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NCT02217410

CCFZ533X2201 - PoC Study in de Novo Renal Transplantation

Completed Phase 1, PHASE2 Results posted Last updated 28 September 2021
What this trial tests

Phase 1, PHASE2 trial testing CFZ533 in Kidney Transplantation in 59 participants. Completed in 29 November 2017.

Timeline
5 February 2015
Primary endpoint
29 November 2017
29 November 2017

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposebasic science
Enrollment59
Start date5 February 2015
Primary completion29 November 2017
Estimated completion29 November 2017
Sites14 locations across Netherlands, United States, Germany, Brazil

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Kidney Transplantation. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean Cmax Pharmacokinetic Parameter- Part I Primary · Day 1

Pharmacokinetics as defined by the systemic concentrations and Cmax of certain immunosuppressant medications used in Part I

GroupValue95% CI
CFZ533 + TAC + MMF (Part 1)66.3± 12.3
Mean Tmax Pharmacokinetic Parameter - Part I Primary · Day 1

Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods.

GroupValue95% CI
CFZ533 + TAC + MMF (Part 1)0.2370 – 1.02
Mean AUClast Pharmacokinetic Parameter - Part I Primary · Day 1

Quantify pharmacokinetics of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods.

GroupValue95% CI
CFZ533 + TAC + MMF (Part 1)367± 52.0
Efficacy as Defined by the Frequency and Severity (Banff Classification) of Treated Biopsy Proven Acute Rejection (tBPAR) Adjudicated Data - Part II Primary · 3, 6, 9, and 12 months

To assess the activity of the investigational arm as compared to the standard of care control arm in de novo renal transplant patients as measured by the frequency and severity of tBPAR as measured on the Banff classification scale. An adjudication was performed on all on cause renal biopsies by an independent expert committee blinded to therapy.

Month 3
GroupValue95% CI
CFZ533 + MMF (Part 2)6
Tac + MMF (Part 2)2
Month 6
GroupValue95% CI
CFZ533 + MMF (Part 2)7
Tac + MMF (Part 2)3
Month 9
GroupValue95% CI
CFZ533 + MMF (Part 2)7
Tac + MMF (Part 2)3
Month 12
GroupValue95% CI
CFZ533 + MMF (Part 2)7
Tac + MMF (Part 2)3
Total Soluble CD40 and Total Soluble CD154 Concentrations in Plasma - Part 1 Secondary · Baseline to end of study (Day 1, Day 29, Day 337)

To quantify the change from baseline and recovery of peripheral blood total soluble CD40 and total soluble CD154

Baseline
GroupValue95% CI
sCD40 (Part I)4.03± 4.08
sCD1540.125± 0.007
Day 1
GroupValue95% CI
sCD40 (Part I)8.86± 0.0585
sCD1540.0585± 0.0711
Day 2
GroupValue95% CI
sCD40 (Part I)16.7± 4.51
sCD1540.139± 0.193
Day 3
GroupValue95% CI
sCD40 (Part I)24.8± 4.47
sCD1540.157± 0.235
Day 4
GroupValue95% CI
sCD40 (Part I)31.3± 6.34
sCD1540.241± 0.418
Day 8
GroupValue95% CI
sCD40 (Part I)54.0± 11.2
sCD1540.399± 0.636
Day 15
GroupValue95% CI
sCD40 (Part I)84.1± 13.8
sCD1540.0879± 0.139
Day 22
GroupValue95% CI
sCD40 (Part I)102± 13.9
sCD1540.0500± 0.132
Free CD40 and Total CD40 on B Cells - Part II Secondary · Baseline to end of study (Day 1/predose)

The magnitude and duration of peripheral blood CD40 occupancy. MESF: molecules of equivalent soluble fluorochrome

CFZ553 + MMF (Baseline)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels30836.00± 13648.69
Total CD40 on Whole Blood B Cells12778.80± 7873.76
CFZ553 + MMF (D1 - 6h post dose)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels1623.81± 1359.85
Total CD40 on Whole Blood B Cells13806.90± 7185.66
CFZ553 + MMF (D15)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels799.62± 762.38
Total CD40 on Whole Blood B Cells15160.38± 7398.57
CFZ553 + MMF (D 29)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels817.63± 1540.16
Total CD40 on Whole Blood B Cells13299.60± 6330.89
CFZ553 + MMF (D 57)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels597.13± 523.55
Total CD40 on Whole Blood B Cells12234.38± 6943.13
CFZ553 + MMF (D 85)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels635.47± 614.68
Total CD40 on Whole Blood B Cells9330.86± 8484.46
CFZ553 + MMF (D 197)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels3699.0± 7298.98
Total CD40 on Whole Blood B Cells2820.72± 2347.11
CFZ553 + MMF (253)
GroupValue95% CI
Free CD40 on Whole Blood B Ceels2667.38± 6146.86
Total CD40 on Whole Blood B Cells1427.14± 740.48
Anti-CFZ533 Antibodies - Part I Secondary · Baseline to end of study

To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies

GroupValue95% CI
CFZ533 + TAC + MMF (Part 1)0
Anti-CFZ533 Antibodies - Part II Secondary · Baseline to end of study (screening, baseline, Day 141, Day 225, Day 309, Study Completion)

To evaluate the immunogenicity of CFZ533 via the quantitative analysis of anti-CFZ533 antibodies

Screening
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Tac + MMF (Part 2)0
Baseline
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Day 141
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Tac + MMF (Part 2)0
Day 225
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Tac + MMF (Part 2)0
Day 309
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Tac + MMF (Part 2)0
Study Completion
GroupValue95% CI
CFZ533 + MMF (Part 2)0
Tac + MMF (Part 2)0
eGFR - Part II Secondary · Day 1, Day 29, Day 337,

Renal function as assessed by MDRD (Modification of Diet in Renal Disease) formula. eGFR: Estimated glomerular filtration rate

Day 1
GroupValue95% CI
CFZ533 + MMF (Part 2)9.88.3 – 11.3
Tac + MMF (Part 2)9.77.7 – 11.8
Day 29
GroupValue95% CI
CFZ533 + MMF (Part 2)55.650.4 – 60.7
Tac + MMF (Part 2)44.337.2 – 51.4
Day 337
GroupValue95% CI
CFZ533 + MMF (Part 2)58.252.2 – 64.2
Tac + MMF (Part 2)44.236.1 – 52.3
CFZ533 Plasma PK Concentrations - Part II Secondary · throughout study period (day 84 to day 336)

Quantify the systemic concentrations of CFZ533 in combination with MMF, CS, and tacrolimus in de novo renal transplant patients during the treatment and follow-up periods. A full pharmacokinetic analysis can be performed on the concentration-time data to evaluate the impact of renal transplantation on the various medications used in the treatment regimen.

Day 84
GroupValue95% CI
CFZ533 + MMF (Part 2)247± 58.2
Day 112
GroupValue95% CI
CFZ533 + MMF (Part 2)211± 51.8
Day 140
GroupValue95% CI
CFZ533 + MMF (Part 2)178± 54.9
Day 168
GroupValue95% CI
CFZ533 + MMF (Part 2)157± 57.4
Day 196
GroupValue95% CI
CFZ533 + MMF (Part 2)148± 53.1
Day 224
GroupValue95% CI
CFZ533 + MMF (Part 2)147± 53.8
Day 252
GroupValue95% CI
CFZ533 + MMF (Part 2)151± 35.2
Day 280
GroupValue95% CI
CFZ533 + MMF (Part 2)160± 87.7
Total sCD40 Plasma Concentrations - Part II Secondary · 12 months

To quantify the change from baseline and recovery of peripheral blood total soluble CD40

Baseline
GroupValue95% CI
CFZ533 + MMF (Part 2)3.02± 2.44
Tac + MMF (Part 2)3.67± 2.15
Day 1
GroupValue95% CI
CFZ533 + MMF (Part 2)6.95± 4.29
Tac + MMF (Part 2)1.16± 1.15
Day 4
GroupValue95% CI
CFZ533 + MMF (Part 2)24.6± 11.0
Tac + MMF (Part 2)1.16± 1.15
Day 15
GroupValue95% CI
CFZ533 + MMF (Part 2)69.6± 21.5
Tac + MMF (Part 2)0.869± 1.55
Day 29
GroupValue95% CI
CFZ533 + MMF (Part 2)101± 18.9
Tac + MMF (Part 2)0.362± 0.0746
Day 57
GroupValue95% CI
CFZ533 + MMF (Part 2)140± 17.4
Tac + MMF (Part 2)0.438± 0.316
Day 85
GroupValue95% CI
CFZ533 + MMF (Part 2)189± 76.4
Tac + MMF (Part 2)0.429± 0.324
Day 113
GroupValue95% CI
CFZ533 + MMF (Part 2)215± 75.5
Tac + MMF (Part 2)0.391± 0.129

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 3 years.. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

CFZ533 + TAC + MMF (Part 1)
Serious: 4/7 (57%)
Deaths: 0/7
CFZ533 + MMF (Part 2)
Serious: 21/34 (62%)
Deaths: 0/34
Tac + MMF (Part 2)
Serious: 12/18 (67%)
Deaths: 0/18
Total
Serious: 37/59 (63%)
Deaths: 0/59

Serious adverse events (59 terms)

ReactionSystemCFZ533 + TAC + MMF (Part 1)CFZ533 + MMF (Part 2)Tac + MMF (Part 2)Total
Kidney transplant rejectionImmune system disorders
Cytomegalovirus infectionInfections and infestations
Polyomavirus-associated nephropathyInfections and infestations
PyelonephritisInfections and infestations
Complications of transplanted kidneyInjury, poisoning and procedural complications
DiarrhoeaGastrointestinal disorders
VomitingGastrointestinal disorders
Abdominal painGastrointestinal disorders
Retroperitoneal haematomaGastrointestinal disorders
Transplant rejectionImmune system disorders
UrosepsisInfections and infestations
Graft lossInjury, poisoning and procedural complications
Transplant dysfunctionInjury, poisoning and procedural complications
Blood creatinine increasedInvestigations
HeadacheNervous system disorders
Acute kidney injuryRenal and urinary disorders
LeukopeniaBlood and lymphatic system disorders
PancytopeniaBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
Tricuspid valve incompetenceCardiac disorders
PhotophobiaEye disorders
Vision blurredEye disorders
Diarrhoea haemorrhagicGastrointestinal disorders
Gastrointestinal inflammationGastrointestinal disorders
Inguinal herniaGastrointestinal disorders
Other adverse events (307 terms — click to expand)

ReactionSystemCFZ533 + TAC + MMF (Part 1)CFZ533 + MMF (Part 2)Tac + MMF (Part 2)Total
ConstipationGastrointestinal disorders
NauseaGastrointestinal disorders
HypophosphataemiaMetabolism and nutrition disorders
DiarrhoeaGastrointestinal disorders
HypertensionVascular disorders
BK virus infectionInfections and infestations
Wound complicationInjury, poisoning and procedural complications
LeukopeniaBlood and lymphatic system disorders
InsomniaPsychiatric disorders
Urinary tract infectionInfections and infestations
VomitingGastrointestinal disorders
Oedema peripheralGeneral disorders
NasopharyngitisInfections and infestations
HyperkalaemiaMetabolism and nutrition disorders
HypokalaemiaMetabolism and nutrition disorders
CoughRespiratory, thoracic and mediastinal disorders
FatigueGeneral disorders
Incision site painInjury, poisoning and procedural complications
HyperglycaemiaMetabolism and nutrition disorders
HeadacheNervous system disorders
TremorNervous system disorders
Procedural painInjury, poisoning and procedural complications
AnaemiaBlood and lymphatic system disorders
Cytomegalovirus infectionInfections and infestations
Muscle spasmsMusculoskeletal and connective tissue disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
TachycardiaCardiac disorders
Abdominal painGastrointestinal disorders
LeukocytosisBlood and lymphatic system disorders
Delayed graft functionInjury, poisoning and procedural complications
Postoperative wound complicationInjury, poisoning and procedural complications
Diabetes mellitusMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
Abdominal pain upperGastrointestinal disorders
Complications of transplanted kidneyInjury, poisoning and procedural complications
Transplant dysfunctionInjury, poisoning and procedural complications
Decreased appetiteMetabolism and nutrition disorders
HyperuricaemiaMetabolism and nutrition disorders
HypocalcaemiaMetabolism and nutrition disorders

Most-reported serious reactions: Kidney transplant rejection, Cytomegalovirus infection, Polyomavirus-associated nephropathy, Pyelonephritis, Complications of transplanted kidney, Diarrhoea, Vomiting, Abdominal pain.

Data from ClinicalTrials.gov NCT02217410 adverse events section.

Sponsor's own description

The purpose of this study was to investigate the safety, tolerability, pharmacokinetics (PK) and potential for CFZ533 to replace calcineurin inhibitors (CNI), while providing a similar rate of acute rejection prophylaxis and renal function in a de novo renal transplant population receiving an allograft from standard criteria donors.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint.
    Tang T, Cheng X, Truong B, Sun L, et al · · 2021 · cited 201× · PMID 33091428 · DOI 10.1016/j.pharmthera.2020.107709
  2. The past, present, and future of costimulation blockade in organ transplantation.
    Schroder PM, Fitch ZW, Schmitz R, Choi AY, et al · · 2019 · cited 43× · PMID 31157670 · DOI 10.1097/mot.0000000000000656
  3. Recent advances in kidney transplantation: a viewpoint from the Descartes advisory board.
    Abramowicz D, Oberbauer R, Heemann U, Viklicky O, et al · · 2018 · cited 40× · PMID 29342289 · DOI 10.1093/ndt/gfx365
  4. Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy.
    Kean LS, Turka LA, Blazar BR. · · 2017 · cited 37× · PMID 28258702 · DOI 10.1111/imr.12523
  5. Translational impact of NIH-funded nonhuman primate research in transplantation.
    Knechtle SJ, Shaw JM, Hering BJ, Kraemer K, et al · · 2019 · cited 27× · PMID 31292263 · DOI 10.1126/scitranslmed.aau0143
  6. Costimulation Blockade in Kidney Transplant Recipients.
    van der Zwan M, Hesselink DA, van den Hoogen MWF, Baan CC. · · 2020 · cited 17× · PMID 31749062 · DOI 10.1007/s40265-019-01226-6
  7. Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions.
    Anwar IJ, DeLaura IF, Gao Q, Ladowski J, et al · · 2022 · cited 10× · PMID 35757745 · DOI 10.3389/fimmu.2022.903068
  8. Current Topics of Relevance to the Xenotransplantation of Free Pig Islets.
    Mou L, Shi G, Cooper DKC, Lu Y, et al · · 2022 · cited 6× · PMID 35432379 · DOI 10.3389/fimmu.2022.854883

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing