Teriflunomid bei Multipler Sklerose
Referencias
References to studies included in this review
References to studies excluded from this review
Additional references
References to other published versions of this review
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ir a:
| Methods | Randomized, double‐blind, placebo‐controlled, phase 3 trial (TOWER study) Population included in data analyses: all randomly assigned participants who received at least 1 dose of study drug or placebo Did not use the ITT analysis principle | |
| Participants | Inclusion criteria: people aged 18‐55 years; with relapsing MS meeting 2005 McDonald criteria; with or without underlying progression; an EDSS score ≤ 5.5 points; at least 1 relapse in the previous year or at least 2 relapses in the previous 2 years, and no relapse in the 30 days before randomization Key exclusion criteria: people with other relevant diseases; pregnant, breastfeeding or planning to conceive or father a child during the study; previously or concomitantly receiving cytokine therapy, IFNβ or glatiramer acetate within 3 months of randomization; ever using natalizumab or other immunosuppressive agents 1169 participants were randomly assigned in a 1:1:1 ratio to receive 3 different interventions. 1 participant in placebo group, 1 participant in teriflunomide 7 mg/day group and 2 participants in teriflunomide 14 mg/day group did not receive treatment Baseline demographic and clinical characteristics were generally well balanced among the study groups Age (mean ± SD): G1 = 38.1 ± 9.1 years, G2 = 37.4 ± 9.4 years, G3 = 38.2 ± 9.4 years Women: G1 = 273 (70%), G2 = 300 (74%), G3 = 258 (69%) Race: white G1 = 318 (82%), G2 = 329 (81%), G3 = 313 (84%); Asian G1 = 60 (15%), G2 = 60 (15%), G3 = 49 (13%); black G1 = 7 (2%), G2 = 8 (2%), G3 = 7 (2%); other G1 = 4 (1%), G2 = 11 (3%), G3 = 3 (1%) Region: Western Europe and Tunisia G1 = 121 (31%), G2 = 127 (31%), G3 = 120 (32%); Eastern Europe G1 = 117 (30%), G2 = 124 (30%), G3 = 116 (31%); America G1 = 84 (22%), G2 = 92 (23%), G3 = 81 (22%); Asia and Australia G1 = 67 (17%), G2 = 65 (16%), G3 = 55 (15%) Time from first symptoms of MS (mean ± SD): G1 = 7.64 ± 6.70 years, G2 = 8.18 ± 6.75 years, G3 = 8.18 ± 6.73 years Time since most recent relapse onset (mean ± SD): G1 = 5.29 ± 3.41 months, G2 = 5.18 ± 3.41 months, G3 = 5.33 ± 3.32 months Relapses per participant: within previous year (mean ± SD): G1 = 1.4 ± 0.8, G2 = 1.4 ± 0.7, G3 = 1.4 ± 0.7; within previous 2 years: G1 = 2.1 ± 1.1, G2 = 2.1 ± 1.1, G3 = 2.1 ± 1.2 MS subtype: relapsing‐remitting G1 = 379 (97%), G2 = 393 (96%), G3 = 366 (99%); secondary progressive G1 = 4 (1%), G2 = 3 (1%), G3 = 2 (1%); progressive relapsing G1 = 6 (2%), G2 = 12 (3%), G3 = 2 (1%) Use of MS medication in the previous 2 years: G1 = 135 (35%), G2 = 123 (30%), G3 = 126 (34%); IFNβ‐1a G1 = 59 (15%), G2 = 63 (15%), G3 = 64 (17%); glatiramer acetate G1 = 52 (13%), G2 = 47 (12%), G3 = 37 (10%); IFNβ‐1b G1 = 38 (10%), G2 = 27 (7%), G3 = 35 (9%) EDSS total score (mean ± SD): G1 = 2.69 ± 1.36, G2 = 2.71 ± 1.39, G3 = 2.71 ± 1.35 FIS score (mean ± SD): G1 = 54.67 ± 37.89, G2 = 56.16 ± 38.20, G3 = 55.25 ± 38.26 | |
| Interventions | Experimental group 1: oral teriflunomide 7 mg once daily (n = 408) Experimental group 2: oral teriflunomide 14 mg once daily (n = 372) Control group: matching oral placebo once daily (n = 389) Core treatment period: 48‐152 weeks (maximum treatment duration 173 weeks). Treatment duration was variable, ending 48 weeks after the last participant was included. The median duration of study treatment was similar across all groups (581 days (IQR 392‐756) in the placebo group vs. 556 days (IQR 385‐749) in the teriflunomide 7 mg group vs. 588 days (IQR 351‐765) in the teriflunomide 14 mg group) | |
| Outcomes | Primary outcome:
Secondary outcomes:
Relapse was defined as new or worsening clinical signs or symptoms lasting at least 24 hours without fever. Protocol‐defined relapses constituted an increase of either 1 point in at least 2 EDSS functional system scores, or 2 points in 1 EDSS functional system score (excluding bowel and bladder function, and cerebral function), or 0.5 points in total EDSS score from a previous clinically stable assessment Sustained accumulation of disability was defined as an increase from baseline of at least 1 EDSS point (or ≥ 0.5 points when baseline EDSS score was > 5.5 points) that persisted for at least 12 weeks | |
| Notes | The investigators obtained the data and the sponsor (Genzyme, owned by Sanofi‐Aventis) analyzed the data. Both the sponsor and the authors interpreted the data. ClinicalTrials.gov number: NCT00751881 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "An interactive voice recognition system generated an allocation sequence using a permuted‐block randomisation schedule with stratification according to study site and baseline EDSS score (≤3.5 or > 3.5)" Comment: sequence generation was adequate |
| Allocation concealment (selection bias) | Low risk | Quote: "Randomisation was done centrally, via an interactive voice recognition system" Comment: allocation concealment was adequate |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Patients, individuals administering the interventions, and those assessing the outcomes were masked to treatment assignment" "The experimental drugs were identical in taste and appearance" Comment: participants and personnel were blinded to the allocated interventions |
| Blinding of outcome assessment (detection bias) | High risk | Quote: "Those assessing the outcomes were masked to treatment assignment." "A treating neurologist was responsible for assessment of patient eligibility, supervision of administration of study drug or placebo, recording of adverse events, and assessment of relapses." "An examining neurologist, certified in the Neurostatus system for consistent EDSS assessment, 12 assigned EDSS scores at screening, randomisation, and every 12 weeks until the last treatment visit, and on any unscheduled visits for assessment of suspected relapse or disability worsening" Comment: treating neurologist who recorded adverse events was responsible for assessment of relapses, blinding of relapse assessment was probably not adequate |
| Incomplete outcome data (attrition bias) | High risk | According to the Figure 1 (Trial profile), overall, 348 (29.8%) participants withdrew from study (115 (29.6%) participants in placebo group, 119 (29.2%) participants in teriflunomide 7 mg/day group and 114 (30.6%) participants in teriflunomide 14 mg/day group) Comment: to a large degree, missing data and reasons were not balanced between groups. The high overall dropout rate of |
| Selective reporting (reporting bias) | Low risk | All listed outcomes were reported adequately. Risk of reporting bias was low |
| Other bias | High risk | Quote: "The study was sponsored by Genzyme." "Data were obtained by the investigators and analysed by the sponsor (Genzyme)," "Interpretation of the data was done by the sponsor and the authors," "4 co‐authors (TB, J‐LD, DD, and PT) of the published paper are all employees of Genzyme" |
| Methods | Phase 2 multicentre, placebo‐controlled, double‐blind, randomized study Follow‐up period: 48 weeks Population included in data analyses: all randomly assigned participants exposed to at least 1 dose of any study medication Did not use the ITT analysis principle | |
| Participants | Inclusion criteria: people aged 18‐55 years; with a diagnosis of MS as per the 2005 McDonald criteria; with a relapsing clinical course; with or without progression; having a score of ≤ 5.5 on the EDSS; with no relapse for 8 weeks; having a clinically stable condition for 4 weeks pre‐study; receiving a stable dose of IFNβ for at least 26 weeks before screening Baseline demographic and disease characteristics were well balanced among the groups. Summary of baseline characteristics of participants in the initial 24‐week study (placebo + IFNβ: G1 (n = 41), teriflunomide 7 mg + IFNβ: G2 (n = 37), teriflunomide 14 mg + INFβ: G3 (n = 38) Age (mean ± SD): G1 = 39.2 ± 9.0 years, G2 = 41.4 ± 6.8 years, G3 = 39.6 ± 8.1 years Women: G1 = 31 (75.6%), G2 = 25 (67.6%), G3 = 25 (65.8%) White: G1 = 40 (97.6%), G2 = 34 (91.9%), G3 = 38 (100%) MS subtype: relapsing‐remitting: G1 = 38 (92.7%), G2 = 30 (81.1%), G3 = 34 (89.5%); secondary progressive: G1 = 2 (4.9%), G2 = 2 (5.4%), G3 = 3 (7.9%); progressive relapsing: G1 = 1 (2.4%), G2 = 5 (13.5%), G3 = 1 (2.6%) Number of relapse within the past 12 months (mean ± SD): G1 = 0.9 ± 0.9, G2 = 0.6 ± 0.8, G3 = 0.9 ± 0.8 Proportion of participants with ≥ 1 relapse in the past 12 months: G1 = 58.5%, G2 = 48.6%, G3 = 65.8% EDSS score: mean ± SD G1 = 2.6 ± 1.3, G2 = 2.4 ± 1.4, G3 = 2.5 ± 1.6; median (range) G1 = 2.5 (0‐5.5), G2 = 2.0 (0‐5.5), G3 = 2.5 (0‐5.5) Proportion with IFNβ neutralizing antibodies: < 20 titre G1 = 86.5%, G2 = 80.6%, G3 = 87.9%; 20‐640 titre: G1 = 10.8%, G2 = 11.1%, G3 = 9.1%; > 640 titre: G1 = 2.7%, G2 = 8.3%, G3 = 3.0% The number of T1‐Gd lesions: 0: G1 = 77.5%, G2 = 78.4%, G3 = 78.9%; ≥ 1: G1 = 22.5%, G2 = 21.6%, G3 = 21.1% Baseline state of IFNβ: high dose: G1 = 68.3%, G2 = 67.6%, G3 = 63.2%; low dose: G1 = 31.7%, G2 = 32.4%, G3 = 36.8% | |
| Interventions | Experimental group 1: teriflunomide 7 mg/day orally added to IFNβ Experimental group 2: teriflunomide 14 mg/day orally added to IFNβ Control group: matching placebo orally added to IFNβ The ongoing IFNβ regimens were IFN‐1a (Avonex; Biogen Idec, Cambridge, MA), 30 g IM once a week (classified as low‐dose), IFNβ‐1a (Rebif; EMD Serono Inc., Rockland, MA), 22 or 44 g SC 3 times per week (classified as low‐dose and high‐dose, respectively), and IFNβ‐1b (Betaseron; Bayer HealthCare Pharmaceuticals Inc, Montville, NJ), 0.25 mg SC every other day (classified as high‐dose) | |
| Outcomes | Primary outcome:
Secondary outcomes:
A relapse was defined as the appearance of a new clinical sign or symptom or worsening of a previous symptom that persisted for ≥ 24 hours in the absence of fever | |
| Notes | NCT00489489 [24‐week study] and NCT00811395 [24‐week extension]. This study was sponsored by Sanofi‐Aventis | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | The authors reported that randomization was stratified by country and IFN regimen (high‐dose or low‐dose). This was an international multicentre clinical trial, the random sequence generation was probably made by software |
| Allocation concealment (selection bias) | Low risk | The authors did not describe the method of allocation concealment. This was an international multicentre clinical trial, central randomization was probably used |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "A phase II multicenter, placebo controlled, double‐blind, randomised study comparing 2 doses of teriflunomide in patients with relapsing MS receiving a stable dose of IFNβ was conducted" Comment: IFNβ regimens were diverse. It was not a truly double‐blind, double‐dummy study |
| Blinding of outcome assessment (detection bias) | High risk | Quote: "Each occurrence of relapse was confirmed by the treating neurologist, based on objective assessments by an independent evaluator who was blinded to treatment allocation." "Adverse events were reported by the patient or the investigator" Comment: relapse was confirmed by the treating neurologist, who was also responsible for reporting. Blinding of outcome assessment was probably not adequate |
| Incomplete outcome data (attrition bias) | High risk | According to the study disposition, 118 participants were randomly assigned. 2 participants (1 in each teriflunomide group) were excluded before treatment because of protocol violations, leaving 116 exposed to study medication for 24 weeks. 86 participants entered the 24‐week extension phase. 75 participants completed 1 year. 43 (36.4%) participants withdrew from study at 48 weeks |
| Selective reporting (reporting bias) | Low risk | All listed outcomes were reported adequately |
| Other bias | High risk | Quote: "The study funding was supported by Sanofi‐Aventis" Comment: conflicts of interest probably existed. There was probably a high risk of bias |
| Methods | Phase 3, multicentre, placebo‐controlled, double‐blind, randomized study (TERACLES study) Treatment duration: 24‐108 weeks ITT population: all randomized and treated participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received | |
| Participants | Inclusion criteria: aged 18‐55 years; diagnosis of MS by McDonald's criteria; participant with relapsing forms of MS treated with IFNβ; stable dose of IFNβ for at least 6 months prior to randomization; disease activity in the 12 months prior to randomization and after first 3 months of IFNβ treatment (at least 1 relapse supported by EDSS or equivalent neurological examination, or, at least 1 brain or spinal cord MRI with at least 1 T1 Gd‐enhancing lesion) Baseline demographic and clinical characteristics were generally well balanced among the study groups Summary of baseline characteristics of participants (placebo + IFNβ: G1 (n = 177), teriflunomide 7 mg + IFNβ: G2 (n = 178), teriflunomide 14 mg + INFβ: G3 (n = 179) Age (mean ± SD): G1 = 38.3 ± 8.9 years, G2 = 38.7 ± 9.5 years, G3 = 37.7 ± 9.2 years Women: G1 = 113 (63.8%), G2 = 125 (70.2%), G3 = 114 (63.7%) Region of enrolment: America G1 = 33 (32.8%), G2 = 30 (16.9%), G3 = 37 (20.7%); Western Europe G1 = 86 (48.6%), G2 = 86 (48.3%), G3 = 79 (44.1%); Eastern Europe G1 = 51 (28.8%), G2 = 51 (28.7%), G3 = 56 (31.3%); Asia, Africa and Australia G1 = 7 (4.0%), G2 = 11 (6.2%), G3 = 7 (3.9%) Time since first diagnosis of MS (mean ± SD): G1 = 7.0 ± 5.6 years, G2 = 6.6 ± 5.6 years, G3 = 6.8 ± 5.9 years MS subtype: relapsing‐remitting: G1 = 174 (98.3%), G2 = 173 (97.2%), G3 = 175 (97.8%); secondary progressive: G1 = 2 (1.1%), G2 = 3 (1.7%), G3 = 4 (2.2%); progressive relapsing: G1 = 1 (0.6%), G2 = 2 (1.1%), G3 = 0 (0%) Number of relapse within the past 12 months (median (range)): G1 = 1 (0‐4), G2 = 1 (0‐3), G3 = 1 (0‐4) Number of relapse within the past 2 years (median (range)): G1 = 2 (0‐6), G2 = 2 (0‐8), G3 = 2 (0‐8) Time since most recent MS relapse onset) (median (range)): G1 = 5.0 (1.0‐75.0) months, G2 = 5.0 (1.0‐36.0) months, G3 = 4.0 (1.0‐174.0) months EDSS score (mean ± SD): G1 = 2.67 ± 1.25, G2 = 2.63 ± 1.37, G3 = 2.64 ± 1.18 Dose level of IFNβ based on IVRS: high dose: G1 = 120 (67.8%), G2 = 128 (71.9%), G3 = 120 (67.0%); low dose: G1 = 57 (32.2%), G2 = 50 (28.1%), G3 = 59 (33.0%) | |
| Interventions | Experimental group 1: teriflunomide 7 mg once daily + IFNβ (any of the IFNβ) (n = 178) Experimental group 2: teriflunomide 14 mg once daily + IFNβ (any of the IFNβ) (n = 179) Control group: matching placebo (for teriflunomide) once daily + IFNβ (any of the IFNβ) (n = 177) | |
| Outcomes | Primary outcome:
Secondary outcomes:
| |
| Notes | The recruitment initiated in January 2011 was discontinued in December 2012 following the decision of the Sponsor (Sanofi‐Aventis) to discontinue the study, the common treatment end date was defined as 28 February 2013 (treatment duration 24‐108 weeks) 846 participants were screened at 185 sites in 28 countries ClinicalTrials.gov number: NCT01252355 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomisation was stratified by investigational site and Interferon‐β dose level (high/low)" Comments: this was an international multicentre clinical trial, the random sequence generation was probably made by software |
| Allocation concealment (selection bias) | Low risk | Quote: "Assignment to groups was done centrally using an IVRS in a 1:1:1 ratio after confirmation of selection criteria" Comments: allocation concealment was adequate |
| Blinding of participants and personnel (performance bias) | High risk | Any of the IFNβ was used, as long as the IFNβ was approved for marketed use in the country where the participant was enrolled Comments: IFNβ regimens were diverse. It was not a truly double‐blind, double‐dummy study |
| Blinding of outcome assessment (detection bias) | High risk | Participant, investigator and outcomes assessor were blinded Comments: unclear whether all outcome assessors were independent of the treating neurologist who recorded and managed adverse events |
| Incomplete outcome data (attrition bias) | High risk | Study was prematurely terminated by the sponsor. All participants did not complete the study Comments: high risk of attrition bias existed |
| Selective reporting (reporting bias) | Low risk | All pre‐set outcomes in the protocol were described in the results Comments: reporting bias was low |
| Other bias | High risk | Quote: "The study was sponsored by Sanofi‐Aventis" |
| Methods | Phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group study (TEMSO study) Follow‐up period: 108 weeks Population included in data analyses: people who underwent randomization and were exposed to study medication for at least 1 day Did not use the ITT analysis principle | |
| Participants | Inclusion criteria: people aged 18‐55 years; meeting the 2001 McDonald criteria for a diagnosis of MS; with a relapsing clinical course; with or without progression; having a score of ≤ 5.5 on the EDSS; having at least 2 clinical relapses in the previous 2 years or 1 relapse during the preceding year, but no relapses in the 60 days before randomization Exclusion criteria: people with other systemic diseases; pregnant; planning to conceive during the trial period All baseline characteristics were well matched among the groups Summary of participant characteristics at baseline (placebo: G1 (n = 363), teriflunomide 7 mg: G2 (n = 366), teriflunomide 14 mg: G3 (n = 359) Age (mean ± SD): G1 = 38.4 ± 9.0 years, G2 = 37.4 ± 9.0 years, G3 = 37.8 ± 8.2 years Women: G1 = 275 (75.8%), G2 = 255 (69.7%), G3 = 225 (71.0%) White: G1 = 356 (98.3%), G2 = 355 (97.3%), G3 = 347 (96.9%) Region: Western Europe G1 = 167 (46.0%), G2 = 167 (45.6%), G3 = 170 (47.4%); Eastern Europe G1 = 114 (31.4%), G2 = 116 (31.7%), G3 = 108 (30.1%); Americas G1 = 82 (22.6%), G2 = 83 (22.7%), G3 = 81 (22.6%) Time from first symptom of MS (mean ± SD): G1 = 8.6 ± 7.1 years, G2 = 8.8 ± 6.8 years, G3 = 8.7 ± 6.7 years Relapse (mean ± SD): in previous year G1 = 1.4 ± 0.7, G2 = 1.4 ± 0.7, G3 = 1.3 ± 0.7; in previous 2 years G1 = 2.2 ± 1.0, G2 = 2.3 ± 1.2, G3 = 2.2 ± 1.0 MS subtype: relapsing‐remitting G1 = 329 (90.6%), G2 = 333 (91.0%), G3 = 333 (92.8%); secondary progressive G1 = 22 (6.1%), G2 = 17 (4.6%), G3 = 12 (3.3%); progressive relapsing G1 = 12 (3.3%), G2 = 16 (4.4%), G3 = 14 (3.9%) Use of DMT in previous 2 years: G1 = 90 (24.8%), G2 = 102 (27.9%), G3 = 102 (28.4%); IFNβ‐1a G1 = 58 (16.0%), G2 = 74 (20.2%), G3 = 62 (17.3%); IFNβ‐1b G1 = 18 (5.0%), G2 = 22 (6.0%), G3 = 27 (7.5%); glatiramer acetate G1 = 36 (9.9%), G2 = 23 (6.3%), G3 = 43 (12.0%) EDSS score (mean ± SD): G1 = 2.68 ± 1.34, G2 = 2.68 ± 1.34, G3 = 2.67 ± 1.24 FIS score (mean ± SD): G1 = 53.2 ± 37.9, G2 = 50.4 ± 35.6, G3 = 50.3 ± 35.9 Total lesion volume on MRI (mean ± SD): G1 = 19.34 ± 18.94 mL, G2 = 20.37 ± 20.59 mL, G3 = 18.08 ± 17.49 mL Number of participants with Gd‐enhancing lesions: G1 = 137 (38.2%), G2 = 127 (35.3%), G3 = 125 (35.2%) Number of Gd‐enhancing lesions on T1‐weighted images (mean ± SD): G1 = 1.66 ± 3.55, G2 = 1.50 ± 3.96, G3 = 1.81 ± 5.17 Volume of hypointense lesions on T1‐weighted images (mean ± SD): G1 = 3.26 ± 3.64, G2 = 3.35 ± 3.96, G3 = 2.91 ± 3.25 Brain parenchymal fraction (mean ± SD): G1 = 0.76 ± 0.02, G2 = 0.76 ± 0.02, G3 = 0.76 ± 0.02 | |
| Interventions | Experimental group 1: oral teriflunomide 7 mg once daily (n = 366) Experimental group 2: oral teriflunomide 14 mg once daily (n = 359) Control group: matching oral placebo once daily (n = 363) | |
| Outcomes | Primary outcome:
Secondary outcomes:
A relapse was defined as the appearance of a new clinical sign or symptom, or clinical worsening of a previous sign or symptom that had been stable for at least 30 days and that persisted for a minimum of 24 hours in the absence of fever. Confirmed relapses required an increase of 1 point in each of 2 EDSS functional‐system scores or of 2 points in 1 EDSS functional‐system score (excluding bowel and bladder function and cerebral function) or an increase of 0.5 points in the EDSS score from the previous clinically stable assessment Sustained disability progression was defined as an increase from baseline of at least 1.0 point in the EDSS score (or at least 0.5 points for participants with a baseline EDSS score > 5.5) that persisted for at least 12 weeks | |
| Notes | This was the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, sponsored by Sanofi‐Aventis. The investigators collected the data and the sponsor analysed the data ClinicalTrials.gov number: NCT00134563 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | The authors reported that randomization was stratified according to the baseline EDSS score (≤ 3.5 or > 3.5) and according to trial site, with a block size of 6. We wrote to the principal author for random sequence generation, the principal author described that the IVRS assigned the randomization number from a list that was loaded in the database Comment: sequence generation was adequate |
| Allocation concealment (selection bias) | Low risk | The method of allocation concealment was not reported. We wrote to the principal author, the principal author offered central randomization via an IVRS Comment: allocation concealment was adequate |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "Treating neurologist was unaware of treatment assignments but was aware of any side effects that could potentially be related to active therapy" The principal author described the study medication teriflunomide (7 mg and 14 mg) and placebo were supplied as identical tablets Comment: participants and personnel were blinded to the allocated interventions |
| Blinding of outcome assessment (detection bias) | High risk | Quote: "A treating neurologist at each site was responsible for recording and managing adverse events, assessing relapses, and monitoring safety assessments." "An independent, specially trained and certified examining neurologist determined all the EDSS scores and performed all assessments of functional systems." "The examining neurologists were unaware of treatment assignments, only the treating neurologist was aware of any side effects that could potentially be related to active therapy" Comment: treating neurologist who recorded adverse events was responsible for assessment of relapses, blinding of relapse assessment was probably not adequate |
| Incomplete outcome data (attrition bias) | Unclear risk | According to the Figure 1, 104 participants in placebo group, 92 participants in teriflunomide 7 mg group and 96 participants in teriflunomide 14 mg group discontinued study treatment Quote: "Of the patients who discontinued the study medication prematurely, 31, 22, and 20 patients in the placebo, teriflunomide 7 mg group, and higher‐dose teriflunomide groups, respectively, completed the planned follow‐up" Comment: overall, 219 (20.1%) participants were lost‐to follow‐up (73 (20.1%) participants in placebo group, 70 (19.1%) participants in teriflunomide 7 mg group, 76 (21.2%) participants in teriflunomide 14 mg group). There was no sufficient information to understand the reasons for study discontinuation and their balance among the 3 groups |
| Selective reporting (reporting bias) | Low risk | All listed outcomes were reported adequately |
| Other bias | High risk | Quote: "The study was sponsored by Sanofi‐Aventis." "Data were collected by the investigators and analysed by the sponsor." "3 co‐authors (HB, PT and LW) of the published paper were affiliated to Sanofi‐Aventis" |
| Methods | Phase 3, multicentre, parallel‐group, rater‐blinded study (TENERE study) Population included in data analyses: efficacy analyses were conducted on the ITT population, which included all randomized participants. The safety analysis included all randomized participants exposed to study medication | |
| Participants | Inclusion criteria: people aged≥ 18 years; meeting the 2005 McDonald criteria for a diagnosis of MS; having a relapsing clinical course; with or without progression; with an EDSS score ≤ 5.5 at screening; being relapse free for 30 days prior to randomization Exclusion criteria: people with prior use of SC IFNβ‐1a, teriflunomide or leflunomide; prior or ongoing use of natalizumab, cladribine, mitoxantrone or other immunosuppressants; use of other interferons, glatiramer acetate, intravenous immunoglobulins or cytokine therapy within 3 months; having other relevant systemic illnesses; being pregnant, breast‐feeding, or both; planning to conceive Baseline demographics and characteristics were balanced except for a lower DMT use in the past 2 years in the teriflunomide 14 mg group compared with the IFNβ‐1a group Summary of participant characteristics at baseline (IFNβ‐1a: G1 (n = 104), teriflunomide 7 mg: G2 (n = 109), teriflunomide 14 mg: G3 (n = 111) Age (mean ± SD): G1 = 37.0 ± 10.6 years, G2 = 35.2 ± 9.2 years, G3 = 36.8 ± 10.3 years Female: G1 = 71 (68.3%), G2 = 70 (64.2%), G3 = 78 (70.3%) White: G1 = 104 (100%), G2 = 109 (100%), G3 = 111 (100%) Region: Eastern Europe G1 = 35 (33.7%), G2 = 39 (35.8%), G3 = 41 (36.9%); Western Europe and Africa G1 = 62 (59.6%), G2 = 62 (56.9%), G3 = 64 (57.7%); Americas G1 = 7 (6.7%), G2 = 8 (7.3%), G3 = 6 (5.4%) Time since first symptom of MS (mean ± SD): G1 = 7.7 ± 7.6 years, G2 = 7.0 ± 6.9 years, G3 = 6.6 ± 7.6 years Relapse (mean ± SD): within previous year G1 = 1.2 ± 1.0, G2 = 1.3 ± 0.8, G3 = 1.4 ± 0.8; within previous 2 years G1 = 1.7 ± 1.1, G2 = 1.7 ± 0.9, G3 = 1.7 ± 0.9 MS subtype: relapsing‐remitting G1 = 104 (100%), G2 = 109 (100%), G3 = 108 (97.3%); secondary progressive G1 = 0, G2 = 0, G3 = 1 (0.9%); progressive relapsing G1 = 0, G2 = 0, G3 = 2 (1.8%) Use of DMT in previous 2 years: G1 = 25 (24.0%), G2 = 23 (21.1%), G3 = 13 (11.7%); IFNβ‐1a G1 = 6 (5.8%), G2 = 6 (5.5%), G3 = 3 (2.7%); IFNβ‐1b G1 = 10 (9.6%), G2 = 9 (8.3%), G3 = 5 (4.5%); glatiramer acetate G1 = 12 (11.5%), G2 = 10 (9.2%), G3 = 7 (6.3%) Baseline EDSS score (mean ± SD): G1 = 2.0 ± 1.2, G2 = 2.0 ± 1.2, G3 = 2.3 ± 1.4 Baseline FIS score (mean ± SD): G1 = 34.2 ± 32.7, G2 = 39.5 ± 34.8, G3 = 42.5 ± 37.8 | |
| Interventions | Experimental group 1: oral teriflunomide 7 mg once daily (n = 109) Experimental group 2: oral teriflunomide 14 mg once daily (n = 111) Control group: IFNβ‐1a 44 μg, SC injection 3 times per week (n = 104) Treatment duration: 48‐115 weeks. The study was completed 48 weeks after the last participant was randomized, resulting in a variable duration of follow‐up. Median duration of exposure was 60.1 weeks in the IFNβ‐1a group, 66.6 weeks in the teriflunomide 7 mg group and 64.2 weeks in the teriflunomide 14 mg group. Median duration of exposure for all treatment groups was 63.6 weeks; actual maximum exposure was 115 weeks in any group | |
| Outcomes | Primary outcome:
Secondary outcomes:
Relapse criteria required the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom (previously stable for at least 30 days) that persisted for at least 24 hours without fever | |
| Notes | Study funded by Genzyme, a Sanofi company. Editorial support was provided by Meg Church, Fishawack Communications, Ltd, also funded by Genzyme ClinicalTrials.gov number: NCT00883337 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomised 1:1:1 to teriflunomide 7 mg or 14 mg (double‐blind) or IFNβ‐1a (open‐label), and stratified by country (Americas, Eastern Europe, Western Europe and Africa) and baseline EDSS score (≤3.5 or >3.5)" Comment: this was an international multicentre clinical trial, the random sequence generation was probably made by software |
| Allocation concealment (selection bias) | Low risk | Comment: this was an international multicentre clinical trial, central randomization was probably used |
| Blinding of participants and personnel (performance bias) | High risk | Participants were randomized 1:1:1 to teriflunomide 7 mg or 14 mg (double‐blind) or IFNβ‐1a (open‐label) Comment: control (IFNβ‐1a) group was open‐label |
| Blinding of outcome assessment (detection bias) | High risk | Quote: "The treating neurologist was responsible for managing adverse events, and relapse and safety assessments, while an examining neurologist scored the Functional Systems and EDSS. The examining neurologist remained blinded to treatment and associated adverse events" Comment: treating neurologist who managed adverse events was responsible for assessment of relapses, blinding of relapse assessment was probably not adequate |
| Incomplete outcome data (attrition bias) | Unclear risk | The number and reasons of drop‐outs from the study were not reported in the published article Comment: incomplete outcome data were unclear, the risk of attrition bias was unclear |
| Selective reporting (reporting bias) | Low risk | All listed outcomes were reported adequately |
| Other bias | High risk | Quote: "This study was funded by Genzyme, a Sanofi company. Editorial support was provided by Meg Church, Fishawack Communications, Ltd, also funded by Genzyme, a Sanofi company" Comment: conflicts of interest probably existed. There was probably a high risk of bias |
CSF: cerebrospinal fluid; DMT: disease‐modifying therapy; EDSS: Expanded Disability Status Scale; FIS: Fatigue Impact Scale; Gd: gadolinium; IFNβ: interferon beta; IM: intramuscular; ITT: intention‐to‐treat; IQR: interquartile range; IVRS: interactive voice response system; MS: multiple sclerosis; MRI: magnetic resonance imaging; n: number of participants; SC: subcutaneous; SD: standard deviation; SF‐36: 36‐item Short Form.
Characteristics of excluded studies [ordered by study ID]
Ir a:
| Study | Reason for exclusion |
| Participants were diagnosed with a first clinical episode suggestive of MS rather than definite diagnosis of MS | |
| An RCT with a length of follow‐up shorter than 1 year |
MS: multiple sclerosis; RCT: randomized controlled trial.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
| Teriflunomide compared to placebo for multiple sclerosis | ||||||
| Patient or population: people with relapsing multiple sclerosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Teriflunomide | |||||
| Proportion of participants with at least 1 relapse at 1 year | 394 per 1000 | 237 per 1000 | RR 0.60 | 761 | ⊕⊕⊝⊝ | This outcome was considered low, because we considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to unblinded assessments for relapse and conflicts of interest (sensitivity analysis according to a likely‐case scenario showed a robustness for the results of this outcome, we considered that the high attrition bias did not influence the robustness of the results on relapse). Therefore, we downgraded the quality of evidence for this outcome by 2 levels |
| The proportion of participants with at least 1 relapse at 2 years | 545 per 1000 | 436 per 1000 | RR 0.80 | 722 | ⊕⊕⊝⊝ | This outcome was considered low, because we considered there were very serious limitation in study design and execution. The bias that influenced the validity of the results for this outcome included: the high risks of bias due to unblinded assessments for relapse and conflicts of interest. (Sensitivity analysis according to a likely‐case scenario showed a robustness for the results of this outcome, we considered that the unclear attrition bias did not influence the robustness of the results on relapse.) Therefore, we downgraded the quality of evidence for this outcome by 2 levels |
| The proportion of participants with disability progression at 1 year | 142 per 1000 | 78 per 1000 | RR 0.55 | 761 | ⊕⊝⊝⊝ | This outcome was considered very low based on the following reasons:
|
| The proportion of participants with disability progression at 2 years | 273 per 1000 | 202 per 1000 | RR 0.74 | 722 | ⊕⊝⊝⊝ | This outcome was considered very low based on the following reasons:
|
| The proportion of participants with diarrhoea at 2 years | 89 per 1000 | 179 per 1000 | RR 2.01 | 718 | ⊕⊕⊕⊝ | The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011 |
| The proportion of participants with hair thinning at 2 years | 33 per 1000 | 131 per 1000 | RR 3.94 | 718 | ⊕⊕⊕⊝ | The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011 |
| The proportion of participants with elevated ALT levels at 2 years | 67 per 1000 | 143 per 1000 | RR 2.14 | 718 | ⊕⊕⊕⊝ | The follow‐up periods were diverse in Confavreux 2014 and O'Connor 2011 (at least 48 weeks (Confavreux 2014) and 108 weeks (O'Connor 2011)). Treatment duration of participants in Confavreux 2014 was variable, ending 48 weeks after the last participant was included (a maximum treatment duration of 173 weeks). Actually, the data on adverse events in Confavreux 2014 were not at 2 years. There was a heterogeneity in follow‐up period between the studies. Therefore, we did not combine the data on adverse events in Confavreux 2014 and O'Connor 2011 |
| *The basis for assumed risk is the placebo group risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). The assumed risk was defined as placebo group risk because only one study was evaluated. | ||||||
| GRADE Working Group grades of evidence | ||||||
| a High risks of bias existed in Confavreux 2014 due to unblinded assessments for relapse and conflicts of interest. b High risks of bias existed in O'Connor 2011 due to unblinded assessments for relapse and conflicts of interest. c High risks of bias existed in Confavreux 2014 due to effects of the high attrition bias on progression disability and conflicts of interest. d High risk of bias existed in O'Connor 2011 due to effects of the unclear attrition bias on progression disability and conflicts of interest. e Serious indirectness existed in Confavreux 2014 or in O'Connor 2011 because disability progression was confirmed at 3 months of follow‐up. f High risk of bias existed in O'Connor 2011 due to an unclear attrition bias and conflicts of interest. | ||||||
