REbif FLEXible Dosing in Early Multiple Sclerosis (MS) - Study Results

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

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)
STARTED	171	175	171
Treated	171	173	171
COMPLETED	119	128	92
NOT COMPLETED	52	47	79
Adverse Event	5	4	6
Pregnancy	0	0	2
Death	0	0	1
Lost to Follow-up	1	2	1
Withdrawal by Subject	11	8	7
Disease progression	3	0	2
Poor compliance	1	0	0
Switched to open label phase	31	30	59
Randomized but not treated	0	2	0
Physician Decision	0	0	1
Unspecified	0	1	0

Period 2: Open Label (up to 24 Month)

	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
STARTED	31	30	59
COMPLETED	28	28	52
NOT COMPLETED	3	2	7
Adverse Event	2	1	1
Pregnancy	0	0	1
Lost to Follow-up	0	1	0
Withdrawal by Subject	0	0	5
Disease progression	1	0	0

Period 3: Open Label Extension (up to 36 Months)

	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	4	5	11
COMPLETED	3	4	9
NOT COMPLETED	1	1	2
Adverse Event	1	1	0
unspecified	0	0	2

Baseline Characteristics

Hide Baseline Characteristics

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 ]

Show Outcome Measure 1

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 ]

Show Outcome Measure 2

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 ]

Show Outcome Measure 3

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 ]

Show Outcome Measure 4

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 ]

Show Outcome Measure 5

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 ]

Show Outcome Measure 6

7. Secondary:

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

Show Outcome Measure 7

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Sponsor has the right to publish any results communication in connection with the study. The PI shall submit any communications including study results to the sponsor for review 30 working days prior to communication submission. The sponsor can request the PI to modify or delete any sponsor's proprietary information. If the PI refuses the modification, the submission shall be postponed for 60 days from PI refusal, to provide the sponsor the opportunity to file a patent or seek legal remedies.

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@merck.de

No publications provided by Merck KGaA

Publications automatically indexed to this study:

Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM, Casset-Semanaz F, Hennessy B, Moraga MS, Rocak S, Stubinski B, Kappos L. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012 Jan;11(1):33-41. Epub 2011 Dec 4.

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:	January 10, 2013
Health Authority:	Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica Australia: Department of Health and Ageing Therapeutic Goods Administration Australia: Human Research Ethics Committee Austria: Agency for Health and Food Safety Austria: Ethikkommission Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment Bulgaria: Bulgarian Drug Agency Bulgaria: Ministry of Health Canada: Canadian Institutes of Health Research Croatia: Ministry of Health and Social Care Czech Republic: Ethics Committee Czech Republic: State Institute for Drug Control Denmark: Danish Dataprotection Agency Denmark: Danish Medicines Agency Denmark: Ethics Committee 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 Germany: Ministry of Health Greece: Ministry of Health and Welfare Hungary: National Institute of Pharmacy Israel: Ministry of Health Italy: Ethics Committee Latvia: State Agency of Medicines Lithuania: Bioethics Committee Lithuania: State Medicine Control Agency - Ministry of Health Macedonia: Ethics Committee Morocco: Ministry of Public Health Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Poland: Ministry of Health Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Romania: Ministry of Public Health Romania: National Medicines Agency Russia: Ethics Committee Russia: Ministry of Health of the Russian Federation Serbia and Montenegro: Agency for Drugs and Medicinal Devices Serbia: Ethics Committee Slovakia: State Institute for Drug Control Spain: Comité Ético de Investigación Clínica Spain: Ministry of Health Switzerland: Ethikkommission Switzerland: Swissmedic Turkey: Ethics Committee Turkey: Ministry of Health

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