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.

Documents

Study, other information

20190306_ms700568-0002-clarion-protocol-v3-0_fully signed_Redacted

DeclarationofInterests-Annex5_signed IB 11JUN2021

Study publications

The CLARION study design and status update: a long-term, registry-based study e…

The CLARION study: first report on safety findings in patients newly initiating…