Clinical trial NCT04384341: Haemophilia and Bone Loss - PHILEOS Study
Official title: Haemophilia and Bone Loss PHILEOS Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Hemophilia
Keywords: Osteoporosis
fVIII
fIX
thrombin
Haemophilia
Hemophilia
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2020-05-12
Enrollment: 480
Sex: MALE
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Osteoporosis defined by a T-score < -2.5 in severe haemophilic patients without prophylaxis and in healthy subjects.
timeFrame: During the procedure
Secondary outcomes:
measure: Osteoporosis defined by a T-score < -2.5 in the different groups of haemophilic patients and in in healthy subjects.
timeFrame: During the procedure
measure: Osteopenia defined by a T-score < -1 in the different groups of haemophilic patients and in in healthy subjects.
timeFrame: During the procedure
measure: Bone mineral density (expressed as a T-score) in the different groups of haemophilic patients and in healthy subjects.
timeFrame: During the procedure
measure: 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)
timeFrame: At the inclusion
measure: Markers influencing bone metabolism in all haemophilic patients included
timeFrame: At the inclusion
Other outcomes:
Locations:
city: Brussel
country: Belgium
facility: BELGIUM - Brussels
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Bordeaux
country: France
facility: Chu de Bordeaux
city: Brest
country: France
facility: Chu Brest Hopital Morvan
city: Bron
country: France
facility: HCL - Groupement Hospitalier Est (Hôpital Louis Pradel)
city: Caen
country: France
facility: CHU Caen
city: Chambéry
country: France
facility: Centre Hospitalier Metropole Savoie
city: Clermont-Ferrand
country: France
facility: Chu Cth Estaing Clermont Ferrand
city: Dijon
country: France
facility: Chu de Dijon
city: Grenoble
country: France
facility: Chu Grenoble Alpes
city: Lille
country: France
facility: CHU Lille
city: Marseille
country: France
facility: Chu La Timone Marseille
city: Montpellier
country: France
facility: CHU - Saint Eloi
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Chu Necker Paris
city: Paris
country: France
facility: APHP - Bicêtre
city: Rennes
country: France
facility: Chu Rennes Hopital Pontchaillou
city: Rouen
country: France
facility: CHU de ROUEN
city: Saint-Étienne
country: France
facility: CHU de Saint-Etienne
city: Strasbourg
country: France
facility: Chu Strasbourg - Hôpital de Hautepierre
city: Budapest
country: Hungary
facility: MHEK
city: Bucharest
country: Romania
facility: ROMANIA - Bucharest
Study officials:
affiliation: CHU de Saint Etienne
name: Brigitte TARDY, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.