The effectiveness and costs of disease-modifying therapies for relapsing-remitting multiple sclerosis
This additional information describes in detail the effectiveness evidence and cost information disease-modifying therapies for relapsing-remitting multiple sclerosis. The selection of the effectiveness evidence had following steps: the literature search and selection of effectiveness evidence, quality appraisal and crosscheck with Current Care Guideline evidence summaries. We chose the network meta-analysis by Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 as the base of the effectiveness evidence. Table «Included studies of chosen interventions in the network meta-analysis by Chen et al. (2022) »3 describe the studies included in the Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 network meta-analysis.
Source of the effectiveness evidence: Chen et al. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systematic review and network meta-analysis. J Am Pharm Assoc (2003). 2022 Aug 1:S1544-3191(22)00241-2. doi: 10.1016/j.japh.2022.07. 009.
Literature search and selection
The literature search included network meta-analyses, meta-analyses, and systematic reviews of disease-modifying therapies for multiple sclerosis. The Current Care working group selected following mutually exclusive disease-modifying therapies for further examination: cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, ofatumumab, peginterferon beta-1a and teriflunomide. The effectiveness outcome selected by the Current Care working group was Annualized relapse rate (ARR).
Information specialist conducted the literature search in October 2022. The timeframe for the search was years 2000-2022. The search found 233 references. We searched for the most recent evidence by viewing only network meta-analyses published in 2022 and 2021, if satisfactory number of comprehensive studies were found. A total of ten network meta-analyses were published in 2022 and 2021 [Table «Description of the network meta-analyses of disease-modifying therapies for multiple sclerosis published in 2021 and 2022»1].
| Citation | Research aim | Number of trials, date of literature search | ARR outcome measure | Interventions | Comments |
|---|---|---|---|---|---|
| Chen et al. 2022 «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 | To conduct a systematic review and network meta- analysis to evaluate the efficacy and safety of disease-modifying therapies in adults with relapsing forms of multiple sclerosis. | 45 RCTs. July 2021. | Yes | alemtuzumab, cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, ozanimod, peginterferon beta-1a, ponesimod, siponimod, teriflunomide | Comprehensive, includes all expect diroximel fumarate intervention. |
| Silva et al. 2022 «Silva GD, Castrillo BB, Apóstolos-Pereira SL, Callegaro D. Is there a role for off-label high-efficacy disease-modifying drugs in progressive multiple sclerosis? A network meta-analysis. Acta Neurol S»2 | To compare on-label and off-label high-efficacy drugs for their effect on disability progression in PMS (progressive forms of multiple sclerosis). | 5 RCTs. December 2021. | No | alemtuzumab, cladribine, fingolimod, natalizumab, ocrelizumab, rituximab, siponimod | No ARR outcome. Only limited number of interventions. Only progressive forms of multiple sclerosis. |
| Asha et al. 2021 «Asha MZI, Al-Asaad Y, Khalil SFH. The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis. IBRO Neurosci Rep. 2021 Au»3 | To assess the comparative efficacy and safety of currently available anti-CD20 monoclonal antibodies (mAbs), including rituximab, ocrelizumab, and ofatumumab, versus a common comparator (interferon beta-1a [INFβ-1a]) in relapsing/remitting MS patients. | 5 RCTs. August 2020. | Yes | interferon beta-1a, ofatumumab, ocrelizumab, rituximab, teriflunomide | Only anti-CD20 monoclonal antibodies interventions. |
| Hennessy et al. 2022 «Hennessy B, Zierhut ML, Kracker H, Keenan A, Sidorenko T. Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized»4 | To assess the effect of ponesimod and other disease modifying treatments compared to placebo, as measured by 12-week confirmed disability accumulation and annualized relapse rate (ARR) in RMS patients. | 40 RCTs. No date of the literature search given. | Yes | alemtuzumab, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a [IM], interferon beta-1a [SC], interferon beta-1b, laquinimod, mitoxantrone natalizumab, ocrelizumab, ofatumumab, ozanimod, peginterferon beta-1a, ponesimod, siponimod teriflunomide. | Model-based meta-analysis (MBMA). Comprehensive, includes all expect diroximel fumarate intervention. |
| Bose et al. 2022 «Bose D, Ravi R, Maurya M, Pushparajan L, Konwar M. Impact of disease-modifying therapies on MRI outcomes in patients with relapsing -remitting multiple sclerosis: A systematic review and network meta-»5 | To investigate the efficacy based on MRI outcomes of FDA approved disease-modifying therapies for relapsing-remitting MS. | 26 RCTs. April 2021. | No. | cladribine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a [IM], interferon beta-1a [SC], interferon beta-1b, mitoxantrone, natalizumab ocrelizumab, ozanimod, pegylated interferon beta-1a, teriflunomide. | No ARR outcome. Only MRI outcomes. |
| Liu et al. 2021 «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 | To compare the efficacy and compliance of up-to-date disease modifying therapies in patients with remitting-relapsing MS. | 21 RCTs. November 2020. | Yes | alemtuzumab, azathioprine, cladribine, cyclophosphamide, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-beta, laquinimod, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, ozanimod, peginterferon beta, rituximab, teriflunomide. | Comprehensive, includes all expect diroximel fumarate intervention. |
| Tong et al. 2021 «Tong J, Zou Q, Chen Y, Liao X, Chen R, Ma L, Zhang D, Li Q. Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis. Neurol Sci. 2021 May;42(5):1687-1695»7 | To compare the efficacy and acceptability of S1P receptors for treating MS patients. | 13 RCTs. May 2020. | Yes | amiselimod, fingolimod, laquinimod, siponimod, ozanimod, ponesimod. | Only S1P receptors. |
| Bartosik-Psujek et al. 2021 «Bartosik-Psujek H, Kaczyński Ł, Górecka M, Rolka M, Wójcik R, Zięba P, Kaczor M. Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in mul»8 | To compare cladribine tablets (CT) with oral disease-modifying drugs (DMDs) – fingolimod (FTY), dimethyl fumarate (DMF), and teriflunomide (TERI) – with regard to NEDA-3 and its clinical (relapse and disability progression) and MRI. | 6 RCTs. June 2018. | No. | cladribine tablets with oral therapies: fingolimod, dimethyl fumarate, and teriflunomide. | Only oral disease-modifying therapies. No ARR outcome. |
| Wu et al. 2022 «Wu X, Xue T, Wang Z, Chen Z, Zhang X, Zhang W, Wang Z. Different Doses of Fingolimod in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. F»9 | To evaluate the efficacy and safety of the three approved anti-CD20 antibodies for the treatment of relapsing multiple sclerosis. | 10 RCTs. May 2022. | Yes | ocrelizumab, ofatumumab, rituximab. | Only anti-CD20 antibodies interventions. |
| Samjoo et al. 2021 «Samjoo IA, Worthington E, Drudge C, Zhao M, Cameron C, Häring DA, Stoneman D, Klotz L, Adlard N. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res. 2021 Apr;10(6):495-5»10 | To classify contemporary DMTs based on their efficacy in accordance with the guidelines set by the Association of British Neurologists (ABN). In addition to a direct comparative approach that closely followed the ABN guidelines, we employed an additional classification approach that used a network meta-analysis. | 32 RCTs. December 2019. | Yes | alemtuzumab, cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, glatiramer acetate, IFN-β-1a, IFN-β-1b, natalizumab, ocrelizumab, ofatumumab, ozanimod, peginterferon β-1a, teriflunomide. | Republished results of the original network meta-analysis (Samjoo et al. 2020) without new literature searches. Trials of diroximel fumarate was not found in the literature review. |
We selected three studies (Chen et al. 2022 «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1; Hennessy et al. 2022 «Hennessy B, Zierhut ML, Kracker H, Keenan A, Sidorenko T. Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized»4; Liu et al. 2021 «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6) for further examination. All three were recently published, included all except diroximel fumarate intervention and reported the ARR effectiveness outcome.
Quality of the selected network meta-analyses
We evaluated the quality of the three network meta-analyses by using AMSTAR 2 «Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non»11. The results of the quality appraisal are shown in Table « Critical appraisal of selected network meta-analyses by using AMSTAR 2 »2.
We also crosschecked the two network meta-analyses with Current Care Guideline evidence summaries to evaluate the comprehensiveness of the network meta-analyses. Compared to evidence summaries, the studies by Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 and Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 had few differences. Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 included all except five RCT studies (Comi et al. 2001; Kappos et al. 2006; Kira et al. 2022; Robert et al. 2020; NCT01252355) included in the evidence summaries. Robert et al. (2006) was not included because follow-up of the study was too short. Kira et al. (2022) was not included because it was published after the systematic review was done. NCT01252355 study was not included because sponsor prematurely decided to stop the study. We could not find reason why Kappos et al. (2006) and Comi et al. (2001) was not included. Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 lacked 9 RCT studies compared to evidence summaries (Bar-Or et al. 2018; Cohen et al. 2010; Comi et al. 2001; Ebers et al. 1998; Kappos et al. 2006; Kira et al. 2022; Robert et al. 2020; Zhang et al. 2016; NCT01252355). Kira et al. (2022) and NCT01252355 study were not included for the same reasons as in Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1. In the remaining studies, follow-up time was too short.
The network meta-analyses differed in the comprehensiveness. Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 lacked 21 studies which were included in the Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1. Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 limited the follow-up duration to 24-months and therefore excluded 12 studies (Cree et al. 2020; Lublin et al. 2013; Panitch et al. 2002; Kappos et al. 2018; Khan et al. 2016; Andersen et al. 2004; Stepien et al. 2013; Saida et al. 2012; Confavreux et al. 2014; Cohen et al. 2010; Olsson et al. 2014; Comi et al. 2019). Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 excluded 3 studies as high-risk bias (Johnnson et al. 1995; IFNB MS group 1993; Vermersch et al. 2014). Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 excluded 2 studies as they did not include interventions of the interests (Calabresi et al. 2014; Selmaj et al. 2013). Kappos et al. (2021) was published after the literature search of the Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6. For 3 studies (Cadavid et al. 2009; Calabrese et al. 2012; Coles et al. 2008), we were unable to find reasons for exclusion from Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6.
Chen al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 lacked 4 studies which were included in the Liu et al. (2021) «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6. Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 excluded Comi et al. (2012) as it did not include interventions of the interests. For 3 studies (Ebers et al. 1998; Saida et al. 2005; Rudick et al. 2006), we were unable to find reasons for exclusion from Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1.
| Chen et al. 2022 «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 | Hennessy et al. 2022 «Hennessy B, Zierhut ML, Kracker H, Keenan A, Sidorenko T. Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized»4 | Liu et al. 2021 «Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/»6 | ||||
| Question | Answer | Comments | Answer | Comments | Answer | Comments |
| Did the research questions and inclusion criteria for the review include the components of PICO? | Yes | Yes | Yes | |||
| Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? | No | No written protocol or guide cited. | No | No written protocol or guide cited. | Yes | |
| Did the review authors explain their selection of the study designs for inclusion in the review? | Yes | Yes | Yes | |||
| Did the review authors use a comprehensive literature search strategy? | Partial yes | Unclear if searched the reference lists or bibliographies of included studies. | No | The search strategy was reported imprecisely.The study did not meet the minimum requirement of searching at least 2 databases and did not provide key word and/or search strategy. | Partial yes | Unclear if searched the reference lists or bibliographies of included studies, searched trial/study registries or searched for grey literature. |
| Did the review authors perform study selection in duplicate? | Yes | No | Unclear if review authors performed study selection in duplicate. | Yes | ||
| Did the review authors perform data extraction in duplicate? | Yes | No | Unclear if review authors performed data extraction in duplicate. | Yes | ||
| Did the review authors provide a list of excluded studies and justify the exclusions? | Partial yes | No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram. | Partial yes | No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram. | Partial yes | No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram. |
| Did the review authors describe the included studies in adequate detail? | Yes | No | Study did not describe the included studies. | No | Study did not describe the populations of the included studies. | |
| Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? | Yes | No | Study authors did not assess the risk of bias (RoB) in individual studies. | Yes | ||
| Did the review authors report on the sources of funding for the studies included in the review? | No | Study did not report the sources of funding of the included studies. | No | Study did not report the sources of funding of the included studies. | No | Study did not report the sources of funding of the included studies. |
| If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? | Yes | Yes | Yes | |||
| If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? | No | Included all RCTs regardless of the RoB and did not perform analyses to investigate possible impact of RoB on estimates. | No | Included all RCTs regardless of the RoB and did not perform analyses to investigate possible impact of RoB on estimates. | Yes | |
| Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review? | No | Included all RCTs regardless of the RoB and did not discuss the likely impact of the RoB on the results. | No | Included all RCTs regardless of the RoB and did not discuss the likely impact of the RoB on the results. | Yes | |
| Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? | Yes | Yes | Yes | |||
| If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? | Yes | No | Did not perform graphical or statistical tests for publication bias and discuss the likelihood and magnitude of impact of publication bias. | Yes | ||
| Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? | Yes | No | Study was industry funded. All authors were employees of the industry. Study did not describe how they managed potential conflict of interest. | Yes | ||
| Summary of the quality | Yes n=10 Partial yes n=2 No n=4 | Yes n=4 Partial yes n=1 No n=11 | Yes n=12 Partial yes n=2 No n=2 | |||
RCT=randomized controlled trial; RoB=risk of bias
We chose the network meta-analysis by Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 as the base of our effectiveness estimates as it was the most comprehensive study by including all except diroximel fumarate of the selected interventions. The crosscheck with the evidence summaries of the Current Care Guideline «MS-tauti»1 showed that the Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 included the most comprehensively relevant effectiveness studies. Even the study did not have written protocol, it had comprehensive description of the literature search, inclusion and exclusion criteria. The study included all RCTs regardless of the RoB and did not perform analyses to investigate possible impact of RoB on estimates or discuss the likely impact of the RoB on the results. The study judged that the overall RoB of the included trials was high. The study reported evidence certainty by GRADE and downgraded the certainty of results owing to serious issues of RoB and imprecision. For all our comparisons, the GRADE was judged as "low quality of evidence".
The effectiveness evidence
The Chen et al. (2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 reported RRs and 95 % CIs for the Current Care working group's selected interventions. We did not convert the RRs to NNTs as the ARR-outcome should not be used to compute NNT (Okwuokenye et al. 2017) «Okwuokenye M, Zhang A, Pace A, Peace KE. Number Needed to Treat in Multiple Sclerosis Clinical Trials. Neurol Ther. 2017 Jun;6(1):1-9. doi: 10.1007/s40120-017-0063-y. Epub 2017 Feb 7. »12.
Network meta-analysis (Chen et al. 2022) «Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systemat»1 included 35 RCTs of selected interventions and outcome. 14 RCTs compared interventions against placebo. Duration of the selected RCTs varied from 1 to 4,5 years. All studies included adult patients with relapsing multiple sclerosis diagnosed according to McDonald's criteria. Average Expanded Disability Status Scale (EDSS) varied from 1.9 to 5.0. The characteristics of original RCTs are presented in the Table «Included studies of chosen interventions in the network meta-analysis by Chen et al. (2022) »3. Diroximel fumarate was missing from all network meta-analyses as it has no evidence from RCT-study. RR-result was assumed to be same as for dimethyl fumarate as FDA has evaluated the two to be bioequivalent «Diroksimeelifumaraatti näyttää lääkehoidon alkuvaiheessa aiheuttavan vähemmän maha-suolikanavan haittavaikutuksia kuin dimetyylifumaraatti.»B.
| Study | Interventions and comparators | Sample size | EDSS (Expanded Disability Status Scale) | Follow-up period |
|---|---|---|---|---|
| ASSESS Cree et al. 2020 | Fingolimod 0,5mg | 352 | 2.74 | 15 months |
| Glatiramer acetate 20mg | 342 | 2.73 | ||
| BECOME Cadavid et al. 2009 | Glatiramer acetate 20 mg | 39 | 2.0 | 2 years |
| IFN beta-1b 250 µg | 36 | 2.0 | ||
| BEYOND O'Connor et al. 2009 | Glatiramer acetate 20 mg | 448 | 2.28 | 2 years |
| IFN beta-1b 250 µg | 897 | 2.35 | ||
| BRAVO Vollmer et al. 2014 | im. IFN-beta-1a 30 µg | 447 | 2.5 | 2 years |
| Placebo | 450 | 2.5 | ||
| Calabrese et al. 2012 | sc. IFN beta-1a 44 µg | 46 | 1.9 | 2 years |
| im. IFN beta-1a 30 µg | 47 | 1.9 | ||
| Glatiramer acetate 20 mg | 48 | 2.1 | ||
| CAMMS223 Coles et al. 2008 | Alemtuzumab 12 mg | 112 | 1.9 | 2 years |
| sc. IFN beta-1a 44 µg | 111 | 1.9 | ||
| CARE-MS 1 Cohen et al. 2012 | Alemtuzumab 12 mg | 376 | 2.0 | 2 years |
| sc. IFN beta-1a 44 µg | 187 | 2.0 | ||
| CARE-MS 2 Coles et al. 2012 | Alemtuzumab 12 mg | 426 | 2.7 | 2 years |
| sc. IFN beta-1a 44 µg | 202 | 2.7 | ||
| CLARITY Giovannoni et al. 2010 | Cladribine 3,5 mg | 433 | 2.8 | 2 years |
| Placebo | 437 | 2.9 | ||
| CombiRx Lublin et al. 2013 | im. IFN beta-1a 30 µg | 250 | 2.0 | 2 years |
| Glatiramer acetate 20mg | 259 | 1.9 | ||
| CONFIRM Fox et al. 2012 | Dimethyl fumarate 240 mg | 359 | 2.6 | 2 years |
| Glatiramer acetate 20mg | 350 | 2.6 | ||
| Placebo | 363 | 2.6 | ||
| Copolymer 1 MS Group Johnnson et al. 1995 | Glatiramer acetate 20mg | 125 | 2.8 | 2 years |
| Placebo | 126 | 2.4 | ||
| DEFINE Gold wet al. 2012 | Dimethyl fumarate 240 mg | 410 | 2.40 | 2 years |
| Placebo | 408 | 2.48 | ||
| EVIDENCE Panitch et al. 2002 | sc IFN beta-1a 44 µg | 339 | 2.0 | 1 year |
| im IFN beta-1a 30 µg | 338 | 2.0 | ||
| FREEDOMS Kappos et al. 2010 | Fingolimod 0.5 µg | 425 | 2.3 | 1 year |
| Placebo | 418 | 2.5 | ||
| FREEDOMS 2 Calabresi et al. 2014 | Fingolimod 0.5 µg | 358 | 2.4 | 2 years |
| Placebo | 355 | 2.4 | ||
| GALA Khan et al. 2013 | Glatiramer acetate 40 mg | 943 | 2.8 | 1 year |
| Placebo | 461 | 2.7 | ||
| IFNB MS Group 1993 | IFN beta-1b 250 µg | 124 | 3.0 | 3 years |
| Placebo | 123 | 2.8 | ||
| INCOMIN Durelli et al. 2002 | im. IFN beta-1a 30 µg | 92 | 1.96 | 2 years |
| IFN beta-1b 250 µg | 96 | 1.97 | ||
| MSCRG Jacobs et al. 1996 | im. IFN beta-1a 30 µg | 158 | 2.4 | 3 years |
| Placebo | 143 | 2.3 | ||
| Andersen et al. 2004 | sc. IFN beta-1a 22 µg | 186 | 4.7 | 3 years |
| Placebo | 178 | 5.0 | ||
| OPERA 1 Hauser et al. 2017 | sc. IFN beta-1a 44 µg | 411 | 2.75 | 2 years |
| Ocrelizumab 600 mg | 410 | 2.86 | ||
| OPERA 2 Hauser et al. 2017 | sc. IFN beta-1a 44 µg | 418 | 2.84 | 2 years |
| Ocrelizumab 600 mg | 417 | 2.78 | ||
| REGARD Mikol et al. 2008 | Glatiramer acetate 20 mg | 378 | 2.33 | 2 years |
| sc. IFN beta-1a 44 µg | 386 | 2.35 | ||
| Stepien et al. 2013 | im. IFN beta-1a 30 µg | 20 | 2.27 | 3 years |
| IFN beta-1b 250 µg | 18 | 2.09 | ||
| Saida et al. 2012 | Fingolimod 0.5 mg | 57 | 2.3 | 2 years |
| Placebo | 57 | 2.1 | ||
| TEMSO O'Connor er al. 2011 | Teriflunomide 7 mg | 366 | 2.68 | 2 years |
| Teriflunomide 14 mg | 359 | 2.67 | ||
| Placebo | 363 | 2.68 | ||
| TENERE Vermersch et al. 2014 | sc. IFN beta-1a 44 µg | 104 | 2.0 | 3 years |
| Teriflunomide 7 mg | 109 | 2.0 | ||
| Teriflunomide 14 mg | 111 | 2.3 | ||
| TOWER Confavreux et al. 2014 | Teriflunomide 7 mg | 408 | 2.71 | 2 years |
| Teriflunomide 14 mg | 372 | 2.71 | ||
| Placebo | 389 | 2.69 | ||
| TRANSFORMS Cohen et al. 2010 | im. IFN beta-1a 30 µg | 435 | 2.19 | 4,5 years |
| Fingolimod 0.5 mg | 431 | 2.24 | ||
| ASCLEPIOS 1 Hauser et al. 2020 | Ofatumumab 20 mg | 465 | 2.97 | 1,6 years |
| Teriflunomide 14 mg | 462 | 2.94 | ||
| ASCLEPIOS 2 Hauser et al. 2020 | Ofatumumab 20 mg | 481 | 2.90 | 1,6 years |
| Teriflunomide 14 mg | 474 | 2.86 | ||
| OPTIMUM Kappos et al. 2021 | Ponesimod 20 mg | 567 | 2.57 | 108 weeks |
| Teriflunomide 14 mg | 566 | 2.56 | ||
| RADIANCE Cohen et al. 2019 | Ozanimod 0,5 mg | 439 | 2.5 | 2 years |
| Ozanimod 1 mg | 433 | 2.6 | ||
| im. IFN Beta-1a 30 µg | 441 | 2.5 | ||
| SUNBEAM Comi et al. 2019 | Ozanimod 0,5 mg | 451 | 2.7 | 1 year |
| Ozanimod 1 mg | 447 | 2.6 | ||
| im. IFN Beta-1a 30 µg | 448 | 2.6 |
Annual medicine prices
The price information is from drug database available at Terveysportti health portal (Duodecim Publishing Company Ltd) «https://www.terveysportti.fi/terveysportti/koti»1. We use retail prices based on the cheapest product price per day of the medical substance in question. Costs exclude the loading doses at the start of the new medication and represent maintenance dose of the medication. Also, any other direct or indirect costs or reimbursements are excluded. For cladribine, the dosing was based on the weight of patient. We used 70-80 kilograms, average weight group, to calculate the cost for the medication. Cladribine is used for 2 years, and effect lasts for 4 years. We calculated the cost relatively for 4 years and divided it by 4 so it would correspond to one-year costs of the medication. The cost per responder was not calculated as effectiveness results could not be presented as number needed to treat (NNT).
References
- Chen C, Zhang E, Zhu C, Wei R, Ma L, Dong X, Li R, Sun F, Zhou Y, Cui Y, Liu Z. Comparative efficacy and safety of disease-modifying therapies in patients with relapsing multiple sclerosis: A systematic review and network meta-analysis. J Am Pharm Assoc (2003). 2022 Aug 1:S1544-3191(22)00241-2. doi: 10.1016/j.japh.2022.07.009. Epub ahead of print. PMID: 36055929
- Silva GD, Castrillo BB, Apóstolos-Pereira SL, Callegaro D. Is there a role for off-label high-efficacy disease-modifying drugs in progressive multiple sclerosis? A network meta-analysis. Acta Neurol Scand. 2022 Nov;146(5):403-409. doi: 10.1111/ane.13697. Epub 2022 Sep 2. PMID: 36052576.
- Asha MZI, Al-Asaad Y, Khalil SFH. The comparative efficacy and safety of anti-CD20 monoclonal antibodies for relapsing-remitting multiple sclerosis: A network meta-analysis. IBRO Neurosci Rep. 2021 Aug 27;11:103-111. doi: 10.1016/j.ibneur.2021.08.003. PMID: 34505112; PMCID: PMC8411244.
- Hennessy B, Zierhut ML, Kracker H, Keenan A, Sidorenko T. Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate. Mult Scler Relat Disord. 2022 Aug;64:103908. doi: 10.1016/j.msard.2022.103908. Epub 2022 May 23. PMID: 35803162.
- Bose D, Ravi R, Maurya M, Pushparajan L, Konwar M. Impact of disease-modifying therapies on MRI outcomes in patients with relapsing -remitting multiple sclerosis: A systematic review and network meta-analysis. Mult Scler Relat Disord. 2022 May;61:103760. doi: 10.1016/j.msard.2022.103760. Epub 2022 Mar 22. PMID: 35381534.
- Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis. Autoimmun Rev. 2021 Jun;20(6):102826. doi: 10.1016/j.autrev.2021.102826. Epub 2021 Apr 18. PMID: 33878488.
- Tong J, Zou Q, Chen Y, Liao X, Chen R, Ma L, Zhang D, Li Q. Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: a meta-analysis. Neurol Sci. 2021 May;42(5):1687-1695. doi: 10.1007/s10072-021-05049-w. Epub 2021 Feb 1. Erratum in: Neurol Sci. 2021 Mar 19;: PMID: 33523319; PMCID: PMC8043952.
- Bartosik-Psujek H, Kaczyński Ł, Górecka M, Rolka M, Wójcik R, Zięba P, Kaczor M. Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in multiple sclerosis-A systematic review and network meta-analysis. Mult Scler Relat Disord. 2021 Apr;49:102769. doi: 10.1016/j.msard.2021.102769. Epub 2021 Jan 16. PMID: 33516133.
- Wu X, Xue T, Wang Z, Chen Z, Zhang X, Zhang W, Wang Z. Different Doses of Fingolimod in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol. 2021 May 17;12:621856. doi: 10.3389/fphar.2021.621856. PMID: 34079453; PMCID: PMC8165387.
- Samjoo IA, Worthington E, Drudge C, Zhao M, Cameron C, Häring DA, Stoneman D, Klotz L, Adlard N. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res. 2021 Apr;10(6):495-507. doi: 10.2217/cer-2020-0267. Epub 2021 Feb 23. PMID: 33620251.
- Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017 Sep 21;358:j4008.
- Okwuokenye M, Zhang A, Pace A, Peace KE. Number Needed to Treat in Multiple Sclerosis Clinical Trials. Neurol Ther. 2017 Jun;6(1):1-9. doi: 10.1007/s40120-017-0063-y. Epub 2017 Feb 7.