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Trial record 58 of 58361 for:    Placebo

Arbaclofen in Children and Adolescents With ASD (AIMS2-CT1)

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ClinicalTrials.gov Identifier: NCT03682978
Recruitment Status : Not yet recruiting
First Posted : September 25, 2018
Last Update Posted : May 29, 2019
Sponsor:
Collaborator:
Hospital General Universitario Gregorio Marañon
Information provided by (Responsible Party):
Inge Winter, UMC Utrecht

Brief Summary:
AIMS-2-CT-01 is a randomized, double-blind, placebo controlled, study to explore the efficacy, safety and tolerability of Arbaclofen administered to children and adolescents (ages 5-17) for the treatment of social adaptive function in participants with ASD. The effects of Arbaclofen on social function in children and adolescents with ASD will be evaluated in a randomized, placebo controlled, parallel-group study of 16 weeks duration. Subjects who meet protocol criteria will be randomly allocated to receive either Arbaclofen or placebo in a 1:1 ratio in the Treatment Period. There will be 7 recruiting sites and randomization will be stratified by site. A sample of 130 patients will be recruited. Blinding will be maintained by utilizing identical tablets containing either Arbaclofen or placebo.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Drug: Arbaclofen Drug: Placebo Phase 2

Detailed Description:

Autism Spectrum Disorder (ASD) is a clinically and etiologically heterogeneous neurodevelopmental condition affecting approximately 1% of the population. The core symptoms of ASD are deficits in social communication and the presence of repetitive and restricted behaviours and interests, including sensory anomalies. Currently, there are no effective medical treatments for the core symptoms of ASD, and families frequently use costly non evidence based interventions. Developing drugs for ASD has been challenging because of a limited understanding of its underlying pathophysiology(ies), and difficulties modelling it in vitro and in vivo.

A recent study from EU-AIMS reported, for the first time in ASD, that differences in E-I balance can be 'shifted' using a GABA acting drug (riluzole), and that abnormalities in functional connectivity can be 'normalised' by targeting E-I, even in adults. This offers promise that drugs targeting specific parts of the GABA pathway may improve symptoms.

The aim of the investigator's project is to conduct a double-blind Randomized Control Trial (RCT) focused on GABA/glutamate equilibrium, to assess the efficacy of a drug that targets core and/or comorbid symptoms in ASD. Arbaclofen is a selective GABA-B receptor agonist and augments GABA-ergic activity, inhibits presynaptic release of glutamate, inhibits postsynaptic transmission, and modulates intracellular signalling. Through elevation of GABA-ergic inhibitory activity, Arbaclofen may act to alleviate ASD symptoms with social anxiety and emotional hyperarousal.

Hypothesis: Arbaclofen will be superior to placebo in improving social function as measured by the Vineland-3 social domain.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: AIMS2-CT-01 is a double-blind study where participants and parent(s)/legal guardians as well as research staff will be unaware of the treatment allocation, with the exception of a dedicated unblinded pharmacist at each individual site. Blinding of the remainder of the study team members will be maintained by utilizing identical tablets, blistercards and boxes containing either Arbaclofen or placebo. Unblinded study drug and placebo supplies will be stocked at each study site pharmacy. An online randomization system will be used, by this unblinded pharmacist, to assign the study treatment. Based on the outcome of the randomisation, the pharmacist prepares the boxes containing the applicable treatment and releases these (blinded) boxes to the investigator for dispensing to the patient. In order to maintain the study blind, the dosing regimen will be consistent whether participants are randomized to Arbaclofen or placebo.
Primary Purpose: Treatment
Official Title: A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arbaclofen

Arbaclofen is provided as orally disintegrating tabs, round, white and beveled edges, at the following strengths: 5mg, 10mg, 15mg and 20mg.

A flexible dose titration schedule will be utilized during the first 5 weeks of the Treatment Period. Dosing regimens will be stratified by age. The total up-titration to 15 mg TID or 20 mg TID, and dose adjustment period to the optimal dose will be 35 days. If a participant does not tolerate a dose increase, he or she should return to the previous dose level and must remain at the dose level for the remainder of the Treatment Period. No changes should be made to dosing after 5 weeks, unless for safety.

5-11 years: Week 0 (BID) 5mg; Week 1 (BID) 5mg; Week 2 (TID) 10mg; Week 3 (TID) 10mg; Week 4-16 (TID) 15mg.

12-17 years: Week 0 (QD) 5mg; Week 1 (BID) 10mg; Week 2 (BID) 10mg; Week 3 (TID) 15mg; Week 4-16 (TID) 20mg.

Drug: Arbaclofen
Arbaclofen tablet.
Other Names:
  • R-4-amino-3-(4-chlorophenyl) butanoic acid (R-baclofen)
  • STX209
  • C10H12ClNO2

Placebo Comparator: Placebo

Placebo tablets will have similar form, colour, smell and taste compared to the Arbaclofen tablets, and will be provided in non-distinguishable packaging.

Dosage level is n/a.

Drug: Placebo
Placebo tablet.
Other Name: Placebo (for Arbaclofen)




Primary Outcome Measures :
  1. Effect of Arbaclofen vs. placebo on social function [ Time Frame: Week 0 + Week 16 ]
    Vineland-3 (socialization domain): The Vineland Adaptive Behavior Scales, Third Edition is designed to assess the personal and social functioning of handicapped and non-handicapped persons. It is a gold standard for the assessment of adaptive functioning. The Socialization domain is one of the 4 adaptive domains assessed by the comprehensive interview form. The other 3 adaptive domains are communication, daily living skills and motor skills. The Socialization domain has 3 subdomains: interpersonal relations, play and leisure and coping skills.


Secondary Outcome Measures :
  1. Effect of Arbaclofen vs. placebo on measures of global function [ Time Frame: Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    CGI-I: Clinical Global Impression - Improvement Scale is used to determine the patient's improvement in response to treatment.

  2. Effect of Arbaclofen vs. placebo on measures of global function [ Time Frame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    CGI-S: The Clinical Global Impression - Severity Scale is used to assess the impairment of neurobehavioral function in study subjects.

  3. Effect of Arbaclofen vs. placebo on other adaptive domains [ Time Frame: Week 0 + Week 16 ]
    Vineland-3 (other adaptive domains): The Vineland Adaptive Behavior Scales, Third Edition, other adaptive domains: communication, daily living skills and motor skills.

  4. Effect of Arbaclofen on measures of social abilities and responsiveness [ Time Frame: Week -2 ]
    ADOS-2: The Autism Diagnostic Observation Schedule, Version 2, will be used to assess autistic symptomatology.The ADOS-2 is a standardized protocol for the observation of social and communicative behaviour in children, adolescents, and adults who are suspected of having an ASD.

  5. Effect of Arbaclofen on measures of social abilities and responsiveness through BOSCC [ Time Frame: Week 0 + Week 16 ]
    BOSCC: The Brief Observation of Social Communication Change will be used to to sensitively measure change of core autistic symptoms by observation of a semi-structured social interaction between a child and an examiner.

  6. Effect of Arbaclofen on measures of social abilities and responsiveness through SRS-2-P [ Time Frame: Week 0 + Week 16 ]
    SRS-2-P: The Social Responsiveness Scale (parent version) measures the severity of social impairment in ASD.

  7. Effect of Arbaclofen on measures of social abilities and responsiveness through SRS-2-T [ Time Frame: Week 0 + Week 16 ]
    SRS-2-T: The Social Responsiveness Scale (teacher version) measures the severity of social impairment in ASD.

  8. Effect of Arbaclofen on measures of problem behaviours [ Time Frame: Week 0 + Week 4 + Week 8 + Week 12 + Week 16 ]
    ABC-C: This is the community version of the original residential version of the Aberrant Behaviour Checklist. It is designed to objectively identify five behaviour subscales through observation by the primary caregiver: irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech.

  9. Effect of Arbaclofen on measures of problem behaviours [ Time Frame: Week 0 + Week 16 ]
    CBCL: Child Behaviour Checklist is a caregiver report form identifying problem behaviour in children.

  10. Effect of Arbaclofen on other measures of core symptoms [ Time Frame: Week 0 + Week 4 + Week 8 + Week 12 + Week 16 ]
    AIM: The Autism Impact Measure is designed to measure change in the core symptoms of autism.

  11. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by the SMURF [ Time Frame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    SMURF: Safety Monitoring Uniform Research Form.

  12. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by the ESS-CHAD [ Time Frame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    ESS-CHAD: The Epworth Sleepiness Scale for Children and Adolescents will be employed to evaluate sedation.

  13. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by the C-SSRS [ Time Frame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    C-SSRS: The Columbia Suicide Severity Rating Scale is used to measure suicidality.

  14. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by pulse [ Time Frame: Week -2 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    Vital signs: pulse

  15. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by blood pressure [ Time Frame: Week -2 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18 ]
    Vital signs: blood pressure

  16. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by weight [ Time Frame: Week -2 + Week 16 ]
    Weight: Weight (in kg) will be assessed with all outer wear and shoes removed.

  17. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by height [ Time Frame: Week -2 + Week 16 ]
    Height: Height (in cm) will be assessed with all outer wear and shoes removed.

  18. Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by blood tests [ Time Frame: Week -2 + Week 16 ]
    Blood tests: this will include CBC, liver enzymes, and renal function.


Other Outcome Measures:
  1. Explore whether P1 & N170 amplitude & latency as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    P1 & N170 amplitude & latency are assessed with a face ERP task.

  2. Explore whether Alpha & Theta power (frontal) and Theta connectivity as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    Alpha & Theta power (frontal) and Theta connectivity are assessed by watching social and non-social videos.

  3. Explore whether induced power at 10Hz & 40Hz as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    Induced power at 10Hz & 40Hz is assessed with an Auditory Steady State Response task.

  4. Explore whether induced and evoked power at 6Hz & 10Hz as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    Induced and evoked power at 6Hz & 10Hz are assessed with a Visual Steady State Response task.

  5. Explore whether P1, N1 amplitude and latency of standard stimuli and Mismatch Negativity (MMN) amplitude and latency as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    P1, N1 amplitude and latency of standard stimuli and Mismatch Negativity (MMN) amplitude and latency are assessed with a Visual Steady State Response task.

  6. Explore whether Alpha & Theta power and connectivity as measures of electrophysiology (EEG) are associated with either response to treatment [ Time Frame: Week 0 + Week 16 ]
    Alpha & Theta power and connectivity are assessed with a Resting State task.

  7. Explore the relationship between optional blood biomarkers (DNA) and safety, efficacy, and optimal dosing of Arbaclofen as assessed by the measurements specified in the previous outcome measures. [ Time Frame: Week 0 + Week 16 ]
    Optional blood biomarkers (DNA): The purpose of this repository is to allow future studies of the relationship between variation in DNA sequence with the safety, efficacy, and optimal dosing of Arbaclofen in the treatment of ASD.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   5 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Written Informed Consent

    1. Participants or their legal representative must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care. Participants who do not have the capacity to consent will give developmentally appropriate assent.
    2. Participants must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
    3. The subject's parent/caregiver/LAR must be able to speak and understand the local language where the study is conducted sufficiently to understand the nature of the study and to allow for the completion of all study assessments. The same parent/caregiver/LAR must be capable of providing reliable information about the subject's condition, agree to oversee the administration of study drug, and accompany the subject to all clinic visits.
    4. Patient must be able to speak and understand the local language where the study is conducted sufficiently to understand the nature of the study and to allow for the completion of all study assessments.
  2. Type of Participant and Target Disease Characteristics

    1. Diagnosis of an Autism Spectrum Disorder according to the DSM-5 criteria
    2. Complex language as defined in ADOS-2 to qualify for a Module 3 or 4.
    3. Current pharmacological treatment regimen affecting behaviour has been stable for at least 6 weeks prior to screening and is expected to be stable during the duration of the study
    4. Current psychotherapeutic/psychosocial interventions affecting behaviour stable for 3 months prior to screening and expected to be stable during the duration of the study (standard regular school breaks and/or annual teacher/classroom change do not qualify for intervention change).
    5. Subjects with a history of seizure disorder must currently be receiving stable treatment with anticonvulsant medication and must have been seizure free for 6 months prior to screening, or must be seizure free for 3 years prior to screening if not currently on a stable (>3 months) dose of antiepileptics.
  3. Age, Residential and Reproductive Status

    1. Male or female participants 5 to 17 years of age at the time of providing consent, inclusive.
    2. Reside with the parent/carer who is interviewed for the Vineland.
    3. Negative pregnancy test for females of childbearing potential (subject has experienced onset of menses) within 24h prior to study treatment starts.
    4. Females of childbearing potential who are sexually active must agree to use an accepted form of contraception (i.e., surgical sterilization, intrauterine contraceptive device, oral contraceptive, diaphragm, or condom in combination with contraceptive cream, jelly, or foam, or abstinence).
    5. Male participants with female partners of childbearing potential are eligible to participate if they agree to the following conditions:

      • Inform any and all partner(s) of their participation in a clinical drug study and the need to comply with contraception instructions as directed by the investigator.
      • Male participants are required to use a condom for study duration and until end of relevant systemic exposure defined as 7 months after the end of study treatment.
      • Female partners of males participating in the study to consider use of effective methods of contraception until the end of relevant systemic exposure, defined as 7 months after the end of treatment in the male participant.
      • Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal intercourse or use a male condom during each episode of penile penetration during the treatment and until 7 months after the end of study treatment.
      • Refrain from donating sperm for the duration of the study treatment and until 7 months after the end of study treatment.

Exclusion Criteria:

  1. Medical Conditions

    a. Subjects with any condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger their own well-being. This includes, but is not limited to impairment of renal function, evidence or history of malignancy or any significant haematological, endocrine, respiratory, hepatic, cardiovascular or gastrointestinal disease, including any clinically significant abnormalities on ECG. In general, any co-morbid conditions that may interact with study procedures.

  2. Prior/Concomitant Therapy

    1. Subjects who are currently receiving treatment with racemic baclofen, vigabatrin, tiagabine, or riluzole or other GABA-related medications. Only regular benzodiazepine use (PM, i.e. at night) will be allowed.
    2. Subjects who are currently receiving pharmacologic treatment affecting behaviour (see concomitant medication section) need to have a stable dose during the 6 weeks prior to the screening visit and for the duration of the study.
    3. Participating in programs including non-pharmacologic educational, behavioural, and/or dietary interventions affecting behaviour, participation in these programs must have been continuous during the 3 months prior to screening and participants or their parent/caregiver/LAR may not electively initiate new or modify ongoing interventions for the duration of the study. Typical school vacations are not considered modifications of stable programming.
    4. Subjects who have taken another investigational drug within the last 30 days.
  3. Physical and Laboratory Test Findings

    a. Patients with evidence of any significant hematological, endocrine, cardiovascular (including uncorrected symptomatic congenital heart disease), respiratory, renal, hepatic, or gastrointestinal disease, not including mild common pediatric diseases in these areas that are stable (e.g. mild asthma, constipation, etc.), as judged by the investigator.

  4. Study Medication Related

    1. Subjects who are not able to take oral medications.
    2. Subjects who have a history of hypersensitivity to racemic baclofen.
    3. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
    4. Active peptic ulceration as Baclofen stimulates gastric acid secretion.
    5. Porphyria.
  5. Other Exclusion Criteria

    1. Subjects who are currently engaged in illicit drug use or alcohol abuse, according to DSM-5 criteria.
    2. Subjects who have previously participated in a clinical trial of Arbaclofen.
    3. Women who are breastfeeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03682978


Contacts
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Contact: Inge Winter, PhD +31 88 75 53 227 I.Winter@umcutrecht.nl

Sponsors and Collaborators
Inge Winter
Hospital General Universitario Gregorio Marañon
Investigators
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Study Chair: Celso Arango, Prof. Hospital General Universitario Gregorio Marañón
Principal Investigator: Mara Parellada, Prof. Hospital General Universitario Gregorio Marañón
Principal Investigator: Richard Delorme, Prof. Robert Debré Hospital
Principal Investigator: Jeremy Parr, Prof. University of Newcastle Upon-Tyne
Principal Investigator: Andrew Stanfield, PhD University of Edinburgh
Principal Investigator: Mallika Punukollu, Dr. University of Glasgow
Principal Investigator: Andre Strydom, Dr. King's College London
Principal Investigator: Rosa Calvo, Dr. Hospital Clinic of Barcelona

Additional Information:
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Responsible Party: Inge Winter, Manager Clinical Trial Center, UMC Utrecht
ClinicalTrials.gov Identifier: NCT03682978     History of Changes
Other Study ID Numbers: AIMS2-CT-01
2018-000942-21 ( EudraCT Number )
First Posted: September 25, 2018    Key Record Dates
Last Update Posted: May 29, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Inge Winter, UMC Utrecht:
Placebo-Controlled
Arbaclofen
Randomized
Double-Blind
Social Function
Efficacy
Safety
Tolerability
Children
Adolescents
ASD

Additional relevant MeSH terms:
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Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders
Baclofen
Muscle Relaxants, Central
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents
GABA-B Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action