A Study to Evaluate the Long-term Safety of Arbaclofen Extended-Release Tablets for Patients With Spasticity Due to MS (OS440-3005)

• ClinicalTrials.gov Identifier: NCT03319732
• Recruitment Status: Completed
• First Posted: October 24, 2017
• Results First Posted: July 15, 2022
• Last Update Posted: August 9, 2022
• Sponsor: RVL Pharmaceuticals, Inc.
• Collaborator: Osmotica Pharmaceutical US LLC
• Information provided by (Responsible Party): RVL Pharmaceuticals, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis; Spasticity, Muscle	Drug: Arbaclofen	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 323 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study to Evaluate the Long-Term Safety of Arbaclofen Extended-Release Tablets in Multiple Sclerosis Patients With Spasticity (Study OS440-3005)
• Actual Study Start Date: April 3, 2018
• Actual Primary Completion Date: January 27, 2020
• Actual Study Completion Date: June 11, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: AERT 80 mg; Arbaclofen extended release tablet, 20 mg	Drug: Arbaclofen; Arbaclofen is the active R enantiomer of baclofen.; Other Name: AERT

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events, Change in Vital Signs, Clinical Laboratory Test Results, 12-lead ECGs, USP Questionnaire, and C-SSRS Results [ Time Frame: over 1 year ]
   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.

Secondary Outcome Measures :

1. Patient Global Impression of Change (PGIC) [ Time Frame: week 60 ]
   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.
2. Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL) [ Time Frame: week 28 ]
   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.
3. Expanded Disability Status Scale (EDSS) [ Time Frame: week 60 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Subjects 18 to 65 years of age, inclusive.
2. 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.
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 pyridine), 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, of >50 mL/minute.
9. 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).
10. Willing to sign the informed consent form (ICF).

Exclusion Criteria:

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 (Appendix 5).
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 (Appendix 6). 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.

Contacts and Locations

Locations

United States, California

Neuro Pain Medical Center

Fresno, California, United States, 93710

Sponsors and Collaborators

RVL Pharmaceuticals, Inc.

Osmotica Pharmaceutical US LLC

Investigators

• Study Director: David Jacobs, MD; Vice President

  Study Documents (Full-Text)

Documents provided by RVL Pharmaceuticals, Inc.:

Study Protocol  [PDF] April 12, 2018

Statistical Analysis Plan  [PDF] January 24, 2020

More Information

• Responsible Party: RVL Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03319732
• Other Study ID Numbers: OS440-3005
• First Posted: October 24, 2017
• Results First Posted: July 15, 2022
• Last Update Posted: August 9, 2022
• Last Verified: February 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Muscle Spasticity; Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations