Haemophilia and Bone Loss - PHILEOS Study (PHILEOS)

Haemophilia and Bone Loss PHILEOS Study

Haemophilia is a rare bleeding disorder, characterized by factor VIII (HA) or factor IX (HB) deficiency. The absence or the reduction of fVIII or fIX result in impaired thrombin generation and clot formation, causing excessive bleeding (mainly haemarthrosis). Osteoporosis is a systemic bone disease characterized by a low bone mineral density (BMD). A decrease of mean BMD has been described in haemophilic patients compared to healthy controls in several studies. So, osteoporosis could be an underestimated haemophilia-related comorbidity. None of the following risk factors (reduced physical activity, joint damage, vitamin D deficiency and /or hepatitis C virus (HCV) infection) has been retained as a cause of osteoporosis in haemophilic patients. Another hypothesis is that bone loss could be directly linked to fVIII or fIX and/or thrombin deficiency. The aim of this study is to evaluate the prevalence of the bone loss in HA and B patients, according to the type, the severity and the presence (or not) of a prophylactic treatment (depending on the age at which it was began) and to compare it to a control population. The investigators will also evaluate the relation between BMD and FVIII, fIX and thrombin potential.

Study Overview

• Status: Recruiting
• Conditions: Hemophilia
• Intervention / Treatment: Radiation: Bone densitometry (BMD); Biological: Blood sampling for patients only

Detailed Description

Recruitment of healthy volunteers through registers (Clinical Investigation Centers) and advertisements.

Recruitment of haemophilic patients during a routine visit at the haemophilia centre.

Information of the subjects that the study requires a BMD measure for all and a blood sampling for patients only.

After inclusion and exclusion criteria have been checked, the subject can sign the consent.

For all subjects, an appointment will be made for BMD measure. For patients and controls: BMD will be measured by Dual Energy X-ray Absorptiometry (DXA) technology, on femoral and lumbar spine (L2-L4) sites.

For patients, fVIII/fIX activity and antigen, thrombin generation potential and plasmatic markers of bone remodelling will be measured centrally.

• Study Type: Interventional
• Enrollment (Estimated): 480
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Brigitte TARDY, MD; Phone Number: (0)477421877; Email: brigitte.tardy@chu-st-etienne.fr
• Study Contact Backup: Name: Carine LABRUYERE, CRA; Phone Number: (0)477120469; Email: carine.labruyere@chu-st-etienne.fr

Study Locations

• Belgium
  • Brussel, Belgium
    • Recruiting
    • BELGIUM - Brussels
    • Principal Investigator: Cedric HERMANS, MD
• France
  • Bordeaux, France, 33076
    • Recruiting
    • CHU de Bordeaux
    • Principal Investigator: SABINE CASTET, MD
    • Sub-Investigator: Nadia MESHEN-CETRE, MD
  • Brest, France, 29200
    • Recruiting
    • CHU Brest Hopital Morvan
    • Principal Investigator: BRIGITTE PAN-PETESCH, MD
  • Bron, France
    • Recruiting
    • HCL - Groupement Hospitalier Est (Hôpital Louis Pradel)
    • Principal Investigator: Anne LIENHART, MD
  • Caen, France
    • Recruiting
    • CHU caen
    • Principal Investigator: Yohann REPESSE, MD
    • Sub-Investigator: Benjamin GILLET, MD
    • Sub-Investigator: Philippe GAUTIER, MD
  • Chambéry, France, 73000
    • Recruiting
    • Centre Hospitalier Metropole Savoie
    • Sub-Investigator: ROMAIN JAILLER, MD
    • Principal Investigator: VALERIE GAY, MD
    • Sub-Investigator: Pascal MEYER, MD
  • Clermont-Ferrand, France
    • Recruiting
    • Chu Cth Estaing Clermont Ferrand
    • Sub-Investigator: Victoria Cacheux, MD
    • Principal Investigator: AURELIEN LEBRETON, MD
    • Sub-Investigator: Alain MARQUES-VERDIER, MD
  • Dijon, France, 21000
    • Recruiting
    • CHU de Dijon
    • Principal Investigator: FABIENNE GENRE-VOLLOT, MD
    • Sub-Investigator: Marc BARDOU, MD-PhD
    • Sub-Investigator: Maxime LUU, MD
    • Sub-Investigator: Inès BEN GHEZALA, MD
  • Grenoble, France, 38700
    • Recruiting
    • CHU Grenoble Alpes
    • Sub-Investigator: RAPHAEL MARLU, MD
    • Principal Investigator: BENOIT POLACK, MD
    • Sub-Investigator: Enkelejda HODAJ, MD
  • Lille, France
    • Recruiting
    • CHU Lille
    • Principal Investigator: Antoine RAUCH, MD
    • Sub-Investigator: Sophie SUSEN, MD PhD
    • Sub-Investigator: Bénédicte WIBAUT-PEGNEAUX, MD
    • Sub-Investigator: Isabelle MENDEL, MD
  • Marseille, France, 13010
    • Recruiting
    • CHU La Timone Marseille
    • Sub-Investigator: CELINE FALAISE, MD
    • Principal Investigator: HERVE CHAMBOST, MD PhD
    • Sub-Investigator: Catherine POUYMAYOU, MD
    • Sub-Investigator: Pierre Emmanuel MORANGE, MD PhD
  • Montpellier, France, 34295
    • Recruiting
    • CHU - Saint Eloi
    • Contact: Christine BIRON ANDREANI, MD
    • Principal Investigator: Christine BIRON ANDREANI, MD
    • Sub-Investigator: Delphine CHIFFRE-RAKOTOARIVONY, MD
    • Sub-Investigator: Robert NAVARRO, MD
  • Nancy, France
    • Recruiting
    • Chu Nancy
    • Principal Investigator: Birgit FROTSCHER
  • Nantes, France
    • Recruiting
    • CHU de Nantes
    • Principal Investigator: Marc FOUASSIER, MD
  • Paris, France, 75015
    • Recruiting
    • Chu Necker Paris
    • Principal Investigator: LAURENT FRENZEL, MD
  • Paris, France
    • Recruiting
    • APHP - Bicêtre
    • Principal Investigator: Roseline D'OIRON, MD
    • Sub-Investigator: Hortense MAYNADIE, MD
    • Sub-Investigator: Guillaume MORELLE, MD
  • Rennes, France, 35000
    • Recruiting
    • Chu Rennes Hopital Pontchaillou
    • Principal Investigator: BENOIT GUILLET, MD
    • Sub-Investigator: Fabrice LAINE, MD
    • Sub-Investigator: Elodie MAINGUY, MD
    • Sub-Investigator: Marie PROVOST-DEWITTE, MD
  • Rouen, France
    • Recruiting
    • CHU de Rouen
    • Principal Investigator: PIERRE CHAMOUNI, MD
    • Sub-Investigator: Virginie BARBAY, MD
    • Sub-Investigator: Marie KOZYREFF-MEURICE, MD
  • Saint-Étienne, France, 42055
    • Recruiting
    • CHU DE SAINT-ETIENNE
    • Contact: BRIGITTE TARDY
    • Sub-Investigator: THIERRY THOMAS, MD-PhD
    • Sub-Investigator: Bernard TARDY, MD-PhD
    • Principal Investigator: BRIGITTE TARDY, MD
    • Sub-Investigator: Anne DEVILLARD, MD
  • Strasbourg, France
    • Recruiting
    • CHU STRASBOURG - Hôpital de Hautepierre
    • Principal Investigator: DOMINIQUE DESPREZ, MD
    • Sub-Investigator: Rose-Marie JAVIER, MD
• Romania
  • Bucharest, Romania
    • Recruiting
    • ROMANIA - Bucharest
    • Principal Investigator: Daniel CORIU, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 58 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy Volunteers :

  • Healthy men aged between 20 to 60 years old

• Haemophilic Patients:

  • Haemophilia A and B patients, irrespective of the disease form (mild, moderate, severe with or without prophylaxis)
  • Haemophilic patients aged between 20 to 60 years old
  • Severe Haemophilia A patients with prophylaxis : last factor VIII injection more than 48 to 120 hours (depending on on the prophylactic treatment) prior blood sampling dedicated to the this research
  • Severe Haemophilia B patients : last factor IX injection more than 5 to 21 days (depending on the prophylactic treatment) prior blood sampling dedicated to the this research

Exclusion Criteria:

• Healthy Volunteers:

  • History of disease known to influence bone metabolism (hyperthyroidism, hyperparathyroidism, hypercorticism, hypogonadism, diseases that require long-term use of corticoids, …)
  • Past or present treatment with any osteoporotic medication other than Vit D or Ca++
  • Presence of two total hip prostheses
  • HIV documented infection
  • HCV documented infection (in progress or cured) at cirrhotic stage

• Haemophilic Patients:

  • Haemophilic patients with current or history of inhibitor anti-fVIII or anti-fIX (>5 Bethesda Units)
  • Treatment with HEMLIBRA (Emicizumab). Unless it is possible to use a result of thrombin generation prior to this treatment and achieved with a residual rate not greater than or equal to 5%.
  • History of disease known to influence bone metabolism and not related to haemophilia (hyperthyroidism, hyperparathyroidism, hypercorticism, hypogonadism, diseases that require long-term use of corticoids, …)
  • Past or present treatment with any anti-osteoporotic medication other than Vit D or Ca++
  • Presence of two total hip prostheses
  • HIV documented infection
  • HCV documented infection (in progress or cured) at cirrhotic stage

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Haemophilic patients; Blood sampling Bone Densitometry (BMD)	Radiation: Bone densitometry (BMD); Recruitment of haemophilic patients during a routine visit at the haemophilia centre. Information of the subjects that the study requires a BMD measure for all and a blood sampling for patients only. After inclusion and exclusion criteria have been checked, the subject can sign the consent. For all subjects, an appointment will be made for BMD measure. For patients and controls: BMD will be measured by Dual Energy X-ray Absorptiometry (DXA) technology, on femoral and lumbar spine (L2-L4) sites. Recruitment of healthy volunteers through registers (Clinical Investigation Centers) and advertisements.; Biological: Blood sampling for patients only; For patients, fVIII/fIX activity and antigen, thrombin generation potential and plasmatic markers of bone remodelling will be measured centrally.
Other: Healthy volunteers; Bone Densitometry (BMD)	Radiation: Bone densitometry (BMD); Recruitment of haemophilic patients during a routine visit at the haemophilia centre. Information of the subjects that the study requires a BMD measure for all and a blood sampling for patients only. After inclusion and exclusion criteria have been checked, the subject can sign the consent. For all subjects, an appointment will be made for BMD measure. For patients and controls: BMD will be measured by Dual Energy X-ray Absorptiometry (DXA) technology, on femoral and lumbar spine (L2-L4) sites. Recruitment of healthy volunteers through registers (Clinical Investigation Centers) and advertisements.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Osteoporosis defined by a T-score < -2.5 in severe haemophilic patients without prophylaxis and in healthy subjects.	Bone mineral densitometry	During the procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Osteoporosis defined by a T-score < -2.5 in the different groups of haemophilic patients and in in healthy subjects.	Bone mineral densitometry	During the procedure
Osteopenia defined by a T-score < -1 in the different groups of haemophilic patients and in in healthy subjects.	Bone mineral densitometry	During the procedure
Bone mineral density (expressed as a T-score) in the different groups of haemophilic patients and in healthy subjects.	Bone mineral densitometry	During the procedure
Basal level of fVIII/fIX (expressed as an Ag level or as a %) or thrombin generation potential (expressed as an endogenous thrombin potential (ETP), nmol/min) and Bone mineral density (expressed as a T-score and Z-score)	Blood test Relation between the basal level of fVIII or fIX (expressed as an Ag level or as a %) or the thrombin generation potential (expressed as an endogenous thrombin potential (ETP), nmol/min) and Bone mineral density (expressed as a T-score and Z-score)	At the inclusion
Markers influencing bone metabolism in all haemophilic patients included	Blood test	At the inclusion

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Brigitte TARDY, MD, CHU de Saint Etienne

Publications and helpful links

General Publications

• Tardy-Poncet B, Play B, Montmartin A, Damien P, Ollier E, Presles E, Garcin A, Tardy B. PHILEOS (haemoPHILia and ostEoporOSis) Study: protocol of a multicentre prospective case-control study. BMJ Open. 2021 Jan 13;11(1):e042283. doi: 10.1136/bmjopen-2020-042283.

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2020
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 11, 2020
• First Posted (Actual): May 12, 2020

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 29, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Osteoporosis; Haemophilia; Hemophilia; thrombin; fVIII; fIX
• 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: 19PH224; 2019-A03358-49 (Other Identifier: ANSM)

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