Complement and Graft-versus-host Disease

Allografted With Myeloablative Conditioning Clinical Trial

Official title:

Role of Complement System in Human Allogeneic Haematopoietic Stem Cell Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01520623
• Other study ID #: CRC 08025
• Status: Completed
• Phase: N/A
• First received: December 26, 2011
• Last updated: April 9, 2015
• Start date: April 2010
• Est. completion date: July 2013

Study information

• Verified date: April 2015
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Allogeneic haematopoietic stem cell transplantation (HSCT) often remains the only curative treatment for haematological malignancies. The anti-leukaemic effect of allogeneic HSCT, called the GvL (Graf-versus-Leukemia) effect, is often associated to the development of an immune response against healthy recipient cells leading to a graft-versus-host disease (GvHD) in 20 to 70% of allogeneic HSCT. Acute GvHD, that usually targets the skin, the gastrointestinal (GI) tract and the liver, is an important cause of morbidity and mortality after allogeneic HSCT, particularly in the case of GI GvHD. The main goal of the research in the field of allogeneic HSCT is to determine strategies that could decrease the risk of GvHD without affecting the GvL effect. According to GVHD experimental models, it is likely that GvL but not GvHD may occur in the absence of inflammatory signals induced by the transplant-associated conditioning. Based on this hypothesis, we have chosen to analyse the role of Complement system in patients who received allogeneic HSCT. Indeed, Complement system is a major actor of inflammation and in the generation of tissue destruction, both of which are involved in the physiopathology of GVHD. Furthermore, it might be a potential target of some available inhibitory drugs (purified C1-Inhibitor, anti-C5 antibodies) in a preventive or curative manner in such patients. Preliminary data obtained from 34 allografted patients in our institution suggest that Complement activation by the classical pathway is correlated to the occurrence of GI GVHD. The goal of our current project, in order to confirm these preliminary results in a larger series, is to explore Complement system activation in patients who received allogeneic HSCT in three Adult Hematology departments in Paris fot two years and to correlate the biological results to the clinical events occurring after HSCT.

Description:

The study will be performed in allografted patients with myeloablative conditioning for an haematological malignancy from 3 adult transplant units.

Patients will be followed for at least12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze:

• serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59.

• serum inflammatory cytokine levels

In addition, patients with clinical signs of gut GVHD will be explored by gastrointestinal endoscopy to perform gut biopsies. C5b9 deposure will be then analyzed by immunohistochemistry on GVHD lesions.

Activation of complement system will be defined by a decrease of complement factor levels of 50% and values under lower physiological limits. The clinical evolution and the inflammatory cytokine profile of patients with such an activation profile will be compared to that of those without complement activation.

A data base containing biological and clinical data will be established. Biological results will be correlated to post-transplant clinical events, in particular the occurrence of gut GVHD but also non relapse mortality and overall survival by adapted statistical tests (comparison of percentages by Chi-2 of Pearson, comparison of survival curves by logrank, multivariate analysis by logistic regression test or cox model).

The number of required patients will be established by comparison of the percentage of gut GVHD in the patients with or without complement activation. Based on our preliminary results, we hypothesize that 2/3 patients will not have complement activation among whose 20% will develop acute gut GVHD. We expect an increase of acute gut GVHD up to 60% of the patients with complement activation that would represent 1/3 of the cohort.

With a bilateral alpha risk of 5% and a power of 80%, the number of required patients is 23 in the activated group and 46 in the non activated group, thus a total of 69 patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: July 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Allografted patients with myeloablative conditioning for an haematological malignancy

• Age > 18 years old and < 65 years.

• The patient must have access to social insurance according to local regulations.

• Patient must give a written informed consent (personally signed and dated) before completing any study related procedure

Exclusion Criteria:

• Age < 18 years old and > 65 years

• Patient with active infection HIV, HTLV1, Hepatite B ou C

• Uncontrolled infection(s), (i.e. documented bacterial, parasitical, or fungal infection).

• Patient with lupus

• Patient with transaminases > 5N, TP<30% with Facteur V < 30% before allogreffe

• Creatinine clearance < 50ml/min

• Absence of any psychological condition potentially hampering signing informed consent

• Patient refused to sign informed consent

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Allografted With Myeloablative Conditioning
• Graft vs Host Disease

Intervention

Other:
• Serum concentration /Serum inflammatory
Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels

Locations

Country	Name	City	State
France	Necker Hospital	Paris
France	Saint Antoine Hospital	Paris
France	Saint Louis Hospital	Paris

Sponsors (5)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Clinical haematology and BMT unit,Necker Hospital, Paris, Clinical haematology and BMT unit,Saint Antoine Hospital, Paris, Clinical haematology and BMT unit,Saint Louis Hospital,Paris, European Georges Pompidou Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Activation of the complement system and the development of acute gut GvHD	Assessment of the activation of the complement system after human allogeneic stem cell transplantation and of its potential correlation with the development of acute gut GvHD	12 weeks	No
Secondary	Overall survival	Overall Survival at 3, 6, 9 , 12 and 24-month Post HCST	2 years	Yes
Secondary	Overall survival without relapse	Relapse	2 Years	Yes