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

• Published in: Clinical pharmacokinetics Vol. 58; no. 3; pp. 325 - 333
• Main Authors: Terranova, Nadia, Hicking, Christine, Dangond, Fernando, Munafo, Alain
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2019; Springer Nature B.V
• Subjects: Administration, Oral; Algorithms; Cancer; Cladribine - administration & dosage; Cladribine - therapeutic use; Clinical trials; Female; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - therapeutic use; Internal Medicine; Jargon; Lymphocyte Count - methods; Lymphocytes; Lymphopenia - chemically induced; Lymphopenia - classification; Male; Medicine; Medicine & Public Health; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; Original; Original Research Article; Patients; Pharmacology/Toxicology; Pharmacotherapy; Practice Guidelines as Topic; Recurrence; Simulation; Time Factors; Time-to-Treatment - trends
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-018-0693-y

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.