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    EudraCT Number:2020-005534-15
    Sponsor's Protocol Code Number:PRO-GLY-002/E2013
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-24
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-005534-15
    A.3Full title of the trial
    Double-blind, placebo-controlled, randomized clinical trial comparing the efficacy and safety of Sialanar plus oral rehabilitation against placebo plus oral rehabilitation for children and adolescents with severe sialorrhoea and neurodisabilties
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparison of the efficacy and safety of Sialanar plus oral rehabilitation against placebo plus oral rehabilitation for children and adolescents with drooling and neurodisabilties
    A.3.2Name or abbreviated title of the trial where available
    SALIVA study
    A.4.1Sponsor's protocol code numberPRO-GLY-002/E2013
    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 SponsorProveca Pharma LTD
    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 supportProveca Pharma Ltd
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKappa Santé
    B.5.2Functional name of contact pointCRO
    B.5.3 Address:
    B.5.3.1Street Address4 Rue de Cléry
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75002
    B.5.4Telephone number003301 85 55 37 52
    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. name Sialanar
    D. of the Marketing Authorisation holderProveca Pharma Ltd
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameSialanar
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPParenteral use (Noncurrent)
    Oral use
    Buccal use
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboOral solution
    D.8.4Route of administration of the placeboBuccal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe sialorrhoea and neurodisabilties in children
    E.1.1.1Medical condition in easily understood language
    Drooling in children
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To measure the efficacy of Sialanar® when used in addition to standard of care in France for children with severe sialorrhoea related to chronic neurodisabilities compared to placebo plus standard of care (SOC).
    E.2.2Secondary objectives of the trial
    To measure the quality of life in relation to drooling of Sialanar® when used in addition to SOC in France compared to placebo plus SOC for children with severe sialorrhoea.
    To assess the tolerability of Sialanar® when used in addition to SOC in France for children with severe sialorrhoea
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Children aged ≥ 3 years old and < 18 years old.
    2. Children with chronic neurological disorders (such as polyhandicap, cerebral palsy, Angelman syndrome, Rett’s syndrome, epilepsy, amyotrophic lateral sclerosis and mental retardation)
    3. Diagnosis of severe sialorrhoea due to a chronic neurological disorder as assessed by a modified Teachers Drooling Scale (mTDS) ≥ 6.
    4. DIS Scale ≥ 50. Impact of drooling as assessed by drooling impact scale.
    5. Children who have completed at least 3 months of non-pharmacological standard of care treatment (i.e. rehabilitation e.g. intraoral stimulation and oral facial exercise).
    6. Children with stable drooling for the past 4 weeks.
    7. Written consent form signed by parents (or, when applicable, the subject’s legally acceptable representative).
    8. Affiliated or beneficiary of a social security scheme.
    9. A nominated parent or carer who can commit to complete parent / carer questionnaires, with good ability to understand and speak French.
    E.4Principal exclusion criteria
    1. Children unwilling to provide assent to participate in the study. (children who are unable to provide assent should be considered eligible).
    2. Botulinum injection for sialorrhoea given within 6 months of enrolment.
    3. Any anticholinergic therapy used in the previous 4 weeks.
    4. Scopoderm patch used in the previous 4 weeks.
    5. History of surgery for drooling in the previous 12 months.
    6. Children prescribed non-permitted concomitant medication as defined in section 7.2.2
    7. Children in whom anticholinergics are contraindicated such as those with glaucoma, myasthenia gravis, urinary retention, severe renal impairment, history of intestinal obstruction, ulcerative colitis, paralytic ileus, pyloric stenosis or hypersensitivity to the active substance or the excipient.
    8. On-going or programmed orthodontic treatment over the study period.
    9. Untreated oro-mandibular dystonia (isolated lingual dystonia accepted), clinical gastro oesophageal reflux, dental inflammatory condition (dental caries, gingivitis…).
    10. Family and carers unable to commit to the schedule of the study protocol.
    11. Female patients who are lacting or pregnant
    12. Female patients who are planning a pregnancy within the study period
    13. Patients having participated in another clinical study within at least 30 days or within 5 half-lives of last dose of IMP (whichever is longer).
    E.5 End points
    E.5.1Primary end point(s)
    The Change in Drooling Impact Scale (DIS) between baseline and D84.
    The DIS scale is a questionnaire of 10 questions with a score of 100 points which is completed by the patient's entourage (family and/or caregivers). This scale has a good validity and sensitivity to changes in the context of the evaluation of the drooling in children with CP, with a score difference of 13.6 points considered as clinically relevant (Reid 2010).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The evaluation of the primary efficacy endpoint will be performed for the full analysis set (ITT) and for the mITT analysis set. The primary analysis set will be the full analysis set. All statistical tests will be two-sided and the significance level will be 5%. Mean difference in DIS between baseline and D84 (+/- 5 days) between the Sialanar and placebo group. A 13.6 points change in DIS Scale score will be considered as a clinically relevant change.
    E.5.2Secondary end point(s)
    Other efficacy endpoints:
    2. Change in DIS Scale between baseline and D28.
    3. Proportion of responders at D84 (a response is defined as a DIS improvement ≥ 13.6 points).
    4. Proportion of responders at D28 (a response is defined as a DIS improvement ≥ 13.6 points).
    5. Proportion of good responders at D84 (a good response is defined as a DIS improvement ≥ 28 points).
    6. Changes in the number of used bibs or clothing over 7 days (Item 3 of the DIS) at D84
    7. Changes in the number of used bibs or clothing over 7 days (Item 3 of the DIS) at D28

    Quality of life endpoints:
    - Change in the DIS 10-point item 9 from baseline. “To what extent did your child’s drooling affect his or her life?” to D28 and D84.
    - Change in in the DIS 10-point item 10 from baseline. “To what extent did your child’s dribbling affect you and your family’s life?” to D28 and D84.
    - The change in DISABKIDS instrument from baseline to D84.
    Safety Endpoints:
    - Adverse events recorded from baseline to day 84, including:
    - all AE,
    - all AE with the exception of dose dependent expected AE related to titration,
    - all SAE.
    - AEs leading to discontinuation of study medication
    - all treatment-related AEs
    - all treatment-related AEs with the exception of dose dependent expected AE related to titration
    Adverse events will be collected at every visit from parent or carer and participant where possible. All adverse events will be recorded at every scheduled visit plus outside of visits as required.

    Open- label study extension endpoints:
    - Changes in DIS Scale between baseline and D252 and between D84 and D252 in the previous ‘Sialanar®-arm’ patients.
    - Change in DIS Scale between D84 and D252 for patients previously taking placebo
    - Change in the DIS 10-point item 9. “To what extent did your child’s drooling affect his or her life?” between baseline and D252.
    - Change in the DIS 10-point item 10. “To what extent did your child’s dribbling affect you and your family’s life?” between baseline and D252.
    - Change in DISABKIDS instrument score between baseline and D252.
    - Adverse events recorded from D84 to D252

    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints assessments: proportion of responders at D84 and D28, changes in DIS at D28, proportion of good responders at D84, changes in bib/ clothes over 7 days at D84 and D28 .
    Patient-reported outcome assessments using general (DISABKIDS) and specific (DIS items 9 and 10) approaches will be analysed to determine if response to therapy and side effects of therapy are accompanied by measurable changes in the quality of life.

    Safety will be evaluated by the incidence of AEs, severity and type of AEs.
    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. 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 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 concerned15
    E.8.5The trial involves multiple Member States No
    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
    The Final visit of the Open Label Study Extension (OLSE) will be performed on D252 or at an Early Termination Visit if the patient discontinued Sialanar® before D252. The following procedures will be performed and documented:
    • Physical examination.

    • Concomitant medications.
    • Concurrent medical conditions.
    • DIS completion.
    • Disabkids completion
    • Pregnancy test (where relevant).
    • Sialanar return/accountability
    • AE assessment / SAE reporting
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months15
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 80
    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) Yes
    F. of subjects for this age range: 40
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 40
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F. of subjects incapable of giving consent
    Trial subjects are children. Some of them could not give their consent personally so their parents or parental authority representative have to give their consent so the child could participate to the trial.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    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 patient will be cared for normally.
    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 Decision2021-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-23
    P. End of Trial
    P.End of Trial StatusOngoing
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