Clinical Trial Results:
Evaluating the Long-Term Outcomes and Durability of Effect Following Treatment with Cladribine Tablets for Multiple Sclerosis: An Exploratory Phase IV Ambispective Study of Patients Who Previously Participated in the CLARITY/CLARITY-EXT and ORACLE MS Clinical Trials
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Summary
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EudraCT number |
2019-000069-19 |
Trial protocol |
CZ SE PT EE BG AT LT BE PL ES HR IT RO |
Global end of trial date |
13 May 2021
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Results information
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Results version number |
v2(current) |
This version publication date |
16 Jun 2022
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First version publication date |
10 Mar 2022
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MS700568_0026
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03961204 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merck Healthcare KGaA, Darmstadt, Germany
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Sponsor organisation address |
Frankfurter Strasse 250, Darmstadt, Germany, 64293
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Public contact |
Communication Center, Merck Healthcare KGaA,Darmstadt, Germany, +49 6151 72 5200, service@merckgroup.com
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Scientific contact |
Communication Center, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 May 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
13 May 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The purpose of this study was to explore the long-term outcomes, durability of effect, and real world treatment patterns in subjects previously participating in the Phase 3 oral cladribine in first clinical demyelinating event (ORACLE MS) and Oral Cladribine in subjects with relapsing remitting multiple sclerosis (RRMS), extension study (CLARITY/CLARITY-EXT) clinical trials with the study number of 28821 (NCT00725985), 25643 (NCT00213135) and 27820 (NCT00641537) respectively.
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Protection of trial subjects |
Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Aug 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 17
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Country: Number of subjects enrolled |
Canada: 29
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Country: Number of subjects enrolled |
Austria: 6
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Country: Number of subjects enrolled |
Belgium: 15
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Country: Number of subjects enrolled |
Finland: 2
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Country: Number of subjects enrolled |
France: 17
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Country: Number of subjects enrolled |
Germany: 9
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Country: Number of subjects enrolled |
Italy: 68
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Country: Number of subjects enrolled |
Norway: 4
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Country: Number of subjects enrolled |
Portugal: 3
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Country: Number of subjects enrolled |
Spain: 7
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Country: Number of subjects enrolled |
Sweden: 3
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Country: Number of subjects enrolled |
Switzerland: 6
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Country: Number of subjects enrolled |
United Kingdom: 7
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Country: Number of subjects enrolled |
Australia: 5
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Country: Number of subjects enrolled |
Bulgaria: 40
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Country: Number of subjects enrolled |
Croatia: 4
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Country: Number of subjects enrolled |
Czechia: 73
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Country: Number of subjects enrolled |
Estonia: 31
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Country: Number of subjects enrolled |
Georgia: 9
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Country: Number of subjects enrolled |
Lithuania: 7
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Country: Number of subjects enrolled |
Poland: 28
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Country: Number of subjects enrolled |
Romania: 15
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Country: Number of subjects enrolled |
Serbia: 22
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Country: Number of subjects enrolled |
Ukraine: 21
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Country: Number of subjects enrolled |
Russian Federation: 182
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Country: Number of subjects enrolled |
Lebanon: 7
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Country: Number of subjects enrolled |
Korea, Republic of: 6
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Country: Number of subjects enrolled |
Tunisia: 19
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Worldwide total number of subjects |
662
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EEA total number of subjects |
332
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
662
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||
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Pre-assignment
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Screening details |
A total of 662 subjects were enrolled in this trial at different sites in United States and Europe. | ||||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Cohort A | ||||||||||||||||
Arm description |
Subjects previously enrolled in parent studies CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE (NCT00725985) and had received Cladribine tablet and Placebo were invited up to 2 visit for follow-up/data collection. | ||||||||||||||||
Arm type |
No intervention | ||||||||||||||||
Investigational medicinal product name |
Cladribine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
No study treatment was administered as part of this study
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Baseline characteristics reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Subjects previously enrolled in parent studies CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE (NCT00725985) and had received Cladribine tablet and Placebo were invited up to 2 visit for follow-up/data collection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Subjects previously enrolled in parent studies CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE (NCT00725985) and had received Cladribine tablet and Placebo were invited up to 2 visit for follow-up/data collection. | ||
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End point title |
Percentage of Subjects Using Wheelchair or Being Bedridden Assessed by Expanded Disability Status Scale (EDSS) Score 7.0 or Higher [1] | ||||||||
End point description |
EDSS scores range from 0.0 (normal) to 10.0 (dead). EDDS is a scale from 0-10 that evaluates a person with Multiple Sclerosis (MS) disability/neurologic function level where 0=normal and 10=death due to MS. Score of 7.0 is defined as unable to walk beyond approximately 5 meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day. Score of 8.0 is defined as Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has effective use of arms. FAS included all subjects participating in CLASSIC study [randomized in CLARITY and have received ≥ 1 course of IMP (Cladribine Tablets or placebo) or subjects randomized in ORACLE study and have received ≥ 1 course of IMP]. Here, "Number of subjects analyzed", signifies those subjects who were evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
3 months prior to study visit 1. Retrospectively from end of parent study (NCT00213135, NCT00641537 and NCT00725985) to study visit 1 (study visit 1 occurred up to 3 months from screening)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive summary statistics was planned for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Clinical and Demographic Characteristic: Age, Disease Duration | ||||||||||||||||
End point description |
Clinical and demographic characteristics including age & disease duration is reported in form of long term responders (LTR) & non-responder (NR). Here LTR is defined as study subjects not requiring DMD 4 years or later following their last dose of IMP, and who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical & imaging outcomes. NR is defined as study subjects requiring DMD < 4 years following their last dose of IMP or who demonstrate any evidence of disease reactivation based on Investigator assessment of clinical & imaging outcomes. Full analysis set population was included. Here, "Number of subjects analyzed", signifies those subjects who were evaluable for this outcome measure. Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Subjects With Expanded Disability Status Scale (EDSS) Score 6.0 or Higher | ||||||||
End point description |
EDDS is a scale from 0-10 that evaluates a person with MS disability/neurologic function level where 0= normal and 10= death due to MS. Score of 6.0 is defined as "intermittent or unilateral constant assistance (cane, crutch and brace) required to walk about 100 meters with or without resting". FAS included all subjects participating in CLASSIC study [randomized in CLARITY and have received ≥ 1 course of IMP (Cladribine Tablets or placebo) or subjects randomized in ORACLE study and have received ≥ 1 course of IMP].
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End point type |
Secondary
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End point timeframe |
At study visit 1. Retrospectively after last IMP administration from parent study (NCT00213135, NCT00641537 and NCT00725985) to study visit 1 (study visit 1 occurred up to 3 months from screening)
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects in Each Category of Clinical and Demographic Characteristics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical characteristics included gender, race, disease classification (RRMS, SPMS, unknown & no MS disease), Prior use of DMDs & high-disease activity (HAD) status, education level, and employment status. Number of subjects in each category of clinical characteristics were reported in form of long-term responder and non-responder. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Clinical Characteristic: Expanded Disability Status Scale (EDSS) Score | ||||||||||||||||
End point description |
EDSS is a scale based on standardized neurological examination which comprised of optic, brain stem, pyramidal, cerebellar, sensory & cerebral functions, as well as walking ability. EDSS scores range from 0.0 (normal) to 10.0 (dead). Clinical characteristics of EDSS score in form of long-term responders & non-responder was reported for at parent study baseline (based on retrospective data collection [based on chart review] at study visit 1) & study visit 1. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Clinical Characteristic: Number of Relapses | ||||||||||||
End point description |
Relapse was defined as participant-reported symptoms & objectively observed signs typical of an acute inflammatory demyelinating event in CNS, developing acutely or sub-acutely with duration of at least 24 hours, in absence of fever or infection. Clinical characteristics of number of relapses during last year before enrollment of parent study (it is reported based on retrospective data collection [based on chart review] at study visit 1) in the form of long-term responders (LTR) & non-responder (NR) was reported. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 1, occurred up to 3 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of total T1-weighted (T1-W) Lesions | ||||||||||||
End point description |
Total number of T1-W lesion were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study. The MRI analysis population includes all FAS subjects who signed the MRI sub- study informed consent. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of total T2-weighted (T2-W) Lesions | ||||||||||||
End point description |
Total number of T2-W lesion were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study. The MRI analysis population includes all FAS subjects who signed the MRI sub- study informed consent. Number of subjects analyzed signifies number of subjects who were evaluable for this outcome measure. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
T1-weighted (T1-W) Lesion Volume | ||||||||||||
End point description |
T1-W lesion volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study. The MRI analysis population includes all FAS subjects who signed the MRI sub- study informed consent. Number of subjects analyzed signifies number of subjects who were evaluable for this outcome measure. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
T2-weighted (T2-W) Lesion Volume | ||||||||||||
End point description |
T2-W lesion volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study. The MRI analysis population includes all FAS subjects who signed the MRI sub- study informed consent. Number of subjects analyzed signifies number of subjects who were evaluable for this outcome measure. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and Here n=Number analyzed, signifies those subjects who were evaluable for this outcome measure for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total Brain Volume | ||||||||||||
End point description |
Brain volume were measured by Using magnetic resonance imaging (MRI) Scans. Here long term responder is defined as study participants not requiring DMD 4 years or later following their last dose of IMP in parent study. Non-responder is defined as study participants requiring DMD less than 4 years following their last dose of IMP in parent study. The MRI analysis population includes all FAS subjects who signed the MRI sub- study informed consent. Number of subjects analyzed signifies number of subjects who were evaluable for this outcome measure. Here, "Overall Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure and Number analyzed refers to number of subjects evaluable for specified categories.
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End point type |
Secondary
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End point timeframe |
At study visit 2, within 6 months from screening (Retrospective analysis of medical record of parent study-NCT00213135, NCT00641537 and NCT00725985)
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to study visit 2 (Up to approximately 6 months and Retrospective AEs data collection based on chart review of subjects from end of parent studies; NCT00213135, NCT00641537 and NCT00725985)
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.1
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Reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Subjects previously enrolled in parent studies CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), ORACLE (NCT00725985) and had received Cladribine tablet and Placebo were invited up to 2 visit for follow-up/data collection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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03 Jul 2020 |
There was updates in study design, objective and endpoint section, schedule of activities, exclusion criteria and adverse event section. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
