Dataset Information

Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial.

ABSTRACT: For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of ? interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct ? interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available ? interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ? 2 relapses in the last 2 years) were randomly assigned to azathioprine or ? interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 ? interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 ? interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as ? interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 ? interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of ? interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.EudraCT 2006-004937-13.

SUBMITTER: Massacesi L

PROVIDER: S-EPMC4234663 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial.

Massacesi Luca L Tramacere Irene I Amoroso Salvatore S Battaglia Mario A MA Benedetti Maria Donata MD Filippini Graziella G La Mantia Loredana L Repice Anna A Solari Alessandra A Tedeschi Gioacchino G Milanese Clara C

PloS one 20141117 11

<h4>Unlabelled</h4>For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple s ...[more]

PMID: 25402490

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Project description:Several treatments are currently available for relapsing-remitting multiple sclerosis. Among them, interferon (IFN) beta remains a valid treatment approach because of its good benefit/risk profile. Due to the need for frequent administration (weekly, at a minimum), the use of IFN beta is limited by uncomfortable side effects that could reduce adherence to and persistence with the treatment. The use of subcutaneous polyethylene glycol (PEG)ylated interferon beta-1a (PEG-IFN) has been proposed to offer a better combination of pharmacokinetic and pharmacodynamic profiles and therapy-related side effects. A 125 μg dose of PEG-IFN given every 2 or 4 weeks was tested in two Phase I studies and shown to be as safe and efficient as IFN beta-1a but with a longer half-life. A Phase III trial (ADVANCE) comparing 125 μg of PEG-IFN given every 2 or 4 weeks with placebo in 1,512 patients with relapsing-remitting multiple sclerosis showed significant reductions in both the annualized relapse rate (ARR) and the occurrence of new or newly enlarged T2 brain lesions in both experimental groups versus placebo after the first year. Moreover, 38% fewer patients showed progression of disability (P=0.04) in the PEG-IFN groups. During the second year, the ARR was further reduced in the PEG-IFN 2-week treatment group (0.230 at 1 year versus 0.178 at 2 years) and was maintained in the 4-week treatment group. Patients who received immediate PEG-IFN treatment showed improved clinical efficacy (ARR, risk of relapse, 12-week disability progression) and magnetic resonance imaging parameters (new T2 and newly enlarging lesions, gadolinium-positive lesions) compared with those with delayed treatment. The effects were more evident with the 2-week dose for all endpoints considered. Furthermore, PEG-IFN was well tolerated, and no new safety concerns arose. In conclusion, PEG-IFN has good efficacy and a good safety profile. The available data support the use of PEG-IFN as a suitable therapeutic option in patients with relapsing-remitting multiple sclerosis.

Project description:BACKGROUND:We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-?) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS:We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-? and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS:We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS:Meta-analyses confirmed that IFN-? and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION:PROSPERO CRD42016043278 .

Project description:In Brazil, inclusion and exclusion of health technologies within the Unified Health System (SUS) is the responsibility of the National Committee for Health Technology Incorporation (CONITEC). A recent Cochrane systematic review demonstrated that intramuscular interferon beta 1a (IFN-?-1a-IM) was inferior to the other beta interferons (IFN-?s) for multiple sclerosis (MS). As a result, CONITEC commissioned an analysis to review possible disinvestment within SUS. The objective of this paper is to describe the disinvestment process for IFN-?-1a-IM in Brazil. The first assessment comprised a literature review and mixed treatment comparison meta-analysis. The outcome of interest was the proportion of relapse-free patients in 2 years. This analysis confirmed the inferiority of IFN-?-1a-IM. Following this, CONITEC recommended disinvestment, with the decision sent for public consultation. More than 3000 contributions were made on CONITEC's webpage, most of them against the preliminary decision. As a result, CONITEC commissioned a study to assess the effectiveness of IFN-?-1a-IM among Brazilian patients in routine clinical care. The second assessment involved an 11-year follow-up of a non-concurrent cohort of 12,154 MS patients developed by deterministic-probabilistic linkage of SUS administrative databases. The real-world assessment further demonstrated that IFN-?-1a-IM users had a statistically higher risk of treatment failure, defined as treatment switching or relapse treatment or death, with the assessment showing that IFN-?-1a-IM was inferior to the other IFN-?s and to glatiramer acetate in both direct and indirect analysis. In the drug ranking with 40,000 simulations, IFN-?-1a-IM was the worst option, with a success rate of only 152/40,000. Following this, CONITEC decided to exclude the intramuscular presentation of IFN-? from the current MS treatment guidelines, giving patients who are currently on this treatment the option of continuing until treatment failure. In conclusion, we believe this is the first example of this new disinvestment process in action, providing an exemplar for other treatments in Brazil as well as other countries.

Dataset Information

Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial.

Publications

Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial.

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