Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis.

OBJECTIVES: The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. METHODS: Analyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. RESULTS: Based on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were -6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. CONCLUSIONS: Thresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

Treatment preferences in relation to fatigue of patients with relapsing multiple sclerosis: A discrete choice experiment.

Background: Treatment decisions for multiple sclerosis (MS) are influenced by many factors such as disease symptoms, comorbidities, and tolerability. Objective: To determine how much relapsing MS patients were willing to accept the worsening of certain aspects of their MS in return for improvements in symptoms or treatment convenience. Methods: A web-based discrete choice experiment (DCE) was conducted in patients with relapsing MS. Multinomial logit models were used to estimate relative attribute importance (RAI) and to quantify attribute trade-offs. Results: The DCE was completed by 817 participants from the US, the UK, Poland, and Russia. The most valued attributes of MS therapy to participants were effects on physical fatigue (RAI = 22.3%), cognitive fatigue (RAI = 22.0%), relapses over 2 years (RAI = 20.7%), and MS progression (RAI = 18.4%). Participants would accept six additional relapses in 2 years and a decrease of 7 years in time to disease progression to improve either cognitive or physical fatigue from "quite a bit of difficulty" to "no difficulty." Conclusion: Patients strongly valued improving cognitive and physical fatigue and were willing to accept additional relapses or a shorter time to disease progression to have less fatigue. The impact of fatigue on MS patients' quality of life should be considered in treatment decisions.

The relevance of fatigue to relapse rate in multiple sclerosis: Applying patient preference data to the OPTIMUM trial.

BACKGROUND: In the OPTIMUM trial in patients with relapsing MS, treatment differences in annualized relapse rate (ARR, 0.088) and change in fatigue at week 108 (3.57 points, measured using the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis, symptom domain (FSIQ-RMS-S)) favored ponesimod over teriflunomide. However, the importance of the fatigue outcome to patients was unclear. OBJECTIVE: To assess the importance of the OPTIMUM FSIQ-RMS-S results using data from an MS discrete choice experiment (DCE). METHODS: The DCE included components to correlate levels of physical and cognitive fatigue with FSIQ-RMS-S scores. Changes in relapses/year and time to MS progression equivalent to the treatment difference in fatigue in OPTIMUM were determined for similar fatigue levels as mean baseline fatigue in OPTIMUM. RESULTS: DCE participants would accept 0.06 more relapses/year or a 0.15-0.17 year decrease in time to MS progression for a 3.57-point difference in physical fatigue on the FSIQ-RMS-S. To improve cognitive fatigue by 3.57-points on the FSIQ-RMS-S, DCE participants would accept 0.09-0.10 more relapses/year or a 0.24-0.28 year decrease in time to MS progression. CONCLUSION: MS patients would accept 0.06 more relapses/year to change their fatigue by a similar magnitude as the between-treatment difference observed in the OPTIMUM trial.

An exposure-response analysis of ponesimod clinical efficacy in a randomized phase III study in patients with relapsing multiple sclerosis.

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder and the most common cause of non-traumatic disability in young adults. The Phase 3 OPTIMUM study evaluated the efficacy and safety of oral ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 modulator, vs. teriflunomide in patients with relapsing multiple sclerosis (RMS). The aim of this analysis was to assess the effect of ponesimod and other disease modifying treatments (DMTs) compared to placebo, as measured by 12-week confirmed disability accumulation (CDA) and annualized relapse rate (ARR) in RMS patients. METHODS: A database was developed by Certara Inc. (USA) based on relevant clinical trials identified from searching the following sources: PubMed, clinicaltrials.gov, FDA and EMEA documents, and conference abstracts. This database consisted of 203 unique randomized controlled trials (RCTs) with 74 MS treatments and was subsequently filtered to include RCTs with more than 25 patients receiving monotherapy to treat RMS for at least 48 weeks. A model-based meta-analysis (MBMA) was performed on the filtered database to assess treatment effects measured by CDA and ARR. Analyzed data for CDA were digitized from published Kaplan-Meier plots. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time (proportional hazards). HRs were estimated for 12-week CDA for 17 DMTs vs. placebo. Additionally, mean ARR for each treatment arm was modelled, where relative effect versus placebo was estimated as a fixed effect parameter for each unique drug. A dose-response relationship was included if data for multiple doses were available. Relative treatment effect covariates explored for CDA and ARR included: percent of patients with relapsing-remitting MS (RRMS), trial start year, mean duration of disease, percent of patients who received DMTs within the prior 2 years (pDMT), mean number of relapses in the prior year, mean age, mean baseline EDSS score, and mean treatment duration (for ARR). RESULTS: The 12-week CDA model utilized longitudinal data from 26 RCTs (18 unique treatments [including placebo]), 69 treatment arms, 31,160 patients). The ARR model utilized data from 40 RCTs (18 unique treatments [including placebo], 100 treatment arms, 33,686 patients). Compared to placebo, ponesimod significantly reduced 12-week CDA by 39% (HR: 0.61; 95% CI: 0.45-0.82) and reduced ARR by 53% (rate ratio [RR]: 0.47; 95% CI: 0.39-0.58). Except for three DMTs (interferon ß-1b, glatiramer acetate, ozanimod), HR of 12-week CDA vs. placebo was significantly lower for the DMTs included in this analysis (HR range: 0.41 to 0.79). The ARR was significantly reduced for all DMTs compared to placebo (RR range: 0.29 to 0.82). A dose-response relationship indicated a potential dose-dependent effect (12-week CDA: 6 treatments; ARR: 8 treatments). Relative treatment effect was found to be significantly smaller in trials including more patients with prior DMT usage. Cross-trial heterogeneity in relative effects was assessed and found to be negligible; however, there is a possibility that confounders remain which may impact estimated relative treatment effects. CONCLUSIONS: Compared to placebo, ponesimod 20 mg significantly reduced both the risk of 12-week CDA and mean ARR, suggesting it has robust efficacy in the treatment of RMS. The study was funded by Janssen Research & Development, LLC.

Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies.

OBJECTIVE: To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated. RESULTS: A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0-9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%). CONCLUSION: The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free. TRIAL REGISTRATION INFORMATION: EudraCT Number 2008-006786-92 (Core study) and EudraCT Number 2009-011470-15 (Extension study).

Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial.

OBJECTIVE: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated. RESULTS: The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥ 1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema. CONCLUSIONS: Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration. TRIAL REGISTRATION NUMBER: NCT01006265.