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    Summary
    EudraCT Number:2019-002625-29
    Sponsor's Protocol Code Number:GWSP19066
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-03-10
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2019-002625-29
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled, 2-way Crossover Trial to Evaluate the Effect of Nabiximols Oromucosal Spray on Clinical Measures of Spasticity in Patients with Multiple Sclerosis
    Randomizované, dvojitě zaslepené, placebem kontrolované, dvouramenné, zkřížené klinické hodnocení hodnotící účinek oromukosálního spreje nabiximols na klinické parametry spasticity u pacientů s roztroušenou sklerózou
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to test how efficient Nabiximols is for treatment of spacticity in patients with Multiple Sclerosis
    Studie, která bude testovat účinnost přípravku Nabiximols při léčbě spasticity u pacientů s roztroušenou sklerózou
    A.4.1Sponsor's protocol code numberGWSP19066
    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 SponsorGW Pharma Limited
    B.1.3.4CountryUnited Kingdom
    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 supportGW Pharma Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGW Pharma Limited
    B.5.2Functional name of contact pointRegulatory affairs manager
    B.5.3 Address:
    B.5.3.1Street AddressSovereign House, Vision Park, Chivers Way, Histon
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeCB24 9BZ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number441223266800
    B.5.5Fax number441223235667
    B.5.6E-mailgwreg@gwpharm.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 Yes
    D.2.1.1.1Trade name Sativex Oromucosal Spray
    D.2.1.1.2Name of the Marketing Authorisation holderGW Pharma (International) B.V.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameNabiximols - Sativex
    D.3.4Pharmaceutical form Oromucosal spray, solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOromucosal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTetrahydrocannabinol Botanical Drug Substance (THC BDS)
    D.3.9.1CAS number 1972-08-3
    D.3.9.3Other descriptive nameDELTA-9-TETRAHYDROCANNABINOL
    D.3.9.4EV Substance CodeSUB27785
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number27
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCannabidiol Botanical Drug Substance (CBD BDS)
    D.3.9.1CAS number 13956-29-1
    D.3.9.3Other descriptive nameCANNABIDIOL
    D.3.9.4EV Substance CodeSUB26600
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Yes
    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 placeboOromucosal spray, solution
    D.8.4Route of administration of the placeboOromucosal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Symptomatic treatment of spasticity in patients with multiple sclerosis (MS)
    E.1.1.1Medical condition in easily understood language
    Treatment of muscle spasm in patients with multiple sclerosis (MS)
    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 PT
    E.1.2Classification code 10028335
    E.1.2Term Muscle spasticity
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone-6; LLMT) in patients with MS who have not achieved adequate relief from spasticity with other antispasticity medications
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of multiple doses of nabiximols as adjunctive therapy compared with placebo on a clinical measure of velocity-dependent muscle tone in the lower limbs (Lower Limb Muscle Tone 4; LLMT-4) in patients with multiple sclerosis (MS) who have not achieved adequate
    relief from spasticity with other antispasticity medications
    • To evaluate the pharmacokinetic (PK) profile of nabiximols after administration of multiple doses
    • To evaluate the safety and tolerability of nabiximols after administration of multiple doses

    Exploratory objectives
    • To evaluate the effect of nabiximols after administration of multiple doses on walking using the Timed 25-Foot Walk (T25FW) test
    • To evaluate the effect of nabiximols after administration of multiple doses on the following patient-reported outcomes:
    − The 11-point Numerical Rating Scale (NRS) spasticity score
    − Daily spasm count
    − The MS Spasticity Scale (MSSS-88) total and subdomain scores
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For inclusion in the trial, patients must fulfill ALL of the following criteria:
    • Male or female, aged 18 years or above.
    • Willing and able to give informed consent for participation in the trial.
    • Willing and able (in the investigator’s opinion) to comply with all trial requirements.
    • Has had a diagnosis with any disease subtype of MS, by revised 2017 McDonald criteria, for at least 12 months
    prior to Visit 1 and is expected to remain stable for the duration of the trial.
    • Has an MAS untransformed score of at least 2 in 2 or more of 6 muscle groups (right knee flexors, left knee flexors, right knee extensors, left knee
    extensors, right plantar flexors, or left plantar flexors) at Visit 1.
    • Currently receiving optimized treatment with at least 1 oral antispasticity drug (baclofen, tizanidine, and/or dantrolene) that has been stable for at least 30 days prior to Visit 1. Despite optimization, the patient does not have adequate relief of spasticity symptoms, including muscle spasms. Optimization of antispasticity medications is defined as having reached the most efficacious and best tolerated dose according to the relevant local prescribing information. The patient must be willing to maintain the same antispasticity medication and not plan to initiate a new course of physiotherapy for the duration of the trial.
    • If currently receiving an approved MS disease-modifying therapy, it must be at a stable dose for at least 3 months prior to Visit 1 and be expected to
    remain stable for the duration of the trial.
    • If currently receiving dalfampridine or fampridine, it must be at a stable dose for at least 3 months prior to Visit 1 and is expected to remain stable for the duration of the trial.
    • Willing to allow the responsible authorities to be notified of participation in the trial, if mandated by local law.
    • Willing to allow his or her primary care practitioner (if he or she has one) and/or treating neurologist (if he or she has one) to be notified of participation in the trial, if the primary care practitioner/treating neurologist is different from the investigator.
    Additional Inclusion Criteria at Randomization (Visit 2)
    Patients are eligible for randomization in the trial if, in addition to continuing to meet the Screening (Visit 1) inclusion criteria, they also meet the following criterion prior to Visit 2 (Day 1):
    • Completed at least 5 of 7 days of their electronic diary reporting during the 7 days immediately preceding Visit 2 (Day 1).
    E.4Principal exclusion criteria
    The patient may not enter the trial if:
    •Has taken nabiximols, cannabis, or a cannabis-derived product for medicinal or recreational purposes in the 30 days prior to Visit 1 and unable to abstain for the duration of the study
    •Did not tolerate or did not respond adequately to treatment with nabiximols or another cannabis-based medication if exposed at any time before the 30-day period prior to Visit 1
    •Any concomitant disease or disorder that has spasticity-like symptoms or that may influence the patient’s level of spasticity
    •Medical history suggests that relapse/remission is likely to occur during the trial, which, in the opinion of the investigator, is expected to influence the patient’s spasticity
    •Has had a relapse of MS within the 60 days prior to Visit 1
    •Currently using botulinum toxin injection for the relief of spasticity (within 6 months of Visit 1) and is unwilling to abstain for the duration of the trial
    •Currently taking antipsychotic medication
    •Currently taking benzodiazepines unless doses and dosing regimen have been stable for at least 30 days prior to Visit 1
    •Clinically suspected to have a contracture in one of the muscle groups of the lower limbs, preventing assessment with the MAS
    •Has any known/suspected hypersensitivity to cannabinoids or any of the excipients of the IMP
    •Has experienced myocardial infarction or clinically significant cardiac dysfunction within the last 12 months prior to Visit 1 or has a cardiac disorder
    that would put the patient at risk of a clinically significant arrhythmia or myocardial infarction
    •Has a diastolic blood pressure of <50 mmHg or >105 mmHg or systolic blood pressure <90 mmHg or >150 mmHg (when measured in a sitting
    position at rest for 5 minutes) or a postural drop in the systolic blood pressure of > 20 mmHg at Visit 1 or Visit 2
    •Has clinically significant impaired renal function at Visit 1, as evidenced by an estimated creatinine clearance lower than 50 mL/min
    •Has moderately impaired hepatic function at Visit 1, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 × upper limit of normal (ULN)
    •Male and fertile (i.e., after puberty unless permanently sterile by bilateral orchiectomy) unless willing to ensure that he uses male contraception (condom or vasectomy) or remains sexually abstinent during the trial and for 3 months thereafter
    •Female and of childbearing potential (i.e., following menarche and until becoming postmenopausal for ≥ 12 consecutive months unless permanently
    sterile by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) unless willing to ensure that she uses a highly effective method of birth
    control during the trial and for 3 months thereafter. Patients using combined hormonal methods or a progestogen-only pill or injection or implant should use an additional barrier method such as a condom or diaphragm during the trial and for 3 months thereafter
    •Female and pregnant (positive pregnancy test at Visit 1 or Visit 2), lactating, or planning pregnancy during the course of the trial or within 3 months
    thereafter
    •Has received an IMP within the 30 days prior to Visit 1
    •Has any other clinically significant disease or disorder (including seizure disorder) that, in the opinion of the investigator, may put the patient, other
    patients, or site staff at risk because of participation in the trial, may influence the interpretation of trial results, or may affect the patient’s ability to take part in the trial
    •Has any abnormalities identified following a physical examination, clinical laboratory, serology, or other applicable screening procedures that, in the
    opinion of the investigator, would jeopardize the safety of the patient or the conduct of the study if he or she took part in the trial
    •Has any history of suicidal behavior in the 5 years prior to Visit 1 or a score of 3, 4, or 5 on the C-SSRS in the month prior to Visit 1
    •Has donated blood during the 3 months prior to Visit 1 and is unwilling to abstain from donation of blood during the trial
    •Has been previously randomized into this trial
    •Has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to Visit 1
    •Currently using an illicit drug or current nonprescribed use of any prescription drug
    •Has a history of psychiatric or neurologic disorder that, in the opinion of the investigator, may interfere with trial participation, data interpretation, or conduct of trial procedures
    •Has a history of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product
    •Has any planned clinical interventions or intends to change any or all medications that may have an effect on spasticity or MS during the trial
    •Currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7
    •Currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort)
    E.5 End points
    E.5.1Primary end point(s)
    Change in Lower Limb Muscle Tone-6 (LLMT-6; defined as the average of the 6 individual MAS transformed scores of knee flexors, knee extensors, and plantar flexors on both sides of the body) from Day 1 predose to Day 21 and from Day 31 predose to Day 51.
    The MAS scores are transformed using the following algorithm: MAS untransformed [to MAS transformed] scores; 0[0], 1[1], 1+[2], 2[3], 3[4], and 4[5].
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1 predose & Day 21
    Day 31 predose & Day 51
    E.5.2Secondary end point(s)
    Efficacy:
    • Change in Lower Limb Muscle Tone-4 (LLMT-4; defined as the average of the 4 individual MAS transformed scores of knee flexors and knee extensors on both sides of the body) from Day 1 predose to Day 21 and from Day 31 predose to Day 51

    Pharmacokinetics:
    • Plasma concentrations for Δ9-tetrahydrocannabinol (THC) and its relevant metabolites (11-hydroxy-Δ9-tetrahydrocannabinol and 11-carboxy-Δ9-tetrahydrocannabinol) and cannabidiol (CBD) and its relevant metabolites (7-hydroxy-cannabidiol and 7-carboxy-cannabidiol) at distinct time points during each treatment period (Visits 2)

    Safety:
    • Frequency of treatment-emergent adverse events (TEAEs)
    • Change from baseline to each assessment timepoint by treatment period for the following:
    - Clinical laboratory parameters
    - Vital signs
    - Physical examination procedures
    - 12-lead electrocardiograms (ECGs)
    - Columbia-Suicide Severity Rating Scale (C-SSRS) at screening, and at each subsequent timepoint with reference to the last assessment (since last visit)

    Exploratory end points
    Efficacy:
    • Difference between treatments in total and subdomain scores of the MSSS-88 at the end of the maintenance-dose phase of each double-blind treatment period
    • Difference between treatments in average 11-point NRS spasticity score over the last 7 days of each double-blind treatment period
    • Difference between treatments in average daily spasm count over the last 7 days of each double-blind treatment period
    • Difference between treatments in the change in Timed 25-Foot Walk (T25FW) test from Day 1 predose to Day 21 and from Day 31 predose to Day 51
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy: Day 1 predose to Day 21, Day 31 predose to Day 51
    Pharmacokinetics: Day 1 predose & postdose, Day 15, Day 21, Day 31 predose & postdose, Day 45, Day 51
    Safety: all visits

    Efficacy
    • MSSS-88: Day 21 & Day 51
    • NRS spasticity score: Day 1 predose, Day 15-31 & Day 45-51
    • daily spasm count: Day 1 predose, Day 15-31 & Day 45-51
    • T25FW: Day 1 predose, Day 21-31 & Day 51
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 No
    E.8.1.6Cross over Yes
    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 trial2
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 104
    F.4.2.2In the whole clinical trial 104
    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)
    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 Decision2021-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-05-10
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