Inter Individual Variability in Initiation Pathway Activation and Regulation and Phenotypic Heterogeneity in Patients With Haemophilia A and B (InPath)

Severe haemophilia A and B (SHA, SHB) are X - linked inherited bleeding disorders, characterised by factor VIII and IX levels of <1 IU/dL respectively. The mainstay of treatment in SHA and SHB is replacement therapy with intravenous infusions of factor VIII and IX. However, there is significant variability in the bleeding phenotype within severe haemophiliacs with some presenting with minimal bleeding episodes even on less intensive treatment regimens. A significant contributor to inter-individual variability in the bleeding phenotype is the coagulation phenotype, but there are no established assays in routine clinical practice that can be used to quantify this. This study aims to study novel assays and characterise the observed phenotypic heterogeneity.

Study Overview

• Status: Unknown
• Conditions: Haemophilia
• Intervention / Treatment: Diagnostic test: Thrombophilia screen; Diagnostic test: Initiation pathway analysis

• Study Type: Observational
• Enrollment (Anticipated): 250

Contacts and Locations

• Study Contact: Name: Thomas Roberts; Phone Number: 02078302068; Email: thomas.roberts1@nhs.net

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Royal Free Hospital
    • Principal Investigator: Pratima Chowdary
    • Contact: Thomas Roberts

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

The study population will include patients severe or moderate haemophilia A or B who are currently attending study sites for routine follow up visits. In addition, 10 healthy volunteers will also be recruited to act as controls

Description

Patients

Inclusion Criteria:

1. Patients with haemophilia A or B (baseline FVIII/FIX level <30%)
2. Age ≥ 18 years
3. Written informed consent in accordance with local and institutional guidelines.

Exclusion Criteria:

1. Patients currently enrolled into a clinical trial of investigational medicinal product for haemophilia.

Healthy Volunteers

Inclusion Criteria:

1. Currently not receiving any antiplatelet or anticoagulant therapy or other drugs that can affect the coagulation system.
2. Age ≥ 18 years
3. Written informed consent in accordance with local and institutional guidelines.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Haemophilia patients; Persons with haemophilia A or B - 240 to be recruited	Diagnostic test: Thrombophilia screen; Thrombophilia screen (including antithrombin activity (AT:Ac), protein S antigen (PS:free), protein C activity (PC:Ac) , genetic analysis for FV Leiden and Prothrombin 3'UTR mutations and screening for lupus anticoagulant.; Diagnostic test: Initiation pathway analysis; Evaluation of inter-individual variability in regulation of TF.VIIa.Xa.TFPI complex (tissue factor, activated Factor VII, activated factor X, tissue factor pathway inhibitor)
Healthy volunteers; Healthy volunteers - 10 to be recruited	Diagnostic test: Thrombophilia screen; Thrombophilia screen (including antithrombin activity (AT:Ac), protein S antigen (PS:free), protein C activity (PC:Ac) , genetic analysis for FV Leiden and Prothrombin 3'UTR mutations and screening for lupus anticoagulant.; Diagnostic test: Initiation pathway analysis; Evaluation of inter-individual variability in regulation of TF.VIIa.Xa.TFPI complex (tissue factor, activated Factor VII, activated factor X, tissue factor pathway inhibitor)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Initiation pathway correlation with clinical phenotype	Correlate lab assays that characterise initiation pathway with clinical phenotype.	Within 18 months of consent

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlation analysis between FVIII:C/FIX:C levels and whole blood clotting time, thrombin generation in platelet poor plasma.	Within 18 months of consent
Evaluation the sensitivity and specificity of global assays for disease severity and clinical phenotype.	Within 18 months of consent
Correlation analysis between activation threshold of initiation pathway to thrombin generation and clinical phenotype	Within 18 months of consent

Collaborators and Investigators

• Sponsor: Royal Free Hospital NHS Foundation Trust
• Investigators: Principal Investigator: Pratima Chowdary, Royal Free Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2017
• Primary Completion (Anticipated): October 2, 2019
• Study Completion (Anticipated): October 2, 2020

Study Registration Dates

• First Submitted: September 13, 2017
• First Submitted That Met QC Criteria: September 15, 2017
• First Posted (Actual): September 19, 2017

Study Record Updates

• Last Update Posted (Actual): March 27, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: 11296

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