E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spasticity in patients with multiple sclerosis |
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E.1.1.1 | Medical condition in easily understood language |
Spasticity in patients with multiple sclerosis |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041416 |
E.1.2 | Term | Spasticity |
E.1.2 | System Organ Class | 100000004852 |
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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 objective of this study is to evaluate the long-term safety and tolerability of AERT in patients with spasticity due to MS. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
• Assess the Patient Global Impression of Change (PGIC) over 1 year.
• Assess the Total Numeric-transformed modified Ashworth Scale score of the most affected limb (TNmAS-MAL) over 1 year.
• Assess the Expanded Disability Status Scale (EDSS) over 1 year. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Male and female subjects will be considered eligible for participation in the study if all the
following inclusion criteria are satisfied at Visit 1 (Baseline).
1. Subjects 18 to 65 years of age, inclusive.
2. An established diagnosis per McDonald Criteria (Polman et al 2011) of MS (either RR or SP course) that manifests a documented history of spasticity for at least 6 months prior to Baseline.
3. Has participated in Study OS440-3004 or is a new US subject (ie, a de novo subject) who fulfills the inclusion/exclusion criteria.
4. Is willing to continue on open-label treatment with AERT as described in this protocol.
5. If receiving disease-modifying medications (eg, interferons approved for MS, glatiramer acetate, natalizumab, fingolimod, or mitoxantrone), there must be no change in dose for at least 3 months prior to Baseline, and the subject must be willing to maintain this treatment dose for the duration of the study. If receiving AMPYRA® (dalfampridine, fampridine, 4-amino puridine), subject must be at a stable dose for at least 3 months prior to Baseline.
6. Stable regimen for at least 1 month prior to Baseline for all medications and non-pharmacological therapies that are intended to alleviate spasticity.
a. De novo subjects being considered for enrollment and taking medications indicated
for the treatment of spasticity (ie, baclofen, benzodiazepines, cannabinoids, carisoprodol, dantrolene, tizanidine, cyclobenzaprine, any neuroleptic, ropinoprole, tolperisone, and clonidine) must wash out from these medications for a minimum of 21 days by Baseline in order to be eligible for study treatment. De novo subjects found not to meet this criterion will be withdrawn from the study and will be considered screen failures.
7. Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement.
8. Creatinine clearance, as calculated by the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease Study (MDRD) formula,1 of >50 mL/minute.
9. Use of a medically highly effective form of birth control during the study and for 3 months thereafter for women of child-bearing potential (including female subjects).
10. Willing to sign the informed consent form (ICF). |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will not qualify for the study.
1. Any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject’s level of spasticity.
2. Inability to rate their level of spasticity or distinguish it from other MS symptoms.
3. Use of high dose oral or intravenous methylprednisolone, or equivalent, within 3 months before Baseline.
4. History of allergy to baclofen or any inactive components of the test formulation.
5. Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables.
6. Pregnancy, lactation, or planned pregnancy during the course of the study and for 3 months after the final study visit.
7. Recent history (within past 12 months) of any unstable psychiatric disease (or yes response to questions 1 or 2 on the Columbia Suicide Severity Rating Scale [C-SSRS] at baseline), or current signs and symptoms of significant medical disorders such as severe, progressive, or uncontrolled pulmonary, cardiac, gastrointestinal, hepatic, renal, genitourinary, hematological, endocrine, immunologic, or neurological disease.
8. History of epilepsy.
9. Current significant cognitive deficit, severe or untreated anxiety, severe or untreated depression.
10. Subjects with abnormal micturition that requires indwelling or intermittent catheterization or with lower urinary tract symptoms (LUTS) that result in a score >26 in the Baseline Urinary Symptom Profile – USP© (USP) questionnaire. Subjects who are proficient in self-catheterization may be included in the study at the investigator’s discretion.
11. Current malignancy or history of malignancy that has not been in remission for more than 5 years, except effectively treated basal cell skin carcinoma.
12. Subject has clinically significant abnormal laboratory values, in the opinion of the investigator at Baseline (at Visit 6 for rollover subjects).
13. Any other significant disease, disorder, or significant laboratory finding, including clinically significant abnormal laboratory values or ongoing serious adverse events (SAEs) at Visit 6 (Final Visit) of Study OS440-3004, which, in the opinion of the investigator, puts the subject at risk because of participation, influences the result of the study, or affects the subject’s ability to participate.
14. Planned elective surgery or other procedures requiring general anesthesia during the course of the study.
15. History of any illicit substance abuse (eg, alcohol, marijuana, cocaine) or prescription for long-acting opioids within the past 12 months (tramadol use will be allowed).
16. Participation in another clinical research study (with the exception of Study OS440-3004) within 1 month of Baseline. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Endpoints:
Patient Global Impression of Change
Total Numeric-Transformed Modified Ashworth Scale
Expanded Disability Status Scale
Safety endpoints will be reported on the Safety population. Subjects will be reported according to the treatment they actually received. Safety assessment will be based on descriptive statistics and individual subject listings. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints are evaluated at baseline, Visit 4 and at the final Visit.
Safety endpoints: AEs are assessed on an ongoing basis throughout the study. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Belarus |
Bosnia and Herzegovina |
Bulgaria |
Croatia |
Moldova, Republic of |
Poland |
Russian Federation |
Serbia |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 3 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
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 |