Clinical trial NCT03682978: Arbaclofen in Children and Adolescents With ASD
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Autism Spectrum Disorder
Keywords: Arbaclofen
Placebo-Controlled
Randomized
Double-Blind
Social Function
Efficacy
Safety
Tolerability
Children
Adolescents
ASD
Lead sponsor: Celso Arango, MD, PhD
Sponsor class: OTHER
Collaborators: name: UMC Utrecht
First posted: 2018-09-25
Enrollment: 124
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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 a highly effective form of contraception (i.e., existing surgical sterilization, complete abstinence, or a combination of two effective forms of contraception, such as, for example, condoms plus hormonal treatment).
   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 (e.g. gabapentin or pregabalin). Only occasional benzodiazepine (or derivative drugs) 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 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.

Primary outcomes:
measure: Effect of Arbaclofen vs. placebo on social function
timeFrame: Week 0 + Week 16
Secondary outcomes:
measure: Effect of Arbaclofen vs. placebo on measures of global function
timeFrame: Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Effect of Arbaclofen vs. placebo on measures of global function
timeFrame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Effect of Arbaclofen vs. placebo on other adaptive domains
timeFrame: Week 0 + Week 16
measure: Effect of Arbaclofen on measures of social abilities and responsiveness
timeFrame: Week -3
measure: Effect of Arbaclofen on measures of social abilities and responsiveness through BOSCC
timeFrame: Week 0 + Week 16
measure: Effect of Arbaclofen on measures of social abilities and responsiveness through SRS-2-P
timeFrame: Week 0 + Week 16
measure: Effect of Arbaclofen on measures of social abilities and responsiveness through SRS-2-T
timeFrame: Week 0 + Week 16
measure: Effect of Arbaclofen on measures of problem behaviours
timeFrame: Week 0 + Week 4 + Week 8 + Week 12 + Week 16
measure: Effect of Arbaclofen on measures of problem behaviours
timeFrame: Week 0 + Week 16
measure: Effect of Arbaclofen on other measures of core symptoms
timeFrame: Week 0 + Week 4 + Week 8 + Week 12 + Week 16
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with the SMURF
timeFrame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with the ESS-CHAD
timeFrame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with the C-SSRS
timeFrame: Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with a pulse rate measurement
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with a body temperature measurement
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with a blood pressure measurement
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by measuring weight
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed by measuring height
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with the Tanner scale
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16 + Week 18
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with blood tests
timeFrame: Week -3 + Week 16
measure: Safety and tolerability of Arbaclofen in children and adolescents with ASD as assessed with blood tests
timeFrame: Drug testing: Week -3 + Week 16, Pregnancy testing: Week -3 + Week 0 + Week 4 + Week 8 + Week 12 + Week 16
measure: To explore the use and feasibility of digital biomarkers
timeFrame: Week -3 + Week 0 + Week 2 + Week 4 + Week 6 + Week 8 + Week 12 + Week 16
Other outcomes:
measure: Explore whether P1 & N170 amplitude & latency as measures of electrophysiology (EEG) are associated with either response to treatment
timeFrame: Week 0 + Week 16
measure: Explore whether Alpha & Theta power (frontal) and Theta connectivity as measures of electrophysiology (EEG) are associated with either response to treatment
timeFrame: Week 0 + Week 16
measure: Explore whether induced power at 10Hz & 40Hz as measures of electrophysiology (EEG) are associated with either response to treatment
timeFrame: Week 0 + Week 16
measure: Explore whether induced and evoked power at 6Hz & 10Hz as measures of electrophysiology (EEG) are associated with either response to treatment
timeFrame: Week 0 + Week 16
measure: 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
timeFrame: Week 0 + Week 16
measure: Explore whether Alpha & Theta power and connectivity as measures of electrophysiology (EEG) are associated with either response to treatment
timeFrame: Week 0 + Week 16
measure: 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.
timeFrame: Week 0 + Week 16
Locations:
city: Paris
country: France
facility: Robert Debré Hospital
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Servicio de Psiquiatría del Niño y del Adolescente, Hospital General Universitario Gregorio Marañón, SERMAS
city: Salamanca
country: Spain
facility: University of Salamanca & Complejo asistencial de Zamora
city: Glasgow
country: United Kingdom
facility: University of Glasgow
city: London
country: United Kingdom
facility: King's College London
city: Newcastle
country: United Kingdom
facility: University of Newcastle upon Tyne
Study officials:
affiliation: Hospital General Universitario Gregorio Marañón
name: Celso Arango, Prof.
role: STUDY_CHAIR
affiliation: Hospital General Universitario Gregorio Marañón
name: Mara Parellada, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Universitaire Robert-Debre
name: Richard Delorme, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Newcastle Upon-Tyne
name: Jeremy Parr, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Glasgow
name: Mallika Punukollu, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: King's College London
name: Andre Strydom, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clinic of Barcelona
name: Rosa Calvo, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Parellada M, San Jose Caceres A, Palmer M, Delorme R, Jones EJH, Parr JR, Anagnostou E, Murphy DGM, Loth E, Wang PP, Charman T, Strydom A, Arango C. 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: Study Protocol for AIMS-2-TRIALS-CT1. Front Psychiatry. 2021 Aug 24;12:701729. doi: 10.3389/fpsyt.2021.701729. eCollection 2021.