| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| An inflammitory disease which damages cells in the spinal cord and brain. |
|
| 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 | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
| To evaluate change in RNFL thickness in RRMS patients followed for up to 36 months compared to a group of reference subjects (without neurologic or ophthalmic disease) to determine whether the optical coherence tomography (OCT) technology is sufficiently sensitive to disease and to change over time. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the correlation of change in RNFL thickness and macular volume with change in brain volume as measured by MRI in RRMS patients followed for up to 36 months.
To evaluate the correlation of change in RNFL thickness and macular volume with change in disability (as assessed by the EDSS and visual function) in RRMS patients followed for up to 36 months.
To evaluate short-team reproducibility of the RNFL thickness measure at study start by test/re-test estimation after a 4–week interval in RRMS patients and reference subjects (without neurologic or ophthalmic disease).
To evaluate short-term reproducibility (4-week interval) in macular volume measure (as above).
To evaluate change in macular volume over 36 months in RRMS patients compared to a group of reference subjects (without neurologic or ophthalmic disease). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill the following criteria:
• Written informed consent must be obtained before any assessment is performed
• Male and female patients aged 18-55 years inclusive
• A diagnosis of MS as defined by the 2005 revision to the McDonald criteria with a relapsingremitting
course
• MS disease duration of more than one year (from diagnosis of MS) before study entry (Screening) Participants of the reference group eligible for inclusion have to fulfill the following criteria:
• Written informed consent must be obtained before any assessment is performed
• Male and female subjects aged 18-55 years inclusive
• Matched to MS patients recruited in terms of age (±3 years),
ethnicity, gender and visual refraction (±2 diopters) with the MS patients recruited. |
|
| E.4 | Principal exclusion criteria |
1. HIV or any other known immunodeficiency syndrome (disease or drug-induced)
2. Any ophthalmologic reason for RNFL pathology other than MS, such as: optic neuropathy, active advanced glaucoma, injury of the optic nerve based on the ophthalmologist’s clinical judgment or • history or presence of severe myopia: a. in patients who have not had refractive surgery, a refractive error of greater than 6.00 diopters b. pathologic fundus changes of high myopia, such as retinal pigmentary atrophy, besides peripapillary atrophy (atrophy involving the macula) or a staphyloma c. in patients that have had previous refractive surgery, an axial eye length of greater than 26 mm
3. Acute optic neuritis within the past 6 months before Baseline
4. Evidence of advanced, non-proliferative or proliferative diabetic retinopathy
5. Presence of retinal conditions associated with edema, subretinal fluid, cysts, etc.
6. History of a severe head trauma
7. Any of the following neurologic/psychiatric disorders:
• history of substance abuse (drug or alcohol) in the past five years or any other factor (i.e., serious psychiatric condition) that may interfere with the subject’s ability to cooperate and comply with the study procedures • specific MRI findings (tumor, subdural haematoma, post-contusional changes, territorial stroke, neurodegenerative disorders, aneurysm/arteriovenous malformation, evidence of past macroscopic haemorrhage, or other relevant MRI findings that would interfere with evaluation) • progressive neurological disorder, other than MS, which may affect participation in the study
8. Concomitant use of drugs that may directly affect retinal structure and function (e.g. chronic systemic corticosteroids [>30 consecutive days; doses higher than Cushing threshold e.g. prednisone 7.5mg/d], intraocular anti-angiogenic drugs [ranibizumab, bevacizumab], intraocular steroids etc.)
9. Any medically unstable condition, progressive disease (other than MS) or other condition that would preclude reliable participation in the study as assessed by the investigator
10. Patients unable to undergo MRI scans including gadolinium enhancement:
• reduced renal clearance (eGFR <45 ml/min) • history of severe hypersensitivity to gadolinium-DTPA • claustrophobia that cannot be overcome otherwise
11. Patients who have received an investigational drug or therapy within 30 days or 5 half lives, which ever is longer, of the baseline visit. No additional exclusions may be applied by the investigator, in order to ensure that the population will be representative of all eligible patients. Participants of the reference group fulfilling any of the following criteria are not eligible for inclusion in this study:
1. HIV or any other known immunodeficiency syndrome (disease or drug-induced)
2. Any ophthalmologic reason for RNFL pathology other than MS, such as: • optic neuropathy, active advanced glaucoma, injury of the optic nerve based on the ophthalmologist’s clinical judgment or • history or presence of severe myopia:
a. in subjects who have not had refractive surgery, a refractive error of greater than 6.00 diopters b. pathologic fundus changes of high myopia, such as retinal pigmentary atrophy, besides peripapillary atrophy (atrophy involving the macula) or a staphyloma c. in subjects that have had previous refractive surgery, an axial eye length of greater than 26 mm
3. Acute optic neuritis within the past 6 months before Baseline
4. Evidence of advanced, non-proliferative or proliferative diabetic retinopathy
5. Presence of retinal conditions associated with e.g. edema, subretinal fluid, cysts
6. History of a severe head trauma
7. Any of the following neurologic/psychiatric disorders:
• history of substance abuse (drug or alcohol) in the past five years or any other factor (i.e., serious psychiatric condition) that may interfere with the subject’s ability to cooperate and comply with the study procedures
• specific MRI findings (tumor, subdural haematoma, post-contusional changes, territorial stroke, neurodegenerative disorders, aneurysm/arteriovenous malformation, evidence of past macroscopic haemorrhage, or other relevant MRI findings that would interfere with evaluation)
• progressive neurological disorder which may affect participation in the study
8. Any medically unstable condition, progressive disease or other condition that would preclude reliable participation in the study as assessed by the investigator
9. Concomitant use of drugs that may directly affect retinal structure and function 10. Unable to undergo MRI scans, including claustrophobia that cannot be overcome otherwise
11. Subjects who have received an investigational drug or therapy within 30 days or 5 half lives, which ever is longer, of the baseline |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of the study is to evaluate the change in RNFL thickness in MS patients followed for up to 36 months compared to a group of reference subjects (without ophthalmic
and neurologic disease). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
To evaluate the correlation of change in RNFL thickness and macular volume with change in
brain volume as measured by MRI in RRMS patients followed for up to 36 months.
To evaluate the correlation of change in RNFL thickness and macular volume with change in disability (as assessed by the EDSS and visual function) in RRMS patients followed for up to
36 months.
To evaluate short-team reproducibility of the RNFL thickness measure at study start by test/re-test estimation after a 4–week interval in RRMS patients and reference subjects (without neurologic or ophthalmic disease).
To evaluate short-term reproducibility (4-week interval) in macular volume measure (as above).
To evaluate change in macular volume over 36 months in RRMS patients compared to a group of reference subjects (without neurologic or ophthalmic disease). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| This study will provide data of importance in the field of MS to determine if the OCT technology can provide a reliable and convenient tool by which to monitor disease progression, estimate the rate of neurodegeneration and assess anti-neurodegenerative treatment effect of MS therapies. Correlations of OCT findings with MRI and clinical findings may enhance our understanding of the relationship between CNS inflammation, tissue injury, regeneration and neurological deficit. |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| longitudinal, pharmacologically non-interventional study design |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| No comparator. Study contains untreated reference subjects without ophthalmologic/neurologic disease |
|
| E.8.2.4 | Number of treatment arms in the trial | 0 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Australia |
| Austria |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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