BACKGROUND: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of MS.
METHODS: The investigators concluded a randomized trial involving 1088 patients with MS, 18 to 55 years of age, with a score of 0 to 5.5 on the EDSS and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks.
RESULTS: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI).
SIDE EFFECTS: Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated liver tests was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred.
CONCLUSIONS: Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo.
“Although the results are old news as they have been presented at several scientific meetings and have been in the press in the past it is a good indicator that some progress in being made in the field of DMTs. Teriflunomide bats in the same efficacy zone as interferon-beta and glatiramer acetate. Its side effect profile seem reasonable. If it gets a favourable European licence and does not cost too much in the UK it may be an alternative first line therapy instead of the injectables.”
“Teriflunomide works as an immunomodulator affecting how activated lymphocytes work. Opportunistic infections, those occurring in patients with a compromised immune system don’t seem to be a problem with teriflunomide.”
“Unfortunately, there is still no news for MS’ers with progressive disease.”
CoI: Multiple, this study was funded by Sanofi-Aventis
I wonder if these trials are followed by an "exit-poll" among patients with the simple question: "do you think you received a drug or a placebo?". Comparison of the answers with the truth about the substance they received would give significant evidence about both placebo (for patients who realized they were given true medication) and nocebo effect (for those who believed correctly they were given placebo).Does anybody know?
Re: "Exit polls.."Yes, these are usually done in trials and depending on the drug they show how well blinded the study was. I am not aware of the Teriflunomide exit poll; some of the side effects associated with drug would certainly expose what they were on. This is why it is important to include objective outcome measures in trials, such as MRI to make sure the changes are real, and to do more than one trial. With some drugs blinding is impossible, for example Alemtuzumab and even interferon beta. The former because of infusion reactions and the latter due to flu-like side effects and injection site reactions.
Re "With some drugs blinding is impossible, for example Alemtuzumab and even interferon beta."Meaning that trials about these drugs should be regarded virtually unblinded?
Re: "Meaning that trials about these drugs should be regarded virtually unblinded?"No not at all; the clinical outcomes will be single-blinded (assessor blinded) and the MRI outcomes double-blinded. With some drugs like cladribine they will be double-blinded; MS'ers had no idea they were taking cladribine. Keeping study subjects blinded will depend on drug specific side effects.
The clinical outcomes are single-blinded because only the accessing physician is unaware of the treatment, right? But why are the MRI outcomes regarded double-blinded?
Re: "he clinical outcomes are single-blinded because only the accessing physician is unaware of the treatment, right?"YES!"But why are the MRI outcomes regarded double-blinded?"The study subjects nor the clinical team see the MRI studies. In fact the people who process the MRIs are also blinded. The code is only broken later when all the MRI data has been loaded into a database. This is why the EMA and FDA place so much importance on MRI outcomes.
Is the assessing physician the one who does the clinical examination? Then I doubt the assessor can remain blinded when the patient knows or guesses his/her treatment. They would both have to be very careful and disciplined about what they ask or say.
Re: "Is the assessing physician the one who does the clinical examination? Then I doubt the assessor can remain blinded when the patient knows or guesses his/her treatment. They would both have to be very careful and disciplined about what they ask or say."Yes, what you have surmised is correct. There is special training the blinded assessor have to prevent unblinding, and study subjects are given strict instructions not to discuss their treatment or side effects with the blinded assessor. Despite these precautions unblinding does happen. My personal experience with the teriflunomide trial was that it was not a problem. It is a much bigger problem in single-blinded studies in which the study subjects know what drug they are on.