Long-term Follow-Up of Patients Who Participated in Study 27025 (REFLEX) (REFLEXION)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00813709
First received: December 22, 2008
Last updated: December 18, 2013
Last verified: December 2013
Results First Received: November 27, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Multiple Sclerosis
Clinically Isolated Syndrome
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
Participants who were randomized in Study 27025 (NCT00404352) were eligible to enroll into extension Study 28981 (NCT00813709) whether or not they completed main study on Investigational Medicinal Product (IMP), or no treatment or received other disease-modifying drugs (DMDs) during course of main study. No re-randomization was done for this study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
517 participants randomized in Study 27025 used in this study as integrated intention to treat (ITT) population. Out of the 517, 402 participants took part in study 28981: 300 comprised the double blind (DB) population and 122 comprised the open label (OL) population (some participants (20) were included in both populations)

Reporting Groups
  Description
Placebo/RNF 44 Mcg Thrice Weekly (DB Population) Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 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 36 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 then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
RNF 44 Mcg Thrice Weekly (DB Population) 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 then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.
Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly Participants after having converted to CDMS during study 28981 (REFLEXION), 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 36 months. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 36 months.
RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly Participants after having converted to CDMS during study 28981 (REFLEXION), 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 36 months. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 36 months.
RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly Participants after having converted to CDMS during study 28981 (REFLEXION), 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 36 months. The participants who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 36 months.

Participant Flow for 2 periods

Period 1:   Double Blind Period
    Placebo/RNF 44 Mcg Thrice Weekly (DB Population)     RNF 44 Mcg Once Weekly (DB Population)     RNF 44 Mcg Thrice Weekly (DB Population)     Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly     RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly     RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly  
STARTED     84     117     99     0     0     0  
Treated     83     114     98     0     0     0  
COMPLETED     70     97     84     0     0     0  
NOT COMPLETED     14     20     15     0     0     0  
Adverse Event                 2                 1                 2                 0                 0                 0  
Lost to Follow-up                 0                 1                 1                 0                 0                 0  
Switched to open label phase                 4                 10                 6                 0                 0                 0  
Randomized but not treated                 1                 3                 1                 0                 0                 0  
Unspecified                 7                 5                 5                 0                 0                 0  

Period 2:   Open Label Period
    Placebo/RNF 44 Mcg Thrice Weekly (DB Population)     RNF 44 Mcg Once Weekly (DB Population)     RNF 44 Mcg Thrice Weekly (DB Population)     Placebo/RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly     RNF 44 Mcg Once Weekly /OL RNF 44 Mcg Thrice Weekly     RNF 44 Mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly  
STARTED     0     0     0     53 [1]   35 [2]   34 [3]
Treated     0     0     0     52     35     33  
COMPLETED     0     0     0     49     34     30  
NOT COMPLETED     0     0     0     4     1     4  
Adverse Event                 0                 0                 0                 0                 1                 0  
Lack of Efficacy                 0                 0                 0                 0                 0                 1  
Randomized but not treated                 0                 0                 0                 1                 0                 1  
Unspecified                 0                 0                 0                 3                 0                 2  
[1] 49 participants in OL period initially + 4 participants from DB converted to CDMS during the study
[2] 25 participants in OL period initially + 10 participants from DB converted to CDMS during the study
[3] 28 participants in OL period initially + 6 participants from DB converted to CDMS during the study



  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.
Baseline data was presented for ITT population (402 participants) which included participants who had completed the REFLEX Study 27025 (NCT00404352) and were enrolled in this extension Study 28981 (REFLEXION).

Reporting Groups
  Description
Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) Participants who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 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 or until conversion to CDMS whichever occurs first. 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 36 months. 84 participants were initially assigned to DB RNF 44 mcg thrice weekly and 49 participants were initially assigned to OL RNF 44 mcg thrice weekly (4 participants from DB converted to CDMS and switched to OL period over course of this study)
RNF 44 Mcg Once Weekly (ITT 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 then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. 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 36 months. 117 participants were initially assigned to DB RNF 44 mcg thrice weekly and 25 participants were initially assigned to OL RNF 44 mcg thrice weekly (10 participants from DB converted to CDMS and switched to OL period over course of this study)
RNF 44 Mcg Thrice Weekly (ITT Population) 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 then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. 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 36 months. 99 participants were initially assigned to DB RNF 44 mcg thrice weekly and 28 participants were initially assigned to OL RNF 44 mcg thrice weekly (6 participants from DB converted to CDMS and switched to OL period over course of this study)
Total Total of all reporting groups

Baseline Measures
    Placebo/RNF 44 Mcg Thrice Weekly (ITT Population)     RNF 44 Mcg Once Weekly (ITT Population)     RNF 44 Mcg Thrice Weekly (ITT Population)     Total  
Number of Participants  
[units: participants]
  133     142     127     402  
Age  
[units: years]
Mean ± Standard Deviation
  31.0  ± 8.2     31.4  ± 8.2     31.8  ± 8.6     31.4  ± 8.3  
Age, Customized  
[units: participants]
       
Less than 30 years     67     66     55     188  
Greater than or equal to 30 years     66     76     72     214  
Gender  
[units: participants]
       
Female     82     88     78     248  
Male     51     54     49     154  
Race/Ethnicity, Customized  
[units: participants]
       
Black     0     1     0     1  
White     133     141     127     401  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to 36 Months   [ Time Frame: Baseline (Day 1 of Study 27025) up to 36 Months ]

2.  Secondary:   Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months   [ Time Frame: Baseline (Day 1 of Study 27025) up to 36 Months ]

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

4.  Secondary:   Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36   [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ]

5.  Secondary:   Percent Change From Baseline in Brain Volume at Month 36   [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ]

6.  Secondary:   Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months   [ Time Frame: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months ]

7.  Secondary:   Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36   [ Time Frame: Baseline (Day of Study 27025), Month 36 ]

8.  Secondary:   Percentage of Relapse-Free Participants at Month 36   [ Time Frame: Month 36 ]

9.  Secondary:   Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36   [ Time Frame: Baseline (Day of Study 27025), Month 36 ]

10.  Secondary:   Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36   [ Time Frame: Baseline (Day 1 of Study 27025), Month 36 ]

11.  Secondary:   Numbers of Participants With Positive Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36   [ Time Frame: Month 36 ]

12.  Secondary:   Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation   [ Time Frame: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION) ]

13.  Secondary:   Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to Month 60   [ Time Frame: Baseline (Day 1 of Study 27025) up to 60 Months ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

14.  Secondary:   Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months   [ Time Frame: Baseline (Day 1 of Study 27025) up to 60 Months ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

15.  Secondary:   Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New T1 Lesions Per Participant Per Scan at Month 60   [ Time Frame: Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

16.  Secondary:   Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60   [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

17.  Secondary:   Percent Change From Baseline in Brain Volume at Month 60   [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

18.  Secondary:   Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60   [ Time Frame: Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

19.  Secondary:   Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60   [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

20.  Secondary:   Percentage of Relapse-Free Participants at Month 60   [ Time Frame: Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

21.  Secondary:   Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60   [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

22.  Secondary:   Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60   [ Time Frame: Baseline (Day 1 of Study 27025), Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

23.  Secondary:   Numbers of Participants With Positive Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60   [ Time Frame: Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   No

24.  Secondary:   Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation   [ Time Frame: Month 24 up to Month 60 ]
Results not yet posted.   Anticipated Posting Date:   06/2014   Safety Issue:   Yes


  Serious Adverse Events


  Other Adverse Events


  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.


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.  


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: Merck KGaA
ClinicalTrials.gov Identifier: NCT00813709     History of Changes
Other Study ID Numbers: 28981
Study First Received: December 22, 2008
Results First Received: November 27, 2012
Last Updated: December 18, 2013
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Austria: Agency for Health and Food Safety
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Bulgaria: Bulgarian Drug Agency
Canada: Canadian Institutes of Health Research
Croatia: Ministry of Health and Social Care
Czech Republic: State Institute for Drug Control
Estonia: The State Agency of Medicine
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: Ministry of Health and Welfare
Israel: Ministry of Health
Italy: Ethics Committee
Latvia: State Agency of Medicines
Morocco: Ministry of Public Health
Poland: Ministry of Health
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency
Russia: Ministry of Health of the Russian Federation
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
Slovakia: State Institute for Drug Control
Spain: Spanish Agency of Medicines