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    Summary
    EudraCT Number:2015-004451-40
    Sponsor's Protocol Code Number:H15/02
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-22
    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 ConcernedCzech Republic - SUKL
    A.2EudraCT number2015-004451-40
    A.3Full title of the trial
    SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS

    THE S A V A N T TRIAL
    Sativex® jako přídatná léčba v porovnání s další optimalizovanou léčbou antispastiky první volby
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    SATIVEX® AS ADD-ON THERAPY VS. FURTHER OPTIMIZED FIRST-LINE ANTISPASTICS
    A.3.2Name or abbreviated title of the trial where available
    SAVANT
    A.4.1Sponsor's protocol code numberH15/02
    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 SponsorAlmirall Hermal GmbH
    B.1.3.4CountryGermany
    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 supportAlmirall Hermal GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlmirall Hermal GmbH
    B.5.2Functional name of contact pointAndreas Prechtl
    B.5.3 Address:
    B.5.3.1Street AddressScholtzstraße 3
    B.5.3.2Town/ cityReinbek
    B.5.3.3Post code21465
    B.5.3.4CountryGermany
    B.5.4Telephone number+4940727040
    B.5.5Fax number+49407229296
    B.5.6E-mailandreas.prechtl@almirall.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
    D.2.1.1.2Name of the Marketing Authorisation holderGW Pharma Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Oromucosal spray
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOromucosal use
    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 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 placeboOromucosal spray
    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
    Moderate to severe spasticity due to MS (multiple sclerosis).
    E.1.1.1Medical condition in easily understood language
    The patients with moderate to severe spasticity due to MS (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 19.0
    E.1.2Level HLT
    E.1.2Classification code 10052785
    E.1.2Term Multiple sclerosis acute and progressive
    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 evaluate the efficacy of Sativex (tetrahydrocannabinol [THC]:cannabidiol [CBD] oromucosal spray) as add-on therapy compared to further optimized standard antispastic therapy with oral baclofen and/or tizanidine and/or dantrolene (mono- or combination therapy) in patients with moderate to severe spasticity due to MS who have not gained adequate relief through 2 optimized standard antispastic drugs.
    E.2.2Secondary objectives of the trial
    To evaluate the effect of Sativex on spasticity and associated symptoms in the study population.
    To further characterize the safety and tolerability of Sativex in the study population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female patients of at least 18 years of age.
    2.Diagnosis of MS (any form) for at least 12 months.
    3.If the patient is taking disease modifying medication or antispastic drugs other than oral baclofen, tizanidine or dantrolene, this must be at a stable dose for 3 months prior to the screening visit.
    4.Moderate to severe spasticity, defined as a score of 4 or more on the MS spasticity 0-10 NRS scale as scored by the patient at the screening visit (considering the previous week), despite optimized previous and current treatment.
    5.Existing MS spasticity symptoms for at least 12 months.
    6.Eligible for treatment with Sativex according to the current SPC.
    7.Previous treatment with at least 2 different optimized oral MS spasticity therapies before inclusion, which must include at least 1 of oral baclofen or oral tizanidine (mono- or combination therapy).
    8.Currently receiving optimized treatment with at least 1 oral antispastic drug (baclofen and/or tizanidine and/or dantrolene as mono- or combination therapy), that has been stable for at least 3 months prior to the screening visit. Despite optimization, the patient does not have adequate relief of spasticity symptoms. Optimization is defined as having reached the most efficacious and best tolerated dose according to the relevant SPCs. The treating physician and the patient must confirm that the current treatment has been optimized.
    9.Able (physical ability or supportive person) to comply with the study preparations correctly and to follow the study procedure and restrictions.
    10.Written informed consent.
    Additional inclusion criterion for treatment in Phase A (at Visit 2):
    11.Moderate to severe spasticity, defined as a mean score of 4 or more on the MS spasticity 0-10 NRS scale as scored by the patient on the day of Visit 2 and recorded in the patient diary for the 6 previous days (i.e. considering the patient’s spasticity over the previous week during the screening period).
    Additional inclusion criteria for continuation into the wash-out phase (at Visit 3):
    12. Sativex responder during Phase A, i.e. spasticity symptoms reduced during Phase A by at least 20% on the MS spasticity 0-10 NRS score compared to the Phase A baseline score (i.e., mean of scores at Visit 2 and the 6 previous days).
    13.Patient received Sativex treatment during Phase A according to the SPC as add-on to optimized standard therapy, and can tolerate the treatment.
    Additional inclusion criterion for randomization in Phase B (at Visit 4):
    14.After the 1 to 4 weeks wash-out phase, patients whose Phase A-improvement in MS spasticity NRS score has been reduced by at least 80% (i.e., mean of scores at Visit 4 and the 2 consecutive previous days).
    E.4Principal exclusion criteria
    1.Contraindication to treatment with Sativex (according to the SPC).
    2.Previous administration of Sativex.
    3.Current consumption of cannabis herb or taking other cannabinoid-based drugs within 30 days prior to study entry, and/or unwillingness to avoid consumption over the study period.
    4.Treatment with botulinum toxin injection for the relief of spasticity from within 6 months prior to the screening visit.
    5.Any medical history or family history of schizophrenia, other psychotic disorders, severe personality disorder or other significant psychiatric disorder other than depression, which is associated with the underlying disease MS.
    6.Current use of illegal drugs, non-prescribed, or off-label prescription drugs. A qualitative urine test for TCH will be performed at screening and after wash-out.
    7.Any known or suspected history of a dependence disorder or current heavy alcohol consumption in the opinion of the investigator, and according to local guidelines.
    8.Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the involved IMPs.
    9.Any concomitant disease or disorder (such as poorly controlled epilepsy or seizures) that may influence the patient’s level of cognition or mood.
    10.Female patients of child bearing potential and male patients whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter. A female is considered to be of childbearing potential unless she has had a hysterectomy, is at least 1 year post-menopausal or has undergone tubal ligation.
    11.Female patient who is pregnant, lactating or planning pregnancy during the course of the study and for 3 months thereafter.
    12.Concurrent participation in another clinical study or participation in another clinical study within 12 weeks prior to the screening visit.
    13.History of myocardial infarction or clinically significant cardiac dysfunction within the last 12 months, or has a cardiac disorder which, in the opinion of the investigator, would put the patient at risk of a clinically significant arrhythmia or myocardial infarction.
    14.Has known clinically significant impaired renal function or impaired hepatic function at baseline.
    15.Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, may influence the result of the study, or the patient’s ability to participate in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Responder selection for the primary endpoint (30% NRS spasticity improvement) will be based on the comparison at Visit 4 (mean of NRS at the day of Visit 4 and the 2 previous days) and Visit 7 (mean of NRS at the day of visit 7 and the 6 previous days).
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    E.5.2Secondary end point(s)
    The secondary efficacy variables are measurements of spasticity and associated symptoms during the randomized treatment period (Phase B):
    Percentage of patients who achieve an improvement from Phase B baseline in MS spasticity 0-10 NRS score of ≥30% (CID) after 4 and 8 weeks of treatment.
    Percentage of patients who achieve an improvement from Phase B baseline in MS spasticity 0-10 NRS score of ≥18% (MCID) after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in the MS spasticity score (0-10 NRS) after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in the frequency and severity of spasm (mild, moderate, severe) after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in sleep disruption (0-10 NRS) after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in the spasticity modified Ashworth scale after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in EDSS score after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in the Barthel ADL index after 4, 8 and 12 weeks of treatment.
    Percentage of patients who achieve the MCID improvement from Phase B baseline in Barthel ADL index after 4, 8 and 12 weeks of treatment.
    Change from Phase B baseline in SF-36 scores after 4, 8 and 12 weeks of treatment.
    Percentage of patients with an MCID improvement from Phase B baseline in SF-36 QoL scores after 4, 8 and 12 weeks of treatment. A reduction of 7.8 points in bodily pain and 3.3 points in physical function NRS scores represent MCIDs for the patient [50].
    Change from Phase B baseline in global assessment of clinical change by the patient (SGIC), and the doctor (PGIC) (7-item categorical scales) after 4, 8 and 12 weeks of randomized treatment.
    Percentage of patients with an MCID improvement from Phase B baseline in SCIG and PGIC after 4, 8 and 12 weeks of treatment (responder analysis).
    Change from Phase B baseline in pain (0-10 NRS) after 4, 8 and 12 weeks of treatment.
    Percentage of patients with an MCID improvement in pain (0-10 NRS) after 4, 8 and 12 weeks of treatment in Phase B. A reduction of 1 point or 15.0% in the NRS represents an MCID for the patient [51].
    Change from Phase B baseline in timed 10 m walk test, after 4, 8 and 12 weeks of treatment.
    Changes in concomitant/underlying antispastic standard therapy.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Not applicable
    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 Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Phase A-single blind, Phase B-double blind
    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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    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 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
    LPLV
    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 months2
    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 months2
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    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 state200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 228
    F.4.2.2In the whole clinical trial 228
    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)
    None
    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 Decision2016-02-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-05-23
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