A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT00436826
First received: February 15, 2007
Last updated: August 4, 2013
Last verified: August 2013
Results First Received: March 28, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Multiple Sclerosis
Interventions: Drug: Cladribine
Drug: Placebo
Drug: Interferon-beta (IFN-beta)

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Initially 42 participants were enrolled and randomized under original protocol but enrollment was terminated because early safety signals related to hematological toxicities. Protocol Amendment 1 and 2 was implemented and 172 participants were enrolled. Results of participants enrolled under Amendment 1 and 2 are reported.

Reporting Groups
  Description
Cladribine 3.5 mg/kg, IFN-beta (DB Period) Participants received cladribine tablets orally as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg along with IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the double blind (DB) period of 96 weeks.
Placebo, IFN-beta (DB Period) Participants received matching placebo tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total matching placebo dose of 3.5 mg/kg along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.) period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext) Participants who received placebo initially and completed DB period entered in the OL Ext. period. In OL Ext. period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up) Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
Placebo, IFN-beta (Safety Follow up) Participants who received placebo initially and completed DB period entered in the OL ext. safety follow up period. In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.

Participant Flow for 3 periods

Period 1:   Double Blind Period
    Cladribine 3.5 mg/kg, IFN-beta (DB Period)     Placebo, IFN-beta (DB Period)     Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)     Placebo, IFN-beta (Safety Follow up)  
STARTED     124     48     0     0     0     0  
COMPLETED     111     37     0     0     0     0  
NOT COMPLETED     13     11     0     0     0     0  
Adverse Event                 2                 0                 0                 0                 0                 0  
Protocol Violation                 1                 0                 0                 0                 0                 0  
Unspecified                 10                 11                 0                 0                 0                 0  

Period 2:   Ext. Period (With Cladribine Treatment)
    Cladribine 3.5 mg/kg, IFN-beta (DB Period)     Placebo, IFN-beta (DB Period)     Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)     Placebo, IFN-beta (Safety Follow up)  
STARTED     0     0     47     28     0     0  
COMPLETED     0     0     3     4     0     0  
NOT COMPLETED     0     0     44     24     0     0  
Sponsor's decision to terminate study                 0                 0                 44                 24                 0                 0  

Period 3:   Ext. Period (No Cladribine Treatment)
    Cladribine 3.5 mg/kg, IFN-beta (DB Period)     Placebo, IFN-beta (DB Period)     Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)     Cladribine 3.5 mg/kg, IFN-beta (Safety Follow up)     Placebo, IFN-beta (Safety Follow up)  
STARTED     0     0     0     0     52     7  
COMPLETED     0     0     0     0     1     0  
NOT COMPLETED     0     0     0     0     51     7  
Sponsor's decision to terminate study                 0                 0                 0                 0                 51                 7  



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Cladribine 3.5 mg/kg, IFN-beta Participants received cladribine tablets orally as cumulative dose of 0.875 milligram per kilogram (mg/kg) over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 mg/kg along with IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the double blind (DB) period of 96 weeks. After completing DB period, participants entered in OL extension period. In OL extension period, participant who met eligibility criteria received OL oral cladribine 3.5 mg/kg and participants who did not meet the eligibility criteria received IFN-beta only and were followed for safety only.
Placebo, IFN-beta Participants received matching placebo tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total matching placebo dose of 3.5 mg/kg along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the double blind (DB) period of 96 weeks. After completing DB period, participants entered in OL extension period. In OL extension period, participant who met eligibility criteria received OL oral cladribine 3.5 mg/kg and participants participants who did not meet the eligibility criteria received IFN-beta only and were followed for safety only.
Total Total of all reporting groups

Baseline Measures
    Cladribine 3.5 mg/kg, IFN-beta     Placebo, IFN-beta     Total  
Number of Participants  
[units: participants]
  124     48     172  
Age  
[units: years]
Mean ± Standard Deviation
  38.5  ± 10.2     40.1  ± 10.3     38.9  ± 10.2  
Gender  
[units: participants]
     
Female     84     36     120  
Male     40     12     52  
Time (years) from first attack to study Day 1  
[units: years]
Mean ± Standard Deviation
  9.98  ± 7.24     10.83  ± 7.98     10.22  ± 7.44  
Expanded disability status scale (EDSS) score [1]
[units: unitĀ onĀ scale]
Mean ± Standard Deviation
  2.9  ± 1.2     3.0  ± 1.2     2.9  ± 1.2  
Number of Gadolinium-enhanced lesions  
[units: lesions]
Mean ± Standard Deviation
  1.1  ± 4.0     0.6  ± 1.2     0.9  ± 3.4  
Number of Time constant 1 (T1) hypointense lesions  
[units: lesions]
Mean ± Standard Deviation
  9.0  ± 9.2     9.3  ± 9.9     9.1  ± 9.3  
[1] 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.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)   [ Time Frame: Baseline up to Week 96 ]

2.  Primary:   Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE]) Hematological or Liver Toxicity   [ Time Frame: Baseline up to Week 96 ]

3.  Primary:   Percentage of Participants With Adverse Events in Infections and Infestations System Organ Class (SOC)   [ Time Frame: Baseline up to Week 96 ]

4.  Secondary:   Number of Qualifying Relapses   [ Time Frame: Baseline up to Week 96 ]

5.  Secondary:   Number of Combined Unique Active (CUA) Lesions, Active Time Constant 2 (T2) Lesions, and Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan   [ Time Frame: Week 96 ]

6.  Secondary:   Annualized Qualifying Relapse Rate   [ Time Frame: Baseline up to Week 96 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The 96-week DB treatment period of study was completed as planned, and safety and exploratory efficacy results are presented here. The duration of OL Ext. period was reduced for some participants, following termination of the development program.


  More Information
  Hide 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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Merck KGaA Communication Center
Organization: Merck Serono, a division of Merck KGaA
phone: +49-6151-72-5200
e-mail: service@merckgroup.com


No publications provided


Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00436826     History of Changes
Other Study ID Numbers: 26593, 2006-003366-33
Study First Received: February 15, 2007
Results First Received: March 28, 2013
Last Updated: August 4, 2013
Health Authority: United States: Food and Drug Administration