Clinically Isolated Syndrome, Multiple Sclerosis
Conditions
Keywords
Interferon 1-beta, Clinical Definite Multiple Sclerosis
Brief 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).
Detailed 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).
Interventions
DRUGRNF
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.
DRUGPlacebo
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).
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline (Day 1 of Study 27025) 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Month 36 | Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans. |
| Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | Baseline (Day 1 of Study 27025), Month 36 | Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions at Month 36 |
| Percent Change From Baseline in Brain Volume at Month 36 | Baseline (Day 1 of Study 27025), Month 36 | Percent change in brain volume was measured by using MRI scans. |
| Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months | Baseline (Day 1 of Study 27025) up to CDMS conversion and/or 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. |
| Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Baseline (Day of Study 27025), 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. |
| Percentage of Relapse-Free Participants at Month 36 | 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. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Baseline (Day of Study 27025), 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. |
| Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | Baseline (Day 1 of Study 27025), 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). |
| Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | 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). |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION) | 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. |
| Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months | Baseline (Day 1 of Study 27025) 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. |
| Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months | Baseline (Day 1 of Study 27025) 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. |
| 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 | Month 60 | Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans. |
| Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Baseline (Day 1 of Study 27025), Month 60 | Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions. |
| Percent Change From Baseline in Brain Volume at Month 60 | Baseline (Day 1 of Study 27025), Month 60 | Percent Change in brain volume was measured by using MRI scans. |
| Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60 | 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. |
| Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Baseline (Day 1 of Study 27025), 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. |
| Percentage of Relapse-Free Participants at Month 60 | 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. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Baseline (Day 1 of Study 27025), 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. |
| Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | Baseline (Day 1 of Study 27025), 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). |
| Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | 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. |
| 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 | Baseline (Day 1 of Study 27025) up to 60 Months | 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. |
Countries
Argentina, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, Israel, Italy, Latvia, Lebanon, Morocco, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Spain
Participant flow
Recruitment details
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
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)
Participants by arm
| Arm | Count |
|---|---|
| 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 60 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 (9 participants from DB converted to CDMS and switched to OL period over course of this study) | 133 |
| 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 60 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 (26 participants from DB converted to CDMS and switched to OL period over course of this study) | 142 |
| 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 60 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 (18 participants from DB converted to CDMS and switched to OL period over course of this study) | 127 |
| Total | 402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double Blind Period | Adverse Event | 4 | 1 | 4 | 0 | 0 | 0 |
| Double Blind Period | Lost to Follow-up | 3 | 2 | 2 | 0 | 0 | 0 |
| Double Blind Period | Other | 14 | 9 | 6 | 0 | 0 | 0 |
| Double Blind Period | Randomized but not treated | 1 | 3 | 1 | 0 | 0 | 0 |
| Double Blind Period | Switched to open label phase | 9 | 26 | 18 | 0 | 0 | 0 |
| Open Label Period | Adverse Event | 0 | 0 | 0 | 5 | 4 | 3 |
| Open Label Period | Lack of Efficacy | 0 | 0 | 0 | 3 | 1 | 1 |
| Open Label Period | Other | 0 | 0 | 0 | 11 | 5 | 6 |
| Open Label Period | Randomized but not treated | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo/RNF 44 Mcg Thrice Weekly (ITT Population) | RNF 44 Mcg Once Weekly (ITT Population) | RNF 44 Mcg Thrice Weekly (ITT Population) | Total |
|---|---|---|---|---|
| Age, Continuous | 31.0 years STANDARD_DEVIATION 8.2 | 31.4 years STANDARD_DEVIATION 8.2 | 31.8 years STANDARD_DEVIATION 8.6 | 31.4 years STANDARD_DEVIATION 8.3 |
| Age, Customized Greater than or equal to 30 years | 66 participants | 76 participants | 72 participants | 214 participants |
| Age, Customized Less than 30 years | 67 participants | 66 participants | 55 participants | 188 participants |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 133 participants | 141 participants | 127 participants | 401 participants |
| Sex: Female, Male Female | 82 Participants | 88 Participants | 78 Participants | 248 Participants |
| Sex: Female, Male Male | 51 Participants | 54 Participants | 49 Participants | 154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 69 / 84 | 97 / 117 | 84 / 99 | 46 / 58 | 37 / 51 | 36 / 46 |
| serious Total, serious adverse events | 7 / 84 | 7 / 117 | 9 / 99 | 2 / 58 | 3 / 51 | 4 / 46 |
Outcome results
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.
Time frame: Baseline (Day 1 of Study 27025) up to 36 Months
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | 41.3 Cumulative % of participants with CDMS |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | 27.6 Cumulative % of participants with CDMS |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | 27.1 Cumulative % of participants with CDMS |
p-value: 0.00295% CI: [0.378, 0.816]Log Rank
p-value: 0.00695% CI: [0.391, 0.839]Log Rank
p-value: 0.94195% CI: [0.654, 1.51]Log Rank
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.
Time frame: Baseline (Day of Study 27025), Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Baseline (n=171,175,171) | 1.53 units on a scale | Standard Deviation 0.77 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Change at Month 36 (n=120,136,116) | -0.21 units on a scale | Standard Deviation 0.93 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Baseline (n=171,175,171) | 1.50 units on a scale | Standard Deviation 0.72 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Change at Month 36 (n=120,136,116) | -0.11 units on a scale | Standard Deviation 0.96 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Baseline (n=171,175,171) | 1.51 units on a scale | Standard Deviation 0.83 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 36 | Change at Month 36 (n=120,136,116) | -0.09 units on a scale | Standard Deviation 0.9 |
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.
Time frame: Baseline (Day 1 of Study 27025), Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Baseline (n=171,175,171) | 1.53 units on a scale | Standard Deviation 0.77 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Change at Month 60 (n=111,133,117) | -0.11 units on a scale | Standard Deviation 0.94 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Baseline (n=171,175,171) | 1.50 units on a scale | Standard Deviation 0.72 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Change at Month 60 (n=111,133,117) | -0.01 units on a scale | Standard Deviation 1.01 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Baseline (n=171,175,171) | 1.51 units on a scale | Standard Deviation 0.83 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 60 | Change at Month 60 (n=111,133,117) | 0.04 units on a scale | Standard Deviation 1.02 |
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).
Time frame: Baseline (Day 1 of Study 27025), Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | MFSC score at Baseline (n=171,175,171) | 0.0352 Z-score | Standard Deviation 0.5844 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.1993 Z-score | Standard Deviation 0.4863 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | MFSC score at Baseline (n=171,175,171) | 0.0071 Z-score | Standard Deviation 0.6653 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.2529 Z-score | Standard Deviation 0.5794 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | MFSC score at Baseline (n=171,175,171) | -0.0575 Z-score | Standard Deviation 0.6226 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.3074 Z-score | Standard Deviation 0.6071 |
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).
Time frame: Baseline (Day 1 of Study 27025), Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | MFSC score at Baseline (n=171,175,171) | 0.0352 Z-score | Standard Deviation 0.5844 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | Change at Month 60 (n=112,132,132) | 0.2290 Z-score | Standard Deviation 0.4824 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | MFSC score at Baseline (n=171,175,171) | 0.0071 Z-score | Standard Deviation 0.6653 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | Change at Month 60 (n=112,132,132) | 0.2213 Z-score | Standard Deviation 0.5602 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | MFSC score at Baseline (n=171,175,171) | -0.0575 Z-score | Standard Deviation 0.6226 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60 | Change at Month 60 (n=112,132,132) | 0.2192 Z-score | Standard Deviation 0.6229 |
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.
Time frame: Baseline (Day of Study 27025), Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Baseline (n=171,175,171) | 0.0358 units on a scale | Standard Deviation 0.8787 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.3483 units on a scale | Standard Deviation 0.6949 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Baseline (n=171,175,171) | -0.0909 units on a scale | Standard Deviation 1.1223 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.5044 units on a scale | Standard Deviation 0.7588 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Baseline (n=171,175,171) | 0.0031 units on a scale | Standard Deviation 1.1387 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36 | Change at Month 36 (n=123,135,118) | 0.4515 units on a scale | Standard Deviation 0.9164 |
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.
Time frame: Baseline (Day 1 of Study 27025), Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Baseline (n=171, 175, 171) | 0.0358 units on a scale | Standard Deviation 0.8787 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Change at Month 60 (n=112, 132, 118) | 0.4109 units on a scale | Standard Deviation 0.6844 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Baseline (n=171, 175, 171) | -0.0909 units on a scale | Standard Deviation 1.1223 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Change at Month 60 (n=112, 132, 118) | 0.4785 units on a scale | Standard Deviation 0.9886 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Baseline (n=171, 175, 171) | 0.0031 units on a scale | Standard Deviation 1.1387 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60 | Change at Month 60 (n=112, 132, 118) | 0.4608 units on a scale | Standard Deviation 0.863 |
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
Time frame: Baseline (Day 1 of Study 27025), Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=171,175,171) | 670.3 cubic millimeter (mm^3) | Standard Deviation 1054.1 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume Change: Month 36(n=124,133,114) | 303.2 cubic millimeter (mm^3) | Standard Deviation 1034.6 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=171,175,171) | 3334.9 cubic millimeter (mm^3) | Standard Deviation 3990.4 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume Change: Month 36(n=124,133,114) | -3.8 cubic millimeter (mm^3) | Standard Deviation 2101.8 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume Change: Month 36(n=124,133,114) | -56.9 cubic millimeter (mm^3) | Standard Deviation 2436.3 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=171,175,171) | 774.8 cubic millimeter (mm^3) | Standard Deviation 1288 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=171,175,171) | 3853.1 cubic millimeter (mm^3) | Standard Deviation 4716.7 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume Change: Month 36(n=124,133,114) | 272.0 cubic millimeter (mm^3) | Standard Deviation 921.4 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume Change: Month 36(n=124,133,114) | -398.1 cubic millimeter (mm^3) | Standard Deviation 1415.4 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume Change: Month 36(n=124,133,114) | 133.3 cubic millimeter (mm^3) | Standard Deviation 763.5 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=171,175,171) | 3110.5 cubic millimeter (mm^3) | Standard Deviation 3410.7 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=171,175,171) | 675.0 cubic millimeter (mm^3) | Standard Deviation 1049.9 |
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.
Time frame: Baseline (Day 1 of Study 27025), Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T1 lesion volume at Baseline (n=171,175,171) | 670.3 mm^3 | Standard Deviation 1054.1 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,120,110) | 415.0 mm^3 | Standard Deviation 1080.3 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T2 lesion volume at Baseline (n=171,175,171) | 3334.9 mm^3 | Standard Deviation 3990.4 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,121,110) | 119.4 mm^3 | Standard Deviation 2225.2 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,121,110) | 25.0 mm^3 | Standard Deviation 2827.1 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T1 lesion volume at Baseline (n=171,175,171) | 774.8 mm^3 | Standard Deviation 1288 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T2 lesion volume at Baseline (n=171,175,171) | 3853.1 mm^3 | Standard Deviation 4716.7 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,120,110) | 412.3 mm^3 | Standard Deviation 1020.8 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,121,110) | -188.5 mm^3 | Standard Deviation 2576.1 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | Change at Month 60 (n=102,120,110) | 261.8 mm^3 | Standard Deviation 1006.1 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T2 lesion volume at Baseline (n=171,175,171) | 3110.5 mm^3 | Standard Deviation 3410.7 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60 | T1 lesion volume at Baseline (n=171,175,171) | 675.0 mm^3 | Standard Deviation 1049.9 |
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.
Time frame: Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). n signifies those participants who were evaluated for this measure at the specified time point for each arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | CUA Lesions (n=102, 121, 110) | 1.46 lesions | Standard Deviation 3.394 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T2 Lesions (n=102, 121, 110) | 1.17 lesions | Standard Deviation 2.576 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions (n=102, 121, 110) | 0.24 lesions | Standard Deviation 0.823 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T1 Lesions (n=102, 120, 110) | 0.57 lesions | Standard Deviation 1.656 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New T1 Lesions (n=102, 120, 110) | 0.69 lesions | Standard Deviation 1.659 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | CUA Lesions (n=102, 121, 110) | 1.60 lesions | Standard Deviation 3.542 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions (n=102, 121, 110) | 0.36 lesions | Standard Deviation 1.225 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New T2 Lesions (n=102, 121, 110) | 1.17 lesions | Standard Deviation 2.628 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T1 Lesions (n=102, 120, 110) | 0.71 lesions | Standard Deviation 1.917 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T2 Lesions (n=102, 121, 110) | 1.35 lesions | Standard Deviation 3.284 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions (n=102, 121, 110) | 0.48 lesions | Standard Deviation 1.618 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | CUA Lesions (n=102, 121, 110) | 1.94 lesions | Standard Deviation 4.803 |
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.
Time frame: Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | CUA Lesions | 1.02 lesions | Standard Deviation 1.85 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T2 Lesions | 0.83 lesions | Standard Deviation 1.545 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions | 0.17 lesions | Standard Deviation 0.506 |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T1 Lesions | 0.69 lesions | Standard Deviation 1.721 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New T1 Lesions | 1.09 lesions | Standard Deviation 2.482 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | CUA Lesions | 1.83 lesions | Standard Deviation 3.317 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions | 0.40 lesions | Standard Deviation 1.354 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | New T2 Lesions | 1.39 lesions | Standard Deviation 2.573 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T1 Lesions | 0.91 lesions | Standard Deviation 4.143 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New T2 Lesions | 1.19 lesions | Standard Deviation 4.217 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | New Gd+ Lesions | 0.41 lesions | Standard Deviation 1.754 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | CUA Lesions | 1.63 lesions | Standard Deviation 5.947 |
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.
Time frame: Month 24 up to Month 60
Population: DB Safety Population 28981 (REFLEXION) included all the participants who discontinued DB treatment in REFLEX study 27025 (NCT00404352) and were enrolled in 28981 (REFLEXION) study and received at least one dose of DB treatment in this study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 7 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 70 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 3 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 7 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 96 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 0 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 84 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 2 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 9 participants |
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.
Time frame: Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)
Population: DB Safety Population 28981 (REFLEXION) included all the participants who discontinued DB treatment in REFLEX study 27025 (NCT00404352) and were enrolled in 28981 (REFLEXION) study and received at least one dose of DB treatment in this study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 3 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 79 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 2 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 2 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 67 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 0 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs | 45 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | AEs leading to discontinuation | 2 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Treatment Discontinuation | SAEs | 4 participants |
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).
Time frame: Month 36
Population: Data has been presented as per planned analysis for integrated DB population which included all participants who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb- | 77 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb+ | 41 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb- | 100 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb+ | 18 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb+ | 22 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb- | 97 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb- | 109 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb+ | 34 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb+ | 19 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb+ | 30 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | NAb- | 99 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36 | BAb- | 88 participants |
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.
Time frame: Month 60
Population: Data has been presented as per planned analysis for integrated DB population which included all participants who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb+ | 25 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb- | 89 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb (Missing) | 1 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb- | 97 participants |
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb+ | 18 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb+ | 20 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb- | 99 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb+ | 30 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb (Missing) | 1 participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb- | 110 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb+ | 15 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb- | 102 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb- | 100 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | NAb+ | 13 participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Numbers of Participants With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60 | BAb (Missing) | 0 participants |
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.
Time frame: Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60 | 84.2 percentage of participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60 | 82.9 percentage of participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) at Month 60 | 72.5 percentage of participants |
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.
Time frame: Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months | 84.2 percentage of participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months | 76.0 percentage of participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Participants With Conversion to McDonald Multiple Sclerosis (MS) up to 36 Months | 66.7 percentage of participants |
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.
Time frame: Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 36 | 42.7 Percentage of participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 36 | 58.3 Percentage of participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 36 | 51.5 Percentage of participants |
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.
Time frame: Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 60 | 34.5 percentage of participants |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 60 | 45.1 percentage of participants |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percentage of Relapse-Free Participants at Month 60 | 40.9 percentage of participants |
Secondary
Percent Change From Baseline in Brain Volume at Month 36
Percent change in brain volume was measured by using MRI scans.
Time frame: Baseline (Day 1 of Study 27025), Month 36
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 36 | -1.02 percent change | Standard Deviation 1.248 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 36 | -0.86 percent change | Standard Deviation 1.073 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 36 | -1.14 percent change | Standard Deviation 1.321 |
Secondary
Percent Change From Baseline in Brain Volume at Month 60
Percent Change in brain volume was measured by using MRI scans.
Time frame: Baseline (Day 1 of Study 27025), Month 60
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352). 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure at this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 60 | -1.82 percent change | Standard Deviation 1.494 |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 60 | -1.54 percent change | Standard Deviation 1.378 |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Percent Change From Baseline in Brain Volume at Month 60 | -2.03 percent change | Standard Deviation 1.644 |
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.
Time frame: Baseline (Day 1 of Study 27025) up to 36 Months
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months | 7.5 % of participants with EDSS progression |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months | 11.8 % of participants with EDSS progression |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 36 Months | 13.2 % of participants with EDSS progression |
p-value: 0.205Log Rank
p-value: 0.263Log Rank
p-value: 0.629Log Rank
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.
Time frame: Baseline (Day 1 of Study 27025) up to 60 Months
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months | 11.0 % of participants with EDSS progression |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months | 18.7 % of participants with EDSS progression |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | Time to Confirmed Expanded Disability Status Scale (EDSS) Progression up to 60 Months | 18.4 % of participants with EDSS progression |
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.
Time frame: Baseline (Day 1 of Study 27025) up to 60 Months
Population: Data has been presented as per planned analysis for integrated ITT population which included all participants who were randomized in REFLEX study 27025 (NCT00404352).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo/RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | 44.6 Cumulative % of participants with CDMS |
| RNF 44 Mcg Once Weekly (Integrated ITT Population) | 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 | 40.7 Cumulative % of participants with CDMS |
| RNF 44 Mcg Thrice Weekly (Integrated ITT Population) | 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 | 39.2 Cumulative % of participants with CDMS |