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REbif FLEXible Dosing in Early Multiple Sclerosis (MS) (REFLEX)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00404352
First Posted: November 28, 2006
Last Update Posted: January 24, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Merck KGaA
Results First Submitted: May 15, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition: Multiple Sclerosis
Interventions: Drug: RNF
Drug: Placebo

  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
The participants were recruited in 78 centers across 28 countries for REFLEX study. REFLEX 12 months open label extension (OLE) was conducted at 11 active centers in 9 countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
RNF 44 Mcg Once Weekly (DB Population) Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
Placebo (DB Population) Single dose of matching placebo administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
RNF 44 Mcg Three Times Weekly/OL RNF 44 Mcg Three Times Weekly After having converted to CDMS, participants received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.
RNF 44 Mcg Once Weekly/OL RNF 44 Mcg Three Times Weekly After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.
Placebo/OL RNF 44 Mcg Three Times Weekly After having converted to CDMS, participants received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months.
RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE) Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year open label extension (OLE). Participants who had received RNF three times a week in the core REFLEX trial, were re-titrated with a single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months in this 12 months open label extension.
RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE) Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received RNF once weekly in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months in this 12 months open label extension.
Placebo/RNF 44 Mcg Three Times Weekly (OLE) Participants who were not converted to CDMS and completed 24 month core REFLEX trial were enrolled in a 1 year OLE. Participants who had received placebo in the core REFLEX trial were re-titrated with a single dose of RNF injection subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months in this 12 months open label extension.

Participant Flow for 3 periods

Period 1:   Double Blind (up to 24 Month)
    RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)   RNF 44 Mcg Once Weekly (DB Population)   Placebo (DB Population)   RNF 44 Mcg Three Times Weekly/OL RNF 44 Mcg Three Times Weekly   RNF 44 Mcg Once Weekly/OL RNF 44 Mcg Three Times Weekly   Placebo/OL RNF 44 Mcg Three Times Weekly   RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)   RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)   Placebo/RNF 44 Mcg Three Times Weekly (OLE)
STARTED   171   175   171   0   0   0   0   0   0 
Treated   171   173   171   0   0   0   0   0   0 
COMPLETED   119   128   92   0   0   0   0   0   0 
NOT COMPLETED   52   47   79   0   0   0   0   0   0 
Adverse Event                5                4                6                0                0                0                0                0                0 
Pregnancy                0                0                2                0                0                0                0                0                0 
Death                0                0                1                0                0                0                0                0                0 
Lost to Follow-up                1                2                1                0                0                0                0                0                0 
Withdrawal by Subject                11                8                7                0                0                0                0                0                0 
Disease progression                3                0                2                0                0                0                0                0                0 
Poor compliance                1                0                0                0                0                0                0                0                0 
Switched to open label phase                31                30                59                0                0                0                0                0                0 
Randomized but not treated                0                2                0                0                0                0                0                0                0 
Physician Decision                0                0                1                0                0                0                0                0                0 
Other                0                1                0                0                0                0                0                0                0 

Period 2:   Open Label (up to 24 Month)
    RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)   RNF 44 Mcg Once Weekly (DB Population)   Placebo (DB Population)   RNF 44 Mcg Three Times Weekly/OL RNF 44 Mcg Three Times Weekly   RNF 44 Mcg Once Weekly/OL RNF 44 Mcg Three Times Weekly   Placebo/OL RNF 44 Mcg Three Times Weekly   RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)   RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)   Placebo/RNF 44 Mcg Three Times Weekly (OLE)
STARTED   0   0   0   31 [1]   30 [2]   59 [3]   0   0   0 
COMPLETED   0   0   0   28   28   52   0   0   0 
NOT COMPLETED   0   0   0   3   2   7   0   0   0 
Adverse Event                0                0                0                2                1                1                0                0                0 
Pregnancy                0                0                0                0                0                1                0                0                0 
Lost to Follow-up                0                0                0                0                1                0                0                0                0 
Withdrawal by Subject                0                0                0                0                0                5                0                0                0 
Disease progression                0                0                0                1                0                0                0                0                0 
[1] From DB period, 31 participants converted to CDMS and switched to OL period in this study
[2] From DB period, 30 participants converted to CDMS and switched to OL period in this study
[3] From DB period, 59 participants converted to CDMS and switched to OL period in this study

Period 3:   Open Label Extension (up to 36 Months)
    RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)   RNF 44 Mcg Once Weekly (DB Population)   Placebo (DB Population)   RNF 44 Mcg Three Times Weekly/OL RNF 44 Mcg Three Times Weekly   RNF 44 Mcg Once Weekly/OL RNF 44 Mcg Three Times Weekly   Placebo/OL RNF 44 Mcg Three Times Weekly   RNF 44Mcg Three Times Weekly/RNF 44Mcg Three Times Weekly(OLE)   RNF 44 Mcg Once Weekly/RNF 44 Mcg Three Times Weekly (OLE)   Placebo/RNF 44 Mcg Three Times Weekly (OLE)
STARTED   0   0   0   0   0   0   4 [1]   5 [2]   11 [3] 
COMPLETED   0   0   0   0   0   0   3   4   9 
NOT COMPLETED   0   0   0   0   0   0   1   1   2 
Adverse Event                0                0                0                0                0                0                1                1                0 
Other                0                0                0                0                0                0                0                0                2 
[1] 4 participants who did not convert to CDMS in 24 months and gave consent to enroll in OLE period
[2] 5 participants who did not convert to CDMS in 24 months and gave consent to enroll in OLE period
[3] 11 participants who did not convert to CDMS in 24 months and gave consent to enroll in OLE period



  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
RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) Single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
RNF 44 Mcg Once Weekly (DB Population) Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
Placebo (DB Population) Single dose of matching placebo administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first.
Total Total of all reporting groups

Baseline Measures
   RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population)   RNF 44 Mcg Once Weekly (DB Population)   Placebo (DB Population)   Total 
Overall Participants Analyzed 
[Units: Participants]
 171   175   171   517 
Age 
[Units: Years]
Mean (Standard Deviation)
 30.6  (8.5)   30.7  (8.1)   30.9  (7.9)   30.7  (8.2) 
Age, Customized 
[Units: Participants]
       
Less than 30 years   86   86   87   259 
Greater than or equal to 30 years   85   89   84   258 
Gender 
[Units: Participants]
       
Female   114   106   112   332 
Male   57   69   59   185 
Race/Ethnicity, Customized 
[Units: Participants]
       
Asian   0   0   0   0 
Black   0   1   0   1 
White   171   174   171   516 
Other   0   0   0   0 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)   [ Time Frame: Various time points from randomization up to 24 months ]

2.  Primary:   Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)   [ Time Frame: Various time points from randomization up to 36 months ]

3.  Secondary:   Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score   [ Time Frame: Various time points from randomization up to 24 months ]

4.  Secondary:   Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score   [ Time Frame: Various time points from randomization up to 36 months ]

5.  Secondary:   Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan   [ Time Frame: Month 24 up to Month 36 ]

6.  Secondary:   Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36   [ Time Frame: Baseline, Month 36 ]

7.  Secondary:   Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36   [ Time Frame: Baseline, Month 36 ]


  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
No text entered.


  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


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

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00404352     History of Changes
Other Study ID Numbers: IMP27025
2006-002982-38 ( EudraCT Number )
First Submitted: November 27, 2006
First Posted: November 28, 2006
Results First Submitted: May 15, 2012
Results First Posted: September 24, 2012
Last Update Posted: January 24, 2014