DELIVER-MS
(2026)Objective
Describe baseline decision-making, cohort selection, and reasons for declining randomization in a pragmatic RCT plus parallel observational study of early highly-effective (EHT) vs escalation (ESC) DMT approaches in treatment-naive relapsing-remitting multiple sclerosis (RRMS).
Study Summary
• Efficacy concerns were higher in the US than UK (27% vs 13%, p=0.002); safety concerns trended higher in the UK (12% vs 5.7%, p=0.061).
• Multivariate predictors of RCT (vs OBS) participation: pre-COVID era (COVID-era OR 0.15, post-vaccine OR 0.39 vs pre-COVID; both p<0.001), higher baseline brain parenchymal fraction (OR 1.34 per z-score, p=0.002), older age (OR 1.02/yr, p=0.037), lower relapse rate (OR 0.79, p=0.043), and lower SDMT (OR 0.98/point, p=0.009).
• Within the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT; US chose EHT more often than UK (82% vs 50%, p<0.001).
• Multivariate predictors of choosing EHT (vs ESC) in the OBS cohort: US site (UK OR 0.22, p<0.001), higher education (low-education OR 0.33, p<0.001), higher relapse rate (OR 1.55, p=0.025), higher T1 lesion volume (OR 1.21, p<0.001).
• Baseline RCT arms were well balanced (ESC n=193 vs EHT n=200); the primary DELIVER-MS efficacy endpoint (36-month brain volume loss) is expected in mid-2027.
Intervention
Baseline analysis of DMT decision-making in DELIVER-MS: EHT (natalizumab, ocrelizumab, ofatumumab, alemtuzumab, rituximab, or ublituximab) vs ESC (interferons, glatiramer acetate, teriflunomide, dimethyl/diroximel fumarate, or S1P modulators such as fingolimod/siponimod/ozanimod/ponesimod).
Inclusion Criteria
Treatment-naive adults 18-60 years with 2017 McDonald-criteria RRMS, EDSS ≤ 6.5, disease duration ≤ 5 years, willing to receive either an EHT or ESC first-line DMT.
Study Design
Arms: RCT (n=393 mITT: ESC 193, EHT 200) + parallel Observational (n=374 mITT: ESC 125, EHT 249) at 31 UK/US sites.
Patients per Arm: 816 enrolled; mITT 767 (RCT 393 [ESC 193 vs EHT 200] + OBS 374 [ESC 125 vs EHT 249]).
Outcome
• OBS cohort DMT choice: ESC 125/374 (33%) vs EHT 249/374 (67%); US 158/193 (82%) EHT vs UK 91/181 (50%) EHT (p<0.001).
• RCT-vs-OBS multivariate predictors: COVID era OR 0.15 (p<0.001), post-vaccine COVID OR 0.39 (p<0.001), BPF OR 1.34/z (p=0.002), age OR 1.02/yr (p=0.037), relapse rate OR 0.79 (p=0.043), SDMT OR 0.98 (p=0.009).
• EHT-choice (OBS) multivariate predictors: UK OR 0.22 (p<0.001), low education OR 0.33 (p<0.001), relapse rate OR 1.55 (p=0.025), T1 lesion volume OR 1.21 (p<0.001).
• Baseline randomized arms well balanced; primary 36-month brain-volume-loss efficacy outcome pending (expected 2027).
Bottom Line
DELIVER-MS enrolled 816 treatment-naive RRMS patients across 31 UK/US sites into a pragmatic RCT (n=393 mITT) and parallel observational study (n=374 mITT). Preference for a specific DMT (85%), efficacy concerns (20%), and safety concerns (9%) were the leading reasons for declining randomization; RCT participation was associated with older age, higher brain parenchymal fraction, and pre-COVID enrollment, while EHT choice in the observational cohort was associated with US enrollment, higher education, higher relapse rate, and greater T1 lesion volume. The RCT arms are well balanced; the definitive efficacy comparison (36-month brain atrophy) is still pending.
Major Points
- Pragmatic 2-arm RCT (EHT vs ESC) plus a parallel observational cohort for those who declined randomization, at 31 US/UK sites; 816 enrolled, 767 in the mITT analysis (393 RCT, 374 OBS).
- Reasons for declining RCT (n=371, multi-select): preference for a specific DMT 317 (85%), efficacy concerns 74 (20%), safety concerns 32 (8.6%), insurance 3 (0.8%), other 25 (6.7%).
- Efficacy concerns were higher in the US (27%) than the UK (13%) (p=0.002); safety concerns trended higher in the UK (12%) than the US (5.7%) (p=0.061).
- Independent predictors of RCT (vs OBS) participation in multivariate logistic regression: COVID-era enrollment (OR 0.15 vs pre-COVID, p<0.001), post-vaccine COVID era (OR 0.39, p<0.001), higher baseline brain parenchymal fraction (OR 1.34 per z-score, p=0.002), older age (OR 1.02/yr, p=0.037), lower SDMT (OR 0.98/point, p=0.009), and lower prior-year relapse rate (OR 0.79, p=0.043).
- OBS cohort DMT selection: 125/374 (33%) chose ESC, 249/374 (67%) chose EHT; US 158/193 (82%) chose EHT vs UK 91/181 (50%) (p<0.001).
- Independent predictors of choosing EHT (vs ESC) in the OBS cohort: UK site (OR 0.22 vs US, p<0.001), lower educational attainment (OR 0.33 for high school or less vs some college+, p<0.001), higher prior-year relapse rate (OR 1.55, p=0.025), and higher T1 lesion volume (OR 1.21, p<0.001).
- RCT arms (n=193 ESC vs n=200 EHT) were well balanced at baseline including the primary endpoint (baseline brain parenchymal fraction 0.839 vs 0.836).
- Among 317 people citing a specific-DMT preference for declining RCT, 100 (32%) ultimately started ESC and 217 (68%) started EHT; safety-driven decliners more often chose ESC (24/32 = 75%).
- The definitive DELIVER-MS efficacy comparison (36-month whole-brain volume loss, EHT vs ESC) is expected mid-2027 and is not reported in this paper.
Study Design
- Study Type
- Multi-center, pragmatic, open-label, rater-blinded, phase 4 randomized controlled trial with a parallel prospective observational cohort (participants who declined randomization); baseline / decision-making analysis paper.
- Randomization
- Yes
- Blinding
- Open-label for treating clinicians and participants; MRI raters (brain-volume analysis) are blinded to treatment allocation.
- Sample Size
- 816
- Follow-up
- 36 months (primary endpoint of the parent trial); baseline analysis in this paper.
- Centers
- 31
- Countries
- USA, United Kingdom
Primary Outcome
Definition: Reasons for declining randomization to the RCT (multi-select from Table 4), among 371/374 OBS participants who provided a reason.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Not applicable (single-arm descriptive outcome). | OBS cohort n=371: preference for a specific DMT 317 (85%); efficacy concerns 74 (20%); safety concerns 32 (8.6%); insurance issue 3 (0.8%); other 25 (6.7%). | - |
Limitations & Criticisms
- Baseline/design paper only - the definitive EHT-vs-ESC efficacy comparison (36-month brain volume loss) is not yet available (expected 2027), so no conclusions about which strategy is better can be drawn from this publication.
- Overrepresentation of academic MS centers, particularly in the US - EHT uptake in the OBS cohort (US 82%) is higher than reported in US population-level cohorts and limits generalizability.
- Upper age limit of 60 years excludes older RRMS patients where the safety/benefit balance of EHT is more uncertain.
- Reasons for declining the RCT were captured via a single questionnaire allowing multiple responses; qualitative interviews are ongoing but not yet reported.
- COVID-19 pandemic dramatically shifted RCT vs OBS participation (pre-COVID 68% RCT vs pandemic 29%), which may confound comparisons and reduce statistical power for the parent trial's ITT analysis.
- Open-label, patient-and-clinician-selected DMTs in the OBS cohort will require propensity-score adjustment for the observational comparisons and cannot fully eliminate confounding.
- The observed association between higher education and EHT choice raises concerns about health-literacy-based disparities in DMT selection but the study cannot separate education from race, deprivation, or clinician bias.
Citation
Mult Scler. 2026 Jun;32(7):722-736. DOI: 10.1177/13524585261449988