Clinical trial with oral cladribine in early Multiple Sclerosis (MS)

• Register: EUCTR
• Last refreshed on: 3 June 2013
• Main ID: EUCTR2008-003706-33-DE
• Date of registration: 09/12/2008
• Prospective Registration: Yes
• Primary sponsor: Merck Serono S.A. - Geneva
• Public title: Clinical trial with oral cladribine in early Multiple Sclerosis (MS)
• Scientific title: A Phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial of oral cladribine in subjects with a first clinical event at high risk of converting to MS - ORAl CLadribine in Early MS (ORACLE MS) Trial
• Date of first enrolment: 31/03/2009
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-003706-33
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3

Countries of recruitment

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

Contacts

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

• Name: Communication Center Merck KGaA
• Affiliation: Merck KGaA

Key inclusion & exclusion criteria

Inclusion 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 the initial Screening visit (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, 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. Has 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
7. ALL the 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: “All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive.”
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), 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Subject has a diagnosis of multiple sclerosis (per McDonald criteria, 2005)
2. Subject has any other disease that could better explain the subject’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 therapy at any time prior to SD1, 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
22. Has prior or current malignancy (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years)
23. Has a positive stool heme-occult test at Screening


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Subjects with a first clinical demyelinating event (Clinically Isolated Syndrome (CIS)) at high risk of converting to Multiple Sclerosis (MS)
MedDRA version: 14.0 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: Cladribine
Pharmaceutical Form: Tablet
INN or Proposed INN: CLADRIBINE
CAS Number: 4291638
Current Sponsor code: EMD280922
Other descriptive name: 2-chloro-2’-deoxy-ß-D-adenosine (2-CdA)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Trade Name: Rebif 44 micrograms solution for injection
Product Name: Interferon beta-1a FBS-free/HSA-free
Pharmaceutical Form: Solution for injection
INN or Proposed INN: INTERFERON BETA-1A
CAS Number: 9008-11-1
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 44-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: The primary analysis will be performed at a cut-off date of August 15, 2011.

Main Objective: The primary objective of this study is to evaluate the effect of oral cladribine on the time to conversion to Clinical Definite Multiple Sclerosis (CDMS) according to the Poser criteria, defined by either a second attack or a sustained increase in EDSS score in subjects with a first clinical demyelinating event at high risk of converting to MS

Primary end point(s): The primary endpoint for the overall study is time to conversion to CDMS (from randomization), according to the Poser Criteria, defined by either a 2nd attack or a sustained increase in the EDSS score (EDSS = 1 point if baseline was =1 and =4.5, or = 1.5 points if baseline EDSS was 0, or =0.5 point if baseline EDSS was =5, over a period of at least three months).

Secondary Objective: Secondary objectives of Initial Treatment Period:
· The main secondary objective of this study, is to evaluate the effect of 2 dosage regimens of oral cladribine vs. placebo on the time to conversion to MS (from randomization) according to the revised McDonald criteria (Polman, et al. 2005) in subjects with a first clinical demyelinating event at high risk of converting to MS
· Evaluate the effect of oral cladribine on selected MRI parameters and disease progression in subjects with a first clinical demyelinating event suggestive of MS.
· Evaluate the effect of oral cladribine on Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test - Revised (BVMT-R) as measures of cognition in subjects with a first clinical demyelinating event suggestive of MS
· Evaluate the safety and tolerability of treatment with oral cladribine in subjects with a first clinical demyelinating event suggestive of MS.

Secondary Outcome(s)

Secondary end point(s): • Main secondary endpoint of the Initial Treatment Period: time to conversion to MS (from randomization), according to the revised McDonald criteria (2005).

• Main secondary endpoint of the Open-Label Maintenance Treatment Period: time to confirmed EDSS progression (EDSS =1 point if baseline EDSS was between = 1.0 and = 4.5, or > 1.5 points if baseline EDSS was 0, or =0.5 if baseline EDSS =5.0 over a period of at least three months) from randomization.

• Main secondary endpoints of the Long-Term Follow-Up Treatment Period: time to conversion to MS according to the revised McDonald criteria and time to conversion to CDMS according to the Poser criteria.

Timepoint(s) of evaluation of this end point: Two main analyses of the ITP will be performed:
1. First Analysis. This will be the primary analysis which will be performed at a cut-off date of August 15, 2011.
2. Second Analysis. This will be performed at the end of the Initial Treatment Period (ITP).
A final analysis that includes all post-ITP collected data will be performed at the end of the study.

Secondary ID(s)

NCT00725985

28821

2008-003706-33-CZ

Source(s) of Monetary Support

Merck Serono S.A. - Geneva