Intranasal Dexmedetomidine vs Oral Triclofos Sodium for EEG in Children With Autism

Phase 4

• Conditions: Autistic Disorder
• Interventions: Drug: Dexmedetomidine; Drug: Triclofos 100 MG/ML

• Registration Number: NCT04270708
• Lead Sponsor: Rabin Medical Center

Brief Summary

Children with Autistic Spectrum Disorder (ASD) often undergo an Electroencephalography (EEG) as part of routine work up. These children present a challenge to successful EEG execution, due to a lack of co-operation, and thus, are often in need of sedation. Historically we have used orally administered, Triclofos Sodium (TFS) - pharmacologically and physiologically similar to chloral hydrate, for sedation in this age group. However success using this drug is limited to approximately 75% in those aged 5 years and above, and possibly lower in this age group when associated with a diagnosis of ASD. The medication is often poorly tolerated by the oral route, and involves patient agitation, spiting (with incomplete drug ingestion), and immediate vomiting upon administration. Recently we have introduced Intra-nasal Dexmedetomidine (IN DEX), with an initial impression of much improved drug acceptance and possibly improved efficacy over TFS.

We designed this pilot study, with the aim of comparing efficacy, tolerance of drug administration and adverse events between TFS and IN DEX, with the goal of generating initial results as well as feasibility of recruitment for a larger trial.

Detailed Description

Study participants will be allocated, amongst patients invited for routine EEG monitoring in the hospitals EEG facility. All patients will be fasted on arrival, with a recommendation to awaken early on the day of the planned examination.

Patients aged 4yrs and above, with a diagnosis of ASD will be allocated and investigated for fulfillment of inclusion and exclusion criteria for study participation. The legal guardians of patients meeting study criteria will be approached for study participation consent. Patients declining consent will be treated with TFS as per current protocol. Patients for whom consent is attained will comprise the study group.

Study group patients will be randomized for treatment and stratified according to age groups: 4-7, 8-12, 12-18. Treatment will consist of 2 alternative pathways:

Oral Trichlofos Sodium (TFS) Pathway:

1. Initial Drug dose: Patients will be treated orally with 50mg/kg of TFS to maximum of 2000gr.

2. Failure to achieve sedate state 45 minutes after drug administration will enable an additional oral dose of 25mg/kg.

3. Patients failing to fall asleep following second drug dose will be regarded as treatment failure.

4. Rescue therapy according to physician's choice can be instituted (Dexmed or Neuleptil).

Intranasal Dexmedetomidine (IN DEX) Pathway:

1. Initial drug dose: Patients will be treated with IN 3mcg/kg of Dexmedetomidine to max dose of 150mcg. The drug will be delivered through MAD nasal atomizer.

2. Failure to achieve sedate state 45 minutes after drug administration will enable an additional dose of IN 1.5mcg/kg by MAD device.

3. Paitients failing to fall asleep following second drug dose will be regarded as treatment failure.

4. Rescue therapy according to physician's choice can be instituted (Neuleptil not recommended due to drug interactions).

All sedated children will be connected to monitoring including ECG chest leads in addition to oxygen pulse saturation monitoring.

Primary outcome assessment: Sedation depth by UMSS will be assessed by the EEG technician, who will be blinded to the drug used for sedation.

Secondary outcome assessment:

1. Satisfaction from sedation depth for completing exam by blinded technician on VAS score.

2. EEG motion artifact by interpreting neurologist, blinded to study drug on VAS score.

3. All other secondary outcomes from drug administration to discharge, including adverse events and needed interventions, will be documented by the nurse who is not blinded to administered drug.

4. ECG monitoring for determination of HR or arrhythmia

5. Assessing incidence of bradycardia, hypotension and their severity:

a. HR and BP age related normal value chart to be used as reference. b. Bradycardia and Hypotension determined in relation to lower normal value for age: i. Mild\<10% decrease from normal value ii. Moderate 10-20% decrease from normal value iii. Severe \>20% or signs of hemodynamic compromise

Ethics: This study is a comparison of two medications currently under routine use for performing sedated EEG's in our medical center. The study will be authorized by the Rabin Campus Helsinki Committee. Informed consent will be requested from the accompanying legal guardian.

Statistics: Based on our experience, we assume a 70% success rate for sedation using TFS and a 90% success rate for IN DEX. Using an alpha of 0.05 and 80% power, two groups of 62 patients would be needed, to demonstrate statistical significance.

This trial is planned as a pilot study aimed at assessing drug effects and recruitment rate, over a limited time period of up to 2 year, or up to 200 patiens (100 TFS + 100 IN DEX).

Randomization and age stratification: Patient allocation will be determined according to an age stratified randomization table. Patients will be stratified by 3 age groups: 4-7, 8-12, 12-18.

Funding: No funding has been allocated for this study. Study will be conducted using routine medications in current practice without additional cost.

Study Timeline

• Status Verified: 2020-02
• Study First Submitted: 2020-02-13
• Study First Submitted QC: 2020-02-13
• Last Update Submitted: 2020-02-13
• Study First Posted: 2020-02-17
• Last Update Posted: 2020-02-17
• Study Start: 2020-03-01
• Primary Completion: 2022-03-01
• Study Completion: 2022-08-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Children aged 4-18 yrs referred for an EEG under sedation..
2. A Neurologist derived diagnosis of Autistic Spectrum Disorder (ASD).
3. ASA 1 or 2

Exclusion Criteria

1. Allergy to study drug

2. Congenital heart disease, bradycardia < 60 or know arrhythmia/AV block.

3. Vasoactive drugs or treatment for arterial HTN.

4. Known Renal dysfunction Creatinine Clearance < 30% or known Liver dysfunction (Elevated LFT's).

5. Concurrent Treatment with drugs know to interact with Dexmedetomidine:

   1. Atipical Antipsychotics / Phenothiazines
   2. Tricyclic anti-depressents
   3. Lacosamide treatment - Antiepileptic.
   4. PDE V inhibitors (Viagra)
   5. Beta-blockers
   6. Phenothiazines
   7. First generation Anti-histamines

6. Significant rhinorrhea.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dexmedetomidine	Dexmedetomidine	Intranasal Dexmedetomidine 3mcg/kg
Triclofos	Triclofos 100 MG/ML	Oral Triclofos Sodium 50mg/kg

Primary Outcome Measures

Name	Time	Method
Maximal Sedation Depth	Within 90 minutes	Maximal Sedation Depth by the University of Michigan Sedation Scale (UMSS)
Technician satisfaction from sedation	Within 90 minutes	Technician Ability to complete exam in satisfactory fashion - VAS score

Secondary Outcome Measures

Name	Time	Method
Resistance to drug administration (1-10 scale)	Immediate upon administration	Resistance to drug administration (1-10 scale): Crying / spitting or Complete or Partial Rejection for TFS/IN DEX
Achieving sedation following rescue dose	within 90 minutes	Achieving sedation following additional rescue dose of Dexmed vs TFS
Sedation onset, duration and recovery periods	Within 4 hours.	Sedation onset, duration and recovery periods
Neurologist satisfaction from EEG motion artifact	Within 7 days	Neurologist satisfaction from EEG motion artifact - VAS score
Compliance with IN vs Oral Delivery	Immediate upon administration	Compliance with IN vs Oral Delivery - Successful drug administration Y/N?
Achieving sedation following single dose	Within 45 minutes	Achieving sedation following single dose of Dexmed vs TFS
Adverse Events	Within 4 hours.	Sedation associated adverse events