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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00404352
First received: November 27, 2006
Last updated: December 18, 2013
Last verified: December 2013
Results First Received: May 15, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition: Multiple Sclerosis
Interventions: Drug: RNF
Drug: Placebo

  Participant Flow
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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  
Unspecified                 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  
unspecified                 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
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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  
Number of Participants  
[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
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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
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  More Information
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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 by Merck KGaA

Publications automatically indexed to this study:

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT00404352     History of Changes
Other Study ID Numbers: IMP27025, 2006-002982-38
Study First Received: November 27, 2006
Results First Received: May 15, 2012
Last Updated: December 18, 2013
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Czech Republic: State Institute for Drug Control
Denmark: Danish Dataprotection Agency
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Estonia: The State Agency of Medicine
Finland: Ethics Committee
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Ministry of Health
France: National Consultative Ethics Committee for Health and Life Sciences
Germany: Federal Institute for Drugs and Medical Devices
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Greece: Ministry of Health and Welfare
Hungary: National Institute of Pharmacy
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Latvia: State Agency of Medicines
Lithuania: Bioethics Committee
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Macedonia: Ethics Committee
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Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Poland: Ministry of Health
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Romania: Ministry of Public Health
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