A Phase III, randomized, double-blind, placebo-controlled, multi-center clinical trial of oral cladribine in subjects with a first clinical event at high risk of converting to MS

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2009/091/000061
• Date of registration: 28-01-2010
• Prospective Registration: No
• Primary sponsor: Merck Serono SA
• Public title: A Phase III, randomized, double-blind, placebo-controlled, multi-center clinical trial of oral cladribine in subjects with a first clinical event at high risk of converting to MS
• Scientific title: A Phase III, randomized, double-blind, placebo-controlled, multi-center clinical trial of oral cladribine in subjects with a first clinical event at high risk of converting to MS.
• Date of first enrolment: 12-08-2009
• Target sample size: 642
• Recruitment status: Completed
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=337
• Study type: Interventional
• Study design: Randomized, Parallel Group, Placebo Controlled Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:Centralized Blinding and masking:Participant, Investigator and Outcome Assessor Blinded
• Phase: Phase 3

Countries of recruitment

Argentina, Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Chile, Croatia, Czech Republic, Estonia, Finland, France, Georgia, Germany, Greece, India, Italy, Lebanon, Mexico, Norway, Poland, Portugal, Republic of Korea, Romania, Saudi Arabia, Serbia , Singapore, Spain, Sweden, Taiwan, Thailand, The former Yugoslav Republic of Macedonia, Turkey, United Arab Emirates, United Kingdom, United States of America

Contacts

• Name: Dr Khokan K Debnath

• Name: Dr Khokan K Debnath

Key inclusion & exclusion criteria

Inclusion criteria: To be eligible for entry into this study, subjects must fulfill all of the following criteria:



1. Be male or female between 18 and 55 years old, inclusive



2. Must weigh between 40-120 kg, inclusive



3. Has experienced a single, first clinical event suggestive of MS within 75 days prior to Screening (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic



4. Has at least two clinically silent lesions on the T2-weighted MRI scan, at screening, with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial on screening MRI



5. Has EDSS 0 - 5.0 at Screening



6. Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by the Mantoux TB skin test or a comparable sensitive test, according to local regulation guidelines, if Mantoux test is not available and/or chest X-ray (Follow TB Guideline; Appendix C)



7. All hematological parameters must be normal at Screening according to the normal ranges provided by the centralized laboratory performing all the assessments.



8. If female, she must:

• be neither pregnant nor breast-feeding, nor attempting to conceive and

• use a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of adequate contraception is defined as one which results in a low failure rate (i.e. less than1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual

abstinence or a vasectomised partner. For the purpose of this trial, women of childbearing potential are defined as: â??All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive.â??



9. If male, he must be willing to use contraception to avoid contributing to pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication



10. Be willing and able to comply with study procedures for the duration of the study



11. Voluntarily provide written informed consent, including, for USA, subject authorization under Health Insurance Portability and Accountability Act (HIPAA) (see Appendix J), prior to any study-related procedure that is not part of normal medical care, and with the understanding that the subject may withdraw consent at any time without prejudice to their future medical care.



12. Must refuse any treatment already available for CIS such as Interferons and Glatiramer Acetate, entering the Initial Treatment Period of the Study.



NOTE: Confirmation that the subject is not pregnant must be established by a negative serum human chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine pregnancy test on Study Day 1. A pregnancy test is not required if the subject is post-menopausal or surgically sterilized.
Exclusion criteria: To be eligible for inclusion in this trial the subject must not meet any of the following criteria:



1. Subject has a diagnosis of multiple sclerosis (per McDonald criteria, 2005)



2. Subject has any other disease that could better explain the subjectâ??s signs and symptoms



3. Subject has complete transverse myelitis or bilateral optic neuritis



4. Subject uses or has used any other approved MS disease modifying drug (DMD)



5. Subject has used any investigational drug or undergone an experimental procedure within 12 weeks prior to SD1.



6. Subject who received oral or systemic corticosteroids or ACTH within 30 days prior to screening MRI. The MRI has to be performed 30 days after the oral or systemic corticosteroids or ACTH treatment. In case this interferes with MRI timing the screening period can be extended accordingly.





7. Subject has abnormal total bilirubin, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 x ULN



8. Subject suffers from current autoimmune disease other than MS



9. Subject suffers from psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol



10. Subject suffers from major medical illness such as cardiac (e.g. angina, congestive heart failure or arrhythmia), endocrinologic, hepatic, immunologic, metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine



11. Subject has a history of seizures not adequately controlled by medications.





12. Subject has a known allergy to cladribine, IFN-beta, the excipient(s) of the study medications, or to gadolinium-DTPA



13. Has any renal condition that would preclude the administration of gadolinium (e.g. acute or chronic severe renal insufficiency (GFR < 30 mL/min/1.73m2)



14. Has a history of chronic or clinically significant hematological abnormalities



15. History of active or chronic infectious disease or any disease that compromises immune function (e.g. HIV+, HTLV-1, Lyme disease, LTBI or TB, insulin-dependent diabetes).



16. Subject has previously been screened in this study thus signed an informed consent and then withdrawn



17. Subject has received any immunomodulatory or immunosuppressive therapyat any time prior to Screening, including, but not limited to, the following products: any interferon, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab,

alemtuzumab/Campath, anti-CD4), intravenous immunoglobuline G (IVIG), cytokines or anti-cytokine therapy



18. Subject has received experimental MS treatment



19. Subject has a history of alcohol or drug abuse



20. Subject has intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen



21. Inability to administer subcutaneous injections either by self or by caregiver



Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: null- Patients with a first clinical event at high risk of converting to Multiple Sclerosis

Intervention(s)

Intervention1: Low-dose oral cladribine: Oral cladribine
Low-dose oral cladribine - 1.75 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
Intervention2: High-dose oral cladribine: Low-dose oral cladribine - 3.5 mg/kg/year. Dosed once/week for 4 weeks at the start of a cycle.
Control Intervention1: Placebo: Placebo will be administered to subjects. The placebo looks exactly like the active treatment.

Primary Outcome(s)

The single primary endpoint for the overall study, which will be determined during the Initial Treatment Period, is time to conversion to MS (from randomization), according to the revised McDonald criteria (2005)Timepoint: 2 years

Secondary Outcome(s)

Time to conversion to clinically definite MS (from randomization), according to the Poser Criteria, defined by either a 2nd attack or a sustained increase (³1.5 points) in the EDSS score which will be determined during the initial treatment periodTimepoint: 2 years

Secondary ID(s)

28821

NCT00725985

Source(s) of Monetary Support

Merck Serono - SA

Secondary Sponsor(s)

PAREXEL International Clinical Research Private Limited

Ethics review

Status: Approved
Approval date: 01/05/2009
Contact:

Institutional Review Board, Christian Medical College - Vellore

Status: Approved
Approval date: 16/07/2009
Contact:

Maulana Azad Medical College Ethics Committee

Status: Approved
Approval date: 01/09/2009
Contact:

Institutional Ethics Committee, Sanjay Gandhi PGIMS

Status: Approved
Approval date: 10/06/2010
Contact:

Institutional Ethical Rewiew Board - St Johns Medical College

Status: Approved
Approval date: 27/07/2010
Contact:

Ethical Review Board - MS Ramaiah Hospital

Status: Approved
Approval date: 27/08/2010
Contact:

Institutional Ethics Committee - Christian Medical College Ludhiana

Status: Approved
Approval date: 15/11/2010
Contact:

Institutional Ethics Committee - Amrita Institute of Medical Sciences

Status: Approved
Approval date: 18/11/2010
Contact:

Institutional Ethics Committee - Sri Venkateshwara Medical College

Status: Approved
Approval date: 08/12/2010
Contact:

Institutional Ethics Committee Sri Ramachandra University