Genotype-phenotype Association in Hereditary Hemorrhagic Telangiectasia (Generate-HHT)

Genotype-phenotype Association Study of ENG and ACVRL1 Genes in the Inflammatory and Endothelial Response in Hereditary Hemorrhagic Telangiectasia (HHT)

The present project aims to study the inflammatory and endothelial responses involved in the differences in clinical events related to both genotypes (ENG vs. ACVRL1) in HHT. Accordingly, a cross-sectional study is proposed to evaluate the differences in circulating inflammatory and endothelial biomarkers, including interleukines, adhesion molecules, chemokines and immune regulatory molecules between both HHT groups.

Study Overview

• Status: Active, not recruiting
• Conditions: Hereditary Hemorrhagic Telangiectasia; HHT; Rendu Osler Weber Disease
• Intervention / Treatment: Other: Registry

Detailed Description

Background and rationale: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease characterized by a multisystemic vascular dysplasia with autosomal dominant inheritance, mainly caused by mutations in ENG and ACVRL1 genes. Even though those mutations have been related to different clinical manifestations, the molecular mechanisms involved in each genetic variant have not been clarified. Methods: A cohort study will be carried out to compare the incidence of clinical events after a 12-months follow-up. The ability of these biomarkers to predict the clinical events will be assessed in a multivariate analysis.

• Study Type: Observational
• Enrollment (Actual): 85

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon Y Cajal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

A consecutive sample of patients with HHT will be selected from the subjects under follow-up in the Internal Medicine Department of the Hospital Universitario Ramón y Cajal.

Description

Inclusion Criteria:

• Age between 18 and 75 years.
• Confirmed diagnosis of HHT, according to the Curaçao criteria or genetic diagnosis.
• Clinically stable condition at the time of inclusion, defined as score < 7 points on the Epistaxis Severity Score (ESS).
• Having signed the informed consent, after having received all the information concerning the study.

Exclusion Criteria:

• Major coronary or cerebrovascular event in the 3 months prior to inclusion.
• Serious intercurrent illnesses, such as acute infections, outbreaks of autoimmune or inflammatory pathology, active cancer, or other pathologies that, at the investigator's discretion, could interfere with the conduct of the study.
• Major surgery during the 2 months prior to inclusion.
• Pharmacological treatment maintained during the 3 months prior to inclusion with NSAIDs, corticosteroids or chemotherapy.
• Toxic habits, including severe smoking, alcohol or drug abuse, which in the opinion of the investigator could interfere with the conduct of the study.
• Pregnancy or puerperium.
• Any other condition that limits compliance with the visits or procedures established in the protocol.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HHT1; Mutations in the ENG (endoglin) gene	Other: Registry; Non-interventional registry
HHT2; Mutations in the ALK-1 (activin receptor-like kinase) gene	Other: Registry; Non-interventional registry

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemorrhagic clinical events	Presence of significant bleeding of any location, recurrent and/or massive, or performance of therapeutic procedures to control them.	12-month follow-up period after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other significant clinical events	Significant clinical events other than hemorrhagic episodes (e.g., infections, neoplasms or other severe diseases)	12-month follow-up period after inclusion
Changes in quality of life	Significant changes in quality of life as measured by the EuroQol 5-level EQ-5D version (EQ-5D-5L) and the EuroQol visual analogue scale (EQ VAS). EQ-5D-5L comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The index ranges from 1 (best state of health) to 0 (death). The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' (100 points) and 'The worst health you can imagine' (0 points).	12-month follow-up period after inclusion

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
• Collaborators: Sociedad Española De Medicina Interna
• Investigators: Principal Investigator: José Luis Patier, MD, Hospital Universitario Ramon Y Cajal

Publications and helpful links

General Publications

• Viteri-Noel A, Gonzalez-Garcia A, Patier JL, Fabregate M, Bara-Ledesma N, Lopez-Rodriguez M, Gomez Del Olmo V, Manzano L. Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management. J Clin Med. 2022 Sep 5;11(17):5245. doi: 10.3390/jcm11175245.
• Sanchez-Martinez R, Iriarte A, Mora-Lujan JM, Patier JL, Lopez-Wolf D, Ojeda A, Torralba MA, Juyol MC, Gil R, Anon S, Salazar-Mendiguchia J, Riera-Mestre A; RiHHTa Investigators of the Rare Diseases Working Group from the Spanish Society of Internal Medicine. Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet J Rare Dis. 2020 Jun 5;15(1):138. doi: 10.1186/s13023-020-01422-8.
• Albinana V, Gimenez-Gallego G, Garcia-Mato A, Palacios P, Recio-Poveda L, Cuesta AM, Patier JL, Botella LM. Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition). TH Open. 2019 Jul 26;3(3):e230-e243. doi: 10.1055/s-0039-1693710. eCollection 2019 Jul.

Helpful Links

• The Multisystemic Diseases Group encompasses several lines of research related to pathologies that involve complex clinical management that usually falls within the scope of Internal Medicine.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2021
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: September 19, 2022
• First Submitted That Met QC Criteria: September 19, 2022
• First Posted (Actual): September 22, 2022

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: HHT; Hereditary Hemorrhagic Telangiectasia; ENG; ALK-1; Genotype-phenotype association; Rendu Osler Weber Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic
• Other Study ID Numbers: 301/20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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