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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

Characteristic	Total	Pretreatment_Naive	DMT_Pretreated
N	482	134	348
Age - Mean (SD)	37.4 years (10.4)	35.2 years (11.3)	38.3 years (9.9)
Female	70.1%	66.4%	71.6%
Time since MS onset - Mean (SD) months	99.1 (89.8)	42.6 (58.7)	120.9 (90.3)
Time since MS diagnosis - Mean (SD) months	73.59 (76.04)	16.40 (32.97)	95.62 (76.47)
EDSS - Median (range)	2.5 (0.0-5.0)	2.0 (0.0-5.0)	2.5 (0.0-5.0)
Relapses in prior 12 months - 0	0.8%		1.1%
Relapses in prior 12 months - 1	53.9%	26.1%	64.7%
Relapses in prior 12 months - ≥2	45.2%	73.9%	34.2%
Prior DMT use in 6 months	59.5%		82.5%
MSQoL-54 PCS - Mean (SD)	60.2 (19.7)	62.5 (19.7)	59.3 (19.6)
MSQoL-54 MCS - Mean (SD)	61.2 (21.7)	61.8 (21.8)	61.0 (21.7)
Prior interferons			24.1%
Prior dimethyl fumarate			18.1%
Prior glatiramer acetate			11.8%
Prior teriflunomide			11.2%
Prior fingolimod			10.9%

Arms

Field	Cladribine tablets
Intervention	Oral 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.
Duration	24 months (2 treatment courses)

Outcomes

Outcome	Type	Control	Intervention	P-value
Change from baseline in MSQoL-54 Physical Health Composite Score (PCS) at Month 24	Primary	N/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 24	Secondary	N/A	LS mean change +4.80 (95% CI 3.13-6.46); 44.5% achieved MCID ≥5 points	<0.0001
MSQoL-54 PCS change at Month 12	Secondary	N/A	LS mean change +4.45 (95% CI 2.82-6.08)	<0.0001
MSQoL-54 MCS change at Month 12	Secondary	N/A	LS mean change +4.67 (95% CI 3.13-6.21)	<0.0001
MSQoL-54 Overall QoL score change at Month 24	Secondary	N/A	LS mean change +2.88 (95% CI 1.41-4.34)	0.0001
Role limitations due to physical problems subscale	Secondary	N/A	LS mean change +12.19 (95% CI 8.78-15.60) at Month 24	<0.0001
Health distress subscale	Secondary	N/A	LS mean change +9.09 (95% CI 6.42-11.76) at Month 24	<0.0001
TSQM Global Satisfaction Score at Month 6	Secondary	N/A	LS mean 72.02 (95% CI 68.76-75.28)
Annualized Relapse Rate (ARR) over 24 months	Secondary	N/A	Total: 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 rate	Secondary	N/A	18.9% had ≥1 qualifying relapse; 17.2% required steroids; 5.0% required hospitalization
6-month confirmed disability progression (6mCDP)	Secondary	N/A	88.0% free from 6mCDP (treatment-naïve: 88.1%; DMT-pretreated: 87.9%)
EDSS at Month 24	Secondary	N/A	Median 2.5 (stable from baseline)
Any TEAE	Adverse	N/A	376/482 (78.0%)
Mild TEAE	Adverse	N/A	191/482 (39.6%)
Moderate TEAE	Adverse	N/A	169/482 (35.1%)
Severe TEAE	Adverse	N/A	16/482 (3.3%)
Serious TEAE	Adverse	N/A	26/482 (5.4%)
Treatment-related serious TEAE	Adverse	N/A	5/482 (1.0%): overdose (3), cervical dysplasia (1), URTI (1)
TEAE leading to discontinuation	Adverse	N/A	9/482 (1.9%)
Death	Adverse	N/A	0
Headache	Adverse	N/A	105/482 (21.8%)
Lymphopenia (as AE)	Adverse	N/A	73/482 (15.1%)
Nasopharyngitis	Adverse	N/A	65/482 (13.5%)
COVID-19	Adverse	N/A	15/482 (3.1%)
Grade 3 lymphopenia (lab)	Adverse	N/A	95/482 (19.7%); Treatment-naïve: 11.2%; DMT-pretreated: 23.0%
Grade 4 lymphopenia (lab)	Adverse	N/A	0/482 (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

Content summarized and formatted by NeuroTrials.ai.

CLARIFY-MS

(2023)

Objective

To evaluate health-related quality of life (HRQoL) using the MSQoL-54 instrument in people with highly active relapsing MS treated with cladribine tablets over 24 months

Study Summary

• MSQoL-54 physical and mental health composite scores improved significantly at 24 months vs baseline (+4.86 and +4.80 points, both p<0.0001)
• 47% achieved clinically meaningful improvement (≥5 points) in physical health, 45% in mental health
• ARR 0.13; 88% free from 6-month confirmed disability progression; no new safety signals

Intervention

Oral cladribine tablets 3.5 mg/kg cumulative dose over 2 years (two treatment weeks per year at weeks 1 and 5)

Inclusion Criteria

Age ≥18 years, EDSS ≤5.0, highly active RMS (1 relapse in prior year with ≥1 Gd+ lesion or ≥9 T2 lesions on DMT, OR ≥2 relapses in prior year regardless of DMT status)

Study Design

Arms: Single arm: Cladribine tablets 3.5 mg/kg (no control group)

Patients per Arm: 482 treated (134 treatment-naïve, 348 DMT-pretreated)

Outcome

• Primary (MSQoL-54 PCS change): +4.86 (95% CI 3.18-6.53), p<0.0001
• Primary (MSQoL-54 MCS change): +4.80 (95% CI 3.13-6.46), p<0.0001
• ARR: 0.13 (95% CI 0.11-0.16); 88% free from 6mCDP

Bottom Line

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

Study Design

Study Type: Phase IV, prospective, open-label, exploratory, single-arm, multicenter study
Randomization: No
Blinding: Open-label (no blinding)
Sample Size: 482
Follow-up: 24 months
Centers: 85
Countries: 18 countries (not individually specified)

Primary Outcome

Definition: Change from baseline in MSQoL-54 Physical Health Composite Score (PCS) at Month 24

Control	Intervention	HR/OR	P-value
N/A (single-arm study)	LS mean change +4.86 (95% CI 3.18-6.53); 47.1% achieved MCID ≥5 points	- (3.18-6.53)	<0.0001

Limitations & 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

Citation

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

View Original Publication →

CLARIFY-MS

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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