, there was a 1.2% and 3.8% reduction in the 22 mcg and 44 mcg groups, respectively (P<0.0001 compared with placebo for each group)
  • The rate of serious adverse events in patients with EDSS >3.5 to 5.0 (regardless of causality) was 20% versus 11.3% for the total patient cohort (EDSS 0 to 5.0) 

T1-GD+ lesions showed a significant reduction compared with placebo6

SIGNIFICANT REDUCTIONS IN T1-GD+ LESIONS AT 9 MONTHSII¶

 

Graph showing SIGNIFICANT REDUCTION IN T1-Gd+ LESIONS AT 9 MONTHS for Placebo, Rebif®22mcg and Rebif®44mcg

 

IIFrom a subgroup of 205 patients who underwent monthly MRI scans for the first 9 months, intent-to-treat population had biannual scans.
¶Analysis of the subgroup of patients undergoing PD/T2 and T1-Gd+ MRI scans at prestudy screening, study day 1, and monthly for the first 9 months of treatment based on ANOVA on the ranks taking center and number of active lesions at baseline into account.

SC: subcutaneous; tiw: 3 times weekly; T1-Gd+: T1-weighted gadolinium-enhancing.

 

 

Disability progression

 

REBIF® DEMONSTRATED A SIGNIFICANT DELAY IN DISABILITY PROGRESSION VS PLACEBO IN PATIENTS WITH A RANGE OF DISABILITY1,2

 

TOTAL PATIENT COHORT (BASELINE EDSS 0 TO 5.0)

 

Graph showing TOTAL PATIENT COHORT (BASELINE EDSS 0 TO 5.0) for Placebo, and Rebif®44mcg

 

#Progression of disability was defined as an increase of at least 1 point in the EDSS, sustained for at least 3 months.

CDP: confirmed disability progression; HR: hazard ratio; SC: subcutaneous; tiw: 3 times weekly.

HIGHER EDSS COHORT (BASELINE EDSS >3.5 TO 5.0)

 

Graph showing HIGHER EDSS COHORT (BASELINE EDSS >3.5 TO 5.0) for Placebo, and Rebif®44mcg

 

**Progression of disability was defined as an increase of at least 1 point in the EDSS, sustained for at least 3 months.

CDP: confirmed disability progression; HR: hazard ratio; SC: subcutaneous; tiw: 3 times weekly.

  • In time to confirmed disability progression, a statistically significant difference was seen between
    Rebif® 22 mcg and placebo in the total patient cohort (0 to 5.0) but was not seen in the high EDSS cohort (>3.5 to 5.0) 
  • The rate of serious adverse events in patients with EDSS >3.5 to 5.0 (regardless of causality) was 20% vs 11.3% for the total patient cohort (EDSS 0 to 5.0)

IMPORTANT SAFETY INFORMATION AND INDICATION

Important Safety Information

Rebif is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation.

Rebif should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including Rebif.

Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking Rebif. The potential for liver injury should be considered when used in combination with other products associated with liver injury. Monitor liver function tests and patients for signs and symptoms of hepatic injury. Consider discontinuing Rebif if hepatic injury occurs.

Anaphylaxis and other allergic reactions (some severe) have been reported as a rare complication of Rebif. Discontinue Rebif if anaphylaxis occurs.

In controlled clinical trials, injection site reactions occurred more frequently in Rebif-treated patients than in placebo-treated and Avonex-treated patients. Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Do not administer Rebif into affected area until fully healed; if multiple lesions occur, discontinue Rebif until skin lesions are healed.

Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in Rebif-treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in Rebif-treated patients than in placebo and Avonex-treated patients. Thrombocytopenia and anemia occurred more frequently in 44 mcg Rebif-treated patients than in placebo-treated patients. Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended.

Cases of thrombotic microangiopathy (TMA), some fatal, have been reported with interferon beta products, including Rebif, up to several weeks or years after starting therapy. Discontinue Rebif if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated.

Caution should be exercised when administering Rebif to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, including Rebif, in clinical trials and in postmarketing reports.

The most common side effects with Rebif are injection-site disorders, headaches, influenza-like symptoms, abdominal pain, depression, elevated liver enzymes, and hematologic abnormalities.

Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal studies. Data from a large human population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent.

Indication

Rebif is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Please see Rebif® Prescribing Information  and Medication Guide.

References: 1. PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-1504. 2. Data on file. EMD Serono, Inc. PRISMS study report. 3. Data on file. EMD Serono, Inc. PRISMS 2010 Confirming analysis. 4. Rebif® [Prescribing Information]. Rockland, MA: EMD Serono, Inc. 5. Freedman MS, Brod S, Wray S, et al. Post hoc Analysis to Evaluate the Effects of Subcutaneous Interferon beta-1a in Subgroups of Patients from the PRISMS Study with Early Onset Versus Late Onset Disease. Poster presented at: ECTRIMS 2019; 11-13 September; Stockholm, Sweden. 6. Li DKB, Paty DW; UBC MS/MRI Analysis Research Group, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized double-blind, placebo-controlled study of interferon-β1a in relapsing-remitting multiple sclerosis. Ann Neurol. 1999;46(2):197-206.