A 6-month study of efficacy and safety comparing concentration-controlled Certican® with MSCs to Certican® with standard tacrolimus in renal transplant recipients
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary end point is to compare fibrosis by quantitative Sirius Red scoring
of MSC treated and untreated groups at 6 months compared
to 4 weeks post transplant.
Secondary outcome
Composite end point efficacy failure (Biopsy Proven Acute Rejection (BPAR),
graft loss, death or loss to follow-up) at 6 months; renal function measured by
cGFR (MDRD formula and iohexol clearance) and proteinuria at 6 months; CMV and
BK infection (viremia, disease and syndrome); adverse events; the presence of
donor specific antibodies (DSA) and immune monitoring in the different
treatment groups; to compare the progression of "subclinical" cardiovascular
disease in the different treatment groups by assessing echocardiography and
pulse wave velocity.
Background summary
Kidney transplantation has improved survival and quality of life for patients
with end-stage renal disease. Despite excellent short-term results, long-term
survival of transplanted kidneys has not improved accordingly in the last
decades. Calcineurin inhibitors (CNI) have been the cornerstone of
immunosuppressive therapy for many years, due to their efficacy in preventing
acute rejection. However, CNI have nephrotoxic side effects that can directly
contribute to renal dysfunction and compromise long-term outcomes. Consequently
there is a strong interest in immunosuppressive (IS) regimens that maintain
efficacy for the prevention of acute rejection, whilst reducing nephrotoxicity.
In this perspective the combination of mesenchymal stromal cells (MSCs) with a
mTor inhibitor (Everolimus (Certican®)) might be an optimal strategy to
facilitate CNI (tacrolimus) withdrawal. MSCs have IS properties and roles in
tissue repair and everolimus is a proliferation signal inhibitor with potent
immunosuppressant effects. In experimental studies the combination of mTor
inhibitor and MSCs was shown to attenuate alloimmune responses and to promote
allograft tolerance. This study will test the hypothesis that MSCs in
combination with Certican® facilitate tacrolimus withdrawal, reduce fibrosis
and decrease the incidence of opportunistic infections compared to standard
tacrolimus dose.
Study objective
A 6-month study of efficacy and safety comparing concentration-controlled
Certican® with MSCs to Certican® with standard tacrolimus in renal transplant
recipients
Study design
Open label, randomized, non blinded, prospective, single centre clinical phase
II study
Intervention
Patients of the MSC treated groups will receive two doses of autologous bone
marrow (BM) derived MSCs IV, 7 days apart, 6 and 7 weeks after transplantation
in combination with Certican® (1.5 mg/b.i.d.). At the time of the second MSC
infusion tacrolimus will be withdrawn in 2 weeks (after 1 week dose of
tacrolimus will be halved, after 2 weeks stopped). Doses of MSCs will be 1-2
million MSCs per/kg body weight. Patients in the control group will receive
Certican® (1.5 mg/b.i.d) and standard dose tacrolimus (through levels 6-8 ng/ml
after 6 weeks).
Study burden and risks
BM aspiration in 35 patients (100-120 ml) (during the renal transplantation,
thus under general anaesthesia), renal biopsy (1 extra biopsy associated with
participation); visits to the hospital (1 extra hospital stay for renal
biopsy), 13 visits, outpatient visits performed as expected in all
transplantation patients; extra blood samples: iohexol 2 times 5 time points,
6ml blood per time point= 60 ml blood; Blood for immune monitoring: 6 times 50
ml blood =300 ml blood; risks MSC infusion and risks CNI withdrawal. Expected
benefit: MSCs in combination with Certican® facilitate tacrolimus withdrawal,
reduce fibrosis and decrease the incidence of opportunistic infections compared
to standard tacrolimus dose.
Albinusdreef 2
Leiden 2333 RC
NL
Albinusdreef 2
Leiden 2333 RC
NL
Listed location countries
Age
Inclusion criteria
1. Female or male, aged between 18 and 75 years.
2. Subject is willing to participate in the study, must be able to give informed consent and the consent must be obtained prior to any study procedure.
3. Recipients of a first kidney graft from a deceased, living-unrelated or non-HLA identical living related donor > 50 years of age.
4. Panel Reactive Antibodies (PRA) <= 10%.
5. Patients must be able to adhere to the study visit schedule and protocol requirements.
6. If female and of child-bearing age, subject must be non-pregnant, non-breastfeeding, and use adequate contraception.
Exclusion criteria
1. Double organ transplant recipient.
2. Biopsy proven acute rejection (according to the Banff criteria) in the first 6 weeks after transplantation (before MSC infusion).
3. Patients with evidence of active infection or abscesses (with the exception of an uncomplicated urinary tract infection) before MSC infusion.
4. Patients suffering from hepatic failure.
5. Patients suffering from an active autoimmune disease.
6. Patients who have had a previous BM transplant.
7. A psychiatric, addictive or any disorder that compromises ability to give truly informed consent for participation in this study.
8. Use of any investigational drug after transplantation.
9. Documented HIV infection, active hepatitis B, hepatitis C or TB according to current transplantation inclusion criteria.
10. Subjects who currently an active opportunistic infection at the time of MSC infusion (e.g., herpes zoster [shingles], cytomegalovirus (CMV), Pneumocystis carinii (PCP), aspergillosis, histoplasmosis, or mycobacteria other than TB, BK) after transplantation.
11. Malignancy (including lymphoproliferative disease) within the past 2-5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence) according to current transplantation inclusion criteria.
12. Known recent substance abuse (drug or alcohol).
13. Contraindications to undergo a BM biopsy.
14. Patients who are recipients of ABO incompatible transplants.
15. Cold ischemia time >30 hrs.
16. Patients with severe total hypercholesterolemia (>7.5 mmol/L) or total hypertriglyceridemia (>5.6 mmol/L) (patients on lipid lowering treatment with controlled hyperlipidemia are acceptable).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-000819-25-NL |
| CCMO | NL43712.000.13 |