Clinical Trials Register

Summary
EudraCT Number:	2017-004419-38
Sponsor's Protocol Code Number:	CL3-95008-001
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2019-12-03
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

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2017-004419-38

A.3

Full title of the trial

Efficacy and safety of bumetanide oral liquid formulation in children and adolescents aged from 7 to less than 18 years old with Autism Spectrum Disorder.
A 6-month randomised, double-blind, placebo controlled multicentre parallel group study to evaluate efficacy and safety of bumetanide 0.5mg twice a day followed by an open label active 6-month treatment period with bumetanide (0.5mg twice a day) and a 6 weeks discontinuation period after treatment stop.

Účinnost a bezpečnost bumetanidu, perorálního roztoku, podávaného dětem a dospívajícím ve věku od sedmi do méně než osmnácti let s poruchami autistického spektra.
6měsíční randomizovaná, dvojitě zaslepená, placebem kontrolovaná multicentrická studie s paralelními skupinami zkoumající účinnost a bezpečnost bumetanidu 0,5mg podávaného dvakrát denně, následovaná otevřenou aktivní 6měsíční léčbou bumetanidem (0,5mg dvakrát denně) a 6týdenním sledováním.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and safety of bumetanide oral liquid formulation in children and adolescents aged from 7 to less than 18 years old with Autism Spectrum Disorder.

Účinnost a bezpečnost bumetanidu, perorálního roztoku, podávaného dětem a dospívajícím ve věku od sedmi do méně než osmnácti let s poruchami autistického spektra.

A.4.1

Sponsor's protocol code number

CL3-95008-001

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/340/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Institut de Recherches Internationales Servier
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ADIR
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut de Recherches Internationales Servier
B.5.2	Functional name of contact point	Clinical Studies Department
B.5.3	Address:
B.5.3.1	Street Address	50, rue Carnot
B.5.3.2	Town/ city	Suresnes Cedex
B.5.3.3	Post code	92284
B.5.3.4	Country	France
B.5.4	Telephone number	+33155 72 43 66
B.5.5	Fax number	+33155 72 54 12
B.5.6	E-mail	clinicaltrials@servier.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	S95008
D.3.2	Product code	S95008
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Bumetanide
D.3.9.2	Current sponsor code	S95008
D.3.9.3	Other descriptive name	BUMETANIDE
D.3.9.4	EV Substance Code	SUB05971MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Autism Spectrum Disorder (ASD)

E.1.1.1

Medical condition in easily understood language

Autism Spectrum Disorder (ASD)

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063844
E.1.2	Term	Autism spectrum disorder
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate the superiority of bumetanide (0.5mg BID) oral liquid formulation compared to placebo in the improvement of ASD core symptoms after 6 months of treatment in ASD children and adolescents aged from 7 to less than 18 years old

E.2.2

Secondary objectives of the trial

- To assess the effect of bumetanide on the other efficacy endpoints
- To assess the safety of bumetanide
- To confirm the acceptability and palatability of the oral liquid formulation
- To describe the bumetanide effects on patients quality of life
- To improve existing pharmacokinetic model of bumetanide in this population

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and female patients from 7 to less than 18 years
- Out patients
- Primary diagnosis of ASD as per DSM-5 criteria
- Criteria met for ASD on Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnosis Interview Revised (ADI-R)
- CGI (Clinical Global Impression) – Severity rating Score ≥ 4
- Childhood Autism Rating Scale second edition (CARS2-ST or HF) total raw score ≥ 34
- Social responsiveness Scale second edition total score (SRS-2 T-Score) ≥ 66
- Absence of known monogenic syndrome (Fragile X, Rett syndrome ...)
- Absence of any clinically significant abnormality likely to interfere with the conduct of the study according to the judgment of the investigator
- Absence of electrolyte imbalance that is likely to interfere with the study conduct or evaluation

E.4

Principal exclusion criteria

- Patients not able to follow the study assessments defined by the protocol, with the exception of self-rating questionnaires which will be assessed by parent/legal representative/caregiver for those patients unable to complete them
- Patients having a high suicidal risk according to the investigator judgement
- Chronic renal dysfunction
- Chronic cardiac dysfunction
- Patient with unstable psychotherapy, behavioural, cognitive or cognitive-behavioural therapy

E.5 End points

E.5.1

Primary end point(s)

CARS2 total raw score

E.5.1.1

Timepoint(s) of evaluation of this end point

Change from baseline to 6 month

E.5.2

Secondary end point(s)

- Each individual CARS2 domain, SRS-2 total raw score, CGI-I score, VABS II subscores
- A dverse events, Paediatric Adverse Event Rating Scale (PAERS), clinical laboratory evaluation, vital signs and clinical examination, electrocardiogram, renal ultrasound, Columbia Suicide Severity Rating Scale Children’s version (C-SSRS-C), Tanner stage
- Acceptability and palatability questionnaire
- Paediatric Quality of Life Inventory (PedsQL), WHOQOL-Bref questionnaire
- PK parameters of bumetanide

E.5.2.1

Timepoint(s) of evaluation of this end point

SRS-2 total raw score: W000/W004/W012/W026/W038/W052
CGI-I score: W000+Day17/W004/W008/W012/W016/W020/W026/W038/W052/WEND
VABS II subscores: W000/W026/W052
Each individual CARS2 domain: W000/W004/W012/W026/W038/W052/WEND
Adverse events/PAERS/Clinical laboratory evaluation/Electrolytes monitoring (sodium, potassium)/Clinical examination: all along the study
Vital signs: ASSE/W000/W000+Day17/W012/W026/W026+Day17/W038/W052
Electrocardiogram: ASSE/W004/W008/W012/W026/W030/W034/W038/W052
Renal ultrasound: ASSE/W026/W052
C-SSRS-C: W000/W012/W026/W038/W052
Tanner stage: W000/W026/W052
Acceptability and palatability questionnaire: W026
PedsQL/WHOQOL-Bref questionnaire: W000/W004/W012/W026/W030/W038/W052 + W008/W034 for WHOQOL-Bref questionnaire
PK parameters of bumetanide: W012/W026

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Double-blind treatment period of 6 months followed by an open-label treatment period of 6 months

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Brazil

Czech Republic

France

Germany

Hungary

Italy

Netherlands

Poland

Portugal

Slovakia

Spain

United Kingdom

United States

E.8.7

Trial 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

Last Visit Last Participant as stated in the protocol

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

200

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

120

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The investigator is to collect written assent from each participant (as much as possible), when of appropriate intellectual maturity and written consent form(s) from his/her parent(s)/legal representative/caregiver before participation in the study.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

200

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 participants’ treatment is left to the physician’s discretion.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-02-04

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

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