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

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ClinicalTrials.gov Identifier: NCT04715256
Recruitment Status : Recruiting
First Posted : January 20, 2021
Last Update Posted : January 20, 2021
Sponsor:
Collaborators:
European Union
Nantes University Hospital
Information provided by (Responsible Party):
Biotrial

Brief 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.

Condition or disease Intervention/treatment Phase
Romano-Ward Syndrome Long QT Syndrome Compulsive Behavior Healthy Individuals Behavioral: Cognitive assessment of obsessive-compulsive and impulsive behaviours Genetic: Genomic analysis Diagnostic Test: Glucoregulation assessment Not Applicable

Detailed 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
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.
Actual Study Start Date : January 8, 2021
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: KCNQ1 mutated subjects

This arm includes :

  • KCNQ1-mutated subjects with long QT Romano-Ward syndrome
  • KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome
  • family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation
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.

Sham Comparator: Healthy subjects
Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, > 28-38 years, > 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; > 30 kg/m2).
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.




Primary Outcome Measures :
  1. Outcome related to glucoregulation : fasted glycemia [ Time Frame: 15 minutes ]
    Plasma glucose concentration

  2. Outcome related to glucoregulation : fasted insulin levels [ Time Frame: 15 minutes ]
    Plasma insulin concentration

  3. Outcome related to glucoregulation : glycated haemoglobin (HbA1c) [ Time Frame: 15 minutes ]
    Blood HbA1c concentration

  4. Outcome related to glucoregulation : glycemia 2hours following an oral glucose challenge [ Time Frame: 2 hours ]
    Plasma glucose concentration


Secondary Outcome Measures :
  1. Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire total score and subscale scores [ Time Frame: 30 minutes ]
    Subscales of OCI-R: washing, obsessing, hoarding, ordering, checking, neutralising

  2. Adult Social Behaviour Questionnaire (ASBQ) total score and subscale scores [ Time Frame: 30 minutes ]
    Subscales of ASBQ : reduced contacts, reduced empathy, reduced interpersonal insight, violations of social conventions, insistence of sameness, sensory stimulation and motor stereotypies.

  3. Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency scale (UPPS-P) subscale scores [ Time Frame: 30 minutes ]
    Subscales of UPPS-P: negative urgency, lack of premeditation, lack of perseverance, sensation-seeking, positive urgency

  4. Childhood Retrospective Perfectionism Questionnaire (CHIRP) total score [ Time Frame: 30 minutes ]
    Total score

  5. Continuous Performance Task (CPT) [ Time Frame: 1 hour ]
    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').


Other Outcome Measures:
  1. Genomic analyses (GWAS) [ Time Frame: 15 minutes ]
    DNA methylation status at the KCNQ1 locus and Polygenic Risk Scores (PRS)



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:   18 Years to 48 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

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): NCT04715256


Contacts
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Contact: Valerie Bertaina-Anglade, PhD +33 (0)2 99 59 91 91 Valerie.Bertaina-Anglade@biotrial.com
Contact: Philippe Danjou, MD +33 (0)9 75 51 88 82 Philippe.Danjou@biotrial.com

Locations
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France
L'Institut du Thorax, Nantes Hospital Recruiting
Nantes, France, 44000
Contact: Vincent Probst, MD    +33 (0)6 15 40 84 13    vincent.probst@univ-nantes.fr   
Biotrial Clinical Unit Not yet recruiting
Rennes, France, 35000
Contact: Sophie Hays, MD    +33 (0)2 99 59 91 91    Sophie.Hays@biotrial.com   
Sponsors and Collaborators
Biotrial
European Union
Nantes University Hospital
Investigators
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Principal Investigator: Sophie Hays, MD Biotrial
Principal Investigator: Probst Vincent, MD Nantes University Hospital
Additional Information:
Publications of Results:
Other Publications:
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.
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
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.

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Responsible Party: Biotrial
ClinicalTrials.gov Identifier: NCT04715256    
Other Study ID Numbers: 2020-A02099-30
847879 ( Other Grant/Funding Number: European Union (Horizon 2020 program) )
First Posted: January 20, 2021    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All anonymized individual participant data will be shared within the PRIME consortium collaborators in accordance with the PRIME Consortium Agreement
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Individual participant data will be available starting in january 2023 and until december 2025

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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 Biotrial:
Romano-Ward Syndrome
Long QT Syndrome
Insulin-related diseases
Compulsive Behavior
ASBQ
CHIRP
OCI-R
UPPS-P
CPT
GWAS
Healthy individuals
KCNQ1 mutations
Additional relevant MeSH terms:
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Long QT Syndrome
Romano-Ward Syndrome
Syndrome
Compulsive Behavior
Disease
Pathologic Processes
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities
Impulsive Behavior