Clinical trial NCT02374736: Effect of Privigen Against Graft Loss
Official title: A Pilot Study on the Effect of Privigen Against Graft Loss: Interventional Study of Kidney Transplant Recipients at Risk for Graft Loss Through Antibody-mediated Rejection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney Transplantation
Keywords: recipients
Subclinical Antibody-mediated rejection (ABMR)
Intravenous immunoglobulins (IVIg)
Donor-specific antibodies (DSA)
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: CSL Behring
name: Association ASLUMARE
First posted: 2015-03-02
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The principal objective of this pilot study is to determine whether the progression of chronic antibody-mediated rejection (ABMR) could be minimized by the post-transplant administration of high dose of Intravenous Immunoglobulins (IVIg).

We test the hypothesis that repetitive IVIg administration reduces or stabilize the progressive loss of transplant function and the evolution to chronic ABMR in stable kidney transplant patients with HLA-DSA developed post-transplantion (de novo HLA-DSA) and concomitant humoral graft injury.

Detailed description: The aim of this study is to assess the effect of IVIg associated to conventional immunosuppressive treatment in 15 stable transplant recipients with post-transplant de novo HLA-DSA and histological humoral lesions.

The study will include 2 periods:

* Treatment period,
* Follow-up period. The treatment will start the day of inclusion (M0): Privigen will be given as 2 g/kg for 2 days/month for 6 months (maximum dose: 80 g/day).

Evaluation at the end of treatment will take place on month 6 (M6). Evaluation at the end of follow up will take place on month 12 (M12).

Blood and urine samples will be collected on day of inclusion (M0), before each infusion of Privigen, at M6 and M12 for biological analysis (serum creatinine, glomerular filtration rate, proteinuria).

Blood samples will be collected on day of inclusion (M0), at M6 and M12 for immunoassay (HLA-DSA mean fluorescence intensity).

Blood sample will be collected on day of inclusion (M0) to provide a DNA bank. Blood samples will be collected on day of inclusion (M0), before each infusion of Privigen and at M6 for IgG dosage.

Blood samples will be collected on day of inclusion (M0), before each infusion of Privigen, at M6 and M12 to provide a serum bank.

Blood samples will be collected on day of inclusion (M0), before each infusion of Privigen, at M6 and M12 for haematology, blood chemistry and Coombs test.

Histological characteristics (kidney biopsies) will be performed on M0 and M6. The M6 biopsy is specifically requested by the protocol and differs from the usual practice, where it is usually performed at M12 post transplantation.

Infectious and clinical events (deceased patients, graft loss, acute biopsy-proven rejection episode and infectious diseases) will be recorded during the follow-up period.

Histology of for-cause biopsies will be performed according to center practice. We recommend a graft biopsy for patients with acute allograft dysfunction (20% increase of creatinine) without current evident causes of graft dysfunction.

The maximum study duration for a subject, between inclusion and follow-up visits, will be 12 months and the estimated length of time needed to complete the entire study (from enrolment of the first subject to completion of the last subject) 18 months.

Eligibility criteria: Inclusion Criteria:

1. Deceased donor kidney transplant recipients between 3 and 12 months post transplantation.
2. At least 18 years old.
3. With stable renal function assessed within 30 days before inclusion and with delta GFR (MDRD) lower than 10 ml/min (latest result versus the average of the two previous values).
4. Presence of at least one circulating HLA-DSA class I or II against HLA-A, -B, -DR, -DQ, -DP, -C (MFI ≥ 1000) as assessed by Luminex single antigen technique within 30 days before inclusion.
5. With histological markers of active antibody-mediated injury as defined by the microcirculation inflammation score (g, ptc scores defined by current Banff criteria) on protocol biopsies performed at M3 or M12 post-transplantation, or if required between three and twelve months post transplantation (1 ≤ g+ptc ≤ 3).
6. Able to comply with the study procedures and follow the study instructions.
7. Who have read the information sheet and signed the informed consent form.

Exclusion Criteria:

1. Acute renal dysfunction at the time of enrolment: decrease of GFR higher or equal to 10 ml/min (latest result versus the average of the two previous values), or 20% increase of serum creatinine.
2. Previous episode of ABMR.
3. Previous treatment with plasmapheresis, IVIg, within 2 months prior to inclusion

3b. Previous treatment with rituximab, eculizumab or bortezomib within 1 year prior to inclusion

4. Major lesions of active antibody-mediated injury, as defined by Banff criteria, such as g + ptc \>3 or chronic transplant glomerulopathy (cg\>0).

5. History of cardiac insufficiency (New York Heart Association \[NYHA\] III/IV), cardiomyopathy, significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic heart disease, congestive heart failure or severe hypertension.

6. History of thrombotic episodes (deep vein thrombosis, myocardial infarction, cerebrovascular accident).

7. Known allergic or other severe reactions to blood products including intolerability to previous IVIg (i.e. severe headache, hypersensitivity, intravascular hemolysis).

8. Subject with a known deficit in IgA, with antibodies against IgA. 9. Known hyperprolinemia.

10. Ongoing HIV, hepatitis C and hepatitis B infection.

11. Any condition (including alcohol, drug or medication abuse) that is likely to interfere with evaluation of the study product or satisfactory conduct of the study.

12. Not able to comply with study procedures and treatment regimen.

13. Pregnant or lactating women or women of childbearing potential without effective method of contraception (oral contraceptive pill, intra-uterine contraceptive device, contraceptive implant or condom).

14. Participation in any other study involving investigational products, concomitantly or within 30 days prior to entry in the study.

Primary outcomes:
measure: Graft function: estimation of change from baseline Glomerular Filtration Rate (GFR) using MDRD
timeFrame: at months 6
measure: Graft function: estimation of change from baseline Glomerular Filtration Rate (GFR) using MDRD
timeFrame: at months 12
Secondary outcomes:
measure: Change of proteinuria from baseline
timeFrame: months 6 and months 12
measure: Change of HLA-DSA from baseline
timeFrame: months 6 and months 12
measure: Change of Histological characteristics from baseline
timeFrame: at months 6
measure: IgG dosage
timeFrame: up to months 6
measure: Infectious events reported during the study period
timeFrame: up to months 12
Other outcomes:
Locations:
city: Paris
country: France
facility: Service de Néphrologie et transplantation rénale - HU Saint-Louis
state: Ile De France
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Denis GLOTZ, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: