| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| cognitive impairment in Multiple Sclerosis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028245 |
| E.1.2 | Term | Multiple sclerosis |
|
| 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 demonstrate that rivastigmine patch (target patch size 10 cm²) has superior efficacy compared to placebo on a change from baseline of the total recall score of the selective reminding test (SRT) of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) in cognitive impaired MS patients after 16 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
effect on different cognitive domains
effect on fatigue in MS-patients treated with rivastigmine patch versus Placebo, the Modified Fatigue Impact Scale (mFIS) will be used after 16 weeks of treatment
effect on depression in MS-patients
effect on the course of disease in MS- patients, the multiple sclerosis functional composite (MSFC) will be used after 16 weeks of treatment
effect on quality of life in MS-patients treated with rivastigmine patch versus Placebo, the QOL subscale of the PRIMuS will be used after 16 weeks of treatment
safety and tolerability in MS patients up to 68 weeks of treatment
the longterm effect on all primary and secondary objectives listed above, the BRB-N, PRIMuS, CGI, mFIS, MADRS and MSFC will be used after 32 and 68 weeks of treatment
longitudinal measurement of screening instruments, the Faces Symbol Test (FST) will be used and compared with BRB after 16, 32 and 68 weeks of treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Written informed consent to participate in the trial
2) Males and females between 18 and 55 years of age;
3) Definite diagnosis of multiple sclerosis as defined by 2005 revised McDonald criteria (Appendix 4)
4) MS-subtype: CIS, RRMS, SPMS;
6) Stable and well tolerated therapy with interferon beta-1b (Extavia®) for at least 60 days immediately prior to baseline. This period does not apply to patients swithed directly from Betaferon.
7) Cognitive Impairment defined as FST score of ≥3.0 and/or MUSIC score of ≤19 at screening
8) Verbal memory impairment defined as a score ≥0.5 standard deviations (SD) below age- and sex-based normative data on the RAVLT score at screening
9) Sufficient education to read, write and communicate comprehensibly
|
|
| E.4 | Principal exclusion criteria |
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
2. Patient with advanced disease serious enough to, under the judgment of the physician-investigator, place the patient at a special risk situation.
3. Women
o who are pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml))
o who are menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception
4. With a physical or sensory disability that can subjectively prevent the patient from completing all study requirements
5. Patients without contractual capability.
6. Patients suffering any other type of concomitant psychiatric and/or neurological disorder other than MS which is known to affect cognition (e.g. severe depressive symptoms, cerebrovascular diseases, epilepsy).
7. Patients suffering an acute relapse of MS in the previous 30 days (treated or not with intravenous or oral glucocorticoid regimens) prior to baseline.
8. Patients on any other treatment for MS than described in inclusion criteria
9. With a history or current problem of drug-addiction and/or alcohol abuse.
10. Current or historical laboratory evidence of vitamin B1 and/or vitamin B12 deficit
11. Known or ‘new’ diagnosis of diabetes mellitus (if screening blood glucose is suspicious for diabetes [≥126 mg/dL or ≥7 mmol/L if fasting and ≥200 mg/dL or 11.1 mmol/L if random testing] a patient should be further evaluated for diabetes mellitus)
12. Any of the following hepatic conditions:
• total or conjugated bilirubin greater than 2 times the upper limit of the normal range, unless in context of Gilbert’s syndrome
• AST (=SGOT), ALT (=SGPT) greater than 3 times the upper limit of the normal range
13. With any of the following abnormal laboratory values at screening:
• serum creatinine >2 ULN or a history of hemodialysis
• white blood cell (WBC) count <3,500/mm³ (<3.5 x 109 / L)
• Serum electrolyte, BUN and Thyroidea stimulating hormone (TSH) concentrations outside the range as specified also in Appendix 2.
14. With a history of severe or moderate-severe cranioencephalic trauma.
15. Study personnel or first degree relatives of investigator(s) must not be included in the study
16. History or presence of any intolerance or contraindication for the application of rivastigmine (or for drugs with similar chemical structures) as listed in the current Investigator’s Brochure and/or SPC, i.e. severe liver insufficiency, pancreatitis, gastric ulcer, convulsions.
17. Patients with any of the following diseases serious or unstable: gastrointestinal disease; clinically significant urinary obstruction under clinical judgement; acute, severe or unstable asthmatic conditions [for instance, severe chronic obstructive pulmonary disease (COPD)]; current and known diagnosis of severe or unstable cardiovascular disease; current and known diagnosis of bradycardia ( 40 bpm), sinus syndrome or conductivity disorders (atrial sinus blockage, 2nd or 3rd degree atrioventricular block).
18. With a history in the past year or a current diagnosis of cerebrovascular disease (for instance, stroke, transient ischemic events, aneurysms).
19. Severe depressive symptoms indicated by a score of more than ≥ 14 on the MADRS at screening
20. Patients who have performed a cognitive testing with Brief repeatable battery (BRB-N) within last year before randomisation
21. Patients participating in any cognitive rehabilitation study or program (eg. continuous cognitive training) in the 3 months prior to the screening visit.
22. Current diagnosis of an active skin lesion/disorder that would prevent accurate assessment of the adhesion and potential skin irritation of the patch (e.g., atopic dermatitis, wounded or scratched skin in the area of the patch application).
23. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
24. Patients using any of the following substances:
- A drug or treatment known to cause significant toxicity in any organic system in the four weeks prior to randomization,
- Start of new psychotropic drugs
- Rivastigmine donepezil, other cholinesterase inhibitors (for instance, tacrine, galanthamine, physostigmine or pyridostigmine), other treatments for Alzheimer’s disease or memantine in the six weeks prior to randomization,
- Muscle relaxants such as succinylcholine in the two weeks prior to randomization,
- Lithium in the two weeks prior to randomization,
- Centrally acting anticholinergics during treatment,
- Medication for Parkinson’s disease during treatment (for instance, selegiline, levodopa, amantadine, dopamine agonists).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change in score of total recall on the SRT (baseline to week 16). The SRT is a widely used measure of verbal learning and memory that is part of the Brief Repeatable Battery of Neuropsychological Test in MS (BRB-N). |
|
| 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 | Yes |
| 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 | No |
| 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) | 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 | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
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