Liver Transplant Rejection
Conditions
Keywords
Liver transplantation, de novo recipients, deceased donor, CFZ533, CNI-free immunosuppression, Transplant rejection
Brief summary
This was a multicenter, open-label, active-controlled study to evaluate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of two CFZ533 maintenance doses in de novo liver transplant recipients.
Detailed description
The study was designed as a randomized, 36-month clinical trial comprised of: * A screening period (up to 2 months) starting from informed consent, screening visit, and including successful liver transplantation (LTx). * A run-in treatment period following successful transplantation that ended on the day of randomization or randomization failure, at Day 8 (with visit window of +/- 2 days) post-LTx. * The primary treatment period (Treatment Period 1) starting at randomization Day 8 +/- 2 post-LTx up to Month 12 followed by a 12-month follow-up treatment period (Treatment Period 2) until Month 24. * The long-term extension period (Treatment Period 3) starting post Month 24 until the end of the study (EOS). * A minimum 12-week safety follow-up period for all patients after EOS. The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.
Interventions
BIOLOGICALCFZ533
Comparison with standard of care immunosuppression
DRUGTacrolimus - MMF - corticosteroids
Standard of care immunosuppresive regimen
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Screening period up to liver transplantation: * Written informed consent obtained before any assessment. * Male or female patients 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. * Transplantation to occur within defined screening period following informed consent signature. At randomization (Day 8 +/- 2): * Recipients with no active HCV and HBV replication. * 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. Key
Exclusion criteria
Screening period up to liver transplantation: * Use of other investigational drugs at screening within 30 days or 5 half-lives of screening. * 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 tested negative for Epstein Barr virus (EBV) within 28 days prior to baseline visit. * 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 was evidence of local recurrence or metastases. * Hepatocellular carcinoma that did 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 HIV positive donor. * Recipients with donors HBsAg positive. * Recipients who were 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. * Recipients with donors with macrovesicular steatosis \> 30%. * Pregnant or nursing (lactating) women. At randomization (Day 8 +/- 2): * 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. Absence of any graft vascular thrombosis or occlusion (by diagnostic method used at the site to assess vascular patency) must be confirmed by imaging prior to randomization. * Recipients with platelet count \< 50,000/mm3. * 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. * Recipients who are in a critical care setting at the time of randomization requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents. * Recipients who were on renal replacement therapy at randomization. * Any episode of acute rejection or suspected rejection prior to randomization. * HCC patients whose explanted liver graft pathology report shows (i) pathologic Tumor-Node-Metastasis (pTNM) stage beyond T2N0M0, (ii) presence of mixed carcinoma, (iii) microvascular invasion despite pTNM stage. * Patients with body weight \< 30 kg or \> 180 kg.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months | Baseline to Month 12 | The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12 | Baseline to Month 12 | Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 \[if female\] x 1.212 \[if Black\]. |
| Number of Participants With Treatment Emergent Adverse Events | Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks. | The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters. |
| Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | Baseline to Month 24 | The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22. |
Countries
Argentina, Belgium, Czechia, France, Germany, Hungary, Italy, Netherlands, Spain, United States
Participant flow
Recruitment details
The patients were enrolled at 3 sites in Argentina, 1 in Belgium, 1 in Czech Republic, 4 in France, 4 in Germany, 1 in Hungary, 1 in Italy, 1 in The Netherlands, 4 in Spain and 9 in United States.
Pre-assignment details
Patients were randomized at a ratio of 2:3:3 to TAC Control (Arm 1) or one of two maintenance regimens of CFZ533: 600 mg CFZ533 subcutaneous (SC) injections every 2 weeks (Arm 2) or 300 mg CFZ533 SC injections every 2 weeks (Arm 3) combined with MMF and CS.
Participants by arm
| Arm | Count |
|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS. | 48 |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS. | 48 |
| TAC Control (TAC + MMF) Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label. | 32 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 | 3 |
| Overall Study | Death | 1 | 4 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 1 |
| Overall Study | Study terminated by sponsor | 39 | 34 | 25 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | TAC Control (TAC + MMF) | Total |
|---|---|---|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 9.94 | 56.2 Years STANDARD_DEVIATION 6.98 | 54.0 Years STANDARD_DEVIATION 9.9 | 55.8 Years STANDARD_DEVIATION 8.92 |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 45 Participants | 46 Participants | 29 Participants | 120 Participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 8 Participants | 34 Participants |
| Sex: Female, Male Male | 37 Participants | 33 Participants | 24 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 48 | 3 / 47 | 0 / 32 | 0 / 47 | 1 / 44 | 0 / 32 |
| other Total, other adverse events | 45 / 48 | 42 / 47 | 30 / 32 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 30 / 48 | 29 / 47 | 20 / 32 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months
The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation.
Time frame: Baseline to Month 12
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months | 8 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months | 12 Participants |
| TAC Control (TAC + MMF) | Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months | 3 Participants |
95% CI: [-0.0729, 0.2165]
95% CI: [0.0072, 0.3276]
Secondary
Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12
Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 \[if female\] x 1.212 \[if Black\].
Time frame: Baseline to Month 12
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12 | 2.05 mL/min/1.73 m^2 |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12 | -9.31 mL/min/1.73 m^2 |
| TAC Control (TAC + MMF) | Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12 | -14.74 mL/min/1.73 m^2 |
Secondary
Number of Participants With Treatment Emergent Adverse Events
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
Population: Safety Set (SAF)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs | 48 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TESAEs | 30 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | Fatal TESAEs | 1 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs leading to discontinuation | 14 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs leading to discontinuation | 17 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs | 44 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | Fatal TESAEs | 4 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Number of Participants With Treatment Emergent Adverse Events | TESAEs | 29 Participants |
| TAC Control (TAC + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs leading to discontinuation | 8 Participants |
| TAC Control (TAC + MMF) | Number of Participants With Treatment Emergent Adverse Events | TESAEs | 20 Participants |
| TAC Control (TAC + MMF) | Number of Participants With Treatment Emergent Adverse Events | Fatal TESAEs | 0 Participants |
| TAC Control (TAC + MMF) | Number of Participants With Treatment Emergent Adverse Events | TEAEs | 32 Participants |
Secondary
Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment
The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22.
Time frame: Baseline to Month 24
Population: Safety Set (SAF)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | CFZ533: Subjects with dose interrupted | 8 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | CFZ533: Subjects with permanent discontinuation of study treatment | 2 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with dose interrupted | 3 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with permanent discontinuation of study treatment | 4 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with dose interrupted | 18 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with permanent discontinuation of study treatment | 9 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with dose interrupted | 23 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | CFZ533: Subjects with dose interrupted | 5 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with permanent discontinuation of study treatment | 5 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | CFZ533: Subjects with permanent discontinuation of study treatment | 3 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with dose interrupted | 3 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with permanent discontinuation of study treatment | 8 Participants |
| TAC Control (TAC + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with dose interrupted | 6 Participants |
| TAC Control (TAC + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with permanent discontinuation of study treatment | 1 Participants |
| TAC Control (TAC + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | TAC: Subjects with permanent discontinuation of study treatment | 4 Participants |
| TAC Control (TAC + MMF) | Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment | MMF: Subjects with dose interrupted | 15 Participants |
Post Hoc
All Collected Deaths
On-treatment deaths were reported from first dose of study treatment to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks. Post-treatment deaths were collected in the post treatment period from 15 weeks after last dose of study medication (CFZ533 participants, Arms 2 & 3) and from 13 weeks for TAC participants (Arm 1), up to approx. 184 weeks. These are not considered Adverse Events.
Time frame: On-treatment deaths: Up to approximately 184 weeks. Post-treatment deaths: Up to approximately 184 weeks.
Population: Safety Set (SAF)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | All Collected Deaths | All deaths | 1 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | All Collected Deaths | Post-treatment deaths | 0 Participants |
| CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) | All Collected Deaths | On-treatment deaths | 1 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | All Collected Deaths | Post-treatment deaths | 1 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | All Collected Deaths | On-treatment deaths | 3 Participants |
| CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) | All Collected Deaths | All deaths | 4 Participants |
| TAC Control (TAC + MMF) | All Collected Deaths | On-treatment deaths | 0 Participants |
| TAC Control (TAC + MMF) | All Collected Deaths | All deaths | 0 Participants |
| TAC Control (TAC + MMF) | All Collected Deaths | Post-treatment deaths | 0 Participants |