A Safety and Efficacy Study of Oral Cladribine in Subjects With Relapsing-remitting Multiple Sclerosis (RRMS) (CLARITY)

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ClinicalTrials.gov Identifier: NCT00213135

Recruitment Status : Completed

First Posted : September 21, 2005

Results First Posted : December 2, 2013

Last Update Posted : February 7, 2014

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

EMD Serono

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Multiple Sclerosis, Relapsing-Remitting
Interventions	Drug: Cladribine 5.25 mg/kg Drug: Cladribine 3.5 mg/kg Other: Placebo
Enrollment	1326

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Period Title: Overall Study
Started	456	433	437
Completed	406	398	380
Not Completed	50	35	57
Reason Not Completed
Adverse Event	9	5	5
Lost to Follow-up	11	8	4
Protocol Violation	4	4	10
Death	1	1	2
Disease progression	4	5	21
Other	21	12	15

Baseline Characteristics

Arm/Group Title		Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo	Total
Arm/Group Description		Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...	Total of all reporting groups
Arm/Group Description		Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		456	433	437	1326
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	456 participants	433 participants	437 participants	1326 participants
		39.1 (9.9)	37.9 (10.3)	38.7 (9.9)	38.6 (10.0)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	456 participants	433 participants	437 participants	1326 participants
	Female	312 68.4%	298 68.8%	288 65.9%	898 67.7%
	Male	144 31.6%	135 31.2%	149 34.1%	428 32.3%

Outcome Measures

1.Primary Outcome


Title	Annualized Qualifying Relapse Rate
Description	A qualifying relapse was defined as an increase of 2 points in at leas...
Description	A qualifying relapse was defined as an increase of 2 points in at least one functional system of the expanded disability status scale (EDSS) or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. The annualized relapse rate for each treatment group was calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population included all participants who were randomized in the study.


Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description:	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description:	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Overall Number of Participants Analyzed	456	433	437
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: relapses per year
	0.15 (0.12 to 0.17)	0.14 (0.12 to 0.17)	0.33 (0.29 to 0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cladribine 5.25 mg/kg, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Wald Chi-square test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.35 to 0.54
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.11
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cladribine 3.5 mg/kg, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Wald Chi-square test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Relative Risk
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.34 to 0.54
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.12
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Percentage of Relapse-free Participants
Description	A qualifying relapse was defined as an increase of 2 points in at leas...
Description	A qualifying relapse was defined as an increase of 2 points in at least one functional system of the EDSS or an increase of 1 point in at least two functional systems (excluding changes in bowel or bladder function or cognition) in the absence of fever, lasting for at least 24 hours and to have been preceded by at least 30 days of clinical stability or improvement. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were randomized in the study.


Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description:	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description:	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Overall Number of Participants Analyzed	456	433	437
Measure Type: Number Unit of Measure: percentage of participants
	78.9	79.7	60.9

3.Secondary Outcome


Title	Time to Disability Progression
Description	Time to disability progression was defined as the time to a sustained ...
Description	Time to disability progression was defined as the time to a sustained increase in EDSS score of at least 1 point if baseline EDSS score between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over a period of at least three months. Expanded disability status scale (EDSS) assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. Tenth Percentile of time to sustained increase in EDSS score was reported using Kaplan-Meier survival curve.
Time Frame	Baseline up to Week 96

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were randomized in the study.


Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description:	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description:	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Overall Number of Participants Analyzed	456	433	437
Measure Type: Number Unit of Measure: months
	13.6	13.6	10.8

4.Secondary Outcome


Title	Mean Number of Combined Unique (CU) Lesions, Active Time Constant 2 (T2) Lesions, and Active Time Constant 1 (T1) Gadolinium-Enhanced (Gd+) Lesions Per Participant Per Scan
Description	Mean Number of CU lesions, active T2 lesions, and active T1 Gd+ lesion...
Description	Mean Number of CU lesions, active T2 lesions, and active T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
Time Frame	Week 96

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were randomized in the study.


Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description:	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description:	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
Overall Number of Participants Analyzed	456	433	437
Least Squares Mean (Standard Error) Unit of Measure: lesions
CU lesions	0.38 (0.08)	0.43 (0.08)	1.72 (0.08)
Active T1 Gd+ lesions	0.11 (0.05)	0.12 (0.05)	0.91 (0.05)
Active T2 lesions	0.33 (0.06)	0.38 (0.07)	1.43 (0.06)

Adverse Events

Time Frame	Baseline up to Week 96
Adverse Event Reporting Description	Safety population included all the randomized participants who received at least one dose of stud medication with follow-up safety data

Arm/Group Title	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
Arm/Group Description	Cladribine tablet administered as c...	Cladribine tablet administered as c...	Placebo matched to cladribine table...
Arm/Group Description	Cladribine tablet administered as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48, and 52 resulting in total cladribine dose of 5.25 mg/kg during the treatment period of 96 weeks.	Cladribine tablet administered 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 and placebo matched to cladribine tablet was administered at Week 9 and 13 resulting in total cladribine dose of 3.5 mg/kg during the treatment period of 96 weeks.	Placebo matched to cladribine tablet administered over a course of 4 or 5 consecutive days of 28-day period at Week 1, 5, 9, 13, 48 and 52 during the treatment period of 96 weeks.
All-Cause Mortality
	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	41/454 (9.03%)	36/430 (8.37%)	28/435 (6.44%)
Blood and lymphatic system disorders
Lymphopenia ^* 1	1/454 (0.22%)	3/430 (0.70%)	0/435 (0.00%)
Neutropenia ^* 1	1/454 (0.22%)	1/430 (0.23%)	0/435 (0.00%)
Leukopenia ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Pancytopenia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Thrombocytopenia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Cardiac disorders
Acute myocardial infarction ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Angina pectoris ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Arrhythmia ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Bundle branch block left ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Cardiac hypertrophy ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Cardio-respiratory arrest ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Cardiomyopathy ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Myocardial infarction ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Prinzmetal angina ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Endocrine disorders
Hyperthyroidism ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Eye disorders
Eyelid ptosis ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Gastrointestinal disorders
Abdominal pain upper ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Colitis ulcerative ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Food poisoning ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Gastric ulcer ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Gastritis erosive ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Gastrointestinal motility disorder ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Haemorrhoids ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Ileus ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Inguinal hernia ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Nausea ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Pancreatitis acute ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Pancreatitis relapsing ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Peritonitis ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Small intestinal perforation ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Toothache ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Vomiting ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
General disorders
Chest pain ^* 1	1/454 (0.22%)	0/430 (0.00%)	1/435 (0.23%)
Pyrexia ^* 1	1/454 (0.22%)	0/430 (0.00%)	1/435 (0.23%)
Asthenia ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Drowning ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Non-cardiac chest pain ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Oedema peripheral ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hepatobiliary disorders
Cholelithiasis ^* 1	2/454 (0.44%)	1/430 (0.23%)	0/435 (0.00%)
Hepatitis toxic ^* 1	0/454 (0.00%)	1/430 (0.23%)	1/435 (0.23%)
Cholecystitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Cholecystitis acute ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Hepatic cyst ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Hepatitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hepatitis acute ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hepatosplenomegaly ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Liver disorder ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Immune system disorders
Hypersensitivity ^* 1	2/454 (0.44%)	0/430 (0.00%)	0/435 (0.00%)
Infections and infestations
Pneumonia ^* 1	3/454 (0.66%)	3/430 (0.70%)	3/435 (0.69%)
Adnexitis ^* 1	2/454 (0.44%)	0/430 (0.00%)	0/435 (0.00%)
Appendicitis ^* 1	0/454 (0.00%)	0/430 (0.00%)	2/435 (0.46%)
Pyelonephritis ^* 1	0/454 (0.00%)	2/430 (0.47%)	0/435 (0.00%)
Urinary tract infection ^* 1	1/454 (0.22%)	1/430 (0.23%)	0/435 (0.00%)
Actinomycosis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Chronic sinusitis ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Cystitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Endometritis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hepatitis C ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Herpes zoster ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Herpes zoster infection neurological ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Herpes zoster oticus ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Influenza ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Lung abscess ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Myocarditis bacterial ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Orchitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Respiratory tract infection ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Salpingo-oophoritis ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Subcutaneous abscess ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Tuberculosis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture ^* 1	0/454 (0.00%)	2/430 (0.47%)	0/435 (0.00%)
Fall ^* 1	0/454 (0.00%)	2/430 (0.47%)	0/435 (0.00%)
Concussion ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Facial bones fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Femoral neck fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Femur fracture ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Joint dislocation ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Lumbar vertebral fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Overdose ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Pneumothorax traumatic ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Postoperative ileus ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Radius fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Rib fracture ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Subdural haematoma ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Tibia fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Upper limb fracture ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Wound dehiscence ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Metabolism and nutrition disorders
Cachexia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hyperglycaemia ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Hypoproteinaemia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Musculoskeletal and connective tissue disorders
Pain in extremity ^* 1	1/454 (0.22%)	0/430 (0.00%)	1/435 (0.23%)
Arthritis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Bone pain ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Intervertebral disc protrusion ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Myalgia ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Osteitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma ^* 1	2/454 (0.44%)	3/430 (0.70%)	0/435 (0.00%)
Cervix carcinoma stage 0 ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Malignant melanoma ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Myelodysplastic syndrome ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Ovarian cancer ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Pancreatic carcinoma metastatic ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Nervous system disorders
Altered state of consciousness ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Convulsion ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Epilepsy ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Facial spasm ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Haemorrhagic stroke ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Syncope ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous ^* 1	1/454 (0.22%)	1/430 (0.23%)	1/435 (0.23%)
Pregnancy ^* 1	1/454 (0.22%)	1/430 (0.23%)	1/435 (0.23%)
Ectopic pregnancy ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Psychiatric disorders
Suicide attempt ^* 1	2/454 (0.44%)	0/430 (0.00%)	0/435 (0.00%)
Completed suicide ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Delirium ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Depression ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Intentional self-injury ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Mental disorder ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Panic attack ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Schizophrenia, paranoid type ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Renal and urinary disorders
Calculus ureteric ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Nephrolithiasis ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Nephrosclerosis ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Renal artery stenosis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Renal colic ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Renal failure chronic ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Reproductive system and breast disorders
Breast dysplasia ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Menorrhagia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Metrorrhagia ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Ovarian cyst ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Uterine haemorrhage ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^* 1	2/454 (0.44%)	0/430 (0.00%)	1/435 (0.23%)
Pulmonary embolism ^* 1	1/454 (0.22%)	0/430 (0.00%)	1/435 (0.23%)
Asthma ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Lung infiltration ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Pulmonary oedema ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Skin and subcutaneous tissue disorders
Hidradenitis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Lichen sclerosus ^* 1	0/454 (0.00%)	1/430 (0.23%)	0/435 (0.00%)
Purpura ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Rash generalised ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Skin reaction ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Vascular disorders
Arterial disorder ^* 1	0/454 (0.00%)	0/430 (0.00%)	1/435 (0.23%)
Deep vein thrombosis ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
Hypertension ^* 1	1/454 (0.22%)	0/430 (0.00%)	0/435 (0.00%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (11.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cladribine 5.25 mg/kg	Cladribine 3.5 mg/kg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	324/454 (71.37%)	286/430 (66.51%)	242/435 (55.63%)
Blood and lymphatic system disorders
Leukopenia ^* 1	39/454 (8.59%)	23/430 (5.35%)	3/435 (0.69%)
Lymphopenia ^* 1	142/454 (31.28%)	92/430 (21.40%)	8/435 (1.84%)
Ear and labyrinth disorders
Vertigo ^* 1	23/454 (5.07%)	14/430 (3.26%)	11/435 (2.53%)
Gastrointestinal disorders
Diarrhoea ^* 1	31/454 (6.83%)	30/430 (6.98%)	29/435 (6.67%)
Nausea ^* 1	49/454 (10.79%)	43/430 (10.00%)	39/435 (8.97%)
General disorders
Fatigue ^* 1	27/454 (5.95%)	20/430 (4.65%)	26/435 (5.98%)
Influenza like illness ^* 1	27/454 (5.95%)	34/430 (7.91%)	31/435 (7.13%)
Infections and infestations
Influenza ^* 1	34/454 (7.49%)	27/430 (6.28%)	27/435 (6.21%)
Nasopharyngitis ^* 1	58/454 (12.78%)	62/430 (14.42%)	56/435 (12.87%)
Upper respiratory tract infection ^* 1	52/454 (11.45%)	54/430 (12.56%)	42/435 (9.66%)
Urinary tract infection ^* 1	32/454 (7.05%)	23/430 (5.35%)	39/435 (8.97%)
Investigations
Lymphocyte count decreased ^* 1	26/454 (5.73%)	13/430 (3.02%)	0/435 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1	23/454 (5.07%)	27/430 (6.28%)	21/435 (4.83%)
Back pain ^* 1	39/454 (8.59%)	34/430 (7.91%)	28/435 (6.44%)
Pain in extremity ^* 1	24/454 (5.29%)	16/430 (3.72%)	20/435 (4.60%)
Nervous system disorders
Headache ^* 1	94/454 (20.70%)	104/430 (24.19%)	75/435 (17.24%)
Psychiatric disorders
Depression ^* 1	25/454 (5.51%)	18/430 (4.19%)	13/435 (2.99%)
Insomnia ^* 1	14/454 (3.08%)	25/430 (5.81%)	17/435 (3.91%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain ^* 1	24/454 (5.29%)	19/430 (4.42%)	25/435 (5.75%)
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (11.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Merck KGaA Communication Center
Organization:	Merck Serono, a division of Merck KGaA
Phone:	+49-6151-72-5200
EMail:	service@merckgroup.com

Publications of Results:

Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):416-26. doi: 10.1056/NEJMoa0902533. Epub 2010 Jan 20.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist TP, Coyle PK, Dangond F, Alexandri N, Galazka A. Relapses in people with multiple sclerosis treated with cladribine tablets followed for up to 5 years: a plain language summary. Neurodegener Dis Manag. 2022 Dec;12(6):303-310. doi: 10.2217/nmt-2022-0019. Epub 2022 Aug 26.

Giovannoni G, Comi G, Rammohan K, Rieckmann P, Dangond F, Jack D, Vermersch P. Disease stability over five years in people with multiple sclerosis treated with cladribine tablets: a plain language summary. Neurodegener Dis Manag. 2022 Dec;12(6):295-301. doi: 10.2217/nmt-2022-0018. Epub 2022 Aug 26.

Vermersch P, Galazka A, Dangond F, Damian D, Wong SL, Jack D, Harty G. The effect of cladribine tablets in people with more active multiple sclerosis: a plain language summary. Neurodegener Dis Manag. 2022 Dec;12(6):285-293. doi: 10.2217/nmt-2022-0009. Epub 2022 Aug 3.

Oh J, Walker B, Giovannoni G, Jack D, Dangond F, Nolting A, Aldridge J, Lebson LA, Leist TP. Side effects that occurred early in people with multiple sclerosis during the first year of treatment with cladribine tablets: a plain language summary. Neurodegener Dis Manag. 2022 Feb 1;12(1):1-7. doi: 10.2217/nmt-2021-0041. Epub 2022 Jan 12.

Giovannoni G, Coyle PK, Vermersch P, Walker B, Aldridge J, Nolting A, Galazka A, Lemieux C, Leist TP. Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets. Front Immunol. 2021 Dec 24;12:763433. doi: 10.3389/fimmu.2021.763433. eCollection 2021.

Giovannoni G, Comi G, Rammohan K, Rieckmann P, Dangond F, Keller B, Jack D, Vermersch P. Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies. Adv Ther. 2021 Sep;38(9):4975-4985. doi: 10.1007/s12325-021-01865-w. Epub 2021 Aug 9.

De Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist T, Coyle PK, Dangond F, Keller B, Alexandri N, Galazka A. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies. Mult Scler. 2022 Jan;28(1):111-120. doi: 10.1177/13524585211010294. Epub 2021 May 10.

Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.

Terranova N, Hicking C, Dangond F, Munafo A. Effects of Postponing Treatment in the Second Year of Cladribine Administration: Clinical Trial Simulation Analysis of Absolute Lymphocyte Counts and Relapse Rate in Patients with Relapsing-Remitting Multiple Sclerosis. Clin Pharmacokinet. 2019 Mar;58(3):325-333. doi: 10.1007/s40262-018-0693-y.

Afolabi D, Albor C, Zalewski L, Altmann DR, Baker D, Schmierer K. Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis. Mult Scler. 2018 Oct;24(11):1461-1468. doi: 10.1177/1352458517726380. Epub 2017 Aug 17.

Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson MO. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis. Clin Pharmacokinet. 2017 Oct;56(10):1245-1253. doi: 10.1007/s40262-017-0516-6.

De Stefano N, Giorgio A, Battaglini M, De Leucio A, Hicking C, Dangond F, Giovannoni G, Sormani MP. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult Scler. 2018 Feb;24(2):222-226. doi: 10.1177/1352458517690269. Epub 2017 Jan 31.

Ali S, Paracha N, Cook S, Giovannoni G, Comi G, Rammohan K, Rieckmann P, Sorensen PS, Vermersch P, Greenberg S, Scott DA, Joyeux A; CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) Study Group. Reduction in healthcare and societal resource utilization associated with cladribine tablets in patients with relapsing-remitting multiple sclerosis: analysis of economic data from the CLARITY Study. Clin Drug Investig. 2012 Jan 1;32(1):15-27. doi: 10.2165/11593310-000000000-00000.

Layout table for additonal information

Responsible Party:	EMD Serono
ClinicalTrials.gov Identifier:	NCT00213135
Other Study ID Numbers:	25643
First Submitted:	September 13, 2005
First Posted:	September 21, 2005
Results First Submitted:	September 30, 2013
Results First Posted:	December 2, 2013
Last Update Posted:	February 7, 2014

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