E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Clinically isolated syndrome (CIS) and multiple sclerosis (MS) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028245 |
E.1.2 | Term | Multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071068 |
E.1.2 | Term | Clinically isolated syndrome |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives are to describe the disease course (conversion to clinically-definite multiple sclerosis [CDMS]), change in disability, cognitive function, resource use, and employment status, in relation to treatment with Interferon beta-1b.
Patients that cannot participate in a physical/face-to-face visit will have the option of being assessed via telephone on selected key outcomes, in an attempt to keep the patient ascertainment as high as possible. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess magnetic resonance imaging (MRI) and optic coherence tomography (OCT) parameters, treatment history, quality of life (QoL) parameters, fatigue and depression, the choice of MS-specific medication, and to investigate tolerability of Interferon beta-1b in the full former clinically-isolated syndrome (CIS) cohort as well as in subgroups of patients. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients with CIS or MS who have been treated at least once in BENEFIT Study 304747.
2. Patients who do not qualify for one or more interventional assessments (eg, MRI due to severe claustrophobia) are invited to participate in the other assessments of this study.
3. Written informed consent |
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E.4 | Principal exclusion criteria |
1. Patients who meet any of the following criteria at the time of screening will be excluded from the study:
● Patients who, according to the investigator’s judgment, have medical, psychiatric, or other conditions that compromise the patient’s ability to understand the purpose of the study.
2. Patients who meet any of the following criteria at the time of screening will be excluded from interventional MRI assessment. However, they should be encouraged to still participate in the study:
● Pregnant or nursing (including pumping for storage and feeding).
● Contraindications to MRI examination (eg, inability to hold breath, severe arrhythmias, very low cardiac output, severe claustrophobia, or patients with implanted defibrillators or other metallic devices not approved for MRI).
3. Patients who meet any of the following criteria at the time of screening will be excluded from contrast media administration. However, they may undergo MRI assessment:
● Contraindication to the use of gadolinium-containing contrast agents (including patients who are suspected for or known to have nephrogenic systemic fibrosis).
● History of severe (as judged by the investigator, taking into account the intensity of the event) allergic or anaphylactoid reaction to any allergen, including drugs and contrast agents.
● Received any contrast agent within 72 hours prior to the study MRI, or scheduled to receive any contrast agent within 72 hours after the study MRI.
● Renal insufficiency, defined by baseline glomerular filtration rate. Estimated value ≥ 30 mL/min/1.73 m2 derived from a serum creatinine result within 2 weeks prior to gadolinium-containing contrast agent injection is needed. Any patient on hemodialysis or peritoneal dialysis is excluded from contrast media administration. If there are multiple creatinine values, the values obtained prior to and closest to the time of the MRI should be used. The core lab value should not be used if not available prior to the MRI.
● Acute renal insufficiency of any intensity, either due to hepato-renal syndrome or occurring in the perioperative liver transplantation period.
● Known history of severe cardiovascular disease (eg, acute myocardial infarction [< 14 days], unstable angina, congestive heart failure New York Heart Association Class IV) or known prolonged QT syndrome.
● Suspected clinical instability or unpredictability of the clinical course during the study (eg, due to previous surgery or acute stroke). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Regular face-to-face site visit:
● Relapses
● Conversion to CDMS, to MS by McDonald criteria (2001, 2010), and / or to secondary progressive multiple sclerosis (disease course)
● Expanded Disability Status Scale (EDSS) including DSS 3 and 6 information, Multiple Sclerosis Functional Composite (MSFC) (disability and disability progression) and Multiple Sclerosis Severity Score (MSSS)
● Paced Auditory Serial Addition Test (PASAT) and Symbol Digit Modalities Test (SDMT) (cognitive function)
● Resource use and employment status
Telephone assessment for patients unable to visit site with selected outcomes:
● Relapses
● Telephone EDSS
● Conversion to CDMS (disease course)
● Resource use and vocational status
● Choice of and adherence to MS-specific medication
● Center of Epidemiological Studies Depression Scale (CES-D) (Depression)
● Fatigue Scale for Sensory and Motor Functions (FSMC) (fatigue)
● Functional Assessment of Multiple Sclerosis (FAMS) and European Quality of Life - 5 Dimensions (EQ-5D) (QoL) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Relapses, disease course, EDSS milestones and medication history - retrospective assessment since subject's last visit in any of the previous BENEFIT studies up to 11 years.
Resource use - retrospective baseline assessment and 11 year visit.
Cognitive function, depression, fatigue, QoL - cross-sectional assessment (only or in addition to a retrospective assessment) at approximately 11 years after randomization.
Please refer to Figure 4.2 in the Protocol for full details of assessments for the different endpoints in this study. |
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E.5.2 | Secondary end point(s) |
Regular face-to-face site visit:
● Diagnosis and disease course
● MRI parameters
● OCT parameters
● Visual acuity and ophthalmological findings
● CES-D (Depression)
● Fatigue Scale for Sensory and Motor Fatigue (Fatigue)
● Choice of and adherence to MS-specific medication
● FAMS and EQ-5D (QoL)
● Deoxyribonucleic acid [DNA], ribonucleic acid [RNA], biomarkers
● Vitamin D |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease course and medication history - retrospective assessment since subject's last visit in any of the previous BENEFIT studies up to 11 years.
MRI, OCT, depression, fatigue, QoL, genetics, evaluation of biomarkers and vitamin D - cross-sectional assessment (only or in addition to a retrospective assessment) at approximately 11 years after randomization.
Please refer to Figure 4.2 in the Protocol for full details of assessments for the different endpoints in this study. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Slovenia |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |