kidney transplantion

The purpose of this study is to investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of:  two CFZ533 dose regimens in de novo kidney transplant recipients, in combination with mycophenolate mofetil (MMF) and corticosteroids, compared to a standard of care control arm of TAC, MMF and corticosteroids.  one CFZ533 dose regimen started 6-24 months post-transplantation in maintenance kidney transplant recipients, in combination with MMF with or without corticosteroids, compared to a standard of care control arm of TAC and MMF with or without corticosteroids. This study will allow the assessment of the ability of CFZ533 to replace CNIs as the standard of care by potentially improving long term outcome (reduced graft loss) while maintaining comparable short term anti-rejection efficacy, and providing better renal function with a better safety and tolerability profile, in de novo and maintenance renal transplant patients. Overall, results of this study will be used to support the regulatory submission of CFZ533.

CFZ533

CFZ533

solution for intravenous infusions and subcutaneous injections

150 mg/ml

Primary Outcome Measures :
Proportion of patients with composite event (BPAR, Graft Loss or Death) [ Time Frame: Month 12 ]
Cohorts 1 and 2-Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months


Secondary Outcome Measures :
Cohorts 1 and 2-Mean eGFR over 12 months [ Time Frame: Baseline to month 12 ]
Renal function at Month 12

Cohorts 1 and 2-Cohorts 1 and 2-safety of CFZ533 regimens compared to a tacrolimus based regimen [ Time Frame: Baseline to month 12 ]
Proportion of patients with AEs, SAEs, infections, malignancies, thromboembolic events, major adverse cardiovascular events, new onset diabetes mellitus (NODM).

Cohorts 1 and 2-Cohorts 1 and 2 - tolerability of CFZ533 regimens compared to a tacrolimus based regimen [ Time Frame: Baseline to month 12 ]
Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment

Cohorts 1 and 2-pharmacokinetics of CFZ533 during the 60 months treatment period and explore the dose-exposure relationship [ Time Frame: Baseline to month 60 ]
Free CFZ533 plasma concentrations over time

Cohorts 1 and 2-immunogenicity of CFZ533 during the 60 months treatment period [ Time Frame: Baseline to month 60 ]
Semi-quantitative analysis of anti-CFZ533 antibodies in plasma


Other Outcome Measures:
Cohort 1 and 2- To evaluate the effect of CFZ533 to a TAC-based regimen on iBox risk prediction score (iBox) at 12 months [ Time Frame: Month 12 ]
Mean iBox risk prediction score(s)

Inclusion criteria
Patients eligible for inclusion in both cohorts must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patient ≥ 18 years old.
3. Up to date vaccination as per local immunization schedules.
4. Able to communicate well with the Investigator, to understand and comply with the
requirements of the study.
Inclusion criteria specific to de novo Cohort 1:
5. Recipients of a primary kidney transplant from a brain-dead donor (DBD), living unrelated
or non-HLA identical living related donor.
6. Recipients of a kidney with a cold ischemia time (CIT) < 24 hours.
Inclusion criteria specific to maintenance Cohort 2:
7. Recipients of a primary graft received 6 to 24 months prior enrollment, on a regimen
containing TAC+MMF±CS.
8. Patients with an actual eGFR (MDRD-4) ≥ 45 mL/min/1.73m2.

Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
Exclusion criteria specific to de novo Cohort 1:
1. Multi-organ transplant recipients, including en bloc and dual kidney transplantation, or prior
kidney transplant.
2. Recipients of an organ from a donor after cardiac death (DCD).
3. Recipient of an organ from an HLA identical living related donor.
4. ABO incompatible or complement-dependent lymphocytotoxic (CDC) crossmatch positive
transplant (isolated positive B cell crossmatches are not an exclusion criterion).
5. Recipients of kidneys from donors who are older (>) than 65 years.
6. Recipients of kidneys from donors with terminal serum creatinine > 2 mg/dL.
7. Patients at high immunological risk for rejection as determined for assessment of anti-donor
reactivity:
- high PRA > 20% or
- presence of pre-formed DSA. Results 12 weeks prior to enrollment are
acceptable if no blood transfusion or abortion occurred during this period.
8. Recipient of a kidney from a donor who tests positive for HIV, HBsAg or HCV.
Exclusion criteria to maintenance Cohort 2:
9. Recipients of a kidney re-transplant.
10. Recipient of a multi-organ transplant, including en bloc and dual kidney transplantation.
11. DSA within 12 weeks prior enrollment.
12. eGFR decline ≥10.0 mL/min within 12 weeks prior enrollment.
In order to account for variances between laboratories, it is recommended to assess any
change in eGFR using results from one laboratory and avoid comparing results from
different laboratories. The eGFR should be calculated using the MDRD-4 formula (MDRD4 formula is more sensitive to relatively small changes in the serum creatinine).
13. Ongoing rejection or rejection that required treatment within 12 weeks prior enrollment.
14. Severe humoral and/or cellular rejection (BANFF ≥ IIb) within 12 weeks before enrollment.
15. Proteinuria > 1 g/day or UPCR >1.2 mg/mg at time of enrollment.
Exclusion criteria applicable to both Cohorts:
16. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives of enrollment, whichever is longer.
17. History of hypersensitivity to any constituent of the study regimen, and of any drugs of similar
chemical classes.
18. Any additional contraindication to the use of TAC or mycophenolate mofetil according to
the national labeling information of these products (see local product label).
19. Recipient who tests positive for anti-HIV, HBsAg or anti-HCV (without proof of sustained
viral response (SVR) after anti HCV treatment) within 28 days prior to baseline visit.
20. Recipient who tests negative for Epstein Barr virus (EBV) within 28 days prior to baseline
visit.
21. Evidence of active tuberculosis (TB) infection with appropriate documentation (after antiTB treatment, patients with history of latent TB may become eligible according to national
guidelines).
22. Evidence of advanced liver disease (Child-Pugh C), or any sign of liver decompensation.
23. Patient with severe systemic infections, current or within the two weeks prior to
randomization.
24. Patient with any history of coagulopathy or medical condition requiring long-term
anticoagulation which would preclude renal biopsy after transplantation (low dose aspirin
treatment or interruption of chronic anticoagulant is allowed).
25. Patient with increased risk of cardiac arrhythmia:
- Patients with long QT-syndrome or QTcF at baseline consistently exceeding
500 msec.
- Patients requiring antiarrhythmic drugs with QT-prolonging properties
(Class 1a and Class 3).
26. History of malignancy of any organ system, treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases, with the exception
of localized excised non-melanomatous skin lesions.
27. Patient with Hbg < 8 g/dL, WBC count ≤ 2,000/mm3
or with platelet count
≤ 50,000/mm3
.
28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
29. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception during
dosing and for 14 weeks after the study medications have been stopped. Highly effective
contraception methods include:
 Total abstinence (when thisis in line with the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception.
 Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.
 Male sterilization (at least 6 months prior to screening). For female patients on the study,
the vasectomized male partner should be the sole partner for that patient, otherwise
highly effective methods to be applied.
 Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS),
or other forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same brand
(or generic equivalent) for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment is she considered not of child
bearing potential (see additional instructions in Section 6.5.6).
If local regulations deviate from the contraception methods listed above to prevent
pregnancy, local regulations apply and will be described in the ICF.
30. Patients who have received a live vaccine within four weeks before enrollment.
No additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.