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ORACLE MS

Oral Cladribine for Early MS: Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event

Year of Publication: 2014

Authors: Thomas P Leist, Giancarlo Comi, Bruce A C Cree, ..., on behalf of the oral cladribine for early MS (ORACLE MS) Study Group

Journal: The Lancet Neurology

Citation: Lancet Neurol 2014;13:257-267

Link: https://doi.org/10.1016/S1474-4422(14)70005-5

PDF: https://journals.sagepub.com/doi/10.1177/13524585231205962

Clinical Question

Does oral cladribine delay conversion from a first clinical demyelinating event (clinically isolated syndrome) to clinically definite multiple sclerosis compared to placebo?

Bottom Line

Both doses of oral cladribine (5.25 mg/kg and 3.5 mg/kg) significantly delayed conversion to clinically definite MS by 62-67% and to McDonald MS by 50-57% compared to placebo, with robust MRI suppression. However, the trial was terminated early due to sponsor decision to halt cladribine development over safety concerns (malignancy/infection risk related to lymphopenia). Cladribine was later approved in 2017 after additional safety data.

        Major Points
        Phase 3 RCT of 616 patients with clinically isolated syndrome (CIS) at 160 centers in 34 countries
Both cladribine doses significantly reduced risk of conversion to CDMS: HR 0.38 (5.25 mg/kg) and HR 0.33 (3.5 mg/kg), both p<0.0001
Cumulative CDMS probability at study end: 15.9% (5.25 mg/kg), 14.0% (3.5 mg/kg) vs 38.0% (placebo)
McDonald MS conversion also significantly delayed: HR 0.43 and HR 0.50, median time 590 days and 338 days vs 120 days
Dramatic MRI suppression: ~90% reduction in new Gd+ lesions, ~75-79% reduction in new T2 lesions
First oral therapy trial in CIS population - prior CIS trials used injectable interferons/glatiramer acetate
Lymphopenia was dose-dependent: 24% (5.25 mg/kg), 12% (3.5 mg/kg), 0% (placebo); median recovery 9-13 weeks
Trial terminated early (October 2011) due to regulatory concerns about malignancy/infection risk; only 34% completed 96 weeks
Two malignancies in cladribine 3.5 mg/kg group (thyroid cancer, SCC) vs none in high-dose or placebo
37% of patients would have met 2010 McDonald criteria at baseline (more stringent than 2005 criteria used)

      

Design

Study Type: Phase 3, randomized, double-blind, three-arm, placebo-controlled, multicenter trial

Randomization: 1

Blinding: Double-blind using two-physician model: treating physician (managed AEs, masked to labs) and evaluating physician (assessed neurology, masked to treatment and labs); central blinded MRI assessment

Enrollment Period: October 21, 2008 to October 11, 2010

Follow-up Duration: 96 weeks planned; early termination October 25, 2011

Centers: 160

Countries: 34 countries across Americas, Western Europe, Eastern Europe, Russia, Asia

Sample Size: 616

Analysis: Intention-to-treat; Kaplan-Meier survival curves; Cox proportional hazards model adjusted for region; negative binomial model for MRI lesion counts; 80% power for HR 0.51 at two-sided α=0.025

Inclusion Criteria

Age 18-55 years
First clinical demyelinating event (monosymptomatic or polysymptomatic) within 75 days before screening
At least two clinically silent lesions ≥3 mm on T2-weighted brain MRI
At least one lesion ovoid, periventricular, or infratentorial
EDSS score ≤5.0
Not meeting 2005 McDonald criteria for MS diagnosis
Required contraception throughout study and 90 days after last dose

Exclusion Criteria

Diagnosis of MS by 2005 McDonald criteria
Any other disease that could better explain initial symptoms
History or evidence of latent or active tuberculosis
Pregnancy or breastfeeding

Baseline Characteristics

Control:

N: 206
Age - Mean (SD): 32.2 years (8.2)
Age <30 years: 45%
Age ≥30 years: 55%
Female: 67%
White: 94%
Black: <1%
Asian: 5%
Americas: 9%
Western Europe: 24%
Eastern Europe: 31%
Russia: 28%
Asia: 3%
Rest of world: 5%
Time from FCDE to randomization - Mean (SD) days: 79.4 (17.9)
Time from FCDE to randomization - Median (IQR) days: 78.0 (68.0-95.0)
Monofocal presentation (investigator): 50%
Monofocal presentation (adjudication): 49%
EDSS - Median (IQR): 1.5 (1.0-2.0)
Steroid treatment for FCDE: 68%
T1 Gd+ lesions - Median (IQR): 0.0 (0.0-1.0)
T2 lesions ≥9: 76%
T2 lesion volume - Median (IQR) mm³: 1793.9 (721.0-3790.8)
Meeting 2010 McDonald criteria at baseline: 33%

Active_3.5mg:

N: 206
Age - Mean (SD): 31.7 years (9.1)
Age <30 years: 47%
Age ≥30 years: 53%
Female: 63%
White: 96%
Black: 0%
Asian: 4%
Americas: 9%
Western Europe: 25%
Eastern Europe: 30%
Russia: 27%
Asia: 3%
Rest of world: 6%
Time from FCDE to randomization - Mean (SD) days: 78.7 (16.0)
Time from FCDE to randomization - Median (IQR) days: 80.0 (68.0-90.0)
Monofocal presentation (investigator): 51%
Monofocal presentation (adjudication): 54%
EDSS - Median (IQR): 1.5 (1.0-2.0)
Steroid treatment for FCDE: 64%
T1 Gd+ lesions - Median (IQR): 0.0 (0.0-1.0)
T2 lesions ≥9: 73%
T2 lesion volume - Median (IQR) mm³: 1692.4 (855.5-4028.3)
Meeting 2010 McDonald criteria at baseline: 35%

Active_5.25mg:

N: 204
Age - Mean (SD): 31.9 years (8.8)
Age <30 years: 46%
Age ≥30 years: 54%
Female: 65%
White: 94%
Black: 2%
Asian: 4%
Americas: 7%
Western Europe: 26%
Eastern Europe: 30%
Russia: 28%
Asia: 3%
Rest of world: 6%
Time from FCDE to randomization - Mean (SD) days: 79.4 (17.6)
Time from FCDE to randomization - Median (IQR) days: 82.0 (66.5-92.0)
Monofocal presentation (investigator): 50%
Monofocal presentation (adjudication): 53%
EDSS - Median (IQR): 1.5 (1.0-2.0)
Steroid treatment for FCDE: 65%
T1 Gd+ lesions - Median (IQR): 0.0 (0.0-1.5)
T2 lesions ≥9: 77%
T2 lesion volume - Median (IQR) mm³: 1820.5 (819.7-4772.7)
Meeting 2010 McDonald criteria at baseline: 44%

Arms

Field	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Control
Intervention	Oral cladribine tablets, cumulative dose 5.25 mg/kg over 96 weeks: 0.875 mg/kg per course for 4 courses in year 1 (day 1, weeks 5, 9, 13), then 2 courses in year 2 (weeks 48, 52). Each course given over 4-5 consecutive days. Weight-based dosing using 10 mg tablets.	Oral cladribine tablets, cumulative dose 3.5 mg/kg over 96 weeks: 0.875 mg/kg per course for 2 courses plus placebo for 2 courses in year 1, then 2 cladribine courses in year 2. Each course given over 4-5 consecutive days.	Matching placebo tablets: 4 courses in year 1, 2 courses in year 2, identical schedule and appearance to cladribine arms
Duration	96 weeks planned; median 52.5 weeks (IQR 16.1-53.9); mean follow-up 75.6 weeks	96 weeks planned; median 52.9 weeks (IQR 18.6-53.9); mean follow-up 79.2 weeks	96 weeks planned; median 52.4 weeks (IQR 14.4-53.6); mean follow-up 66.0 weeks

Outcomes

Outcome	Type	Control	HR / OR / RR	P-value
Time to conversion to clinically definite MS (CDMS) according to Poser criteria (diagnosis at second clinical event) during the double-blind period	Primary	71/206 (34%) converted; cumulative probability 38.0%	0.33 (3.5 mg/kg); 0.38 (5.25 mg/kg)	<0.0001 for both doses
Time to conversion to McDonald MS (2005 criteria)	Secondary	169/206 (82%); cumulative probability 87.1%; median 120 days (95% CI 95-163)	HR 0.50 (3.5 mg/kg), HR 0.43 (5.25 mg/kg)	<0.0001 for both
New or persisting T1 Gd+ lesions - Median cumulative (IQR)	Secondary	2.0 (0.0-5.0)		<0.0001 for both
New or enlarging T2 lesions - Median cumulative (IQR)	Secondary	2.0 (0.0-8.0)		<0.0001 for both
Combined unique active lesions - Median cumulative (IQR)	Secondary	4.0 (1.0-13.5)		<0.0001 for both
Any TEAE	Adverse	162/206 (79%)
Drug-related TEAE	Adverse	59/206 (29%)
Serious TEAE	Adverse	21/206 (10%)
TEAE leading to discontinuation	Adverse	4/206 (2%)
Death	Adverse	0
Lymphopenia (any)	Adverse	0 (0%)
Severe lymphopenia	Adverse	0 (0%)
Herpes virus infections	Adverse	2/206 (1%)
Malignancies	Adverse	0 malignant

Subgroup Analysis

Not reported in main publication due to early trial termination.

Criticisms

Trial terminated early (October 2011) due to sponsor decision to halt cladribine development - reduced power and 2-year completion rate (only 34% completed 96 weeks)
Regulatory concerns about potential malignancy and infection risk related to lymphopenia mechanism
Differential follow-up times: placebo group had shorter mean follow-up (66 weeks) than cladribine groups (76-79 weeks) due to higher conversion rates triggering exit from double-blind period
Two malignancies occurred in cladribine 3.5 mg/kg group vs none in other groups - causality uncertain but concerning
37% of patients would have met 2010 McDonald criteria at baseline - some may have already had MS by modern standards
Unable to assess long-term efficacy or durability of treatment effect due to early termination
Induction therapy concept (cladribine followed by maintenance DMT) could not be evaluated as planned
Limited ethnic diversity (94% White)
Dose-response paradox: 3.5 mg/kg appeared as effective as 5.25 mg/kg for CDMS (HR 0.33 vs 0.38) with fewer adverse events

Funding

Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany. Study designed by steering committee and sponsor. Data collected, analyzed, and interpreted by sponsor. All authors had data access.

Based on: ORACLE MS (The Lancet Neurology, 2014)

Authors: Thomas P Leist, Giancarlo Comi, Bruce A C Cree, ..., on behalf of the oral cladribine for early MS (ORACLE MS) Study Group

Citation: Lancet Neurol 2014;13:257-267

Content summarized and formatted by NeuroTrials.ai.

ORACLE MS

(2014)

Objective

Cladribine - To assess the effect of oral cladribine on time to conversion to clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event (clinically isolated syndrome)

Study Summary

• Oral cladribine significantly delayed conversion to CDMS vs placebo (HR 0.38 for 5.25 mg/kg, HR 0.33 for 3.5 mg/kg, both p<0.0001)
• Cumulative CDMS probability: 15.9% (5.25 mg/kg), 14.0% (3.5 mg/kg) vs 38.0% (placebo)
• Trial terminated early due to sponsor decision; lymphopenia was main safety concern (24% vs 12% vs 0%)

Intervention

Oral cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg vs placebo over 96 weeks (6 treatment courses)

Inclusion Criteria

Age 18-55 years, first clinical demyelinating event within 75 days of screening, ≥2 clinically silent T2 lesions (≥3mm, at least one ovoid/periventricular/infratentorial), EDSS ≤5.0, no MS diagnosis by 2005 McDonald criteria

Study Design

Arms: Cladribine 5.25 mg/kg vs Cladribine 3.5 mg/kg vs Placebo

Patients per Arm: Cladribine 5.25 mg/kg: 204, Cladribine 3.5 mg/kg: 206, Placebo: 206

Outcome

• Primary (time to CDMS): HR 0.38 (95% CI 0.25-0.58) for 5.25 mg/kg, HR 0.33 (95% CI 0.21-0.51) for 3.5 mg/kg, both p<0.0001
• McDonald MS conversion: HR 0.43 and HR 0.50, both p<0.0001
• ~90% reduction in new Gd+ lesions with cladribine

Bottom Line

Major Points

Phase 3 RCT of 616 patients with clinically isolated syndrome (CIS) at 160 centers in 34 countries
Both cladribine doses significantly reduced risk of conversion to CDMS: HR 0.38 (5.25 mg/kg) and HR 0.33 (3.5 mg/kg), both p<0.0001
Cumulative CDMS probability at study end: 15.9% (5.25 mg/kg), 14.0% (3.5 mg/kg) vs 38.0% (placebo)
McDonald MS conversion also significantly delayed: HR 0.43 and HR 0.50, median time 590 days and 338 days vs 120 days
Dramatic MRI suppression: ~90% reduction in new Gd+ lesions, ~75-79% reduction in new T2 lesions
First oral therapy trial in CIS population - prior CIS trials used injectable interferons/glatiramer acetate
Lymphopenia was dose-dependent: 24% (5.25 mg/kg), 12% (3.5 mg/kg), 0% (placebo); median recovery 9-13 weeks
Trial terminated early (October 2011) due to regulatory concerns about malignancy/infection risk; only 34% completed 96 weeks
Two malignancies in cladribine 3.5 mg/kg group (thyroid cancer, SCC) vs none in high-dose or placebo
37% of patients would have met 2010 McDonald criteria at baseline (more stringent than 2005 criteria used)

Study Design

Study Type: Phase 3, randomized, double-blind, three-arm, placebo-controlled, multicenter trial
Randomization: Yes
Blinding: Double-blind using two-physician model: treating physician (managed AEs, masked to labs) and evaluating physician (assessed neurology, masked to treatment and labs); central blinded MRI assessment
Sample Size: 616
Follow-up: 96 weeks planned; early termination October 25, 2011
Centers: 160
Countries: 34 countries across Americas, Western Europe, Eastern Europe, Russia, Asia

Primary Outcome

Definition: Time to conversion to clinically definite MS (CDMS) according to Poser criteria (diagnosis at second clinical event) during the double-blind period

Control	Intervention	HR/OR	P-value
71/206 (34%) converted; cumulative probability 38.0%	-	0.33 (3.5 mg/kg); 0.38 (5.25 mg/kg) (0.21-0.51 (3.5 mg/kg); 0.25-0.58 (5.25 mg/kg))	<0.0001 for both doses

Limitations & Criticisms

Trial terminated early (October 2011) due to sponsor decision to halt cladribine development - reduced power and 2-year completion rate (only 34% completed 96 weeks)
Regulatory concerns about potential malignancy and infection risk related to lymphopenia mechanism
Differential follow-up times: placebo group had shorter mean follow-up (66 weeks) than cladribine groups (76-79 weeks) due to higher conversion rates triggering exit from double-blind period
Two malignancies occurred in cladribine 3.5 mg/kg group vs none in other groups - causality uncertain but concerning
37% of patients would have met 2010 McDonald criteria at baseline - some may have already had MS by modern standards
Unable to assess long-term efficacy or durability of treatment effect due to early termination
Induction therapy concept (cladribine followed by maintenance DMT) could not be evaluated as planned
Limited ethnic diversity (94% White)
Dose-response paradox: 3.5 mg/kg appeared as effective as 5.25 mg/kg for CDMS (HR 0.33 vs 0.38) with fewer adverse events

Citation

Lancet Neurol 2014;13:257-267

View Original Publication →

ORACLE MS

Oral Cladribine for Early MS: Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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