Autism Spectrum Disorder (ASD)
Conditions
Brief summary
The purpose of this study was to evaluate the efficacity and the safety of bumetanide/S95008 in the improvement of Autism Spectrum Disorder core symptoms.
Detailed description
The present study (CL3-95008-002) was performed in children from 2 to less than 7 years old presenting with ASD. A 6-month double-blind treatment period was performed in which efficacy and safety of bumetanide 0.5mg BID were assessed versus placebo. This double-blind period was followed by a 6-month open label treatment period of bumetanide 0.5mg twice daily in which long term safety was evaluated.
Interventions
DRUGBUMETANIDE (S95008) for week 0 - 26
Oral solution dosed at 0.5 mg/mL Taken twice daily.
DRUGPLACEBO for week 0 - 26
Oral solution Taken twice daily.
DRUGOpen-Label BUMETANIDE (S95008) for weeks 26 - 52
Oral solution dosed at 0.5 mg/mL Taken twice daily.
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
6-month, randomized, double-blind, placebo-controlled, parallel groups followed by an open label active 6-month treatment period with bumetanide.
Eligibility
Sex/Gender
ALL
Age
2 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients from 2 to less than 7 * Primary diagnosis of ASD as per Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria * Criteria met for ASD on Autism Diagnostic Observation Schedule-Generic (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 (SRS-2) total score ≥ 66 T-Score * Absence of diagnosis of Fragile X or Rett Syndrome * Absence of any clinically significant abnormality likely to interfere with the conduct of the study according to the judgment of the investigator.
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 * Severe electrolyte imbalance that is likely to interfere with the study conduct or evaluation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score | Change from baseline to Week 26 | The CARS2 total raw score range from 15 to 60. This scale is a behaviour rating scale intended to diagnose autism. A total score of 15 indicates that an individual behaviour is within normal limits, whereas a value of 60 indicates that the individual's behaviour is severly abnormal. In term of change from baseline, the greater the mean value decreases, the better it is. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression - Global Improvement (CGI-I) Score | At Week 26 | Scale which assesses the severity of the illness and the global improvement of the patient under study treatment. It ranges from 1 (normal) through to 7 (amongst the most severely ill patients). |
| Vineland Adaptative Behaviour Scale II (VABS II) | Change from baseline to Week 26 | Scale designated to measure adaptative behaviour The scale for behaviour ranges from 1 to 67. The more the score decreases, the better it is. |
| Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters | Week 26 | Number of patients with clinically significant ECG abnormalities The 12-lead electrocardiogram (ECG) is a medical test that is recorded using leads, or nodes, attached to the body. Electrocardiograms (ECGs), capture the electrical activity of the heart and transfer it to graphed paper where abnormalities are reported and interpretated by the cardiologist. |
| Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score | Change from baseline to Week 26 | The SRS-2 total raw score serves as an index of severity of social deficits in the autism spectrum. The total raw score ranges from 65 to 260. A value of 65 represents no symptoms disorders, a value of 260 represents a severe autism spectrum disorder. In terms of change from baseline, the greater the mean value decreases, the better it is. |
| Acceptability and Palatability Questionnaires - Only Descriptive Analyses | Week 26 | Acceptability and palatability criterion Based on your child's reactions (indirect rating), do you think that he/she found the administration method to be |
| Paediatric Quality of Life Inventory (PedsQL) Questionnaire | Change from baseline to week 26 | It represents the assessment of parent/legal representative perception of patient health related quality of life The values of the questionnaire range from 0 to 100. Higher scores indicate better HRQOL (Health-Related Quality of Life) |
| Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) | through week 52 | — |
| Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | Week 26 | Number of patients with suicidal ideation or suicidal behavior. The scale is 0 to 5 with the highest suicidal behavior being a 5 and the absence of suicidal behavior or very minor behaviors are 0. However, statistical analysis was done by looking at the number of patients with suicidal behavior or suicidal ideation during their lifetime and during the last 6 months of treatment. |
Countries
Australia, Brazil, Czechia, France, Hungary, Italy, Poland, Portugal, Slovakia, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
The following study periods are presented: 1. Double-blind period of 6 months (Week 0-Week 26): randomized groups are Bumetanide and Placebo. 2. Open-label active treatment period (Week 26-Week 52): all patients received Bumetanide.
Participants by arm
| Arm | Count |
|---|---|
| BUMETANIDE (S95008) Followed by Open-Label S95008 BUMETANIDE/S95008: Oral solution dosed at 0.5 mg/mL. Taken twice daily from weeks 0-26, followed by open-label S95008 for weeks 26-52. | 107 |
| PLACEBO Followed by Open-Label S95008 PLACEBO: Oral solution. Taken twice daily from weeks 0-26, followed by open-label S95008 for weeks 26-52. | 104 |
| Total | 211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Period (From W0 to W26) | Adverse Event | 8 | 6 |
| Double-blind Period (From W0 to W26) | Non medical reason | 8 | 2 |
| Double-blind Period (From W0 to W26) | Protocol Violation | 1 | 1 |
| Open-label Period (From W26 to W52) | Adverse Event | 8 | 3 |
| Open-label Period (From W26 to W52) | Non medical reason | 31 | 38 |
| Open-label Period (From W26 to W52) | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | PLACEBO Followed by Open-Label S95008 | Total | BUMETANIDE (S95008) Followed by Open-Label S95008 |
|---|---|---|---|
| Age, Categorical <=18 years | 104 Participants | 211 Participants | 107 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.6 years STANDARD_DEVIATION 1.1 | 4.5 years STANDARD_DEVIATION 1.2 | 4.4 years STANDARD_DEVIATION 1.2 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Australia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Brazil | 15 participants | 30 participants | 15 participants |
| Region of Enrollment Czechia | 6 participants | 12 participants | 6 participants |
| Region of Enrollment France | 11 participants | 23 participants | 12 participants |
| Region of Enrollment Hungary | 8 participants | 16 participants | 8 participants |
| Region of Enrollment Italy | 15 participants | 30 participants | 15 participants |
| Region of Enrollment Poland | 13 participants | 27 participants | 14 participants |
| Region of Enrollment Portugal | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Slovakia | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Spain | 17 participants | 33 participants | 16 participants |
| Region of Enrollment United Kingdom | 11 participants | 22 participants | 11 participants |
| Region of Enrollment United States | 1 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 17 Participants | 35 Participants | 18 Participants |
| Sex: Female, Male Male | 87 Participants | 176 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 0 / 104 | 0 / 84 | 0 / 92 |
| other Total, other adverse events | 103 / 107 | 96 / 104 | 84 / 84 | 81 / 92 |
| serious Total, serious adverse events | 7 / 107 | 3 / 104 | 7 / 84 | 2 / 92 |
Outcome results
Primary
Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score
The CARS2 total raw score range from 15 to 60. This scale is a behaviour rating scale intended to diagnose autism. A total score of 15 indicates that an individual behaviour is within normal limits, whereas a value of 60 indicates that the individual's behaviour is severly abnormal. In term of change from baseline, the greater the mean value decreases, the better it is.
Time frame: Change from baseline to Week 26
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BUMETANIDE (S95008) | Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score | -3.66 score on a scale | Standard Deviation 4.52 |
| PLACEBO | Childhood Autism Rating Scale, Second Edition (CARS2) Total Raw Score | -3.88 score on a scale | Standard Deviation 5.06 |
p-value: 0.61795% CI: [-1.04, 1.75]t-test, 2 sided
Secondary
Acceptability and Palatability Questionnaires - Only Descriptive Analyses
Acceptability and palatability criterion Based on your child's reactions (indirect rating), do you think that he/she found the administration method to be
Time frame: Week 26
Population: Missing values are cancelled
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BUMETANIDE (S95008) | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 4 (Satisfactory) | 30 Participants |
| BUMETANIDE (S95008) | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 2 (Not very satisfactory) | 5 Participants |
| BUMETANIDE (S95008) | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 3 (Acceptable) | 10 Participants |
| BUMETANIDE (S95008) | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 1 (Not satisfactory) | 1 Participants |
| BUMETANIDE (S95008) | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 5 (Very satisfactory) | 53 Participants |
| PLACEBO | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 1 (Not satisfactory) | 1 Participants |
| PLACEBO | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 5 (Very satisfactory) | 58 Participants |
| PLACEBO | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 4 (Satisfactory) | 23 Participants |
| PLACEBO | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 3 (Acceptable) | 17 Participants |
| PLACEBO | Acceptability and Palatability Questionnaires - Only Descriptive Analyses | 2 (Not very satisfactory) | 3 Participants |
Secondary
Clinical Global Impression - Global Improvement (CGI-I) Score
Scale which assesses the severity of the illness and the global improvement of the patient under study treatment. It ranges from 1 (normal) through to 7 (amongst the most severely ill patients).
Time frame: At Week 26
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BUMETANIDE (S95008) | Clinical Global Impression - Global Improvement (CGI-I) Score | 2.9 score on a scale | Standard Deviation 0.8 |
| PLACEBO | Clinical Global Impression - Global Improvement (CGI-I) Score | 3.1 score on a scale | Standard Deviation 0.9 |
95% CI: [-0.24, 0.16]
Secondary
Columbia-Suicide Severity Scale Children's Version (C-SSRS-C)
Number of patients with suicidal ideation or suicidal behavior. The scale is 0 to 5 with the highest suicidal behavior being a 5 and the absence of suicidal behavior or very minor behaviors are 0. However, statistical analysis was done by looking at the number of patients with suicidal behavior or suicidal ideation during their lifetime and during the last 6 months of treatment.
Time frame: Week 26
Population: As this measure was collected through week 26, only data gathered during the double-blind period for arms Bumetanide and Placebo were collected.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BUMETANIDE (S95008) | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During lifetime: suicidal behavior | 0 Participants |
| BUMETANIDE (S95008) | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During lifetime: suicidal ideation | 0 Participants |
| BUMETANIDE (S95008) | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During the last 6 months in the study: suicidal behavior | NA Participants |
| BUMETANIDE (S95008) | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During the last 6 months in the study: suicidal ideation | 0 Participants |
| PLACEBO | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During the last 6 months in the study: suicidal ideation | 1 Participants |
| PLACEBO | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During lifetime: suicidal behavior | 0 Participants |
| PLACEBO | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During the last 6 months in the study: suicidal behavior | NA Participants |
| PLACEBO | Columbia-Suicide Severity Scale Children's Version (C-SSRS-C) | During lifetime: suicidal ideation | 0 Participants |
Secondary
Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE)
Time frame: through week 52
Population: The overall number of participants analyzed reflects the total number of individual patients analyzed. However, since the statistical analysis of TEAE occurrence was separated by period (double-blind, and open-label) many patients were counted once for each period, and thus the sum of participants in each row is greater than the total number of individual participants analyzed. Not all patients who participated in the double-blind period continued into the open-label period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BUMETANIDE (S95008) | Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) | Reported during the double-blind period (Week 0 - 26) | 103 Participants |
| BUMETANIDE (S95008) | Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) | Reported during the open-label period (Week 26-52) | 84 Participants |
| PLACEBO | Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) | Reported during the double-blind period (Week 0 - 26) | 96 Participants |
| PLACEBO | Number of Participants Experiencing at Least 1 Treatment Emergent Adverse Event (TEAE) | Reported during the open-label period (Week 26-52) | 81 Participants |
Secondary
Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters
Number of patients with clinically significant ECG abnormalities The 12-lead electrocardiogram (ECG) is a medical test that is recorded using leads, or nodes, attached to the body. Electrocardiograms (ECGs), capture the electrical activity of the heart and transfer it to graphed paper where abnormalities are reported and interpretated by the cardiologist.
Time frame: Week 26
Population: As this measure was collected through week 26, only data gathered during the double-blind period for arms Bumetanide and Placebo were collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BUMETANIDE (S95008) | Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters | 0 Participants |
| PLACEBO | Number of Patients With Abnormalities in 12-leads Electrocardiogram (ECG) Parameters | 0 Participants |
Secondary
Paediatric Quality of Life Inventory (PedsQL) Questionnaire
It represents the assessment of parent/legal representative perception of patient health related quality of life The values of the questionnaire range from 0 to 100. Higher scores indicate better HRQOL (Health-Related Quality of Life)
Time frame: Change from baseline to week 26
Population: As this measure was collected through week 26, only data gathered during the double-blind period for arms Bumetanide and Placebo were collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BUMETANIDE (S95008) | Paediatric Quality of Life Inventory (PedsQL) Questionnaire | 5.87 score on a scale | Standard Deviation 16.37 |
| PLACEBO | Paediatric Quality of Life Inventory (PedsQL) Questionnaire | 5.47 score on a scale | Standard Deviation 21.41 |
95% CI: [-5.12, 4.59]
Secondary
Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score
The SRS-2 total raw score serves as an index of severity of social deficits in the autism spectrum. The total raw score ranges from 65 to 260. A value of 65 represents no symptoms disorders, a value of 260 represents a severe autism spectrum disorder. In terms of change from baseline, the greater the mean value decreases, the better it is.
Time frame: Change from baseline to Week 26
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BUMETANIDE (S95008) | Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score | -16.3 score on a scale | Standard Deviation 21.9 |
| PLACEBO | Social Responsiveness Scale, Second Edition (SRS-2) Total Raw Score | -18.7 score on a scale | Standard Deviation 24.8 |
95% CI: [-5.91, 6.88]
Secondary
Vineland Adaptative Behaviour Scale II (VABS II)
Scale designated to measure adaptative behaviour The scale for behaviour ranges from 1 to 67. The more the score decreases, the better it is.
Time frame: Change from baseline to Week 26
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BUMETANIDE (S95008) | Vineland Adaptative Behaviour Scale II (VABS II) | 1.1 score on a scale | Standard Deviation 6.1 |
| PLACEBO | Vineland Adaptative Behaviour Scale II (VABS II) | 0.7 score on a scale | Standard Deviation 5.3 |
95% CI: [-1.42, 1.75]