This study will allow the assessment of the ability of CFZ533 to replace calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while providing potentially better renal function with an expected similar safety and tolerability profile.…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Mental impairment disorders
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Evaluate the rate of composite efficacy failure (Biopsy Proven Acute Rejection
(BPAR), graft loss (GL) or death) with CFZ533 600 mg and 300 mg regimens
compared to tacrolimus (TAC) Control at Month 12 post-transplantation.
Secondary outcome
To evaluate the renal function (estimated Glomerular Filtration Rate (eGFR) by
MDRD-4 formula) with CFZ533 600 mg and 300 mg regimens compared to TAC Control
at Month 12 post-transplantation.
To evaluate the composite of BPAR, Death, Graft Loss and Loss to Follow-up with
CFZ533 600 mg and 300 mg regimens compared to TAC Control at Month 12 and Month
24 post-transplantation.
To evaluate whether CFZ533 600 mg or 300 mg regimens have lower incidence rates
over 12 months and 24 months post-transplantation compared to the control arm
for the following events:
- BPAR
- Treated Biopsy Proven Acute Rejection (tBPAR)
- Acute Rejection (AR)
- Treated Acute rejection (tAR)
- Antibody mediated (humoral) rejection
- Graft Loss (GL)
- Death.
To evaluate eGFR and change in eGFR up to Month 24 post-transplantation.
To assess the safety and tolerability of CFZ533 regimens compared to control to
Month 12 and Month 24.
To assess the pharmacokinetics of multiple doses of CFZ533 over the 12-month
and 24-month treatment and explore the dose-exposure relationship.
To assess the levels of peripheral soluble CD40 (sCD40) at baseline, over the
12-month and 24-month treatment period (to inform target biology, target
engagement).
To evaluate the immunogenicity of CFZ533 by analysis of anti-CFZ533 antibodies
(over the 12-month and 24-month treatment period).
Background summary
The purpose of the study is to investigate the safety, efficacy,
pharmacokinetics (PK) and pharmacodynamics (PD) of two calcineurin inhibitor
(CNI)-free regimens of CFZ533, compared to standard of care control, in adult
de novo liver transplant recipients.
Study objective
This study will allow the assessment of the ability of CFZ533 to replace
calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while
providing potentially better renal function with an expected similar safety and
tolerability profile.
The study results will be used to inform the CFZ533 dose and regimen selection
for a pivotal Phase III trial in de novo liver transplant population.
Study design
Study CFZ533A2202 is a randomized, 12-month, active-controlled, open-label,
multi-center, dose range finding study to evaluate the efficacy, safety,
tolerability, PK and PD of two CFZ533 regimens with a 12-month additional
follow-up and a long-term extension in adult de novo liver transplant
recipients.
Intervention
- Arm 1 - TAC Control: Tacrolimus + MMF + CS (n=32).
- Arm 2 - CFZ533 600 mg regimen: 30 mg/kg IV (Day 8±1), 15 mg/kg IV (Day 15),
then CFZ533 SC 600 mg every 2 weeks from Day 29 to End of Study (EOS) + MMF +
CS (n=48).
- Arm 3 - CFZ533 300 mg regimen: 30 mg/kg IV (Day 8±1), and then CFZ533 300 mg
every 2 weeks SC from Day 29 to EOS + MMF + CS (n=48).
- For Arm 2 and 3, use of vials from Day 29 to Month 12, and then switch to
pre-filed syringes once available.
Study burden and risks
Duration: 2 years, 20-53 hospital visits, 0-28 in-home visits.
Blood pressure, pulse, temperature: 16x
Blood and urine tests: on every (hospital) visit
Pregnancy test: monthly
Liver biopsy: optional at Baseline and M12, and if medically required
ECG: 4-5x
Optional Neurocognitive Tests: 5x
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
Screening period up to liver transplantation:
-Male or female subjects between 18 to 70 years of age.
-Recipients of a primary liver transplant from a deceased donor.
-Up to date vaccination as per local immunization schedules.
-Recipients tested negative for HIV.
-MELD score <=30 (based on laboratory values, using the United Network for Organ
Sharing (UNOS) MELD calculator: MELD calculator:
https://unos.org/resources/allocation-calculators/).
-Transplantation to occur within defined screening period following informed
consent signature.
At randomization:
-Recipients with no active HCV and HBV replication. Recipients with HCV
antibody positive should have no detectable HCV-RNA. Recipients with Hepatitis
B infection should have no detectable HBV DNA. Cases of spontaneous HCV
clearance should be discussed with sponsor.
-Allograft is functioning at an acceptable level by the time of randomization
as defined by AST, ALT, and Alkaline Phosphatase levels <= 5 times ULN and Total
Bilirubin <= 2 times ULN.
-Renal function (eGFR, MDRD-4 formula) >= 30 mL/min/1.73 m2 based on most recent
post-transplant value prior to randomization.
-Recipients who have been initiated on an immunosuppressive regimen that
contains TAC, mycophenolate mofetil (MMF) and corticosteroids (CS) as per
protocol.
Exclusion criteria
Screening period up to liver transplantation:
-Recipients of multiple solid organ or islet cell transplants, or recipients
that have previously received a tissue transplant, or a combined liver-kidney
transplant.
-Recipients of a liver from a donor after cardiac death (DCD), from a living
donor, or of a split liver.
-Recipient who tests negative for Epstein Barr virus (EBV).
-Recipients receiving an ABO incompatible allograft.
-History of malignancy of any organ system (except hepatocellular carcinoma
(HCC) or localized basal cell carcinoma of the skin), treated or untreated,
within the past 5 years, regardless of whether there is evidence of local
recurrence or metastases.
-Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule <= 5
cm, 2-3 nodules all <= 3 cm, without evidence of metastatic disease or vascular
invasion) at the time of transplantation.
-Recipients transplanted for acute liver failure (does not apply to acute on
chronic liver failure).
-Any use of antibody induction therapy, or use of any immunosuppressive
medications (or other medications prohibited by the protocol)
-Patients who have received a live vaccine within four weeks prior to
transplantation.
-Recipients with donors positive for HIV.
-Recipients with donors positive for HBsAg.
-Recipients who are HCV antibody-positive without documented sustained viral
response (SVR) at 12 weeks after finishing anti HCV treatment (e.g.
direct-acting antivirals).
-Recipients with HCV RNA-positive donors.
At randomization:
-Any post-transplant history of thrombosis, occlusion or stent placement in any
hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time
during the run-in period prior to randomization.
-Recipients with an absolute neutrophil count of < 1,000/mm³ or white blood
cell count of < 2,000/mm³.
-Recipients with clinically significant systemic infection requiring use of
intravenous (IV) antibiotics.
-Evidence of active tuberculosis (TB) infection (after anti-TB treatment,
patients with history of latent TB may become eligible according to national
guidelines).
-Recipients who are on renal replacement therapy at randomization.
-Any episode of acute rejection or suspected rejection prior to randomization.
-HCC participants whose explanted liver graft pathology report shows i) pTNM
stage beyond T2N0M0, ii) presence of mixed carcinoma, iii) microvascular
invasion despite pTNM stage.
-Participants with body weight < 30 kg or > 180 kg
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 | EUCTR2018-001836-24-NL |
| ClinicalTrials.gov | NCT03781414 |
| CCMO | NL68970.078.19 |