Evaluation of the Effects of KCNQ1 Mutation on Insulin Tolerance and Obsessive Compulsive Features in Long QT Romano-Ward Syndrome Patients.

Long QT Syndrome Clinical Trial

— PRIME  

Official title:

Interventional Study With Low Risks and Constraints on the Effect of KCNQ1 Mutation (Romano-Ward Syndrome) on Insulin Tolerance and Obsessive Compulsive Features, a Cross-sectional Study With Matched Controls With an Attempt of Linkage to Whole Genome Scanning.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04715256
• Other study ID #: 2020-A02099-30
• Secondary ID: 847879
• Status: Recruiting
• Phase: N/A
• Start date: January 8, 2021
• Est. completion date: December 2021

Study information

• Verified date: January 2021
• Source: Biotrial
• Contact: Valerie Bertaina-Anglade, PhD
• Phone: +33 (0)2 99 59 91 91
• Email: Valerie.Bertaina-Anglade[@]biotrial.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objectives of the study are to investigate if KCNQ1 mutation in Romano-Ward long QT patients can be associated with changes in insulin regulation and with psychological features of compulsivity, impulsivity and behavioural rigidity.

Description:

Romano-Ward Syndrome (RWS) is a rare disorder characterized by prolongation of the QT interval, as well as T-wave abnormalities and possibly polymorphic ventricular fibrillation. RWS is inherited in an autosomal dominant fashion. Mutations in the potassium voltage-gated channel subfamily Q Member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), sodium voltage-gated channel alpha subunit 5 (SCN5A), potassium voltage-gated channel subfamily E regulatory subunit 1 (KCNE1), and potassium voltage-gated channel subfamily E regulatory subunit 2 (KCNE2) genes are known to be causative, and these five genes together are responsible for virtually 100% of cases of RWS.

Dysregulation of insulin signalling has been implicated in multimorbidity across the lifespan, in particular in type 2 diabetes, metabolic syndrome, obesity and RWS. Numerous studies have shown a relationship between RWS and hyperinsulinemia. More recently, altered insulin signalling has also been implicated in neurodegenerative brain disorders, dementias and Alzheimer's disease. Diseases characterized by dysregulation of insulin signalling (i.e. insulinopathies) present a major health, societal, and economic burden. These insulin signalling-associated diseases are mostly chronic, and with limited or absent curative treatments. At the current time, the recognition and clinical management of insulin comorbidity remains poorly established; brain-based comorbidity is generally neglected, and medical efforts are only devoted to the management of the primary, somatic diagnosis.

The present study will be a part of the European Union (EU)-funded PRIME (for Prevention and Remediation of Insulin Multimorbidity in Europe) research program, which primary goal is to identify and specify the molecular mechanisms underlying the insulin multimorbidities through investigation of the diseases that cause the highest burden and costs to patients and society, and to outline new directions for research and clinical care thereof. The primary hypothesis of the PRIME project is that comorbidity observed in these somatic diseases (DM2, metabolic syndrome, obesity, RWS) is a result of dysregulated central and peripheral insulin signalling, downstream of synaptic dysfunction and of learning, memory, and executive functions impairments. This non-competitive EU Horizon2020 project will study the role of KCNQ1, a key molecule in insulin regulation, in the insulinopathies across different levels of organismal organisation.

The study will include 50 KCNQ1-mutated subjects (mainly RWS patients but also subjects carrying the KCNQ1 mutation but without phenotypic manifestation of long QT syndrome, and, because of the strong interest of the PRIME project in genetic analyses, family relatives carrying the same KCNQ1 mutation) and 50 matched healthy subjects. By comparing the test population to healthy subjects, the main objective of the trial is to test the hypothesis of an involvement of KCNQ1 in compulsivity, impulsivity and cognitive rigidity.

The insulin regulation evaluations will be performed by measuring glucose, insulin and glycated haemoglobin (HbA1c) in subjects. Compulsivity, impulsivity and behavioural rigidity will be assessed using 4 neuropsychological questionnaires (OCI-R, ASBQ, UPPS-P, CHIRP) and one objective test, the CPT.

Moreover, DNA extraction will be performed in order to search for associations between mutations, insulin regulation and psychological features in conducting a Genome-Wide Association Study (GWAS) (exploratory objective).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 2021
• Est. primary completion date: December 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 48 Years

Eligibility

Inclusion Criteria:

• In the investigator's opinion, the subject is generally healthy based on their medical records (subjects with KCNQ1 mutation only), medical history, physical examination, vital signs, body weight, ECG (except long QT if applicable), and based on the results of haematology, clinical chemistry, urinalysis, urine drug screen (UDS) and serology;

• Subjects with a KCNQ1 mutation: genotyped as having a mutation on the KCNQ1 gene with or without phenotypic manifestation of long QT syndrome;

• Relatives of subjects with a KCNQ1 mutation: KCNQ1-mutated family relatives (with or without phenotypic expression) of a subject carrying a KCNQ1 mutation (Romano-Ward patients or subjects without phenotypic manifestation of long QT syndrome);

• Relatives of subjects with a KCNQ1 mutation must live in a different household than the subject with the KCNQ1 mutation;

• All subjects: negative UDS by dipstick analysis: opiates, methadone, cocaine, amphetamines (including ecstasy), barbiturates, benzodiazepines, and cannabinoids at admission to the assessment visit;

• All subjects: negative alcohol breath test at admission to the assessment visit.

Exclusion Criteria:

• All subjects: having taken within 1 year before the assessment visit or currently taking any of the following medications: a. Antidiabetics: metformin, pioglitazone, acarbose, miglitol, sitagliptin, vildagliptin, saxagliptin, exenatide, liraglutide, semaglutide, repaglinide, nateglinide, insulin. b. Medications interfering with the central nervous system (CNS) such as any antipsychotic, antidepressant or regular use of anxiolytic medications > once a week, or any attention deficit/hyperactivity disorder (ADHD) medication (e.g. methylphenidate);

• Healthy subjects and relatives of subjects with a KCNQ1 mutation not phenotypically affected: any of the following on a de novo ECG: a. Heart rate (HR) < 40 bpm or > 100 bpm; b. PR interval <120 msec; c. Abnormal repolarization; d. QT interval corrected for HR using Fridericia's formula (QTcF) > 450 msec for male subjects or > 470 msec for female subjects.

Related Conditions & MeSH terms

• Compulsive Behavior
• Healthy Individuals
• Long QT Syndrome
• Romano-Ward Syndrome
• Syndrome

Intervention

Behavioral:
• Cognitive assessment of obsessive-compulsive and impulsive behaviours
The content of the assessment will be the same for all subjects and will consist of a cognitive assessment (attention, impulsivity) and a clinical assessment (impulsive behaviour, autistic traits,obsessive-compulsive behaviour).

Genetic:
• Genomic analysis
A genome-wide association study (GWAS) will be performed for all subjects to search for associations between KCNQ1 mutations, insulin regulation and psychological features.

Diagnostic Test:
• Glucoregulation assessment
Fasted glycaemia and insulinaemia, glycated haemoglobin (HbA1c) and glycaemia following an oral glucose challenge test will be measured in all study subjects.

Locations

Country	Name	City	State
France	L'Institut du Thorax, Nantes Hospital	Nantes
France	Biotrial Clinical Unit	Rennes

Sponsors (3)

Lead Sponsor	Collaborator
Biotrial	European Union, Nantes University Hospital

Country where clinical trial is conducted

France, 

References & Publications (9)

Fatima SS, Chaudhry B, Khan TA, Farooq S. KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women. Pak J Med Sci. 2016 Nov-Dec;32(6):1380-1385. doi: 10.12669/pjms.326.11052. — View Citation

Foa EB, Huppert JD, Leiberg S, Langner R, Kichic R, Hajcak G, Salkovskis PM. The Obsessive-Compulsive Inventory: development and validation of a short version. Psychol Assess. 2002 Dec;14(4):485-96. — View Citation

Lynam, D.R., Smith, G.T., Whiteside, S.P., Cyders, M.A. (2006). The UPPS-P: Assessing five personality pathways to impulsive behavior (Technical Report). West Lafayette: Purdue University.

Southgate L, Tchanturia K, Collier D, Treasure J. The development of the childhood retrospective perfectionism questionnaire (CHIRP) in an eating disorder sample. Eur Eat Disord Rev. 2008 Nov;16(6):451-62. doi: 10.1002/erv.870. — View Citation

Torekov SS, Iepsen E, Christiansen M, Linneberg A, Pedersen O, Holst JJ, Kanters JK, Hansen T. KCNQ1 long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia. Diabetes. 2014 Apr;63(4):1315-25. doi: 10.2337/db13-1454. Epub 2013 Dec 18. — View Citation

van de Vondervoort I, Poelmans G, Aschrafi A, Pauls DL, Buitelaar JK, Glennon JC, Franke B. An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive-compulsive disorder. J Psychiatry Neurosci. 2016 Jun;41(4):280-5. Review. — View Citation

van de Vondervoort IIGM, Amiri H, Bruchhage MMK, Oomen CA, Rustogi N, Cooper JD, van Asten JJA, Heerschap A, Bahn S, Williams SCR, Buitelaar JK, Poelmans G, Glennon JC. Converging evidence points towards a role of insulin signaling in regulating compulsive behavior. Transl Psychiatry. 2019 Sep 12;9(1):225. doi: 10.1038/s41398-019-0559-6. — View Citation

Van der Linden, M., d'Acremont, M., Zermatten, A., Jermann, F., Laroi, F., Willems, S., Juillerat, A., Bechara, A. (2006). A French Adaptation of the UPPS Impulsive Behavior Scale: Confirmatory factor analysis in a sample of undergraduate students. Eur J Psychol Assess. 22:38-42.

Zermatten, A., Van der Linden, M., Jermann, F., Ceschi, G. Validation of a French version of the Obsessive-Compulsive Inventory-Revised in a non-clinical sample. (2006). Revue Européenne de Psychologie Appliquée. 56:151-155

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Genomic analyses (GWAS)	DNA methylation status at the KCNQ1 locus and Polygenic Risk Scores (PRS)	15 minutes
Primary	Outcome related to glucoregulation : fasted glycemia	Plasma glucose concentration	15 minutes
Primary	Outcome related to glucoregulation : fasted insulin levels	Plasma insulin concentration	15 minutes
Primary	Outcome related to glucoregulation : glycated haemoglobin (HbA1c)	Blood HbA1c concentration	15 minutes
Primary	Outcome related to glucoregulation : glycemia 2hours following an oral glucose challenge	Plasma glucose concentration	2 hours
Secondary	Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire total score and subscale scores	Subscales of OCI-R: washing, obsessing, hoarding, ordering, checking, neutralising	30 minutes
Secondary	Adult Social Behaviour Questionnaire (ASBQ) total score and subscale scores	Subscales of ASBQ : reduced contacts, reduced empathy, reduced interpersonal insight, violations of social conventions, insistence of sameness, sensory stimulation and motor stereotypies.	30 minutes
Secondary	Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency scale (UPPS-P) subscale scores	Subscales of UPPS-P: negative urgency, lack of premeditation, lack of perseverance, sensation-seeking, positive urgency	30 minutes
Secondary	Childhood Retrospective Perfectionism Questionnaire (CHIRP) total score	Total score	30 minutes
Secondary	Continuous Performance Task (CPT)	Variables of the CPT : omission errors, commission errors/false alarms, hits, hit rate, hit reaction time, difference between hit rate and false alarms rate (d').	1 hour

External Links

•   Biotrial's website
•   Official website of the PRIME project