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

Multiple Sclerosis Clinical Trial

— REFLEXION  

Official title:

Double-blind Extension of the Study 27025 (REFLEX) to Obtain Long-term Follow-up Data in Patients With Clinically Definite MS and Patients With a First Demyelinating Event at High Risk of Converting to MS, Treated With Rebif® New Formulation (REFLEXION)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00813709
• Other study ID #: 28981
• Status: Completed
• Phase: Phase 3
• First received: December 22, 2008
• Last updated: July 23, 2015
• Start date: December 2008
• Est. completion date: September 2013

Study information

• Verified date: July 2015
• Source: Merck KGaA
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustria: Agency for Health and Food SafetyBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentBulgaria: Bulgarian Drug AgencyCanada: Canadian Institutes of Health ResearchCroatia: Ministry of Health and Social CareCzech Republic: State Institute for Drug ControlEstonia: The State Agency of MedicineFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: Ministry of Health and WelfareIsrael: Ministry of HealthItaly: Ethics CommitteeLatvia: State Agency of MedicinesMorocco: Ministry of Public HealthPoland: Ministry of HealthPortugal: National Pharmacy and Medicines InstituteRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSerbia and Montenegro: Agency for Drugs and Medicinal DevicesSlovakia: State Institute for Drug ControlSpain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

REFLEXION is a double blind extension of the study 27025 (NCT00404352) (REFLEX). The purpose of the study is to obtain long-term follow-up data in subjects with clinically definite multiple sclerosis (MS) and subjects with a first demyelinating event at high risk of converting to MS, treated with fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF).

Description:

The objective of the study is to investigate whether RNF treatment initiated after the first clinical event versus delayed treatment results in the prolongation of time to Clinically Definite Multiple Sclerosis (CDMS) conversion up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). Furthermore, the study is intended to explore whether RNF treatment initiated after the first clinical event versus delayed treatment delays disability (including development of secondary progressive MS) and reduces disease activity (including the annual relapse rate [ARR]) in the long term (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX). The study will also assess the long-term safety profile of RNF (up to Month 36 and up to Month 60 since randomization in Study 27025 (REFLEX).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 402
• Est. completion date: September 2013
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Reach scheduled end of study in Study 27025 (REFLEX) (completion of 24 months participation)

• Medical assessment by the Investigator/treating physician from study 27025 that there is no objection to the subject's participation in this extension trial considering the medical experience from Study 27025 (REFLEX). Special attention should be given to laboratory abnormalities and clinically significant liver, renal and bone-marrow dysfunction

• If female, subject must:

• be neither pregnant nor breast-feeding, nor attempting to conceive

• use a highly effective method of contraception. A highly effective method of contraception is defined as those which result in a low failure rate (that is [i.e.] less than 1 percent [%] per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner

• Subject is willing to follow study procedures

• Subject has given written informed consent

Exclusion Criteria:

• Subject has any disease other than MS that could better explain the subject's signs and symptoms

• Subject has a primary progressive course of MS

• Subject has total bilirubin greater than 2.5 times upper limit of normal (ULN) at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)

• Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN values at both Month 24 and at the previous visit (i.e. Month 21) (subjects with greater than 2.5 times ULN at Month 24 only are eligible for enrollment and should be managed as per label recommendations until normalization of the value)

• Subject suffers from another current autoimmune disease

• Subject suffers from major medical or psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol

• Subject has a history of seizures not adequately controlled by treatment

• Subject has cardiac disease, such as angina, congestive heart failure or arrhythmia

• Subject has a known allergy to IFN-beta or the excipient(s) of the study medication

• Subject has any condition that could interfere with the MRI evaluation

• Subject has a known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA)

• Subject has a history of alcohol or drug abuse

• Subject has previously participated in this study

• Subject has moderate to severe renal impairment

• Subject is pregnant or lactating

• Subject has any medical, psychiatric or other conditions that compromise his/her ability to understand the subject information, to give informed consent, to comply with the study protocol, or to complete the study

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Clinically Isolated Syndrome
• Multiple Sclerosis

Intervention

Drug:
• RNF
Single dose of RNF will be 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 60 months.
• RNF
Single dose of RNF will be administered subcutaneously once weekly 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 60 months.
• RNF
Participants who were initially randomized in Study 27025 (REFLEX) to the placebo treatment group will be switched to single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.
• Placebo
Single dose matching placebo will be administered subcutaneously twice weekly. Placebo is supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 milliliter (mL).

Locations

Country	Name	City	State
Argentina	Research Site	Mendoza
Austria	Research Site	Graz
Belgium	Research Site	Brugge
Belgium	Research Site	Leuven
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Rousse
Bulgaria	Research Site	Shumen
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Ontario
Canada	Research Site	Victoria British Columbia
Croatia	Research Site	Karlovac
Croatia	Research Site	Osijek
Croatia	Research Site	Rijeka
Croatia	Research Site	Split
Croatia	Research Site	Zagreb
Czech Republic	Research Site	Hradec Kralove
Czech Republic	Research Site	Olomouc
Czech Republic	Research Site	Prague
Estonia	Research Site	Tallinn
Estonia	Research Site	Tartu
Finland	Research Site	Oulu
France	Research Site	Paris
France	Research Site	Poissy Cedex
Germany	Research Site	Hannover
Germany	Research Site	Henningsforf
Greece	Research Site	Athens
Israel	Research Site	Safed
Israel	Research Site	Tel-Hashomer
Italy	Research Site	Milano
Italy	Research Site	Padova
Latvia	Research Site	Riga
Lebanon	Research Site	Beirut
Morocco	Research Site	Rabat
Poland	Research Site	Bialystok
Poland	Research Site	Lodz
Poland	Research Site	Warsaw
Poland	Research Site	Wroclaw
Portugal	Research Site	Lisbon
Romania	Research Site	Bucharest
Romania	Research Site	Iasi
Romania	Research Site	Targu-Mures
Romania	Research Site	Timisoara
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novgorod
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Samara
Russian Federation	Research Site	Saratov
Serbia	Reserch Site	Belgrade
Serbia	Research Site	Nis
Slovakia	Research Site	Presov
Spain	Research Site	Barcelona
Spain	Research Site	Bilbao
Spain	Research Site	Madrid
Spain	Research Site	Seville

Sponsors (1)

Lead Sponsor	Collaborator
Merck KGaA

Countries where clinical trial is conducted

Argentina,  Austria,  Belgium,  Bulgaria,  Canada,  Croatia,  Czech Republic,  Estonia,  Finland,  France,  Germany,  Greece,  Israel,  Italy,  Latvia,  Lebanon,  Morocco,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	CDMS was defined by the occurrence of a second attack or relapse over 36 months in participants who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with CDMS.	Baseline (Day 1 of Study 27025) up to 36 Months	No
Secondary	Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. Time to confirmed EDSS progression was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with confirmed EDSS progression.	Baseline (Day 1 of Study 27025) up to 36 Months	No
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	Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans.	Month 36	No
Secondary	Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36	Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions at Month 36	Baseline (Day 1 of Study 27025), Month 36	No
Secondary	Percent Change From Baseline in Brain Volume at Month 36	Percent change in brain volume was measured by using MRI scans.	Baseline (Day 1 of Study 27025), Month 36	No
Secondary	Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months	The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.	Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months	No
Secondary	Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36	The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Score ranges from '0-60'. Higher scores reflect better neurological function and a positive change from baseline indicates improvement.	Baseline (Day of Study 27025), Month 36	No
Secondary	Percentage of Relapse-Free Participants at Month 36	A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition.	Month 36	No
Secondary	Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 36 was calculated as EDSS score at Month 36 minus EDSS score at baseline.	Baseline (Day of Study 27025), Month 36	No
Secondary	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36	The MSFC is a multidimensional clinical outcome measure which consists of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these three Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3).	Baseline (Day 1 of Study 27025), Month 36	No
Secondary	Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36	BAbs are all antibodies which are capable of binding to the investigational drug molecule (RNF) irrespective of their binding site. NAbs are defined as a subgroup of BAbs which bind to the active sites of the RNF and therefore neutralize its potency. NAbs were detected using a viral cytopathic assay. BAbs were measured by using an ELISA (Enzyme-linked immunosorbent assay).	Month 36	No
Secondary	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation	An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.	Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)	Yes
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	CDMS was defined by the occurrence of a second attack or relapse over 60 months in participants who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with CDMS.	Baseline (Day 1 of Study 27025) up to 60 Months	No
Secondary	Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. Time to confirmed EDSS progression was represented by Kaplan-Meier estimates of the cumulative percentage (%) of participants with confirmed EDSS progression.	Baseline (Day 1 of Study 27025) up to 60 Months	No
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	Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans.	Month 60	No
Secondary	Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60	Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions.	Baseline (Day 1 of Study 27025), Month 60	No
Secondary	Percent Change From Baseline in Brain Volume at Month 60	Percent Change in brain volume was measured by using MRI scans.	Baseline (Day 1 of Study 27025), Month 60	No
Secondary	Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60	The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions.	Month 60	No
Secondary	Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60	The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Score ranges from '0-60'. Higher scores reflect better neurological function and a positive change from baseline indicates improvement.	Baseline (Day 1 of Study 27025), Month 60	No
Secondary	Percentage of Relapse-Free Participants at Month 60	A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition.	Month 60	No
Secondary	Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 60 was calculated as EDSS score at Month 60 minus EDSS score at baseline.	Baseline (Day 1 of Study 27025), Month 60	No
Secondary	Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60	The MSFC is a multidimensional clinical outcome measure which consists of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity (arm and hand) function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these three Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3).	Baseline (Day 1 of Study 27025), Month 60	No
Secondary	Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60	BAbs are all antibodies which are capable of binding to the RNF irrespective of their binding site. NAbs are defined as a subgroup of BAbs which bind to the active sites of the RNF and therefore neutralize its potency. NAbs were detected using a viral cytopathic assay. BAbs were measured by using an ELISA.	Month 60	No
Secondary	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation	An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.	Month 24 up to Month 60	Yes