Clazakizumab for Kidney Transplant Rejection

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stanley Jordan, MD

Must not be taking: Live vaccines, Investigational agents

Disqualifiers: HIV, HBV, HCV, TB, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores clazakizumab for individuals whose previous kidney transplant has failed and who face difficulty obtaining another due to a highly sensitized immune system. The researchers aim to help these patients receive a new kidney transplant by using clazakizumab to make their immune system more accepting of a donor kidney. Participants will receive up to six doses of the treatment before a transplant and, if successful, additional doses afterward to support kidney function. Potential candidates include those on the transplant list with a history of pregnancy, blood transfusions, or previous kidney transplants. As a Phase 1, Phase 2 trial, this research focuses on understanding how clazakizumab works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in kidney transplant treatments.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you have used investigational agents within 4 weeks of the trial or if you have had a recent infection requiring antibiotics.

Is there any evidence suggesting that clazakizumab is likely to be safe for humans?

Research has shown that clazakizumab has been tested for safety in people with kidney transplant issues. Past studies suggest that this treatment is generally well-tolerated. For example, in a study with 20 patients, clazakizumab did not cause serious side effects, indicating that most participants did not experience major negative reactions.

Every treatment can have some side effects, but clazakizumab's safety appears promising based on current data. Researchers continue to study its use for people needing kidney transplants, especially when other treatments have not been effective. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Clazakizumab is unique because it targets the interleukin-6 (IL-6) pathway, which plays a key role in inflammation and immune response. Unlike standard treatments for kidney transplant rejection that primarily focus on broadly suppressing the immune system, clazakizumab specifically inhibits IL-6, potentially reducing rejection while minimizing side effects associated with generalized immunosuppression. Researchers are excited about this targeted approach because it could lead to better outcomes for transplant patients, offering a more precise way to manage rejection with fewer complications.

What evidence suggests that clazakizumab might be an effective treatment for kidney transplant rejection?

Research has shown that clazakizumab might help treat kidney transplant rejection. This medication blocks a protein called IL-6, which can cause inflammation and harm to transplanted kidneys. Studies have found that clazakizumab could reduce the body's immune response against the transplanted organ. Early clinical data suggest this treatment might prevent or manage kidney damage after a transplant. While more research is needed, initial results are promising for those facing transplant rejection issues. In this trial, all participants will receive clazakizumab to evaluate its effectiveness in managing transplant rejection. ^{1 3 6 7 8}

Who Is on the Research Team?

Stanley Jordan, MD

Principal Investigator

Cedars-Sinai Medical Center Comprehensive Transplant Center

Are You a Good Fit for This Trial?

This trial is for highly-HLA sensitized patients aged 15-75 awaiting a kidney transplant, who have had previous allograft failure, pregnancies, transfusions or transplants. They must be on the UNOS list with a cPRA≥50%, vaccinated against pneumococcus and TB-free. It excludes those intolerant to IL-6 inhibitors, pregnant or lactating women, HIV/HBV/HCV positive individuals, recent live vaccine recipients and those with certain infections or malignancies.

Inclusion Criteria

I am a highly sensitized patient waiting for a kidney transplant.

I am between 15 and 75 years old.

I have had pregnancies, blood transfusions, or a kidney transplant.

Exclusion Criteria

I cannot tolerate clazakizumab or similar medications.

I have tested positive for hepatitis B or C.

I have an active CMV or EBV infection confirmed by blood tests.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Desensitization Treatment

Participants receive up to 6 doses of clazakizumab 25 mg monthly pre-transplantation for desensitization

6 months

6 visits (in-person)

Post-Transplant Treatment

Participants who receive an HLAi transplant continue to receive 6 doses of clazakizumab monthly post-transplantation

6 months

6 visits (in-person)

Extended Treatment

Participants may continue to receive another 6 doses of clazakizumab if improvements are seen after the 6th dose post-transplant

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including protocol biopsies at 6 and 12 months post-transplant

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Clazakizumab

Trial Overview The study tests Clazakizumab in patients needing desensitization before a kidney transplant. Participants will receive up to six monthly pre-transplant doses of Clazakizumab (25 mg), continuing post-transplant if successful. The treatment aims to improve chances of receiving an HLA incompatible renal transplant and reduce rejection.

How Is the Trial Designed?

Group I: Clazakizumab Experimental Treatment 1 Intervention

All twenty patients will receive clazakizumab monthly. Patients will receive up to 6 doses pre-transplantation. If patients are transplanted during the study, they will then receive 6 doses of clazakizumab (monthly) and a 6 month protocol biopsy will be performed. Based on the biopsy results and clinical labs PI will determine if patients should continue monthly doses for up to another 6 doses and day 330 post-transplantation. Patients who received 12 post-transplant doses of clazakizumab will then undergo a 12 month protocol biopsy.

Who Is Running the Clinical Trial?

Stanley Jordan, MD

Lead Sponsor

Trials

4

Recruited

90+

Published Research Related to This Trial

Clazakizumab, an anti-IL-6 treatment, was well tolerated in a pilot study of 20 highly HLA-sensitized patients, leading to significant reductions in HLA alloantibodies and enabling 18 out of 20 patients to successfully receive transplants without a rebound of donor-specific antibodies.

The treatment was associated with an increase in regulatory immune cells post-transplant, although antibody-mediated rejection occurred in three patients, indicating that while clazakizumab shows promise for desensitization, further randomized controlled trials are needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation. Vo, AA., Huang, E., Ammerman, N., et al.[2023]

The Phase 3 IMAGINE study is the first large-scale trial evaluating clazakizumab, a monoclonal antibody targeting interleukin-6, for treating chronic active antibody-mediated rejection (AMR) in approximately 350 kidney transplant recipients.

Clazakizumab aims to reduce donor-specific antibody production and stabilize kidney function, with the trial using the eGFR slope as a key measure to predict graft loss, potentially leading to faster approval of new treatments for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design. Nickerson, PW., Böhmig, GA., Chadban, S., et al.[2022]

In a study of 27 kidney transplant patients with severe, steroid-resistant rejection, treatment with rituximab led to significant improvements in kidney function, as indicated by a decrease in serum creatinine levels from 5.6 mg/dL to 0.95 mg/dL at discharge.

Only three patients experienced graft loss not related to patient death during a follow-up period of about 605 days, suggesting that rituximab may effectively help reverse rejection episodes and improve transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab as treatment for refractory kidney transplant rejection. Becker, YT., Becker, BN., Pirsch, JD., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33443079/

A Randomized Clinical Trial of Anti-IL-6 Antibody ... Our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2468024925005339

The Effects of Clazakizumab on Peripheral Blood and ... Overall, our results provide mechanistic insights into the effects and limitations, of IL-6 neutralization in humans in the context of AMR.

3. academic.oup.com academic.oup.com/ckj/article/18/5/sfaf108/8113983

Targeting IL-6 in antibody-mediated kidney transplant rejection Early clinical data suggest that blocking IL-6 activity could be a promising strategy for the prevention and management of kidney allograft injury.

4. trialsjournal.biomedcentral.com trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06897-3

Clazakizumab for the treatment of chronic active antibody ... In conclusion, chronic active AMR is a major cause of graft loss, with no effective treatments, and there is a lack of clinical data to support ...

5. asn-online.org asn-online.org/about/press/releases/ASN_PR_20241026_Djamali10.17FINAL.pdf

Trial Assesses Antibody Therapy for Chronic Active ... Study: “Clazakizumab in Chronic Active Antibody-Mediated Kidney Transplant Rejection: Results of the IMAGINE Phase 3 Study”. Join ASN and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9772593/

Clazakizumab for the treatment of chronic active antibody ... We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR.

7. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/77/NCT03380377/Prot_000.pdf

Clazakizumab (Anti-IL-6 monoclonal) In this trial, we found that tocilizumab improved renal transplant rates in patients who had failed desensitization with IVIG. + rituximab +/- ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2468024922011366

Evaluation of Clazakizumab (Anti–Interleukin-6) in Patients ... Reports have shown that kidney transplant recipients frequently exhibit elevated serum and urinary IL-6 levels after transplantation and during rejection ...