Screening of Pulmonary Veino Occlusive Disease in Heterozygous EIF2AK4 Mutation Carriers (DELPHI-4)

Pulmonary Veino Occlusive Disease (PVOD) is a rare form of pulmonary arterial hypertension, characterised by a poor prognosis. Recent studies demonstrated that heritable form of pulmonary veino occlusive diseaseis due to bi-allelic mutations in EIF2AK4 gene. heritable pulmonary veino occlusive disease is an autosomal recessive disease. In the french referal center of severe PH, ulmonary veino occlusive disease patients carriers of bi-allelic mutations in EIF2AK4 gene were identified. Genetic counselling in these families allowed to identified herozygous carriers of a single mutation in EIF2AK4 gene. However, to date, nothing is known about the risk of these persons of developping pulmonary diseases. It appears essential to determine the clinical, functional, echocardiographic and radiologics characteristics of these persons, and their risk of developping Pulmonary veino occlusive disease

Study Overview

• Status: Unknown
• Conditions: Genetic Syndrome; Mutation
• Intervention / Treatment: Other: Screening of adult without diagnosis of PH carrying an heterozygous EIF2AK4 mutation.

Detailed Description

the investigators will evaluate the subjects at inclusion after informed by a clinical evaluation (dyspnea assessed by New York Heart Association functional class (I-IV), signs of right heart failure), a 6min walk test, a Computerized Tomography scan of the chest, an electrocardiogram, an echocardiography , an abdomina ulstrasound, a Cardiopulmonary exercise testing, a lung function tests , arterial blood gases.

At one and two years, a phone call will be made to to participants evaluate dyspnea and intercurrent events in all subjects. In the presence of pulmonary veino occlusive diseaseis symptoms, a new evaluation will be proposed in order to confirm of not pulmonary veino occlusive diseaseis.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Krémlin Bicêtre
    • Le Kremlin-Bicêtre, Krémlin Bicêtre, France, 94270
      • Recruiting
      • David MONTANI
      • Contact: David MONTANI, MD; Phone Number: 01.45.21.79.76; Email: david.montani@aphp.fr
      • Contact: Marc HUMBERT, PhD; Phone Number: 01.45.21.79.76; Email: marc.humbert@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female adult (age ≥18 years of age at the date of inclusion),
• With an identification of the presence of a mutation of the EIF2AK4 gene in the heterozygous state,
• Having given free and informed consent.

Exclusion Criteria:

• Minor (age <18 years),
• Patient with known Pulmonary veino occlusive disease or Pulmonary arterial hypertension
• Woman having started a pregnancy or breastfeeding
• protected adult persons,
• Persons deprived of their liberty,
• People in emergency,
• Those who refused or were unable to give informed consent,
• Contraindication to the exercise test (acute coronary syndrome, syncope, tight stenotic valve disease ...) See the list of relative and absolute contraindications to the exercise test (chapter 6.2).
• No affiliation to a social security scheme (beneficiary or beneficiary).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Adults without diagnosis of PH; Adults without diagnosis of PH carrying an heterozygous EIF2AK4

Other: Screening of adult without diagnosis of PH carrying an heterozygous EIF2AK4 mutation.; will be performed : a clinical evaluation (dyspnea assessed by New York Heart Association functional class (I-IV), signs of right heart failure), a 6min walk test, a Computerized Tomography scan of the chest, an electrocardiogram, an echocardiography (measurement of the velocity of tricuspid regurgitation, measurement of Tricuspid Annular Plane Systolic Excursion (TAPSE) and Tei index, pericardial effusion, dilatation and hypertrophy of the right ventricle), an abdomina ulstrasound, a stress Test (ventilation oxygen peak and ventilation oxygen specific, minute ventilation, dead-space ventilation / dead space, ventilatory reserve, alveolar-arterial gradient, pulse oxygen, PaO2), a lung function tests and measurement of Diffusing capacity or transfer factor of the Lung for Carbon mOnoxide (DLCO) and Nitric Oxide (DLNO), and a blood sample.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of characteristics of asymptomatic heterozyous EIF2AK4 mutation carriers and monitor these subjects' clinical, functional, biological, echocardiographic	frequency of abnormalities observed	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
predictive factors of the occurrence of PVOD follow prospectively a cohort of asymptomatic heterozyous EIF2AK4 mutation carriers to determine predictive factors of the occurrence of VOD	number of heterozygous EIF2AK4 mutation carriers who will develop Pulmonary Veno-Occlusive Disease	1 year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: MONTANI David, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Lechartier B, Girerd B, Eyries M, Beurnier A, Humbert M, Montani D. Screening for pulmonary veno-occlusive disease in heterozygous EIF2AK4 variant carriers. Eur Respir J. 2022 Aug 18;60(2):2200760. doi: 10.1183/13993003.00760-2022. Print 2022 Aug. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2019
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): September 1, 2021

Study Registration Dates

• First Submitted: March 14, 2019
• First Submitted That Met QC Criteria: April 1, 2019
• First Posted (Actual): April 4, 2019

Study Record Updates

• Last Update Posted (Actual): January 21, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Pulmonary veino occlusive disease, pulmonary hypertension
• Other Study ID Numbers: K180501J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No