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    Summary
    EudraCT Number:2017-004100-22
    Sponsor's Protocol Code Number:OS440-3004
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-08
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2017-004100-22
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Parallel Group Study to Investigate the Safety and Efficacy of Arbaclofen Extended-Release Tablets for the Treatment of Spasticity in Patients with Multiple Sclerosis (Study OS440-3004)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Arbaclofen Extended-Release Tablets for Treatment of Spasticity in Patients with Multiple Sclerosis
    A.4.1Sponsor's protocol code numberOS440-3004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03290131
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOsmotica Pharmaceutical US LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOsmotica Pharmaceutical US LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOsmotica Pharmaceutical US LLC
    B.5.2Functional name of contact pointDavid Jacobs
    B.5.3 Address:
    B.5.3.1Street Address400 Crossing Boulevard
    B.5.3.2Town/ cityBridgewater
    B.5.3.3Post codeNJ 08807
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1908809 1364
    B.5.5Fax number+1908809 1301
    B.5.6E-maildjacobs@osmotica.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameArbaclofen Extended Release Tablets
    D.3.2Product code OS440
    D.3.4Pharmaceutical form Prolonged-release tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNArbaclofen
    D.3.9.1CAS number 69308-37-8
    D.3.9.2Current sponsor codeOS440
    D.3.9.3Other descriptive nameAERT, (R)-Baclofen
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboProlonged-release tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Spasticity in patients with multiple sclerosis
    E.1.1.1Medical condition in easily understood language
    Spasticity in patients with multiple sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10041416
    E.1.2Term Spasticity
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to demonstrate the safety and efficacy of Arbaclofen Extended-Release Tablets (AERT) for treatment of spasticity in patients with Multiple Sclerosis (MS)
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal 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 (Screening).
    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 screening.
    3. Spasticity due to MS as shown by a TNmAS-MAL score ≥21.
    4. Expanded Disability Status Scale (EDSS) score ≥3.0.
    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 Visit 1 (Screening), 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 Visit 1 (Screening).
    6. Stable regimen for at least 3 months prior to Visit 2 (Baseline) for all medications and non-pharmacological therapies that are intended to alleviate spasticity.
    a. Subjects taking medications indicated for the treatment of spasticity (eg, baclofen,benzodiazepines, cannabinoids, carisoprodol, dantrolene, tizanidine, cyclobenzaprine, any neuroleptic, ropinoprole, tolperisone, and clonidine) at Visit 1 (Screening) must wash out from these medications for at most 21 days by Visit 2 (Baseline) in order to be eligible for randomization (see Section 7.7 for washout periods for specific medications). 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,2 of >50 mL/minute.
    9. Use of a medically highly effective form of birth control (see Section 7.8) during the study and for 3 months thereafter for women of child-bearing potential (including female subjects and female partners of non-sterile male subjects). Use of a medically highly effective form of birth control (see Section 7.8) during the study and for 3 months thereafter for any subject whose partner is not sterilized or post menopausal.
    10. Willing to sign the informed consent form (ICF).
    E.4Principal 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. Acute MS exacerbation/relapse requiring treatment or disease modifying drug dose alteration within 3 months of Visit 1 (Screening).
    4. Use of high dose (120 mg daily) oral or intravenous methylprednisolone, or equivalent, within 3 months before Visit 1 (Screening).
    5. Concomitant use of medications that would potentially interfere with the actions of the study medication or outcome variables.
    6. Use of botulinum toxin A or B for spasticity within 6 months of Visit 1 (Screening).
    7. Pregnancy, lactation, or planned pregnancy during the course of the study and for 3 months after the final study visit.
    8. Recent history (within past 12 months) of any unstable psychiatric disease (or any yes response to questions 1 or 2 on the Columbia–Suicide Severity Rating Scale [C-SSRS] at Screening), 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.
    9. History of epilepsy.
    10. Current significant cognitive deficit, severe or untreated anxiety, severe or untreated depression.
    11. 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 Visit 2 (Baseline) Urinary Symptom Profile – USP© (USP) questionnaire. Subjects who are proficient in selfcatheterization may be included in the study at investigator discretion.
    12. Subject has clinically significant abnormal laboratory values, in the opinion of the investigator, at Visit 1 (Screening).
    13. Current malignancy or history of malignancy that has not been in remission for more than 5 years, except effectively treated basal cell skin carcinoma.
    14. Any other significant disease, disorder, or significant laboratory finding 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.
    15. Planned elective surgery or other procedures requiring general anesthesia during the course of the study.
    16. History of any illicit substance abuse (eg, alcohol, cocaine) or prescription for long-acting opioids within the past 12 months (tramadol use will be allowed).
    17. Participation in another clinical research study within 1 month of Visit 1 (Screening).
    E.5 End points
    E.5.1Primary end point(s)
    Co-Primary Efficacy Endpoints:

    The AERT 40 mg dose will be compared with placebo first (for both TNmAS-MAL and CGIC). If both comparisons are significant at the 0.05 level then the AERT 80 mg dose will be tested at the 0.05 level (both TNmAS-MAL and CGIC). Both co-primary efficacy endpoints need to meet the 0.05 level for the AERT 40 mg dose comparison with placebo for the study to be considered a success. Therefore, no adjustment for multiplicity is needed. The Day 84 comparison is the primary time point for both co-primary endpoints.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 84
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints

    Secondary efficacy endpoints include:
    * EDSS
    * PGIC
    * TNmAS – Total Limbs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pairwise comparisons between the AERT doses and placebo will be provided at each visit where data are collected.
    * EDSS- assessed at screening, baseline and final visits
    * PGIC- assessed at final visit
    * TNmAS – assessed at screening, baseline, Visit 4, Visit 5 and final visits
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 490
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 78
    F.4.2.2In the whole clinical trial 510
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The subject may be assessed for entry into the concurrent open-label extension study (Study OS440-3005). Otherwise, the treatment should be provided in accordance with the local standard of care.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-12-03
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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