CLARITY Extension Study

• Register: EUCTR
• Last refreshed on: 21 August 2017
• Main ID: EUCTR2007-000381-20-BE
• Date of registration: 20/12/2007
• Prospective Registration: Yes
• Primary sponsor: Merck Serono S.A. - Geneva
• Public title: CLARITY Extension Study
• Scientific title: A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects with Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY). - CLARITY EXTENSION
• Date of first enrolment: 21/01/2008
• Target sample size: 1100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-000381-20
• 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: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Italy, Latvia, Lebanon, Lithuania, Morocco, Netherlands, Poland, Portugal, Russian Federation, Saudi Arabia, Serbia, Switzerland, Turkey, Ukraine, 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:
° Were randomised in Trial 25643 and satisfy one of the following:
- Completed their randomised treatment course and scheduled visits for the full 96 weeks (a)(b); or
- Did not complete the randomized treatment course in Trial 25643, but who elected to receive rescue treatment with Rebif or another beta-interferon or glatiramer acetate, and who completed scheduled clinic visits for the full 96 weeks; or
- Did not complete the randomised treatment course in Trial 25643, declined rescue with Rebif or another beta-interferon or glatiramer acetate, and still completed scheduled clinic visits for the full 96 weeks; or
- Did not complete the randomised treatment course in Trial 25643, were not eligible for rescue option with Rebif, and still completed scheduled clinic visits for the full 96 weeks.

° Be male or female and between 18 and 65 years of age (inclusive, at time of informed consent prior to entry into Trial 25643)

° Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray;
NOTE: For subjects with medical history or LTBI ot TB, please refer to Appendices L, M, N. Subjects who should be excluded from blinded medication could be proposed to be followed for safety according to the same scheduled visits

° All of the following laboratory hematologic parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at SD1:
- Hemoglobin = 11.6 – 16.2 G/DL
- Leukocyctes (total white blood cells [WBC]) = 4.1 – 12.3 x 10E3/UL
- Absolute lymphocytes = 1.02 – 3.36 x 10E3/UL
- Absolute neutrophil count (ANC) = 2.03 – 8.36 x10E3/UL
- Platelet count = 140-450 x 10E3/UL
NOTE: For subjects with abnormal laboratory hematological parameters, please refer to section 6.2.1 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

° Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either:
- Be post-menopausal or surgically sterilized; or
- Using 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 contraception is defined as those which result in a low failure rate (i.e. less that 1% per year) when used consistently and correctly such as implants, injectables, comined with oral contraceptives, IUSs, sexual abstinence or vasectomised partner.
- Treatment of pregnant and nursing women with cladribine is prohibited.

° If male, he must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication or following early termination or early withdrawal.

° Voluntarily provide written informed consent, and for USA sites only, a subject authorization under Health Insurance Portability and Accountability Act (HIPAA)

° Absence of history or available abnormal laboratory results indicative of any significant or unstable cardiac, endocrinologic, hematologic (other than abnormal laboratory results consistent with prior exposure to oral cladribine), hepatic, immunologic (other than MS), metabolic, urologic, pulmonary, gastrointestinal, derma
Exclusion criteria:
° Have prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening;

° Have a history of chronic or clinically significant hematological abnormalities;

° Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase > 2.5 times the upper limit of the normal values;

° Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine.

° Suffers from major 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;

° History of active or chronic infectious disease or any disease which compromises immune function (e.g. HIV+, HTLV-1, Lyme disease);

° Have an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-b or any of its excipient(s);

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

° Have a positive stool heme-occult test at Pre-Study Evaluation (PSE);
NOTE: For subjects with positive heme-occult test, please refer to section 6.4.6 for retesting guidelines. Subjects who should be excluded from blinded medication during the current yearly dosing could be proposed to be followed for safety according to the same scheduled visits.

° Subject has a history of seizures not adequately controlled by treatment.

° Concurrent enrolment in any other investigational drug trial with the exception of any Sponsor sub-trial of this protocol that is approved by the Medical Director

° Any other reason(s) that, in the opinion of the Investigator and/or the Sponsor, would indicate that the subject is unsuitable for inclusion in this extension trial

° Treatment with a beta-interferon or glatiramer acetate less than 3 months prior to Study Day 1 during any gap between completion of CLARITY Trial 25643 and CLARITY Extension Trial 27820

° Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at anytime during and since Study 25643

NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion whereby there was a gap interval of varying duration, who subsequently, during the gap interval were treated with a DMD or Rebif should discontinue the DMD or Rebif for a period of at least 3 months prior to Study Day 1. For those subjects who are unable or are unwilling to discontinue their DMD, they may not be re- randomized to receive study medication. These subjects are encouraged to enter the study but will be followed for safety only.

NOTE: For subjects who had to delay entry into the CLARITY Extension study or the 24-Week Supplemental Follow-up portion, whereby there was a gap interval of varying duration, who subsequently during the gap interval were treated with a prohibited medication (See exclusion criteria section 5.2.2.) will not be eligible for the enrollment in the future open-label study. These s

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

Health Condition(s) or Problem(s) studied

Relapsing Remitting Multiple Sclerosis (RRMS)
MedDRA version: 13.1 Level: PT Classification code 10028245 Term: Multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Name: cladribine
Product Code: Not Applicable
Pharmaceutical Form: Tablet
INN or Proposed INN: CLADRIBINE
CAS Number: 4291638
Current Sponsor code: EMD280922
Other descriptive name: 2-chloro-2’-deoxyadenosine (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

Primary Outcome(s)

Main Objective: Safety Objectives:
• Evaluate the safety of extended treatment with oral cladribine when administered according to a fixed annual dosing schedule to subjects who completed Trial 25643 (CLARITY)
• To assess the safety of cladribine with an emphasis on cardiac repolarization as measured by changes in QT interval (in a subset of patients also partipating in the PK sampling and analysis).

Primary end point(s): Safety endpoints:
° Proportion of subjects with at least one grade 4 CTCAE toxicity on the following parameters of hematologic and hepatic function: absolute lymphocyte count (ALC),
hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin
° Proportion of subjects with grades 3 or 4 adverse events (AEs) for hematologic and hepatic indices
° Mean change in absolute lymphocyte count, hemoglobin level, WBC, ANC, platelets, ALT, AST, and bilirubin
° Incidence of all treatment emergent AEs and SAEs
° Proportion of subjects developing infections, infection-related AEs and malignancies
° Time to first grade 3 and 4 hematological toxicity or liver toxicity
° Median and mean time to recovery from hemtological and liver toxicity
° Median and mean time to nadir of absolute lymphocyte count and mean time to recovery to normal values
° Mean change in QTc interval from baseline

Clinical Efficacy Endpoints:
° Proportion of subjects relapse free (qualifying and/or non-qualifying)
° Disability progression. The following three progression endpoints will be used:
o Time to confirmed EDSS progression, confirmed after 3 months
o Time to confirmed EDSS progression, confirmed after 6 months
o Confirmed progressions (sustained over a period of at least 3 months) assessed at annual intervals
° Time to treatment start with rescue medication
° Annualized relapse rate (qualifying and/or non-qualifying)
° Time to first relapse (qualifying and/or non-qulaifying)
° Time to second relapse (qualifying and/or non-qualifying)

MRI endpoints:
° Number of new T1 gadolinium-enhanced lesions
° Number of active T2 lesions
° Number of combined unique (CU) lesions defined as 1) new T1 gadoliniumenhancing, or 2) new T2 non-enhancing or enlarging lesions, or 3) both, without double-counting
° Total T2 lesion volume (the proton density/T2-weighted (T2) burden of disease (BOD))
° Proportion of T1 gadolinium-enhanced lesions assessed at Baseline of Trial 25643
transformed in T1 hypointense lesions (black holes)
° Percent brain volume changes
° Proportion of subjects with no new T1 gadolinium-enhanced lesions
° Proportion of subjects with no active T2 lesions
° Proportion of subjects with no combined unique lesions
° Number of new T1 hypointense lesions
° Mean change in volume of T1 hypointense lesions

Secondary Objective: • Explore the long-term benefit of treatment with oral cladribine vs. placebo
• Explore the relationship between oral cladribine treatments and various immunologic parameters, MRI measures of disease activity, clinical relapses and disease progression in subjects previously randomised in Trial 25643
• Determine the benefit of continued oral cladribine treatment on health-related quality of life and economic outcome measures
• Explore the association between genetic variants, clinical efficacy, MRI endpoints and groups of subject with adverse events (grade 3 and 4 toxicity)
• Explore the effect of oral cladribine on gene expression profiles
• Assess population pharmacokinetics

Timepoint(s) of evaluation of this end point: 96 weeks and 120 weeks

Secondary Outcome(s)

Secondary end point(s): Not Applicable

Secondary ID(s)

2007-000381-20-FI

27820

NCT00641537

Source(s) of Monetary Support

Merck Serono S.A. - Geneva