CLASSIC-MS
Research type
Research Study
Full title
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
IRAS ID
265172
Contact name
Basil Sharrack
Contact email
Sponsor organisation
Merck KGaA
Eudract number
2019-000069-19
Duration of Study in the UK
1 years, 5 months, 30 days
Research summary
Research Summary:
The purpose of this study is to help understand the long-term effectiveness of cladribine tablets. This study will specifically explore the long-term health status and treatment effectiveness in patients previously participating in the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials (i.e. parent studies). The study also aims to learn more about how these patients were treated for their multiple sclerosis (MS) after the parent studies have completed (i.e. the real-world treatment patterns). Patients could have received either cladribine tablets or placebo during the parent studies. All eligible patients, irrespective if they have received cladribine tablets or placebo, are invited to participate in CLASSIC-MS. The results from this study may be of benefit to patients with MS and clinicians by helping to inform future treatment approaches and treatment decision-making.Lay summary of study results: Publication(s):
G. Giovannoni, T. Leist, A. Aydemir, E. Verdun Di Cantogno. LB1229. Classic-MS: Long-term efficacy and real-world treatment patterns for patients receiving cladribine tablets – interim data with 8–14 years follow-up. Available at: Multiple Sclerosis Journal 2020; 26: (S3) 90–117. Access Date: 24 Sep 2021 G. Giovannoni, A. Aydemir, E. Verdun Di Cantogno, T. Leist. CLASSIC MS: Long-term efficacy and real-world treatment patterns for patients with relapsing multiple sclerosis who received cladribine tablets in Phase III parent trials. 2021 Available at: American Academy of Neurology Abstract Website. Access Date: 24 Sep 2021 Study Period: This study was completed; this report is based on the final analysis. The initiation date was 15 August 2019 and end date (date of database lock) was 29 March 2021.
Rationale: The purpose of this study was to explore the long-term outcomes, durability of effect, and real-world treatment patterns in patients previously participating in the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials (i.e. parent studies). The results from this study may be of benefit to patients with MS and clinicians by helping to inform future treatment approaches and treatment decision-making.
Objectives, Endpoints, and Statistical Methods: Data was collected retrospectively and prospectively to evaluate the long-term outcomes, durability of effect, and real-world treatment patterns following treatment with cladribine tablets or placebo among patients with MS who were part of the parent studies. The objectives of this study were all exploratory and for hypothesis generating purposes.
Exploratory Objectives Endpoints (Outcome Measures)
Primary
To evaluate long-term mobility after treatment with an IMP; cladribine (tablets or placebo) as part of the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials. Proportion of study participants using a wheelchair (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) the majority of the time in the 3 months prior to SV1 or participants are bedridden any time prior to SV1 determined via:
1). EDSS score of 7.0 or higher, or
2). Alternative clinical description data in medical records.
Secondary
To assess the long-term disability status after treatment with IMP as part of the Phase III ORACLE MS and CLARITY/CLARITY-EXT clinical trials for the CLARITY/CLARITY-EXT and ORACLE MS populations. Proportion of study participants with EDSS of 6.0 or higher as determined by EDSS documentation or alternative clinical description in medical records after last IMP from parent study.
To evaluate differences in clinical characteristics between long-term responders and study participants requiring alternate therapies following treatment with IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations. Clinical characteristicsa at SV1 of long-term responders (defined as study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical and imaging outcomes until Year 4 or later following their last doseb of IMP and who did not receive disease modifying treatment until Year 4 or later following their last doseb of IMP) compared to those of other study participants who started on alternate therapy less than 4 years following their last doseb of IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations.
To evaluate differences in MRI characteristics between long-term responders and study participants requiring alternate therapies following treatment with IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations. MRI characteristicsc at SV2 of long-term responders (defined as study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical and imaging outcomes until Year 4 or later following their last doseb of IMP and who did not receive disease modifying treatment until Year 4 or later following their last doseb of IMP) compared to those of other study participants who started on alternate therapy less than 4 years following their last doseb of IMP for the CLARITY/CLARITY-EXT and ORACLE MS populations.
EDSS=Expanded Disability Status Scale, IMP=investigational medicinal product, MRI=magnetic resonance imaging, MS=multiple sclerosis, RRMS =relapsing–remitting MS, SPMS =secondary progressive MS SV=Study Visit.
a Specific clinical and demographic characteristics may include gender, age, race, ethnicity, education, disease duration, years of previous disease modifying treatment (before start of CLARITY/CLARITY-EXT/ORACLE MS) and disease classification (RRMS or SPMS).
b One dose is equivalent to 1 tablet. One course of IMP is defined as 1 year of treatment with IMP (2 treatment cycles [weeks]). A treatment cycle is defined as daily administration of IMP given consecutively over 4-5 days during a 28-day period. One treatment week is equivalent to 1 treatment cycle.
c Total volume of T2 lesions; Total number of T2 lesions; Number of hypointense lesions on T1-spin echo MRI; Volume of hypointense lesions on T1-spin echo MRI; Brain volume or surrogate; Ventricular volume.
Methodology: This Phase IV, low-interventional, multicenter, ambispective study involved the evaluation of medical records of study participants treated with cladribine tablets or placebo in the previously conducted parent studies. Long-term retrospective data was collected through evaluation of medical charts/records (e.g., sociodemographic and clinical characteristics, medical and disease history, SPMS conversion, EDSS, details of subsequent DMDs, including physician questions on treatment decisions, date of first use of an ambulatory device or wheelchair, date of first time bedridden, and relapse history from end of parent study to SV1 as well as, for ORACLE MS patients only, CDMS and PPMS diagnosis).
Additional prospective data was collected at SV1 (e.g., physical assessment, EDSS, PRO, cognitive assessments, AEs and concomitant medications). An optional blood sample for pharmacogenetic testing was taken from patients who consented to the optional testing. A sub study at SV2 involved an MRI scan without gadolinium in approximately 150 patients who were willing to participate in this MRI sub-study.
Number of Participants (Planned and Analyzed): No formal sample size calculation was performed for this exploratory study as enrollment was limited to eligible study participants from the parent studies.
Analysis Set Never Exposed to Cladribine
(N=113) Exposed to Cladribine
(N=562) Total
(N=675)
Screened analysis set, n (%) 113 (100.0) 562 (100.0) 675 (100.0)
FAS, n (%) 112 (99.1) 550 (97.9) 662 (98.1)
MRISS, n (%) 8 (7.1) 40 (7.3) 48 (7.3)
FAS=Full analysis set; MRISS=Magnetic resonance imaging sub-study analysis set.
Diagnosis and Main Criteria for Inclusion and Exclusion: This study enrolled patients with MS who participated in the CLARITY/CLARITY-EXT clinical trial(s) and who received ≥1 course of IMP, or study participants with their FCDE who were randomized in the ORACLE MS study and received ≥1 course of IMP.
Duration of Study Intervention: No IMP was administered as part of this study. The duration of the study for most patients was no more than 2 weeks from the time of the Screening Visit to SV1, except in the case of relapse at Screening in which case the duration between Screening and SV1 was between 1 and 3 months. An optional blood sample was collected at SV1 from patients who consented to the optional pharmacogenetic testing. Pharmacogenetic testing also occurred during a subsequent clinical visit up to 6 months after the Screening Visit. For patients participating in the MRI sub-study, an additional visit was required (SV2) that occurred within a maximum of 3 months of SV1, and these patients’ total study duration was no more than 6 months. Patients who were eligible were given the option of completing Screening, SV1, and SV2 on the same day if they preferred to do so and met the eligibility criteria on that day. Patients who were undergoing relapse or suspected relapse at the time of Screening were invited for SV1 after a stabilization period determined through consultation with the medical monitor.
Summary of Results:
Demographics and Other Baseline Characteristics:
Demographic and baseline characteristics are presented by cohort. Cohort A includes patients who meet the protocol inclusion and exclusion criteria and are drawn from the pooled CLARITY, CLARITY EXT and ORACLE MS studies. Cohort B includes patients who meet the protocol inclusion and exclusion criteria and are drawn from the CLARITY study. Cohort C includes patients who meet the protocol inclusion and exclusion criteria and are drawn from the CLARITY EXT study only (a subset of Cohort B, the CLARITY study). Cohort D includes patients who meet the protocol inclusion and exclusion criteria and are drawn from the ORACLE MS study only.
EXT = extension, MS = multiple sclerosis.Of note, Cohort A combines all patients from different study populations in Cohorts B (CLARITY and CLARITY-EXT parent study) and D (ORACLE MS parent study) and provides an average of observed effects in the separate cohorts. Cohort C is a subset of Cohort B. This report will focus primarily on the results for Cohorts B and D as they represent different disease cohorts; results for Cohort A will be summarized for results as appropriate i.e. for assessments of representativeness of the dataset, or where overall study numbers were lower such as MRI.
Variable Cohort A
[FAS]
(n=662)a Cohort B
(n=435) Cohort C
(n=345) Cohort D
(n=227)
Mean ± SD Age at CLASSIC MS SV11 (years) 49.3 ± 10.32 52.7 ± 9.62 53.3 ± 9.59 42.7 ± 8.28
Mean ± SD Age at Parent Study baseline (years) 36.4 ± 9.66 38.5 ± 9.66 39.1 ± 9.62 32.4 ± 8.28
Female, n (%) 444 (67.1) 295 (67.8) 224 (64.9) 149 (65.6)
n (missing)
Mean ± SD Disease durationb (years) 586 (76)
18.63 ± 8.84 435 (0)
22.36 ± 6.97 345 (0)
22.37 ± 6.99 151 (76)
7.87 ± 2.69
Mean ± SD EDSS score at Parent Study baseline 2.43 ± 1.27 2.82 ± 1.29 2.82 ± 1.26 1.69 ± 0.83
n (missing)
Mean ± SD EDSS score at CLASSIC MS SV1c 625 (37)
3.26 ± 2.10 403 (32)
3.87 ± 2.07 328 (17)
3.87 ± 2.03 222 (5)
2.15 ± 1.65
n (missing/pts from ORACLE MS)
Mean ± SD No. of relapses during last year before enrollment of Parent Study 435 (227)
1.3 ± 0.62 435 (0)
1.3 ± 0.62 345 (0)
1.3 ± 0.61 N/A
Type of MS at CLASSIC MS Screening
RRMS
SPMS
Unknown
No MS disease 454 (68.6)
120 (18.1)
14 (2.1)
74 (11.2) 321 (73.8)
114 (26.2)
0 (0.0)
0 (0.0) 251 (72.8)
94 (27.2)
0 (0.0)
0 (0.0) 113 (58.6)
6 (2.6)
14 (6.2)
74 (32.6)
Prior use of DMD at Parent Study baseline, n (%) n (missing/pts from ORACLE MS)
Yes 435 (227)
94 (21.6) 435 (0)
94 (21.6) 345 (0)
71 (20.6) N/A
HDAd status at Parent Study baseline, n (%) n (missing/pts from ORACLE MS)
Yes 435 (227)
128 (29.4) 435 (0)
128 (29.4) 345 (0)
98 (28.4) N/A
DMD=disease modifying drug, EDSS=Expanded Disability Status Scale, FAS=Full Analysis Set, HDA=high disease activity, MS: multiple sclerosis, N/A=not applicable, PPMS=primary progressive MS, RRMS=relapsing–remitting MS, SPMS=secondary progressive MS, SD= Standard Deviation.
a 675 patients screened for the study.
b Disease duration = (CLASSIC MS SV1 − date of MS diagnosis + 1) / 365.25.
c Maximum score assessed clinically/by phone.
d Using definition for HDA specified in CLASSIC MS study protocol.
Long-term responders, sensitivity definition B, included study participants not requiring DMD 4 years following their last dose of IMP. In Cohort A, more than half of patients were classified as long-term responders using sensitivity definition B (n=378, 57.1%); the corresponding proportions for Cohorts B, C, and D were 63.4%, 65.5%, and 44.9%, respectively.
Long-term responders, sensitivity definition D, included study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical outcomes 4 years following the last dose of IMP. For sensitivity definition D, the proportion of patients classified as long-term responders was similar across Cohort A (48.8%), Cohort B (48.0%), Cohort C (47.8%), and Cohort D (50.2%).
Exposure: Not applicable, as no IMP was administered as part of this study. Study participants were treated with cladribine tablets or placebo in the previously conducted parent studies.
Efficacy Results
Primary Endpoint:
In Cohort B, the proportion of patients never exposed to cladribine tablets who reported the use of wheelchair within 3 months prior to SV1 or being bedridden any time prior to SV1 was 22.2% [95% CI: 10.1; 39.2; n=8/41]; the corresponding proportion among patients exposed to cladribine tablets was 10.0% [95% CI: 7.2; 13.5; n=38/394]. The adjusted OR for use of a wheelchair within 3 months prior to SV1 or being bedridden any time prior to SV1 was 0.39 [95% CI: 0.17; 0.93; p value 0.0336] for patients exposed to cladribine tablets vs never exposed.
In Cohort D, the proportion of patients never exposed to cladribine tablets who reported the use of wheelchair in the past 3 months or being bedridden anytime prior to SV1 was 5.8% [95% CI: 1.6; 14.2; n=4/71]; the corresponding proportion among patients exposed to cladribine tablets was 1.30% [95% CI: 0.2; 4.7; n=2/156]; the adjusted OR (fixed effects for treatment group, disease duration and parent study) for use of a wheelchair or being bedridden was 0.40 [95% CI: 0.07; 2.32; p value 0.3079] for patients exposed to cladribine tablets vs never exposed.
Secondary Endpoint 1:
In Cohort B, 80.7% of all patients had an EDSS score < 6 since last dose of IMP. An EDSS score ≥6 since last dose of IMP was recorded for 24.4% [95% CI: 12.4; 40.3] of patients never exposed to cladribine tablets (n=10/41), and for 18.8% [95% CI: 15.0; 23.0] of patients exposed to cladribine tablets (n=74/394).
In Cohort D, an EDSS score ≥6 since last dose of IMP was recorded for 5.6% [95% CI: 1.6; 13.8] of patients never exposed to cladribine tablets (n=4/71), and for 2.6% [95% CI: 0.7; 6.54] of patients exposed to cladribine tablets (n=4/156).
Secondary Endpoint 2:
In Cohort B, overall, clinical characteristics were similar for long-term responders compared to nonresponders under responder definitions B (participants not requiring DMT 4 years following their last dose of IMP), D (study participants who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical outcomes 4 years following the last dose of IMP), and E (study participants not requiring DMD 4 years following their last dose of IMP and who did not demonstrate any evidence of disease reactivation based on Investigator assessment of clinical outcomes 4 years following the last dose of IMP). For definition D, more patients in the responders group had RRMS at CLASSIC MS SV1 (78.0% for responders, 70.9% for nonresponders); a similar pattern was detected for definition E.
In Cohort D, there were some differences across the groups for disease characteristics. For definition B, the average disease duration (mean ± SD) was shorter among long-term responders (5.79 [± 2.94] years) compared to nonresponders (9.04 [± 1.69] years), respectively; the proportion of long-term responders with RRMS (51.0%) was lower than among nonresponders (66.7%); and the proportion of long-term responders with no MS disease (47.1%) was higher than among nonresponders (17.9%). For definition D, the mean disease duration (± SD) at SV1 was longer for nonresponders compared to responders (8.88 years [± 1.649)] vs 6.43 [± 3.201], respectively). Also, more patients in the nonresponders group had RRMS at CLASSIC MS SV1 (72.5% for nonresponders, 49.1% for responders), and more patients in responders group had no MS disease (12.7% for nonresponders, 48.2% for responders). For definition E, the mean disease duration at SV1 was over 5 years longer for nonresponders compared to responders (8.82 years [± 1.855] vs 5.30 years [± 2.978], respectively). Also, more patients in the nonresponders group had RRMS at CLASSIC MS SV1 (66.0% for nonresponders, 48.7% for responders), and more patients in responders group had no MS disease (20.6% for nonresponders, 50.0% for responders) Safety Results:
No safety endpoints were assessed as part of this study. One SAE (prostate cancer) was observed for a patient exposed to cladribine tablets in the CLARITY parent study. No AEs leading to death occurred during the CLASSIC MS study.
Comparison Between non-CLASSIC MS/CLASSIC MS patients:
The WPS Analysis Set includes all parent study patients (enrolled in CLASSIC MS or not) randomized in CLARITY or ORACLE who have received > 1 course of IMP (cladribine tablets or placebo).
Patients who participated in CLASSIC MS (n=662) were similar to non-CLASSIC MS patients (n=1232) with respect to mean EDSS score at parent study baseline (mean [± SD] 2.43 [± 1.271] and 2.56 [± 1.375], respectively) and the number of relapses during last year before enrollment of parent study age (mean [± SD] 1.3 [± 0.62]) and 1.4 ([± 0.60]), respectively). Among non-CLASSIC MS patients compared to CLASSIC MS patients, there was a relatively higher proportion of patients reporting prior use of DMDs (33.8%, n=293 vs 21.6%, n=94).
Conclusions:
Primary objective
In Cohorts B and D, fewer patients who were exposed to cladribine tablets used a wheelchair for the majority of time in the 3 months prior to SV1 or were bedridden at any time prior to SV1, compared with those patients who were never exposed to cladribine tablets.
Secondary objective 1: Long-term disability status In Cohorts B and D, fewer patients exposed to cladribine tablets had an EDSS score ≥6.0 compared to patients never exposed to cladribine tablets. Half as many patients exposed to cladribine tablets from Cohort D had an EDSS score ≥6.0 since the last dose of IMP, versus patients who were never exposed to cladribine tablets.
Secondary objective 2: Differences in clinical characteristics by long-term responder In Cohorts B and D, there were no differences in clinical characteristics between responders and nonresponders, except in mean disease duration and disease type.
Study representativeness:
Of 1894 patients enrolled in the parent studies, 662 (35.0%) enrolled in CLASSIC MS (435 [66%] from CLARITY and 227 [34%] from ORACLE); baseline characteristics of CLASSIC MS patients were representative of the population from the parent studies Report Date: 14 October 2021 Version No.: 1.0REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
19/YH/0277
Date of REC Opinion
30 Sep 2019
REC opinion
Further Information Favourable Opinion