Clinical trial NCT01541527: Non Neutralizing Antibodies: Prevalence and Characterization
Official title: Prevalence and Epitope Specificity of Non-neutralizing Antibodies in Haemophilia A Patients Without Inhibitors, Immunogenicity of B Domain: A Prospective Study
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Hemophilia A
Keywords: non neutralizing antibody
Epitopic profile
Clinical relevance
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
Collaborators: name: Hôpital de la Timone
name: University Hospital, Clermont-Ferrand
name: Centre Hospitalier Universitaire de Saint Etienne
name: University Hospital, Toulouse
name: Centre Hospitalier Universitaire de Nice
name: Centre Hospitalier Universitaire de Nīmes
First posted: 2012-03-01
Enrollment: 0
Sex: MALE
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: severe, moderate and mild HA patients (sex: Male and age \> 6 years)

Brief summary: Antibodies (Abs) directed against factorVIII (FVIII) remain the main iatrogenic complication in haemophilia A (HA) patients. Anti-FVIII Abs inhibiting pro-coagulant properties of the molecule are named inhibitors whereas Abs directed towards non-functional epitopes are named non-neutralizing antibodies (NNA). These NNA are poorly studied and their prevalence is ill-defined.

In a recent retrospective study the investigators evaluated, in a cohort of 210 patients without inhibitor, the NNA prevalence and the NNA epitope specificity against the heavy chain (HC)or the light chain(LC). For the first time, the investigators used two x-MAP based assays: the first to determine the specificity of anti-FVIII Abs against the HC or the LC, the second to display Abs directed towards the B domain. NNA were found in 38 out of 210 patients (18).

Among this NNA positive population, 74% and 13% of patients had anti-FVIII Abs against both chains. The proportion of NNA directed towards the B domain was 18%.

Considering an approximate inhibitor prevalence of 30% and a NNA prevalence of 19% in severe HA patients, approximately 50% of severe HA patients develop an immune response against infused FVIII. Due to their unclear relevance, the NNA detection does not yet belong to the routine clinical practice.

However, in 2006, Dimichele advancedf a hypothesis concerning the influence of NNA on the variations in the kinectics of FVIII observed in certain patients.

The mechanism explaining the role of these NNA in the FVIII in the FVIII kinectics has not still been demonstrated.

The investigators propose to perform a multicentre prospective study with the aim to confirm, in severe, moderate and mild HA treated patietns, the NNA prevalence observed in our retrospective study, to study the evolution over time of the epitopemapping of these NNA and to explore the correlation between these NNA and clinical/biological parameters.


Eligibility criteria: Inclusion Criteria:

* male with Age \> 6 years
* Severe, moderate or mild treated HA patients with negative inhibitor titer (\<0.6UB)
* An information form will be presented to the patient or his/her legal representative by the physician who includes the patient in the study protocol
* Patient with national insurance

Exclusion Criteria:

* Patient without his agreement for this study
* Patient deprived of freedom
* Patient without national insurance

Primary outcomes:
measure: NNA prevalence
timeFrame: 18 months
Secondary outcomes:
measure: Relationship between clinical and biological parameters and NNA presence
timeFrame: 18 months
Other outcomes:
Locations:
city: Montpellier
country: France
facility: CHU de Montpellier- Centre administratif André Benech
Study officials:
References:
citation: Lavigne-Lissalde G, Rothschild C, Pouplard C, Lapalud P, Gruel Y, Schved JF, Granier C. Characteristics, mechanisms of action, and epitope mapping of anti-factor VIII antibodies. Clin Rev Allergy Immunol. 2009 Oct;37(2):67-79. doi: 10.1007/s12016-009-8119-0.
citation: Lavigne-Lissalde G, Tarrade C, Lapalud P, Chtourou S, Schved JF, Granier C, Villard-Saussine S. Simultaneous detection and epitope mapping of anti-factor VIII antibodies. Thromb Haemost. 2008 Jun;99(6):1090-6. doi: 10.1160/TH07-08-0497.
citation: Lavigne-Lissalde G, Lacroix-Desmazes S, Wootla B, Tarrade C, Schved JF, Kaveri SV, Granier C, Villard-Saussine S. Molecular characterization of human B domain-specific anti-factor VIII monoclonal antibodies generated in transgenic mice. Thromb Haemost. 2007 Jul;98(1):138-47.