Clinical trial NCT01844232: One Year, Open Label, Dose Escalation Long-term Safety Study in Multiple Sclerosis (MS) Subjects With Spasticity
Official title: A One Year, Open Label, Dose Escalation Study To Evaluate the Long-Term Safety of Arbaclofen Extended Release Tablets (AERT) in Multiple Sclerosis Subjects With Spasticity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Spasticity
Keywords: Multiple sclerosis
spasticity
arbaclofen
Lead sponsor: RVL Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Osmotica Pharmaceutical US LLC
First posted: 2013-05-01
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: All subjects will begin treatment with arbaclofen at 20 milligrams (mg) per day (2 X 10 mg) for two weeks, then increase to 30 mg per day (2 X 15 mg) for two weeks, and then increase to 40 mg per day (2 X 20 mg) based on the Dose Escalation Criteria. Once the subject reaches the Maintenance Dose, they will remain on that dose for approximately 1 year. The Maintenance Dose is the highest tolerated dose, not to exceed 40 mg per day.
Primary purpose: TREATMENT

Brief summary: Clinical protocol OS440-3003 is a multicenter, open-label, non-randomized, uncontrolled, dose escalation study to evaluate the safety and tolerability of Arbaclofen Extended Release Tablets over 1 year in Multiple Sclerosis (MS) subjects with spasticity. All subjects in this study will receive arbaclofen in the extended release tablet formulation.

Detailed description: Clinical protocol OS440-3003 is a multicenter, open-label, non-randomized, uncontrolled, dose escalation study to evaluate the safety and tolerability of Arbaclofen Extended Release Tablets (AERT) over 1 year in MS subjects with spasticity. All subjects in this study will receive arbaclofen in the extended release tablet formulation.

All subjects will begin treatment with arbaclofen at 20 milligrams (mg) per day (2 X 10 mg) for two weeks, then increase to 30 mg per day (2 X 15 mg) for two weeks, and then increase to 40 mg per day (2 X 20 mg) based on the Dose Escalation Criteria. Once the subject reaches the Maintenance Dose, they will remain on that dose for approximately 1 year. The Maintenance Dose is the highest tolerated dose, not to exceed 40 mg per day.

In this study, the Up Titration Period begins with Visit 2 and ends when the Maintenance Dose is determined. The Maintenance Period is the time from establishment of the Maintenance Dose until the down-titration visit. For subjects that complete the study, the Maintenance Period is for approximately 1 year in duration. The Down Titration Period will be 2 weeks for subjects on the maintenance dose of 40 mg per day and 1 week for subjects on the maintenance dose of 30 mg per day. There is no down titration phase for subjects on a 20 mg per day maintenance dose.

Subjects for whom the Maintenance Dose is 20 mg per day (i.e., subjects who did not tolerate the 30 mg/ day dose) will begin the 1 year Maintenance Period at Visit 4 and complete the study at Visit 8. Subjects for whom the Maintenance Dose is either 30 mg or 40 mg per day will begin the Maintenance Period at Visit 5 and complete the maintenance portion of the study at Visit 9.

The next portion of the study is down titration. The subjects on the 20 mg per day Maintenance Dose will not have a down-titration. For subjects on the 30 mg per day Maintenance Dose, down-titration will begin at Visit 9 and continue for 1 week. These subjects will return for Visit 10 after the 1 week down-titration. For subjects on the 40 mg per day Maintenance Dose, down titration will begin at Visit 9 and continue for 2 weeks. These subjects will return for Visit 10 after the 2 week down-titration.

Study visits will occur every two weeks until the Maintenance Dose is reached and then study visits will occur every three months with telephone follow-up calls monthly in between visits

Eligibility criteria: Inclusion Criteria:

* Patients (male or female) 18 to 70 years of age, inclusive, at the time of the first dose.
* Have an established diagnosis (per McDonald 2005 Criteria, of Multiple Sclerosis Appendix C (either relapsing remitting or secondary progressive course), that manifests spasticity.
* If receiving disease-modifying medications (immunomodulatory treatment), these must have been at a stable dose for at least one (1) months prior to screening, and the subject must be willing to maintain this treatment for the duration of the study.
* If receiving botulinum toxin must be on a stable treatment regimen (e.g. every 12 weeks).
* If receiving phenol or alcohol injections, should have been received 60 days before enrolment in the study.
* Absence of infections and peripheral vascular disease.
* Have a creatinine clearance, as calculated by Glomerular Filtration Rate using the Modification of Diet in Renal Disease (MDRD) formula , greater than 60 milliliters/minute.
* Use of a medically highly effective form of birth control during the study and for 90 days thereafter for women of child-bearing potential (including female subjects and female partners of non-sterile male subjects. .
* Willing to allow his or her general practitioner and consultant, if appropriate, to be notified of participation in the study

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.
* History of allergy to baclofen.
* Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables (Appendix D Prohibited Concomitant Medications)
* Pregnancy, lactation or planned pregnancy during the course of the study and for three months thereafter. (Confirmation that the subject is not pregnant must be established by a negative serum pregnancy test at baseline).
* History of, or current unstable psychiatric disease, or signs and symptoms of significant medical disorders such as severe, progressive, or uncontrolled renal, hepatic, gastrointestinal, hematological, endocrine, immunologic, pulmonary, cardiac or neurological disease which, in the opinion of the investigator, may; put the subject at risk because of participation, influence the result of the study, or affect the subject's ability to participate.
* Seizures requiring medication.
* 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 greater than twenty-six (\>26) in the Baseline Urinary Symptom Profile© questionnaire.
* Current malignancy or history of malignancy that has not been in remission for more than five years, except effectively treated basal cell skin carcinoma.
* History of substance abuse within the past twelve (12) months.
* Participation in another interventional research study within thirty (30) days of Screening except OS440-3002.
* Patients who are uncooperative or unwilling to sign consent form.

Primary outcomes:
measure: Assessment of Adverse Events
timeFrame: From the beginning of dose titration to end of study (day 393 of dosing)
Secondary outcomes:
measure: Determination of Change in Spasticity by Total Number-transformed Modified Ashworth Scale (TNmAS)
timeFrame: From baseline (Day1, Visit 2) to end of treatment (Day 393)
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Osmotica Study Site-154
state: Arizona
city: Phoenix
country: United States
facility: Osmotica Study Site-158
state: Arizona
city: Pasadena
country: United States
facility: Osmotica Study Site-165
state: California
city: Torrance
country: United States
facility: Osmotica Study Site-164
state: California
city: Torrance
country: United States
facility: Osomtica Study Site-164
state: California
city: Bradenton
country: United States
facility: Osmotica Study Site-173
state: Florida
city: Pompano Beach
country: United States
facility: Osmotica Study Site-178
state: Florida
city: Tampa
country: United States
facility: Osmotica Study Site-170
state: Florida
city: Northbrook
country: United States
facility: Osmotica Study Site-179
state: Illinois
city: Lenexa
country: United States
facility: Osmotica Study Site-174
state: Kansas
city: Ann Arbor
country: United States
facility: Osmotica Study Site-175
state: Michigan
city: Plainview
country: United States
facility: Osmotica Study Site-161
state: New York
city: Charlotte
country: United States
facility: Osmotica Study Site-151
state: North Carolina
city: High Point
country: United States
facility: Osmotica Study Site-157
state: North Carolina
city: Raleigh
country: United States
facility: Osmotica Study Site-155
state: North Carolina
city: Wilmington
country: United States
facility: Osmotica Study Site-152
state: North Carolina
city: Dayton
country: United States
facility: Osmotica Study Site-156
state: Ohio
city: Philadelphia
country: United States
facility: Osmotica Study Site-163
state: Pennsylvania
city: Franklin
country: United States
facility: Osmotica Study Site-162
state: Tennessee
city: San Antonio
country: United States
facility: Osmotica Study Site-171
state: Texas
city: Vienna
country: United States
facility: Osmotica Study Site-166
state: Virginia
city: Krasnoyarsk
country: Russian Federation
facility: Osmotica Study Site-554
city: Krasnoyarsk
country: Russian Federation
facility: Osmotica Study Site-552
city: Moscow
country: Russian Federation
facility: Osmotica Study Site-557
city: Moscow
country: Russian Federation
facility: Osmotica Study Site-556
city: Pyatigorsk
country: Russian Federation
facility: Osmotica Study Site-553
city: Sestroretsk
country: Russian Federation
facility: Osmotica Study Site-560
city: St. Petersburg
country: Russian Federation
facility: Osmotica Study Site-551
city: Tonnel'nyy
country: Russian Federation
facility: Osmotica Study Site-555
city: Dnipropetrovsk
country: Ukraine
facility: Osmotica Study Site-653
city: Dnipropetrovsk
country: Ukraine
facility: Osmotica Study Site-655
city: Donetsk
country: Ukraine
facility: Osmotica Study Site-651
city: Kharkov
country: Ukraine
facility: Osmotica Study Site-654
city: Lviv
country: Ukraine
facility: Osmotica Study Site-656
city: Poltava
country: Ukraine
facility: Osmotica Study Site-657
Study officials:
affiliation: Osmotica Pharmaceutical
name: Praveen Tyle, Ph.D.
role: STUDY_CHAIR
References: