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A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection
A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection
- Source :
- J Am Soc Nephrol
- Publication Year :
- 2020
-
Abstract
- Background Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. Methods We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. Results Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. Conclusions Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.
- Subjects :
- Adult
Graft Rejection
Male
medicine.medical_specialty
030232 urology & nephrology
Renal function
030230 surgery
Placebo
Antibodies, Monoclonal, Humanized
Infections
Gastroenterology
law.invention
03 medical and health sciences
Young Adult
0302 clinical medicine
Randomized controlled trial
Double-Blind Method
law
Isoantibodies
Clinical Research
Internal medicine
medicine
Clinical endpoint
Humans
Kidney transplantation
Proteinuria
business.industry
Interleukin-6
General Medicine
Middle Aged
medicine.disease
Allografts
Kidney Transplantation
Tissue Donors
Treatment Outcome
Nephrology
Diverticular disease
Anti-IL-6
Female
medicine.symptom
business
Glomerular Filtration Rate
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 32
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....a78c4052cd7b20146363d17ecfac000f