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21 December 2011
Summary:
Data from the two year TEMSO trial have shown that teriflunomide, a once daily oral drug for the treatment of relapsing forms of multiple sclerosis, was more effective than placebo at reducing the annualised relapse rate, and, at the higher treatment dose, significantly fewer patients had sustained disability progression compared to placebo. Adverse events associated with teriflunomide included diarrhoea, nausea, hair thinning and elevated alanine aminotransferase levels.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
It is anticipated that teriflunomide will be submitted to the European Medicines Agency (EMA) for licensing in the first half of 2012. Local decision making bodies may wish to plan ahead with stakeholders for its possible introduction, in the context of the existing NICE clinical guideline on the treatment of multiple sclerosis.
This study represents the best currently available evidence relating to this new medicine. These data, together with their limitations, should be taken into account by local decision-makers when planning for the entry of this new medicine and the commissioning of appropriate services. Local decision-makers may need to consider additional published data about this product as they emerge.
What is the background to this?
Multiple sclerosis (MS) is characterised by periods of relapse and remission of neurological impairment; some patients have a single episode whilst others have a progressive form of the disease without remissions. The exact prevalence is unknown, but it has been estimated that 100,000 people in the UK currently have MS, with 2500 new cases diagnosed each year. Relapsing-remitting MS (RRMS) accounts for approximately 40% of all MS cases, equating to around 34,000 people in the UK. Information on the management of MS can be found on the NICE website. A decision to update the clinical guideline was made in summer 2011.
Currently available disease-modifying preparations for MS are given by injection. Teriflunomide, like fingolimod▼ and laquinimod is an oral preparation. If, following submission to the EMA, it receives a licence it is likely to generate considerable interest from patients and clinicians. The product has been proposed for scoping for a NICE technology appraisal.
What does this study claim?
The primary outcome measure reported in this study was the adjusted annualised relapse rate. Both the 7 mg and 14 mg once daily doses of teriflunomide reduced the annualised relapse rate compared to placebo. The annualised relapse rate was 0.54 in the placebo group (95% confidence interval [CI] 0.47 to 0.62); 0.37 in the teriflunomide 7 mg group (95% CI 0.32 to 0.43); and 0.37 in the teriflunomide 14 mg group (95% CI 0.31 to 0.44), [p < 0.001 for either dose against placebo]. This corresponds to a reduction of 0.17 relapse per patient per year.
A key secondary outcome reported in the study was the time to disability progression, as assessed by the Expanded Disability Status Scale (EDSS). This is defined as a 1.0 point increase in EDSS score from baseline (or 0.5 point increase if baseline EDSS score > 5.5), sustained for 12 weeks. Teriflunomide was superior to placebo at the higher (14 mg) dose only. The proportion of patients with sustained disability progression (greater than 12 weeks) was 27.3% in the placebo group (95% CI 22.3 to 32.3), 21.7% in the teriflunomide 7 mg group (95% CI 17.1 to 26.3; p = 0.08 vs. placebo), and 20.2% in the teriflunomide 14 mg group (95% CI 15.6 to 24.7; p = 0.03 vs. placebo).
The proportions of participants free of disability progression at the time intervals stated and the significance of these data were not reported.
A range of magnetic resonance imaging (MRI) outcomes were recorded. The primary MRI variable in this study, the composite change in total lesion volume from baseline, was 2.21 ml (standard deviation (SD) ± 7.00 ml) in the placebo group, 1.31 ml (SD ± 6.80 ml) in the teriflunomide 7 mg group (p = 0.03 vs. placebo), and 0.72 (SD ± 7.59 ml) in the teriflunomide 14 mg group (p < 0.001 vs. placebo).
The Fatigue Impact Scale is a questionnaire of 40 questions (each scored 0-4 on a Likert scale), with a possible total score of 160; the higher the score, the greater the impact of fatigue on the patient. Baseline FIS scores were 53.2 (SD ± 37.9) in the placebo group; 50.4 (SD ± 35.6) in the teriflunomide
7 mg group; and 50.3 (SD ± 35.9) in the teriflunomide 14mg group. Patients reported only small changes in fatigue levels from baseline, with no significant differences among the three study groups; change in FIS score from baseline was 4.3 (SD ±1.7) in the placebo group, 2.3 (SD ±1.6) in the teriflunomide 7 mg group (p = 0.39 vs. placebo), and 3.8 (SD ±1.7) in the teriflunomide 14 mg group (p = 0.83 vs. placebo).
Adverse events were observed in similar proportions of patients in the three treatment groups (placebo, 87.5%, teriflunomide 7mg, 89.1%, teriflunomide 14mg, 90.8%); as were serious adverse events (12.8%, 14.1% and 15.9% respectively); and adverse events leading to discontinuation (8.1%, 9.8% and 10.9% respectively), p values not given for adverse event data. Adverse events that occurred more commonly in the teriflunomide treatment groups were diarrhoea, nausea, hair thinning and elevated aminotransferase levels.
The incidence of serious infections was similar across groups (2.2%, 1.6% and 2.5% with placebo, teriflunomide 7mg and teriflunomide 14mg respectively).
For other secondary outcome measures see study details.
How does this relate to other studies?
Oral fingolimod▼ has been shown to reduce the annualised relapse rate in patients with RRMS compared to both placebo and interferon beta-1a. These trials have been discussed in a previous Rapid Review. Adverse events associated with fingolimod▼ included bradycardia, hypertension and macular oedema. A NICE single technology appraisal on the use of fingolimod▼ in RRMS is in process.
Two phase III placebo-controlled trials of oral laquinimod have been completed, but only limited results from press releases are currently available. One study reported a reduction in annualised relapse rate in patients with RRMS compared to placebo; in the second study the laquinimod treatment group did not show a significant reduction in annualised relapse rate, the primary endpoint of the study.
Several more clinical trials are in progress to assess the role of teriflunomide in both relapsing forms of MS and clinically isolated syndrome, including a study against an active comparator (interferon beta-1a); and placebo-controlled studies of teriflunomide as adjuvant treatment. As there are currently no head-to-head studies with other disease-modifying agents, it is not clear where teriflunomide will be placed in relation to other treatments in the management of patients with MS.
So what?
An effective oral preparation to treat relapsing forms of MS is likely to be more acceptable and convenient for patients. However, although teriflunomide has been shown to reduce the annualised relapse rate compared to placebo, and, at the 14 mg dose, reduces disability progression over two years compared to placebo, the long term benefits and the safety profile of the drug need further assessment. Accumulation of disability in multiple sclerosis usually takes place over many years, and safety issues with disease-modifying agents require long-term monitoring. Follow-up trials are on-going. Trials comparing teriflunomide to other disease-modifying treatments will be required to assess its place in the management of multiple sclerosis.
Study details
O’Connor P, Wolinsky JS, Confavreux C, et al for the TEMSO Trial Group. Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293-303.
Design: Phase III, randomised, double-blind placebo controlled study
Patients: 1088 patients aged 18 to 55 years (mean age 38 years) with relapsing multiple sclerosis (with or without progression). Patients had a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS); that is, they were able to walk at least 100 metres, with impairment of full daily activities; the baseline mean EDSS score was 2.68 (a score of 2.5 = minimal disability in two functional systems (FS); a score of 3 = moderate disability in one FS, or minimal disability in three or four FS). Patients had experienced at least one relapse in the previous year or at least two relapses in the previous two years. Patients had experienced MS symptoms for about nine years, and 73% of patients had not received disease-modifying therapy during the two years prior to study entry.
Intervention and comparison
Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks.
Outcomes and results
The primary outcome measure was the annualised relapse rate (number of relapses per subject per year): 0.54 in the placebo group (n=363) (95% CI 0.47 to 0.62); 0.37 in the teriflunomide 7 mg group (n=365) (95% CI 0.32 to 0.43); and 0.37 in the teriflunomide 14 mg group (n=358) (95% CI 0.31 to 0.44; p < 0.001 for both doses against placebo) in the modified intention-to-treat (ITT) population (all patients who underwent randomisation and received at least one dose of a study drug).
Secondary outcome measures were: time to sustained disability progression assessed by EDSS; proportion of subjects free of disability progression (measured at six months, one year and two years); burden of disease (change from baseline in the volume of abnormal brain tissue as assessed by cerebral MRI); subject-reported fatigue (assessed by the Fatigue Impact Scale [FIS]); and adverse events (based on clinical and laboratory findings).
The proportion of patients with sustained disability progression (>12 weeks) was 27.3% with placebo (95% CI 22.3 to 32.3), 21.7% with teriflunomide at 7 mg (95% CI 17.1 to 26.3; p = 0.08 vs. placebo), and 20.2% with teriflunomide at 14 mg (95% CI 15.6 to 24.7; p = 0.03 vs. placebo).
The proportions of subjects free of disability progression at the time intervals stated and the significance of these data were not reported.
A range of MRI outcomes were measured: volume of hypointense lesions, number of gadolinium-enhancing lesions, absence of gadolinium-enhancing lesions (all on T1-weighted images); volume of hyperintense lesions on T2-weighted images, and composite measures of total lesion volume, unique active lesions per scan and brain parenchymal fraction.
Correlation between clinical and MRI findings has been found to be weak, and not of predictive value for clinical outcomes, according to the EMA. Total lesion load, chronic T1 hypointensity and brain atrophy have been related to tissue loss in MS trials. The primary MRI variable in this study, the mean change in total lesion volume (the proportion of total lesion volume that is hyperintense on T2 weighted images, and not hypointense on T1 post-gadolinium enhanced images) from baseline, was 2.21 ml (SD ± 7.00 ml) in the placebo group, 1.31 ml (SD ± 6.80 ml) in the teriflunomide 7 mg group (p = 0.03), and 0.72 ml (SD ±7.59 ml) in the teriflunomide 14 mg group (p < 0.001).
Small changes in fatigue levels were reported by patients, which were not statistically different among treatment groups. Change in fatigue levels, measured as change in FIS score from baseline was 4.3 (SD ±1.7) in the placebo group, 2.3 (SD ±1.6) in the teriflunomide 7 mg group (p = 0.39 vs. placebo), and 3.8 (SD ±1.7) in the teriflunomide 14 mg group (p = 0.83 vs. placebo).
Discontinuation due to adverse events occurred in 8.1% of the placebo group, 9.8% of the teriflunomide
7 mg group, and 10.9% of the teriflunomide 14 mg group (p values not given for adverse event data). Serious adverse events also occurred in similar proportions in the three treatment groups: 12.8% in the placebo group, 14.1% in the 7 mg group, and 15.9% in the 14 mg group. The most common adverse events reported with greater frequency in the teriflunomide groups were diarrhoea (8.9% in the placebo group, 14.7% in the 7 mg group and 17.9% in the 14 mg group), nausea (7.2% in the placebo group, 9.0% in the 7 mg group and 13.7% in the 14 mg group), hair thinning (3.3% in the placebo group, 10.3% in the 7 mg group and 13.1% in the 14 mg group), and elevated alanine aminotransferase (ALT) levels (ALT > 1x upper limit in 35.9% of the placebo group, 54% of the 7 mg group and 57.3% of the 14 mg group, although these elevated levels were not always reported as adverse events). No deaths occurred.
Sponsorship
The TEMSO study was funded by Sanofi-Aventis
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