Author Of 5 Presentations
LB1151 - Clinical outcomes in patients with COVID-19 infection during phase IV studies of cladribine tablets for treatment of multiple sclerosis (ID 947)
Abstract
Background
The COVID-19 pandemic has become a significant concern for patients (pts) with multiple sclerosis (MS) and their healthcare providers, prompting various guidelines on the appropriate use of disease-modifying drugs (DMDs) such as cladribine tablets.
Objectives
We report on clinical outcomes in pts who developed COVID-19 infection during two ongoing Phase IV studies of cladribine tablets (CLARIFY-MS [NCT03369665] and MAGNIFY-MS [NCT03364036]). Post-approval cases of COVID-19 infection are reported elsewhere.
Methods
CLARIFY-MS is investigating the impact of cladribine tablets on health-related quality of life in pts with highly active relapsing MS, while MAGNIFY-MS aims to determine the onset of action of cladribine tablets in such pts. Both studies utilize an open-label, single-arm, multicenter design, in which pts are treated with cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years). Some 680 pts are continuing in both studies. Cases of suspected COVID-19 infection were identified from adverse event reports and reviewed in terms of patient baseline characteristics, comorbidity, disease/treatment history (including most recent Extended Disability Status Scale [EDSS] score before COVID-19), and timing of cladribine tablets dosing/lymphocyte counts in relation to COVID-19 severity and outcomes.
Results
Three cases of suspected COVID-19 infection were identified (CLARIFY-MS, n=2; MAGNIFY-MS, n=1). Patient #1 (21-year history of MS; most recent EDSS score, 4.5; concomitant cardiovascular disease/asthma; prior DMD use) developed severe COVID-19 infection (confirmed) necessitating hospitalization but recovered and was discharged with residual cough/fatigue. Patient #2 (2-year history of MS; most recent EDSS score, 2; previous deep vein thrombosis during pregnancy; no prior DMDs) was also hospitalized for severe COVID-19 symptoms (not confirmed) but self-discharged and was recovering with chest tightness, fatigue, and neuropathic pain under self-isolation. The remaining patient (7-year history of MS; most recent EDSS score, 1; prior use of interferon β-1a) experienced mild symptoms of COVID-19 infection (confirmed); hospitalization was not required and the patient recovered under self-isolation. None of the pts required mechanical ventilation or died.
Conclusions
All 3 pts who developed COVID-19 infection during two ongoing Phase IV studies of cladribine tablets recovered or were recovering, and none required mechanical ventilation.
P0201 - Disability improvement in relapsing-remitting multiple sclerosis patients receiving cladribine tablets, evaluated by expanded disability status scale (ID 416)
Abstract
Background
In CLARITY, treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates and slowed disability progression versus placebo in RRMS patients. A key question is to evaluate whether and for how long cladribine tablets can improve EDSS scores.
Objectives
To evaluate post hoc long-term prevalence of disability improvement assessed by Expanded Disability Status Scale (EDSS) score in relapsing-remitting multiple sclerosis (RRMS) patients treated with cladribine tablets enrolled into CLARITY Extension.
Methods
Patients enrolled into CLARITY Extension were included and pooled by early (CT3.5 in CLARITY then CT3.5 or placebo in CLARITY Extension; n = 284), versus delayed (placebo in CLARITY then CT3.5 in CLARITY Extension; n = 244) treatment. Disability improvement was defined as a decrease in EDSS from baseline of ≥ 1 point for baseline EDSS < 5.5, or ≥ 0.5 points for baseline EDSS ≥ 5.5, confirmed at 6 months. Improvement was considered lost when EDSS returned to ≥ baseline (regression of improvement confirmed at 6 months). Prevalence of improved EDSS was estimated by a new statistical approach, accounting for not only the onset of improvement but also the duration. Prevalence was estimated as the difference between the Kaplan-Meier (KM) estimators for the probability of having an improvement before time t and the probability of returning to baseline before time t. P values were estimated using a bootstrap technique on the area under the modified KM curve.
Results
The prevalence of disability improvement (KM estimate) for the early versus delayed treatment groups at 2-years post-CLARITY baseline was 15.6% (95% confidence interval [CI]: 11.9–19.3) versus 9.3% (95% CI: 6.1–12.4), respectively and at 5-years was 12.7% (95% CI: 8.8–16.6) versus 8.6% (95% CI: 4.8–12.4), respectively (early versus delayed treatment group: P = 0.048 for 5-years difference).
Conclusions
Patients receiving early treatment with cladribine tablets had a greater prevalence of disability improvement over 5 years versus those with delayed treatment.
P0202 - Durable efficacy of cladribine tablets: cumulative relapse incidence over 5 years in CLARITY and CLARITY Extension (ID 960)
Abstract
Background
In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.
Objectives
To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.
Methods
Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.
Results
A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).
Conclusions
Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.
P0231 - Reduced grey matter atrophy in patients with relapsing multiple sclerosis treated with cladribine tablets (ID 951)
Abstract
Background
It is increasingly understood that grey matter (GM) atrophy is associated with disability progression and cognitive decline in patients with multiple sclerosis (MS). Previously, we demonstrated that treatment with cladribine tablets 3.5 mg/kg bodyweight (CT3.5; cumulative dose over 2 years) in the CLARITY study (NCT00213135) decreased brain atrophy compared with placebo, which was closely associated with a lower risk of disability progression [De Stefano et al. MSJ 2018].
Objectives
Post hoc evaluation of GM and white matter (WM) volume changes in patients with relapsing MS randomized to CT3.5 or placebo in the CLARITY study.
Methods
Images from pre-gadolinium T1-weighted magnetic resonance imaging scans of patients randomized to CT3.5 or placebo for 2 years in CLARITY were evaluated using SIENA-XL software. Images from 0–6 months (CT3.5, n=267; placebo, n=265) were analyzed independently of images from 6–24 months (CT3.5, n=184; placebo, n=186) to account for the potential effects of pseudoatrophy. Annualized mean changes in percentage of GM volume (PGMV) or WM volume (PWMV) between CT3.5 and placebo for 0–6 and 6–24 months were compared using a variance model.
Results
CT3.5 reduced GM and WM volume vs placebo in the first 6 months, consistent with pseudoatrophy [PGMV change: CT3.5 -0.53 vs placebo -0.25 (p=0.045); PWMV change: CT3.5 -0.49 vs placebo -0.34 (p=0.137)]. Brain volume loss from 6–24 months was reduced in patients randomized to CT3.5 with the difference between CT3.5 and placebo significant for GM [PGMV change: CT3.5 -0.90 vs placebo -1.27 (p=0.026); PWMV change: CT3.5-0.32 vs placebo -0.40 (p=0.52)].
Conclusions
Volume loss reduction in WM and, particularly, in GM was noted from 6-24 months in CT3.5-treated patients vs placebo, after a period of pseudoatrophy (0-6 months). Such findings suggest that CT3.5 significantly reduces brain atrophy predominantly in the GM, an effect that may contribute to lower risk of disability progression.
P1066 - Treatment satisfaction in patients with highly-active relapsing multiple sclerosis treated with cladribine tablets: CLARIFY-MS study interim analysis (ID 968)
Abstract
Background
Multiple sclerosis (MS), a chronic disabling disease requiring long-term treatment and regular monitoring, is associated with negative effects on health-related quality of life (HRQoL). CLARIFY-MS (NCT03369665) aims to assess the impact of cladribine tablets (CT) 10 mg (3.5 mg/kg cumulative dose over 2 years; CT3.5) on HRQoL and treatment satisfaction in patients with highly-active relapsing MS (RMS).
Objectives
To present an interim analysis of CLARIFY-MS at 6 months after initiating treatment with CT, assessing treatment satisfaction through the Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and safety through the collection of safety assessments in highly-active RMS patients.
Methods
CLARIFY-MS is an ongoing phase IV, open label, single arm, multicenter, 2-year study. Patients with RMS received CT3.5, with 2 weeks of active treatment per course (week 1 and 5 of each year). TSQM v1.4 was used to assess patient-reported treatment satisfaction (a score of 100 is the best possible rating). The TSQM measures 14 items across four domains: effectiveness (three items), side effects (five items), convenience (three items), and global satisfaction (three items).Treatment-emergent adverse events (TEAEs), serious adverse events (AEs), and lymphocyte counts were recorded.
Results
Treatment satisfaction: Of 554 patients screened, 482 received CT. The age and Expanded Disability Status Scale adjusted global treatment satisfaction score (95% confidence interval) at Month 6 was 70.0 (66.6–73.5). Treatment-experienced patients (prior treatment with disease-modifying drugs [DMDs]) reported similar treatment satisfaction scores to DMD-naïve patients (70.2 vs 68.7). At Month 6, >75% of patients rated the TSQM side effects score with 100. The mean side effects score was 91.9, mean convenience 86.6. Safety: 275 patients (57.1%) experienced ≥1 TEAE after drug initiation, most commonly headache and lymphopenia. Most post-baseline lymphopenias were of grade 1-2; 33 patients (6.8%) experienced grade 3 lymphopenia and no grade 4 lymphopenia was observed.
Conclusions
This interim analysis of CLARIFY-MS found that at 6 months, patients were generally satisfied with CT treatment. The convenience of CT treatment and side effect profile were especially important to patients. Safety results at 6 months post-treatment are consistent with the known safety profile, with no new emerging safety signal; most lymphopenias were grade 1-2.