Effects of Postponing Treatment in the Second Year of Cladribine Administration: Clinical Trial Simulation Analysis of Absolute Lymphocyte Counts and Relapse Rate in Patients with Relapsing-Remitting Multiple Sclerosis

Abstract

Introduction: Cladribine Tablets (MAVENCLAD®) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4-5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3-4 lymphopenia, especially those patients with Grade ≥ 2 lymphopenia at the start of year 2. Guidelines allowing treatment postponements during year 2 have been proposed for patients with a low ALC, subsequent to CLARITY, the pivotal clinical trial.

Methods: A virtual population was generated using characteristics from CLARITY patients. A clinical trial simulation was performed to determine the impact of alternative treatment scenarios on ALC and relapse rate, by postponing treatment in year 2 to allow for longer ALC recovery time in patients who required it. Should a patient not recover to normal ALC (Grade 0) or Grade 1 lymphopenia within the period defined in the treatment algorithm, treatment in year 2 was suspended.

Results: Results were similar across considered scenarios, which implemented different postponement durations. Specifically, ~ 92% of virtual subjects did not require treatment postponement and < 1% discontinued due to Grade 2-4 lymphopenia at the end of the maximally permitted postponement. Less severe lymphopenia was observed during year 2 when a treatment algorithm was applied. The effect on relapse rate over 2 years was negligible.

Conclusions: Results support treatment guidelines to decrease the risk of severe lymphopenia following treatment with Cladribine Tablets, while preserving efficacy.

Trial registration: CLARITY; ClinicalTrials.gov: NCT00213135.

Conflict of interest statement

Nadia Terranova and Alain Munafo are employees of Merck Serono SA, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. Christine Hicking is an employee of Merck KGaA, Darmstadt, Germany. Fernando Dangond is an employee of EMD Serono, Inc., a business of Merck KGaA, Billerica, MA, USA.

Figures

Fig. 1

Distribution of sampled covariates. a Probability distribution of experiencing a different total number of relapses in the 12 months preceding study entry in simulated and observed patients. b Probability density functions of both resampled and observed creatinine clearance and body weight for female (top) and male (bottom) subjects. The density of each resampled covariate (green area) well reproduces the correspondent observed density (orange area), as shown by area overlapping and very similar mean values (dashed lines). BW body weight, CLCR creatinine clearance, EXNB number of relapses in the 12 months preceding study entry

Fig. 2

Absolute lymphocyte count time-course profiles (treatment scenario 2). The blue dashed line denotes the upper limit for Grade 1 lymphopenia (1.0 × 109 cells/L). The red dashed lines denote upper limits for Grades 2, 3 and 4 lymphopenia (0.8, 0.5 and 0.2 × 109 cells/L, respectively). ALC absolute lymphocyte count

Fig. 3

Probability distribution of predicted relapse-free survival for percentiles from 10 to 90% shown over 24 months for the base scenario (left panel) and treatment scenario 2 (right panel)

Fig. 4

Repeated time-to-event model predictions of relapse risk for the typical patient (weight = 69.3 kg; creatinine clearance = 104.5 mL/min; number of relapses in the 12 months preceding study entry = 1) treated without postponement and with postponements of different month blocks (from 1 month up to 9 months) during year 2