Ivermectin Neurotoxicity and ABCB1 Gene Mutations

NCT04174469 | Completed

• 1 other identifier: RECHMPL19_0176
• Study Type: observational
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

The study report a unique case of severe intoxication in a child treated with oral ivermectin to prevent scabies infection. The ABCB1 gene sequencing found the child compound heterozygote for two nonsense mutations, one in each gene copy. The child had inherited from each parent one of the alleles. Each mutation generate a predicted truncated protein that likely lead to ABCB1 loss of function, and the undesirable effects observed. The study report a unique case of severe intoxication in a child treated with oral ivermectin to prevent scabies infection. The ABCB1 gene sequencing found the child compound heterozygote for two nonsense mutations, one in each gene copy. The child had inherited from each parent one of the alleles. Each mutation generate a predicted truncated protein that likely lead to ABCB1 loss of function, and the undesirable effects observed. While in some animals, nonsense ABCB1 mutations can lead to neurotoxicity of several ABCB1-substrate drugs, in humans, ivermectin was considered to have an especially high margin of safety, and nonsense mutations have never been reported before, nor has the neurotoxicity of ivermectin apparently caused by these two mutations never been reported before. This discovery is of critical importance for the child, since it dictates that clinicians would need to optimize any ABCB1 substrate-based therapy in the future. More generally, such information must be brought to the attention of clinicians' medics, and in particular infectious disease specialists, pediatricians, and general practitioners. It points the importance of pharmacovigilance, and the benefit of pharmacogenomic genotyping in well-defined phenotype, still too rarely considered in clinical practice before the implementation of a drug treatment. This work results from a multidisciplinary approach, combining several areas of expertise in clinical pediatrics, pharmacology, biology, and bioinformatics.

Conditions

DNA Sequencing

Keywords

ivermectin; neurotoxicity; ATP binding cassette subfamily B member 1; ABCB1/P-glycoprotein (P-gp); multidrug transporter; drug adverse event; Ivermectin toxicity

Outcome Measures

Primary Outcomes (1)

• Patient DNA sequencing

  Biological diagnostic: genotyping of ABCB1 (NM\_000927.4) by using next generation sequencing (Agilent SureSelectQXT®, Miseq® Illumina). Bio-informatic analysis on JSI medical system GmbH sequence pilot CE v4.3.1 software. Identified mutations were subsequently checked using Sanger sequencing on 3130XL (Applied Biosystems®). Bio-informatic analysis on SeqScape v2.5 software.

  1 day

Secondary Outcomes (2)

• ivermectin dosage

  1 day

• cerebral spinal fluid dosages

  1 day

Eligibility Criteria

• Age: 10 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Child followed in the pediatric ward of Toulouse University Hospital for the episode of neurotoxicity and his parents

You may qualify if:

• episode of neurotoxicity

Sponsors & Collaborators

• University Hospital, Montpellier: lead
• University Hospital, Toulouse: collaborator
• INRAE, Toulouse France: collaborator
• Université Paris-Saclay, Gif-sur-Yvette, France: collaborator
• University Hospital, Montpellier France: collaborator

Study Sites (1)

Uh Montpellier

Montpellier, 34295, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood sample and DNA sample

MeSH Terms

Conditions

Neurotoxicity Syndromes; Drug-Related Side Effects and Adverse Reactions

Condition Hierarchy (Ancestors)

Nervous System Diseases; Poisoning; Chemically-Induced Disorders

Study Officials

• Séverine CUNAT, PharmD, PhD

  University Hospital, Montpellier

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2019
• First Posted: November 22, 2019
• Study Start: October 10, 2017
• Primary Completion: April 1, 2019
• Study Completion: April 30, 2019
• Last Updated: September 2, 2020

Record last verified: 2019-05

Locations

FR (1)