Long term, prospective, observational cohort study evaluating the safety profile in patients with highly active relapsing multiple sclerosis (RMS) newly started on oral cladribine − CLARION

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness
• Data collection methods:
  Combined primary data collection and secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  FINGOLIMOD

  MAVENCLAD 10 MG - TABLET
• Study drug International non-proprietary name (INN) or common name:
  CLADRIBINE

  FINGOLIMOD HYDROCHLORIDE
• Anatomical Therapeutic Chemical (ATC) code:
  (L04AA40) cladribine

  cladribine

  (L04AE01) fingolimod

  fingolimod
• Medical condition to be studied:
  Multiple sclerosis

  Relapsing multiple sclerosis

Population studied

• Short description of the study population:
  Patients newly initiating oral cladribine or fingolimod according to the local label for MS, after the date of oral cladribine launch in the relevant country.
• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Estimated number of subjects:
  8000

Study design details

• Study design:
  Multi-country, multi-center, long-term, prospective, observational cohort study. ; The study is projected to last 15 years, with an anticipated 5-year recruitment period until both cohorts have reached 4,000 patients and with a follow-up of 10 years for each patient.
• Main study objective:
  To further characterize and compare the risk, in terms of incidence of AESI (malignancies [all], severe infections, herpes zoster, tuberculosis, PML, other opportunistic infections, and seizures) in patients with highly active R(R)MS newly initiating oral cladribine or fingolimod.
• Setting:
  The study will only use pre-existing registries or databases and is based on a mixed data collection model relying on secondary use of data and primary data collection.
• Comparators:
  R(R)MS patients newly initiating fingolimod.
• Outcomes:
  Primary outcomes (on cohort level):; • Number of AESIs (malignancies [all], severe infections, herpes zoster, tuberculosis, PML, other opportunistic infections, and seizures) in patients with highly active R(R)MS newly initiating oral cladribine or fingolimod.; Secondary outcomes (on cohort level):; • Number of AESIs in patients with highly active R(R)MS newly initiating oral cladribine or fingolimod by prior use of immunomodulatory/ immunosuppressive agents;; • Number of severe lymphopenia events in patients with highly active R(R)MS newly initiating oral cladribine;; • Number of patients by DMT (immunosuppressive or immunomodulatory agents) after oral cladribine treatment in patients with highly active R(R)MS newly initiating oral cladribine;; • Number of AESIs in patients with highly active R(R)MS by first subsequent use of DMT (immunomodulatory / immunosuppressive agents) after oral cladribine treatment.; Exploratory outcomes (on cohort level):; • Number of patients switching treatment, overall and by reasons for stopping study drug in patients with highly active R(R)MS newly initiating oral cladribine or fingolimod;; • Number and time points of severe lymphopenia events and AESI in patients with highly active R(R)MS newly initiating oral cladribine.
• Data analysis plan:
  Data analysis will be performed using a pooled aggregated dataset based on the data source specific aggregated datasets.; In the primary analysis, using the intention-to-treat (ITT) exposure definition, the crude and adjusted incidence rates of the different AESIs along with 95% CIs will be estimated in both oral cladribine patients and fingolimod patients.; To compare the adjusted incidence of AESI between oral cladribine and fingolimod patients, the incidence rates ratios of the AESI together with the 95% CIs will be estimated by Poisson regression models adjusted for the key prognostic factors (including prior use of immunomodulatory/ immunosuppressive agents).; The impact of the prior use of DMT classified as immunomodulatory/ immunosuppressive agents on the incidence of AESI in patients initiating oral cladribine or fingolimod will be assessed by stratifying the analyses.; The impact of first subsequent DMT used on the incidence of AESI in patients after oral cladribine treatment will be assessed grouping DMT in IM or in IS.; In the secondary analyses, using the as-treated exposure definition, the crude and adjusted incidence rate of severe lymphopenia among oral cladribine patients as well as the 95% CI will be estimated using Poisson regression models. As for the primary analysis, the adjustments will be done for the key prognostic factors and results displayed by means of forest plots.