CLARITY Extension Study

Relapsing-Remitting Multiple Sclerosis Clinical Trial

Official 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00641537
• Other study ID #: 27820
• Secondary ID: 2007-000381-20
• Status: Completed
• Phase: Phase 3
• Start date: February 29, 2008
• Est. completion date: December 31, 2011

Study information

• Verified date: October 2020
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 867
• Est. completion date: December 31, 2011
• Est. primary completion date: December 31, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Relapsing-Remitting Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Cladribine
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.
• Placebo
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.
• Cladribine
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.
• Cladribine
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.
• Placebo
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.

Locations

Country	Name	City	State
Australia	Research Site	Camperdown
Australia	Research Site	Melbourne
Australia	Research Site	Victoria
Austria	Research Site	Linz
Belgium	Research Site	Diepenbeek
Belgium	Research Site	Esneux
Brazil	Research Site	Recife
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Shuman
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Bulgaria	Research Site	Zagora
Canada	Research Site	Burnaby
Canada	Research Site	Greenfield Park
Canada	Research Site	Ottawa
Canada	Research Site	Quebec
Croatia	Research Site	Karlovac
Croatia	Research Site	Sisak
Croatia	Research Site	Split
Czechia	Research Site	Hradec Králové
Czechia	Research Site	Olomouc
Czechia	Research Site	Praha
Denmark	Research Site	Copenhagen
Estonia	Research Site	Tallinn
Estonia	Research Site	Tartu
Finland	Research Site	Oulu
Finland	Research Site	Turku
France	Research Site	Clermont-Ferrand
France	Research Site	Lille
France	Research Site	Nancy
France	Research Site	Nimes
France	Research Site	Paris
France	Research Site	Rennes
France	Research Site	Saint Herblain
Germany	Research Site	Bochum
Germany	Research Site	Frankfurt
Germany	Research Site	Giessen
Germany	Research Site	Hannover
Germany	Research Site	Regensburg
Germany	Research Site	Rostock
Greece	Research Site	Athens
Italy	Research Site	Bari
Italy	Research Site	Cagliari
Italy	Research Site	Catania
Italy	Research Site	Firenze
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Roma
Latvia	Research Site	Riga
Lebanon	Research Site	Beirut
Lebanon	Research Site	Beyrouth
Lithuania	Research Site	Kaunas
Morocco	Research Site	Casablanca
Morocco	Research Site	Fes
Morocco	Research Site	Rabat
Netherlands	Research Site	Sittard- Geleen
Poland	Research Site	Gdansk
Poland	Research Site	Krakow
Poland	Research Site	Lodz
Poland	Research Site	Poznan
Poland	Research Site	Warszawy
Portugal	Research Site	Lisboa
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Kaluga
Russian Federation	Research Site	Kazan
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Kursk
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Rostov-on-Don
Russian Federation	Research Site	Samara
Russian Federation	Reseach Site	Saratov
Russian Federation	Research Site	St-Petersburg
Russian Federation	Research Site	Tomsk
Russian Federation	Research Site	Vladimir
Russian Federation	Research Site	Yaroslavl
Saudi Arabia	Research Site	Riyadh
Serbia	Research Site	Belgrade
Switzerland	Research Site	Lausanne
Switzerland	Research Site	St. Gallen
Tunisia	Research Site	Monastir
Tunisia	Research Site	Sfax
Tunisia	Research Site	Tunis
Turkey	Research Site	Bursa
Turkey	Research Site	Izmir
Ukraine	Research Site	Kharkov
Ukraine	Research Site	Kiev
Ukraine	Research Site	Lviv
Ukraine	Research Site	Vinnitsa
United Kingdom	Research Site	Hull
United Kingdom	Research Site	London
United Kingdom	Research Site	Nottingham
United Kingdom	Research Site	Oxford
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Stoke-on-Trent
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boulder	Colorado
United States	Research Site	Charleston	West Virginia
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Chicago	Illinois
United States	Research Site	Columbus	Ohio
United States	Research Site	Durham	North Carolina
United States	Research Site	Henderson	Nevada
United States	Research Site	Medford	Oregon
United States	Research Site	Newark	New Jersey
United States	Research Site	Northbrook	Illinois
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Seattle	Washington
United States	Research Site	Tacoma	Washington
United States	Research Site	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Croatia,  Czechia,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Italy,  Latvia,  Lebanon,  Lithuania,  Morocco,  Netherlands,  Poland,  Portugal,  Russian Federation,  Saudi Arabia,  Serbia,  Switzerland,  Tunisia,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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

External Links

•   Trial Awareness and Transparency website
•   US Medical Information website, Medical Resources