Multiple Sclerosis
Conditions
Keywords
Rebif New Formulation, Clinical Isolated Syndrome, Multiple Sclerosis
Brief summary
The study is a 24 months randomized, double-blind, Placebo-controlled, multi-center clinical trial with an optional 12 months open label extension. The primary objective of the study is to evaluate the effect of fetal bovine serum \[FBS\]-free/human serum albumin \[HSA\]-free formulation of Interferon \[IFN\] beta-1a (RNF) 44 microgram (three times weekly and once weekly) versus placebo on the time to conversion to McDonald multiple sclerosis (MS) criteria (2005) in subjects with a first clinical demyelinating event at high risk of converting to MS. The main secondary objective of study is to evaluate the effect of RNF 44 microgram (three times weekly and once weekly) versus placebo on the Time to conversion to clinically definite MS (CDMS) in subjects with a first clinical demyelinating event at high risk of converting to MS. At the end of 24 month double-blind core REFLEX trial, subjects who will not convert to CDMS and decide to receive open-label (OL) treatment will be enrolled into an open-label, 12 month extension period to evaluate the effect of RNF 44 mcg three times weekly treatment on the time to conversion to McDonald MS and time to conversion to CDMS.
Interventions
DRUGRNF
Single dose of RNF administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months, or 36 months for patients enrolled in the OL extension.
DRUGPlacebo
Placebo was supplied as a transparent, sterile solution for injection in pre-filled syringes matching the RNF pre-filled syringes, each containing 0.5 mL.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Single, first clinical event suggestive of MS within 60 days prior to study Day 1, which is the day of randomization (clock starts 24 hours after onset). The event must be a new neurological abnormality present for at least 24 hours, either mono- or polysymptomatic, other than a paresthesia, vegetative or cerebral dysfunction * At least two clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 millimeter (mm), at least one of which is ovoid or periventricular or infratentorial * EDSS 0 - 5.0 at least one time point during the screening period before start of treatment * 18 and 50 years old, inclusive * Willing to follow study procedures * Written informed consent * 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 vasectomised partner
Exclusion criteria
* Diagnosis of MS (per McDonald criteria 2005) * Any other disease that could better explain the subject's signs and symptoms * Complete transverse myelitis or bilateral optic neuritis * Subject uses or has used any other approved MS disease-modifying drug (DMD) * Any investigational drug or undergone an experimental procedure within 12 weeks prior to study Day 1 * Oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to study Day 1 * Total bilirubin greater than 2.5 times upper limit of normal (ULN) * Subject has total aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase (ALP) greater than 2.5 times the ULN * Inadequate bone marrow reserve, defined as a total white blood cell count less than 3.0 x 109 per liter (/L), platelet count less than 75 x 109/L, hemoglobin less than 100 gram per liter (g/L) * Current autoimmune disease * 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 * History of seizures not adequately controlled by treatment * Cardiac disease, such as angina, congestive heart failure or arrhythmia * Known allergy to IFN-beta or the excipient(s) of the study medication * Any condition that could interfere with the MRI evaluation; * Known allergy to gadolinium-diethylene triamine pentaacetic acid (DTPA) * Previously participated in this study * Participated in any clinical trial within the past 6 months * Any immunomodulatory or immunosuppressive therapy at any time prior to enrollment, including, but not limited to, the following products: any IFN, glatiramer acetate (Copolymer I), cyclophosphamide, cyclosporine, methotrexate, linomide, azathioprine, mitoxantrone, teriflunomide, laquinimod, cladribine, total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment (e.g. natalizumab, alemtuzumab/Campath, anti-cluster of differentiation 4 \[CD4\]), intravenous, immunoglobulins (Igs), cytokines or anti-cytokine therapy * Any experimental MS treatment prior to trial entry, including, but not limited to, any statins (if given to prevent MS) and pentoxyfylline * History of alcohol or drug abuse * Intolerance or any contraindication to both paracetamol (acetaminophen) and ibuprofen * Inability to administer subcutaneous injections either by self or by caregiver * Moderate to severe renal impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | Various time points from randomization up to 24 months | The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | Various time points from randomization up to 24 months | CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (FCDE) accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. |
| Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | Month 24 up to Month 36 | Number of CUA lesions, new T2 lesions, Gd+ lesions and new T1 hypointense lesions were measured by using MRI scans. |
| Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Baseline, Month 36 | Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions. |
| Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Baseline, 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 at Month 36 was calculated as EDSS at Month 36 minus EDSS at baseline. |
Countries
Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, Israel, Italy, Latvia, Lebanon, Morocco, Poland, Portugal, Romania, Russia, Saudi Arabia, Serbia, Slovakia, Spain, Turkey (Türkiye)
Participant flow
Recruitment details
The participants were recruited in 78 centers across 28 countries for REFLEX study. REFLEX 12 months open label extension (OLE) was conducted at 11 active centers in 9 countries.
Participants by arm
| Arm | Count |
|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) Single dose of fetal bovine serum \[FBS\]-free/human serum albumin \[HSA\]-free formulation of interferon \[IFN\]-beta-1a (RNF) injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. | 171 |
| RNF 44 Mcg Once Weekly (DB Population) Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first. | 175 |
| Placebo (DB Population) Single dose of matching placebo administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 24 months or until conversion to CDMS whichever occurs first. | 171 |
| Total | 517 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Double Blind (up to 24 Month) | Adverse Event | 5 | 4 | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Death | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Disease progression | 3 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Lost to Follow-up | 1 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Other | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Poor compliance | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Pregnancy | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Randomized but not treated | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Switched to open label phase | 31 | 30 | 59 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind (up to 24 Month) | Withdrawal by Subject | 11 | 8 | 7 | 0 | 0 | 0 | 0 | 0 | 0 |
| Open Label Extension (up to 36 Months) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Open Label Extension (up to 36 Months) | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Open Label (up to 24 Month) | Adverse Event | 0 | 0 | 0 | 2 | 1 | 1 | 0 | 0 | 0 |
| Open Label (up to 24 Month) | Disease progression | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Open Label (up to 24 Month) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Open Label (up to 24 Month) | Pregnancy | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Open Label (up to 24 Month) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 5 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | RNF 44 Mcg Once Weekly (DB Population) | Placebo (DB Population) | Total |
|---|---|---|---|---|
| Age, Continuous | 30.6 years STANDARD_DEVIATION 8.5 | 30.7 years STANDARD_DEVIATION 8.1 | 30.9 years STANDARD_DEVIATION 7.9 | 30.7 years STANDARD_DEVIATION 8.2 |
| Age, Customized Greater than or equal to 30 years | 85 participants | 89 participants | 84 participants | 258 participants |
| Age, Customized Less than 30 years | 86 participants | 86 participants | 87 participants | 259 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 171 participants | 174 participants | 171 participants | 516 participants |
| Sex: Female, Male Female | 114 Participants | 106 Participants | 112 Participants | 332 Participants |
| Sex: Female, Male Male | 57 Participants | 69 Participants | 59 Participants | 185 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 149 / 171 | 156 / 173 | 133 / 171 | 20 / 31 | 20 / 30 | 47 / 59 | 3 / 4 | 2 / 5 | 5 / 11 |
| serious Total, serious adverse events | 6 / 171 | 8 / 173 | 12 / 171 | 1 / 31 | 0 / 30 | 1 / 59 | 0 / 4 | 0 / 5 | 0 / 11 |
Outcome results
Primary
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)
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 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: Various time points from randomization up to 36 months
Population: Open label (OL) ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | NA days |
| RNF 44 Mcg Once Weekly (DB Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | NA days |
| Placebo (DB Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | NA days |
Primary
Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005)
The McDonald criteria use dissemination in time and space established by magnetic resonance image (MRI) findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new time constant 2 (T2) or gadolinium-enhancing (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: Various time points from randomization up to 24 months
Population: Intent-to-treat (ITT) population included all participants who were randomized to the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | 310 days |
| RNF 44 Mcg Once Weekly (DB Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | 182 days |
| Placebo (DB Population) | Time to Conversion to Multiple Sclerosis (MS) According to the McDonald Criteria (2005) | 97 days |
p-value: <0.001Log Rank
p-value: 0.008Log Rank
p-value: 0.009Log Rank
Secondary
Change From Baseline in Expanded Disability Status Score (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 at Month 36 was calculated as EDSS at Month 36 minus EDSS at baseline.
Time frame: Baseline, Month 36
Population: OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period. 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 |
|---|---|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Baseline (n=4,5,11) | 1.88 unit on a scale | Standard Deviation 0.85 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Change at Month 36 (n=2,4,8) | -0.25 unit on a scale | Standard Deviation 1.06 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Baseline (n=4,5,11) | 1.60 unit on a scale | Standard Deviation 0.96 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Change at Month 36 (n=2,4,8) | -0.63 unit on a scale | Standard Deviation 0.48 |
| Placebo (DB Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Baseline (n=4,5,11) | 1.64 unit on a scale | Standard Deviation 0.67 |
| Placebo (DB Population) | Change From Baseline in Expanded Disability Status Score (EDSS) Score at Month 36 | Change at Month 36 (n=2,4,8) | -0.50 unit on a scale | Standard Deviation 0.65 |
Secondary
Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36
Change from baseline in lesion volume was measured by using MRI scans for T2 lesions, T1 hypointense lesions and (Gd+) lesions.
Time frame: Baseline, Month 36
Population: OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period. 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 |
|---|---|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=4,5,11) | 675.20 cubic millimeter (mm^3) | Standard Deviation 940.87 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume change at Month 36 (n=2,4,8) | 180.25 cubic millimeter (mm^3) | Standard Deviation 198.34 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=4,5,11) | 30.05 cubic millimeter (mm^3) | Standard Deviation 60.1 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume change at Month 36 (n=2,4,8) | 55.75 cubic millimeter (mm^3) | Standard Deviation 78.84 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume at Baseline (n=4,5,11) | 103.70 cubic millimeter (mm^3) | Standard Deviation 151.17 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume change at Month 36 (n=2,4,8) | -47.20 cubic millimeter (mm^3) | Standard Deviation 66.75 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume change at Month 36 (n=2,4,8) | 0.00 cubic millimeter (mm^3) | Standard Deviation 0 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=4,5,11) | 1703.48 cubic millimeter (mm^3) | Standard Deviation 1324.41 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume change at Month 36 (n=2,4,8) | 216.68 cubic millimeter (mm^3) | Standard Deviation 310.06 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume at Baseline (n=4,5,11) | 0.00 cubic millimeter (mm^3) | Standard Deviation 0 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume change at Month 36 (n=2,4,8) | -22.63 cubic millimeter (mm^3) | Standard Deviation 382.14 |
| RNF 44 Mcg Once Weekly (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=4,5,11) | 302.70 cubic millimeter (mm^3) | Standard Deviation 358.58 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume change at Month 36 (n=2,4,8) | -1155.63 cubic millimeter (mm^3) | Standard Deviation 3348.36 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume at Baseline (n=4,5,11) | 488.72 cubic millimeter (mm^3) | Standard Deviation 589.06 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume change at Month 36 (n=2,4,8) | -246.08 cubic millimeter (mm^3) | Standard Deviation 848.99 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T1 lesion volume change at Month 36 (n=2,4,8) | 138.89 cubic millimeter (mm^3) | Standard Deviation 339.99 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | T2 lesion volume at Baseline (n=4,5,11) | 3533.37 cubic millimeter (mm^3) | Standard Deviation 3914.98 |
| Placebo (DB Population) | Change From Baseline in Time Constant 2 (T2) Lesion Volume , Time Constant 1 (T1) Hypointense Lesion Volume and Gadolinium Enhanced (Gd+) Lesion Volume at Month 36 | Gd+ lesion volume at Baseline (n=4,5,11) | 287.15 cubic millimeter (mm^3) | Standard Deviation 649.68 |
Secondary
Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan
Number of CUA lesions, new T2 lesions, Gd+ lesions and new T1 hypointense lesions were measured by using MRI scans.
Time frame: Month 24 up to Month 36
Population: OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period. 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 |
|---|---|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | CUA lesions (n=3,5,9) | 0.33 lesions | Standard Deviation 0.58 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T2 lesions (n=3,5,9) | 0.17 lesions | Standard Deviation 0.29 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New Gd+ lesions (n=3,5,9) | 0.17 lesions | Standard Deviation 0.29 |
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T1 Hypointense lesions (n=3,5,9) | 0.17 lesions | Standard Deviation 0.29 |
| RNF 44 Mcg Once Weekly (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T1 Hypointense lesions (n=3,5,9) | 0.00 lesions | Standard Deviation 0 |
| RNF 44 Mcg Once Weekly (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | CUA lesions (n=3,5,9) | 0.00 lesions | Standard Deviation 0 |
| RNF 44 Mcg Once Weekly (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New Gd+ lesions (n=3,5,9) | 0.00 lesions | Standard Deviation 0 |
| RNF 44 Mcg Once Weekly (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T2 lesions (n=3,5,9) | 0.00 lesions | Standard Deviation 0 |
| Placebo (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T1 Hypointense lesions (n=3,5,9) | 0.56 lesions | Standard Deviation 0.88 |
| Placebo (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New T2 lesions (n=3,5,9) | 0.94 lesions | Standard Deviation 1.61 |
| Placebo (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | New Gd+ lesions (n=3,5,9) | 0.56 lesions | Standard Deviation 1.21 |
| Placebo (DB Population) | Mean Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Hypointense Lesions Per Participant Per Scan | CUA lesions (n=3,5,9) | 1.56 lesions | Standard Deviation 2.93 |
Secondary
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score
CDMS was defined by the occurrence of a second exacerbation or relapse over 36 months in participants who presented with FCDE accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Time frame: Various time points from randomization up to 36 months
Population: OL ITT population included all participants who were randomized at baseline in core REFLEX trial and entered the 12 months OLE period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
| RNF 44 Mcg Once Weekly (DB Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
| Placebo (DB Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
Secondary
Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score
CDMS was defined by the occurrence of a second exacerbation or relapse over 24 months in participants who presented with first clinical demyelinating event (FCDE) accompanied by an abnormal MRI scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated.
Time frame: Various time points from randomization up to 24 months
Population: ITT population included all participants who were randomized to the assigned study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RNF 44 Mcg Three Times Weekly (Double Blind [DB] Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
| RNF 44 Mcg Once Weekly (DB Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
| Placebo (DB Population) | Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a 3-Month Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score | NA days |
p-value: <0.001Log Rank
p-value: 0.002Log Rank
p-value: 0.774Log Rank