CLARITY Extension Study

Study Overview
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Brief Summary
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The purpose of this extension trial was to further evaluate the safety and tolerability of oral cladribine in subjects who have previously completed treatment within Trial 25643 (CLARITY). This trial also explored clinical benefit of prolonged 192-week versus 96-week treatment.

Official Title
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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)

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Cladribine
* Drug: Placebo
* Drug: Cladribine
* Drug: Cladribine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Randomized in Trial 25643 and satisfied one of the following: Completed randomized treatment course and scheduled visits for the full 96 weeks; or Did not complete the randomized treatment course in Trial 25643 but elected to receive rescue treatment with Rebif®, another beta-interferon, or glatiramer acetate and completed scheduled clinic visits for the full 96 weeks; or Did not complete the randomized treatment course in Trial 25643, declined rescue with Rebif®, another beta-interferon, or glatiramer acetate and still completed scheduled clinic visits for the full 96 weeks; or Did not complete the randomized treatment course in Trial 25643, were not eligible for rescue option with Rebif®, and still completed scheduled clinic visits for the full 96 weeks Male or female, between 18 and 65 years of age (inclusive, at time of informed consent for Trial 25643) No medical history or evidence of latent tuberculosis infection (LTBI) or tuberculosis (TB), as evidenced by TB skin test or chest X-ray All of the following laboratory hematologic parameters evaluated as normal (as define below, inclusively) within 28 days of first dosing of blinded study medication at study Day 1: Hemoglobin = 11.6 to 16.2 gram per deciliter (g/dL) Leukocytes (total white blood cell) = 4.1 to 12.3*10^3 per microliter Absolute lymphocyte count (ALC) = 1.02 to 3.36*10^3 per microliter Absolute neutrophil count (ANC) = 2.03 to 8.36*10^3 per microliter Platelet count = 140 to 450*10^3 per microliter Other protocol-defined inclusion/exclusion criteria may apply Exclusion Criteria: Participants who were not enrolled in Trial 25643 Participant has moderate to severe renal impairment Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at any time during and since Trial 25643 Use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIG) or plasmapheresis at any time during and since Trial 25643 Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days before Study Day 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cladribine Low/Placebo (LLPP)<br> | Drug: Placebo<br>* Participants who received Cladribine 3.5 mg/kg in the previous study 25643 (NCT00213135) and completed will be re-randomized in this extension study and receive placebo matched to cladribine tablet 0.875 mg/kg orally administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 during the treatment period of 96 weeks.<br>|
| Placebo Comparator: Cladribine High Dose/Placebo (HLPP)<br> | Drug: Placebo<br>* Participants who received Cladribine 5.25 mg/kg in the previous study 25643 (NCT00213135) and completed will be re-randomized in this extension study and receive placebo matched to cladribine tablet 0.875 mg/kg orally administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 during the treatment period of 96 weeks.<br>|
| Experimental: Cladribine Low/Low Dose (LLLL)<br> | Drug: Cladribine<br>* Participants who received Cladribine 3.5 mg/kg in the previous study 25643 (NCT00213135) and completed will be re-randomized in this extension study and receive cladribine tablet orally as cumulative dose of 0.875 mg/kg over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.<br>|
| Experimental: Cladribine High/Low Dose (HLLL)<br> | Drug: Cladribine<br>* Participants who received Cladribine 5.25 mg/kg in the previous study 25643 (NCT00213135) and completed will be re-randomized in this extension study and receive cladribine tablet orally as cumulative dose of 0.875 mg/kg over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.<br>|
| Experimental: Placebo/Cladribine Low Dose (PPLL)<br> | Drug: Cladribine<br>* Participants who received placebo in the previous study 25643 (NCT00213135) and completed will be re-randomized in this extension study and receive cladribine tablet orally as cumulative dose of 0.875 mg/kg over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.<br>|
| No Intervention: Placebo/No Treatment<br> | |
| No Intervention: Cladribine 3.5 mg/kg/No Treatment<br>Participants who received cladribine 3.5 mg/kg in previous study 25643 (NCT00213135) and completed were enrolled in this extension study and received no cladribine treatment and were followed up for safety assessment for 96 weeks (during the treatment period) and followed up for 24 weeks (during supplemental follow-up period). | |
| No Intervention: Cladribine 5.25 mg/kg/No Treatment<br>Participants who received cladribine 5.25 mg/kg in previous study 25643 (NCT00213135) and completed were enrolled in this extension study and received no cladribine treatment and were followed up for safety assessment for 96 weeks (during the treatment period) and followed up for 24 weeks (during supplemental follow-up period). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Population: Percentage of Participants With at Least 1 Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 4 Hematologic and Hepatic Toxicity | Hematologic and hepatic toxicity was assessed using Common Terminology Criteria for Adverse Events v 3.0 (CTCAE). Hematologic and hepatic function included absolute lymphocyte count (ALC), hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin. According to CTCAE v3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. | Baseline up to Week 120 | 
| Safety Population: Mean Change From Baseline in Absolute Lymphocyte Count, Platelet, Neutrophils and Leukocytes at Week 120 | Mean change from baseline in absolute lymphocyte count, platelet, neutrophils and leukocytes at week 120 were reported. | Baseline, Week 120 | 
| Safety Population: Mean Change From Baseline in Hemoglobin at Week 120 | Mean change from baseline in hemoglobin at Week 120 was reported. | Baseline, Week 120 | 
| Safety Population: Mean Change From Baseline in Aspartate Aminotransferase and Alanine Aminotransferase at Week 120 | Mean change from baseline in aspartate aminotransferase and alanine aminotransferase at week 120 were reported. | Baseline, Week 120 | 
| Safety Population: Mean Change From Baseline in Bilirubin at Week 120 | Mean Change From Baseline in Bilirubin at week 120 was reported. | Baseline, Week 120 | 
| Safety Population: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. Serious AE (SAE): Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. Number of participants with TEAEs included participants with both non-serious TEAEs and serious TEAEs. | Baseline up to Week 120 | 
| SAFUP Analysis Set: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. Number of participants with TEAEs included participants with both non-serious TEAEs and serious TEAEs. | Baseline up to Week 120 | 
| Safety Population: Number of Participants Who Developed Infections (Herpes Viral Infection, Viral Infectious Disorder and Opportunistic Infection), Infection-related Adverse Events and Malignancies | Number of participants who developed Herpes viral infection, Viral infectious disorder and Opportunistic infection are reported. Number of participants with infection related adverse events are the number of participants who had at least one adverse event coded to medical dictionary for regulatory activities (MedDRA) preferred terms under infection and infestation system organ class. Malignancy is defined as having at least one adverse event coded to MedDRA preferred terms under the pre-specified grouping Malignant and unspecified tumors. | Baseline up to Week 120 | 
| SAFUP Analysis Set: Number of Participants Who Developed Infections (Herpes Viral Infection, Viral Infectious Disorder and Opportunistic Infection), Infection-related Adverse Events and Malignancies | Number of participants who developed Herpes viral infection, Viral infectious disorder and Opportunistic infection were reported. Number of participants with infection related adverse events are the number of participants who had at least one adverse event coded to medical dictionary for regulatory activities (MedDRA) preferred terms under infection and infestation system organ class. Malignancy is defined as having at least one adverse event coded to MedDRA preferred terms under the pre-specified grouping Malignant and unspecified tumors. | Baseline up to Week 120 | 
| Safety Population: Time to First Grade 3 or 4 Hematological Toxicity and Liver Toxicity | Hematologic and hepatic toxicity was assessed using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Hematologic and hepatic function included absolute lymphocyte count (ALC), hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin. Time to first CTCAE Grade 3 or 4 hematological or liver toxicity was analyzed by treatment group using Kaplan-Meier plots of probability of surviving toxicity-free and point estimates of percentiles. According to CTCAE version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. 10th, 20th, 25th, 50th and 75th percentiles were estimated from Kaplan-Meier survival curve. | Baseline up to Week 120 | 
| Safety Population: Median Time to Recovery From Grade 3 or 4 Hematological and Hepatic Toxicity | Hematologic and hepatic toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE). Hematologic and hepatic function included absolute lymphocyte count (ALC), hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin. According to CTCAE version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. Time to recovery from grade 3 or 4 hematological or liver toxicity were reported: lymphocytes, platelets, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin. Recovery from a Grade 3 or 4 toxicity is defined as a return to a Grade 0 or 1. | Baseline up to Week 120 | 
| Safety Population: Mean Time to Recovery From Grade 3 or 4 Hematological and Liver Toxicity | Hematologic and hepatic toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE). Hematologic and hepatic function included absolute lymphocyte count (ALC), hemoglobin level, white blood cell (WBC) count, absolute neutrophil count (ANC), platelets, alanine transaminase (ALT), aspartate transaminase (AST) and bilirubin. According to CTCAE v3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death. Time to recovery from grade 3 or 4 hematological or liver toxicity were reported: lymphocytes, platelets, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST) and Platelets. Recovery from a Grade 3 or 4 toxicity is defined as a return to a Grade 0 or 1. | Baseline up to Week 120 | 
| Safety Population: Median Time to Nadir of Absolute Lymphocyte Count | Median time to nadir of absolute lymphocyte count was reported. | Baseline up to Week 120 | 
| Safety Population: Mean Time to Nadir of Absolute Lymphocyte Count | Mean time to nadir of absolute lymphocyte count was reported. | Baseline up to Week 120 | 
| Safety Population: Mean Time to Recovery From Nadir of Absolute Lymphocyte Count to Normal Value | Mean time to recovery from nadir of absolute lymphocyte count to normal was reported. Recovery from Nadir is defined as a return to baseline value. Normal absolute lymphocyte count is 1.02 x 10^3 cells/microliter. | Baseline up to Week 120 | 
| Safety Population: Mean Change in Corrected QT (QTc) Interval From Baseline | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. Mean change in corrected QT (QTc) interval from baseline was reported. | Baseline, Week 5, 48, 52 and 96 |