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, (SALIVA)

Double blind, placebo-controlled, randomised trial, multicentre in France with open-label tolerability phase.

The double-blind placebo-controlled study duration will be scheduled for 3 months with the final visit of the double-blind period at D84. After the D84 assessment, patients will be invited to continue into a 6-month openlabel study extension (OLSE) with ex-Sialanar® patients continuing the treatment and ex-placebo patients starting Sialanar®

Study Overview

• Status: Recruiting
• Conditions: Neurodevelopmental Disorders; Sialorrhea
• Intervention / Treatment: Drug: Sialanar; Other: Oral Rehabilitation; Other: Placebo

Detailed Description

This is a phase 4, double-blind, placebo-controlled, randomised trial, multicentre study conducted in France to evaluate the efficacy and safety of glycopyrronium bromide (Sialanar®) versus placebo in addition to Standard of Care (SOC) management (rehabilitation) in children with severe sialorrhea related to chronic neurodisabilities, i.e cerebral palsy, Angelman syndrome, Rett's syndrome, epilepsy, amyotrophic lateral sclerosis and mental retardation. The patient population will be children aged from 3 to 17-year-old with severe sialorrhea due to chronic neurological disorders, defined as a score of at least 6 on the modified Teachers Drooling Scale (mTDS), after at least 3 months of non pharmalogical rehabilitation. A total of 80 patients who meet the eligibility criteria (see section 6.3) will be enrolled in the study. General eligibility criteria will be assessed and the DIS scale (French validated version) performed at the enrolment visit. Patients, enrolled in the study, will be randomized to receive the study drug in a doubleblind fashion, either Sialanar® of placebo. Eligible patients will be randomized in a 1:1 ratio into the 2- treatment arms with no additional stratification. Patients will receive the study drug, an oral solution, 3 times daily during the 3-month blind period. The titration will be performed during the first 5 weeks as detailed in section 7.1.3 Outpatient visits will occur at D28 and D84. Telephone interviews will occur every week during the titration period and at D56.

The double-blind placebo-controlled study duration will be scheduled for 3 months with the final visit of the double-blind period at D84. After the D84 assessment, patients will be invited to continue into a 6-month open-label study extension (OLSE) with ex-Sialanar® patients continuing the treatment and ex-placebo patients starting Sialanar®. An period of titration will be performed for patients starting Sialanar®, monitored by weekly telephone interviews. Telephone interviews will also be scheduled at D140. Clinic visit will be scheduled at D168 for all patients. Final OLSE visit will occur at D252. Patients will be assessed for disease response with the Drooling Impact Scale (DIS) including 10 items rated on a scale from 1 to 10 at D0 and during follow-up visits at D28, D84 and D252. Quality of Life will be evaluated through the DISABKIDS self-reported instrument completed by parents/ caregivers as well as children, when possible. 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. All SAEs and SUSARs will be recorded and reported as per standard EMA guidelines (cf. Section 9.2).

The duration of the study will approximately be 15 months including 6 months of enrolment and 9 months of follow up from the last patient enrolled (3 months for the blind period and 6 months for the OLSE). The end of the blind period will correspond to the last patient completed D84 visit. The end of the OLSE will correspond to the last patient completed D252 visit. After all patients complete the blind period, the final analysis of the primary outcome (change in DIS at D84) will be performed. The follow up analysis of the OLSE period will be carried after all patients ended the study. All safety data will be analysed regardless of the outcome of the trial.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nick Probert; Phone Number: 07767630041; Email: nickprobert@proveca.com
• Study Contact Backup: Name: Helen Shaw; Phone Number: 07775704497; Email: helen@proveca.com

Study Locations

• France
  • Lille, France
    • Recruiting
    • CHU Lille
    • Contact: Pierre Fayoux

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Children aged ≥ 3 years old and < 18 years old.
2. Children with weight ≥ 13 kg
3. Children with chronic neurological disorders (such as polyhandicap, cerebral palsy, Angelman syndrome, Rett's syndrome, epilepsy, amyotrophic lateral sclerosis and mental retardation)
4. Diagnosis of severe sialorrhoea due to a chronic neurological disorder as assessed by a modified Teachers Drooling Scale (mTDS) ≥ 6.
5. DIS Scale ≥ 50. Impact of drooling as assessed by drooling impact scale.
6. 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).
7. Children with stable drooling for the past 4 weeks.
8. Written consent form signed by parents (or, when applicable, the subject's legally acceptable representative).
9. Affiliated or beneficiary of a social security scheme.
10. A nominated parent or carer who can commit to complete parent / carer questionnaires, with good ability to understand and speak French.
11. Children testing negative for COVID-19 at start of the trial. (Asymptomatic children with a positive test have the opportunity to have a re-test at least 2 weeks following the initial test and must be negative on the re-test for inclusion).

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).
14. Patients receiving systemic immunosuppressive treatment including cyclosporin, methotrexate, azathioprine cyclophosphamide, mycophenolic acid, anti TNFα, monoclonal antibodies or with congenital immunodeficiency

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sialanar; Sialanar administered as per the SmPC - titration over 4 weeks to reach a dose balancing efficacy with tolerability.	Drug: Sialanar; Sialanar - a licensed glycopyrronium bromide product; Other: Oral Rehabilitation; Standard oral rehabilitation for provided drooling
Placebo Comparator: Placebo; Placebo administered as per the Sialanar SmPC - titration over 4 weeks to reach a dose balancing efficacy with tolerability.	Other: Oral Rehabilitation; Standard oral rehabilitation for provided drooling; Other: Placebo; Sialanar placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change in Drooling Impact Scale (DIS) between baseline and D84.	DIS possible range is 10-100. Lower score indicates a better outcome.	84 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Drooling Impact Scale (DIS) between baseline and D28.	DIS possible range is 10-100. Lower score indicates a better outcome.	28 days
Proportion of responders at D84 (a response is defined as a DIS improvement ≥ 13.6 points).	DIS possible range is 10-100. Lower score indicates a better outcome.	84 days
Proportion of responders at D28 (a response is defined as a DIS improvement ≥ 13.6 points).	DIS possible range is 10-100. Lower score indicates a better outcome.	28 days
Proportion of good responders at D84 (a good response is defined as a DIS improvement ≥ 28 points).	DIS possible range is 10-100. Lower score indicates a better outcome.	84 days
Changes in the number of used bibs or clothing over 7 days (Item 3 of the DIS) at D84		84 days
Changes in the number of used bibs or clothing over 7 days (Item 3 of the DIS) at D28		28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	DIS possible range is 10-100. Lower score indicates a better outcome.	28 and 84 days
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.	DIS possible range is 10-100. Lower score indicates a better outcome.	28 and 84 days
The change in DISABKIDS instrument from baseline to D84.		84 days
Adverse events recorded from baseline to day 84, including all AEs and SAE.		84 days
Changes in DIS Scale between baseline and D252 and between D84 and D252 in the previous 'Sialanar®-arm' patients.	DIS possible range is 10-100. Lower score indicates a better outcome.	up to 252 days
Change in DIS Scale between D84 and D252 for patients previously taking placebo	DIS possible range is 10-100. Lower score indicates a better outcome.	168 days
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.	DIS question 9 possible range is 1-10. Lower score indicates a better outcome.	252 days
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.	DIS question 10 possible range is 1-10. Lower score indicates a better outcome.	252 days
Change in DISABKIDS instrument score between baseline and D252.		252 days
Adverse events recorded from D84 to D252		168 days

Collaborators and Investigators

• Sponsor: Proveca Pharma Limited
• Investigators: Study Director: Nick Probert, Proveca Pharma Limited; Principal Investigator: Pierre Fayoux, CHU Lille

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2021
• Primary Completion (Anticipated): December 10, 2022
• Study Completion (Anticipated): June 10, 2023

Study Registration Dates

• First Submitted: April 27, 2021
• First Submitted That Met QC Criteria: April 29, 2021
• First Posted (Actual): May 5, 2021

Study Record Updates

• Last Update Posted (Actual): July 8, 2022
• Last Update Submitted That Met QC Criteria: July 5, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Pediatric; sialorrhea; neurodisability
• Additional Relevant MeSH Terms: Mental Disorders; Stomatognathic Diseases; Mouth Diseases; Salivary Gland Diseases; Neurodevelopmental Disorders; Sialorrhea
• Other Study ID Numbers: PRO-GLY-002 / E2013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No