Pegylated Interferon another placebo trial in RRMSers

Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S, Deykin A; for the ADVANCE Study Investigators.Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 . pii: S1474-4422(14)70068-7. doi: 10.1016/S1474-4422(14)70068-7. [Epub ahead of print]

BACKGROUND:Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis.
METHODS:We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399.
FINDINGS:We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common.
INTERPRETATION:After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments.
 
Adding PEG (a type of anti-freeze) onto the  interferon beta can make it hang around longer and so you don't need to inject it as often but it still works and side effects are there. ProfG has reported on this study in the past and on the licencing

I wonder if a non-inferiority trial against standard interferon would have been more ethical than a trial against placebo. 

Surely this would have told the company, if their new drug was as good as its own beta interferon product it was hoping to replace. Obiviously they were not willing to risk this on the off cahnce its worse. Without a head to head how do we know?

This would not have destined 500 people (on placebo) to accumulate some damage because of the attacks they would invariably have. 

Surely it is time for the regulators and ethics committees to get some spine and say time to stop the placebo for RRMS. Maybe neuros need to take some affirmative action and question whether it is unethical to recruit in their neck of the woods, because it is not so much ADVANCE as BACKWARDS as far are MSers are concerned. Some may say this allows some who would slip through the current treatment net due to restrictions say from NICE, to access drug. Many of the study participants however may not have such an easy fall back position.

Whilst it is clear it is easier to see an effect against nothing, surely this situation cannot continue.....What do you think?

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