A Study to Evaluate the Long-term Safety of Arbaclofen Extended-Release Tablets for Patients With Spasticity Due to MS

Study Overview
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Brief Summary
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Spasticity is a common complication in MS and occurs in up to 84% of patients. The main sign of spasticity is resistance to passive limb movement characterized by increased resistance to stretching, clonus, and exaggerated deep reflexes. Osmotica Pharmaceutical is currently developing arbaclofen extended-release tablets (AERT) for the treatment of spasticity in patients with MS.

Detailed Description
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This is a multicenter, open-label, long-term extension study to evaluate the safety and tolerability of oral AERT in patients with spasticity due to MS. Subjects from the double blind study (Study OS440-3004) may rollover into this open-label extension study, as well as de novo subjects. The maintenance dose will be 80 mg/day or the highest tolerated dose. Once the subject has reached the maintenance dose, they will remain on that dose for approximately 1 year.

Official Title
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An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release Tablets in Multiple Sclerosis Patients With Spasticity (Study OS440-3005)

Conditions
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Multiple Sclerosis, Spasticity, Muscle

Intervention / Treatment
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* Drug: Arbaclofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects 18 to 65 years of age, inclusive. An established diagnosis per McDonald Criteria (Polman et al 2011) of MS (either relapsing-remitting [RR] or secondary-progressive [SP] course) that manifests a documented history of spasticity for at least 6 months prior to Baseline. Has participated in Study OS440-3004 or is a new US subject (ie, a de novo subject) who fulfills the inclusion/exclusion criteria. Is willing to continue on open-label treatment with AERT as described in this protocol. 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 pyridine), subject must be at a stable dose for at least 3 months prior to Baseline. 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. Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement. Creatinine clearance, as calculated by the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease Study (MDRD) formula, of >50 mL/minute. Use of a medically highly effective form of birth control (see Section 7.8 of the protocol) during the study and for 3 months thereafter for women of child-bearing potential (including female subjects). Willing to sign the informed consent form (ICF). Exclusion Criteria: Any concomitant disease or disorder that has symptoms of spasticity or that may influence the subject's level of spasticity. Inability to rate their level of spasticity or distinguish it from other MS symptoms. Use of high dose oral or intravenous methylprednisolone, or equivalent, within 3 months before Baseline. History of allergy to baclofen or any inactive components of the test formulation. Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables (Appendix 5). Pregnancy, lactation, or planned pregnancy during the course of the study and for 3 months after the final study visit. 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. History of epilepsy. Current significant cognitive deficit, severe or untreated anxiety, severe or untreated depression. 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 (Appendix 6). Subjects who are proficient in self-catheterization may be included in the study at the investigator's discretion. Current malignancy or history of malignancy that has not been in remission for more than 5 years, except effectively treated basal cell skin carcinoma. Subject has clinically significant abnormal laboratory values, in the opinion of the investigator at Baseline (at Visit 6 for rollover subjects). 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. Planned elective surgery or other procedures requiring general anesthesia during the course of the study. 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). Participation in another clinical research study (with the exception of Study OS440-3004) within 1 month of Baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AERT 80 mg<br>Arbaclofen extended release tablet, 20 mg | Drug: Arbaclofen<br>* Arbaclofen is the active R enantiomer of baclofen.<br>* Other names: AERT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events, Change in Vital Signs, Clinical Laboratory Test Results, 12-lead ECGs, USP Questionnaire, and C-SSRS Results | Safety and tolerability will be assessed by the monitoring of adverse events volunteered, observed, and elicited by general questions in a non-suggestive manner. Changes in vital signs, clinical laboratory test results, 12-lead ECGs, the urinary symptom profile (USP) questionnaire, and the C-SSRS results will also be assessed. | over 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Change (PGIC) | Patient Global impression of Change (PGIC) is a scale to evaluate the change in activity limitations, symptoms, emotions, and overall quality of life using scores from 1 to 7 with 1 being no change and 7 being a great deal better, and a considerable improvement that has made all the difference. Minimum value is 1 and the maximum value is 7. | week 60 | 
| Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL) | The abbreviated scale title is TNmAS. It is considered the primary clinical measure of muscle spasticity in subjects with neurological conditions. It is a useful 6-point rating scale (0 to 5) to measure abnormality in tone or the resistance to passive movements. Minimum value is 0 and maximum value is 5. A higher score means a worse outcome. | week 28 | 
| Expanded Disability Status Scale (EDSS) | Expanded Disability Status Scale (EDSS) is a method of quantifying disability in MS and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5-unit increments that represent higher levels of disability. A score of 0 represents a normal neurological exam, and 10 represents death due to MS. | week 60 |