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CLARIFY-MS

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study

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Year of Publication: 2023

Authors: Bruno Brochet, Alessandra Solari, Jeannette Lechner-Scott, ..., on behalf of the CLARIFY-MS Investigators

Journal: Multiple Sclerosis Journal

Citation: Mult Scler 2023;29(14):1808-1818

Link: https://doi.org/10.1177/13524585231205962

PDF: https://journals.sagepub.com/doi/epub/10...524585231205962

Clinical Question

Does cladribine tablets treatment improve health-related quality of life (HRQoL) in people with highly active relapsing multiple sclerosis over 24 months?

Bottom Line

In this single-arm, open-label phase IV study, cladribine tablets significantly improved MSQoL-54 physical and mental health composite scores over 24 months, with approximately 45-47% of participants achieving clinically meaningful improvement. ARR and disability outcomes were consistent with phase III data, and no new safety signals emerged. However, the lack of a control group limits causal inference.

Major Points

  • Phase IV, open-label, single-arm study of 482 patients with highly active RMS at 85 centers in 18 countries
  • Primary endpoints: MSQoL-54 physical (PCS) and mental health (MCS) composite score changes at 24 months
  • Both primary endpoints achieved: PCS improved +4.86 points (p<0.0001), MCS improved +4.80 points (p<0.0001)
  • 47.1% achieved MCID (≥5 points) for PCS, 44.5% for MCS - clinically meaningful improvements
  • Results consistent between treatment-naïve (n=134) and DMT-pretreated (n=348) subgroups
  • Largest improvements in role limitations due to physical problems (+12.19), health distress (+9.09), and emotional problems (+6.97)
  • ARR 0.13 (95% CI 0.11-0.16) over 24 months, consistent with CLARITY trial
  • 88% free from 6-month confirmed disability progression; median EDSS stable at 2.5
  • TSQM global satisfaction score 72.02 at 6 months, maintained through 24 months
  • Grade 3 lymphopenia in 19.7% (transient); no Grade 4 lymphopenia; no new severe/opportunistic infections
  • Study conducted June 2018 - August 2021; Month 24 visits all occurred during COVID-19 pandemic

Design

Study Type: Phase IV, prospective, open-label, exploratory, single-arm, multicenter study

Randomization:

Blinding: Open-label (no blinding)

Enrollment Period: June 2018 to August 2021

Follow-up Duration: 24 months

Centers: 85

Countries: 18 countries (not individually specified)

Sample Size: 482

Analysis: Repeated-measures mixed-effects linear model adjusted for baseline scores, EDSS, age, and within-country correlations; Poisson regression for ARR; MCID defined as ≥5 points; no adjustment for multiple testing on secondary/tertiary endpoints

Inclusion Criteria

  • Age ≥18 years
  • EDSS score ≤5.0
  • Highly active relapsing MS defined as:
  • - One relapse in the previous year AND ≥1 T1 Gd+ lesion or ≥9 T2 lesions while on DMT, OR
  • - ≥2 relapses in the previous year regardless of DMT status

Exclusion Criteria

  • Not specified in detail in this publication
  • Detailed criteria reported in prior interim analysis publication (reference 10)

Baseline Characteristics

Total:

  • N: 482
  • Age - Mean (SD): 37.4 years (10.4)
  • Female: 70.1%
  • Time since MS onset - Mean (SD) months: 99.1 (89.8)
  • Time since MS diagnosis - Mean (SD) months: 73.59 (76.04)
  • EDSS - Median (range): 2.5 (0.0-5.0)
  • Relapses in prior 12 months - 0: 0.8%
  • Relapses in prior 12 months - 1: 53.9%
  • Relapses in prior 12 months - ≥2: 45.2%
  • Prior DMT use in 6 months: 59.5%
  • MSQoL-54 PCS - Mean (SD): 60.2 (19.7)
  • MSQoL-54 MCS - Mean (SD): 61.2 (21.7)

Pretreatment_Naive:

  • N: 134
  • Age - Mean (SD): 35.2 years (11.3)
  • Female: 66.4%
  • Time since MS onset - Mean (SD) months: 42.6 (58.7)
  • Time since MS diagnosis - Mean (SD) months: 16.40 (32.97)
  • EDSS - Median (range): 2.0 (0.0-5.0)
  • Relapses in prior 12 months - 1: 26.1%
  • Relapses in prior 12 months - ≥2: 73.9%
  • MSQoL-54 PCS - Mean (SD): 62.5 (19.7)
  • MSQoL-54 MCS - Mean (SD): 61.8 (21.8)

DMT_Pretreated:

  • N: 348
  • Age - Mean (SD): 38.3 years (9.9)
  • Female: 71.6%
  • Time since MS onset - Mean (SD) months: 120.9 (90.3)
  • Time since MS diagnosis - Mean (SD) months: 95.62 (76.47)
  • EDSS - Median (range): 2.5 (0.0-5.0)
  • Relapses in prior 12 months - 0: 1.1%
  • Relapses in prior 12 months - 1: 64.7%
  • Relapses in prior 12 months - ≥2: 34.2%
  • Prior DMT use in 6 months: 82.5%
  • Prior interferons: 24.1%
  • Prior dimethyl fumarate: 18.1%
  • Prior glatiramer acetate: 11.8%
  • Prior teriflunomide: 11.2%
  • Prior fingolimod: 10.9%
  • MSQoL-54 PCS - Mean (SD): 59.3 (19.6)
  • MSQoL-54 MCS - Mean (SD): 61.0 (21.7)

Arms

FieldCladribine tablets
InterventionOral cladribine tablets at cumulative dose of 3.5 mg/kg over 2 years. Treatment given in 2 weeks per year (Weeks 1 and 5 of each year). Each treatment week comprised 4-5 days of 10-20 mg daily (1-2 tablets) depending on body weight.
Duration24 months (2 treatment courses)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline in MSQoL-54 Physical Health Composite Score (PCS) at Month 24PrimaryN/A (single-arm study)LS mean change +4.86 (95% CI 3.18-6.53); 47.1% achieved MCID ≥5 points<0.0001
MSQoL-54 Mental Health Composite Score (MCS) change at Month 24SecondaryN/ALS mean change +4.80 (95% CI 3.13-6.46); 44.5% achieved MCID ≥5 points<0.0001
MSQoL-54 PCS change at Month 12SecondaryN/ALS mean change +4.45 (95% CI 2.82-6.08)<0.0001
MSQoL-54 MCS change at Month 12SecondaryN/ALS mean change +4.67 (95% CI 3.13-6.21)<0.0001
MSQoL-54 Overall QoL score change at Month 24SecondaryN/ALS mean change +2.88 (95% CI 1.41-4.34)0.0001
Role limitations due to physical problems subscaleSecondaryN/ALS mean change +12.19 (95% CI 8.78-15.60) at Month 24<0.0001
Health distress subscaleSecondaryN/ALS mean change +9.09 (95% CI 6.42-11.76) at Month 24<0.0001
TSQM Global Satisfaction Score at Month 6SecondaryN/ALS mean 72.02 (95% CI 68.76-75.28)
Annualized Relapse Rate (ARR) over 24 monthsSecondaryN/ATotal: 0.13 (95% CI 0.11-0.16); Treatment-naïve: 0.08 (0.05-0.13); DMT-pretreated: 0.15 (0.12-0.18)
Qualifying relapse rateSecondaryN/A18.9% had ≥1 qualifying relapse; 17.2% required steroids; 5.0% required hospitalization
6-month confirmed disability progression (6mCDP)SecondaryN/A88.0% free from 6mCDP (treatment-naïve: 88.1%; DMT-pretreated: 87.9%)
EDSS at Month 24SecondaryN/AMedian 2.5 (stable from baseline)
Any TEAEAdverseN/A376/482 (78.0%)
Mild TEAEAdverseN/A191/482 (39.6%)
Moderate TEAEAdverseN/A169/482 (35.1%)
Severe TEAEAdverseN/A16/482 (3.3%)
Serious TEAEAdverseN/A26/482 (5.4%)
Treatment-related serious TEAEAdverseN/A5/482 (1.0%): overdose (3), cervical dysplasia (1), URTI (1)
TEAE leading to discontinuationAdverseN/A9/482 (1.9%)
DeathAdverseN/A0
HeadacheAdverseN/A105/482 (21.8%)
Lymphopenia (as AE)AdverseN/A73/482 (15.1%)
NasopharyngitisAdverseN/A65/482 (13.5%)
COVID-19AdverseN/A15/482 (3.1%)
Grade 3 lymphopenia (lab)AdverseN/A95/482 (19.7%); Treatment-naïve: 11.2%; DMT-pretreated: 23.0%
Grade 4 lymphopenia (lab)AdverseN/A0/482 (0%)

Subgroup Analysis

MSQoL-54 improvements were consistent between treatment-naïve (PCS +5.15, MCS +6.59) and DMT-pretreated (PCS +4.86, MCS +3.99) subgroups with overlapping CIs. Grade 3 lymphopenia was more common in DMT-pretreated (23.0%) vs treatment-naïve (11.2%) subgroup. Post hoc analyses showed baseline scores, time since diagnosis impacted outcomes; age and EDSS had marginal impact; gender had no predictive value.

Criticisms

  • Single-arm study with no control group - cannot establish causality or compare to natural history/other treatments
  • Open-label design introduces potential bias in patient-reported outcomes (participants knew they were receiving active treatment)
  • PRO improvements may reflect placebo effect, natural disease fluctuation, or regression to the mean
  • 49 participants (10%) excluded from MSQoL-54 analysis due to missing baseline or follow-up data
  • Month 24 visits all occurred during COVID-19 pandemic which may have affected HRQoL assessments
  • No MRI outcomes reported - cannot correlate QoL improvements with radiological disease activity
  • Sponsored by drug manufacturer (Merck) with several employees as authors
  • Highly selected population (highly active RMS) - may not generalize to broader MS population
  • Treatment satisfaction scores may be influenced by convenience of oral dosing schedule (2 weeks/year) rather than efficacy

Funding

Merck (CrossRef Funder ID: 10.13039/100009945). Medical writing provided by Merck affiliate. Four authors (N.A., A.Sm., A.N., B.K.) are Merck employees.

Based on: CLARIFY-MS (Multiple Sclerosis Journal, 2023)

Authors: Bruno Brochet, Alessandra Solari, Jeannette Lechner-Scott, ..., on behalf of the CLARIFY-MS Investigators

Citation: Mult Scler 2023;29(14):1808-1818

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