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

• Sponsor: RVL Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03319732
• Collaborator: Osmotica Pharmaceutical US LLC (Industry)
• Enrollment: 323
• Location: 1
• Arm: 1
• Actual Duration (Months): 26.3
• Patients Per Site Per Month: 12.3

Study Details

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
• 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: Apr 3, 2018
• Actual Primary Completion Date: Jan 27, 2020
• Actual Study Completion Date: Jun 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 Names: 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 [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) [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) [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) [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

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

1. Absence of infections, peripheral vascular disease, painful contractures, advanced arthritis, or other conditions that hinder evaluation of joint movement.

2. 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.

3. 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).

4. 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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol - Apr 12, 2018
• Statistical Analysis Plan - Jan 24, 2020

More Information

Publications

None provided.

• Responsible Party: RVL Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03319732
• Other Study ID Numbers: OS440-3005
• First Posted: Oct 24, 2017
• Last Update Posted: Aug 9, 2022
• Last Verified: Feb 1, 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

Study Results

Participant Flow

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg (Two 20-mg tablets twice daily for a total of 80 mg daily dose)
Period Title: Overall Study
STARTED	323
COMPLETED	218
NOT COMPLETED	105

Baseline Characteristics

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg Arbaclofen: Arbaclofen is the active R enantiomer of baclofen.
Overall Participants	323
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	323 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	190 58.8%
Male	133 41.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 1.9%
White	312 96.6%
More than one race	1 0.3%
Unknown or Not Reported	4 1.2%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.6 (8.94)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	71.67 (15.704)
Body Mass Index (BMI) ("kg/m^2") [Mean (Standard Deviation) ]
Mean (Standard Deviation) ["kg/m^2"]	24.825 (4.7760)
Total Numeric-Transformed Modified Ashworth Scale-Total Limbs (TNmAS-TL) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	13.0 (8.06)
Total Numeric-Transformed Modified Ashworth Scale-Most Affected Limb (TNmAS-MAL) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.3 (3.25)
Expanded Disability Status Scale (EDSS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.98 (1.29)
Patient Global Impression of Change (PGIC) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.3 (1.61)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg (two 20 mg tablets twice a day for a total of 80 mg daily dose)
Measure Participants	323
Count of Participants [Participants]	276 85.4%

2. Secondary Outcome

Title	Patient Global Impression of Change (PGIC)
Description	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.
Time Frame	week 60

Outcome Measure Data

Analysis Population Description

Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg Arbaclofen: Arbaclofen is the active R enantiomer of baclofen.
Measure Participants	323
Mean (Standard Deviation) [units on a scale]	2.7 (1.63)

3. Secondary Outcome

Title	Total Numeric-transformed Modified Ashworth Scale Score or the Most Affected Limb (TNmAS-MAL)
Description	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.
Time Frame	week 28

Outcome Measure Data

Analysis Population Description

Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg Arbaclofen: Arbaclofen is the active R enantiomer of baclofen.
Measure Participants	323
Mean (Standard Deviation) [units on a scale]	5.6 (3.22)

4. Secondary Outcome

Title	Expanded Disability Status Scale (EDSS)
Description	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.
Time Frame	week 60

Outcome Measure Data

Analysis Population Description

Safety population included all subjects who received at least one dose of study treatment and had at least one-post dose visit.

Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg Arbaclofen: Arbaclofen is the active R enantiomer of baclofen.
Measure Participants	323
Mean (Standard Deviation) [units on a scale]	5.01 (1.3)

Adverse Events

Time Frame	60 weeks
Arm/Group Title	AERT 80 mg
Arm/Group Description	Arbaclofen extended release tablet, 20 mg
All Cause Mortality
	AERT 80 mg
	Affected / at Risk (%)	# Events
Total	1/323 (0.3%)
Serious Adverse Events
	AERT 80 mg
	Affected / at Risk (%)	# Events
Total	21/323 (6.5%)
Cardiac disorders
Acute Myocardial Infarction	1/323 (0.3%)
Myocardial Infarction	1/323 (0.3%)
Gastrointestinal disorders
Constipation	1/323 (0.3%)
Nausea	1/323 (0.3%)
Pancreatitis chronic	1/323 (0.3%)
Hepatobiliary disorders
Cholecystitis	1/323 (0.3%)
Infections and infestations
Osteomyelitis	1/323 (0.3%)
Toxicity to various agents	1/323 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma	1/323 (0.3%)
Adenocarcinoma of colon	1/323 (0.3%)
Nervous system disorders
Multiple Sclerosis relapse	7/323 (2.2%)
Paraparesis	1/323 (0.3%)
Restless Legs Syndrome	1/323 (0.3%)
Somnolence	1/323 (0.3%)
Renal and urinary disorders
Atonic Urinary Bladder	1/323 (0.3%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	1/323 (0.3%)
Dermatitis Allergic	1/323 (0.3%)
Vascular disorders
Hypertension	1/323 (0.3%)
Other (Not Including Serious) Adverse Events
	AERT 80 mg
	Affected / at Risk (%)	# Events
Total	278/323 (86.1%)
Gastrointestinal disorders
Nausea	70/323 (21.7%)
Vomiting	29/323 (9%)
General disorders
Asthenia	61/323 (18.9%)
Gait Disturbance	20/323 (6.2%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	77/323 (23.8%)
Nervous system disorders
Dizziness	52/323 (16.1%)
Somnolence	41/323 (12.7%)
Headache	24/323 (7.4%)
Renal and urinary disorders
Urinary Tract Disorder	112/323 (34.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.