CSL300 for Kidney Failure

(POSIBIL6ESKD Trial)

Recruiting at208 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: CSL Behring

Must not be taking: Immunosuppressants

Disqualifiers: Abnormal LFTs, Life-threatening disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing CSL300, a new treatment, to see if it helps people with heart disease or diabetes who are on dialysis. The study aims to find the right dose and check if it improves heart health by reducing inflammation.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using systemic immunosuppressant drugs.

Is CSL300 (Clazakizumab) safe for use in humans?

Clazakizumab, also known as CSL300, has been studied in kidney transplant patients and was generally found to be safe, with a manageable safety profile. It was well tolerated in studies, allowing many patients to receive transplants without significant adverse effects. ^{1 2 3 4 5}

What makes the drug CSL300 unique for treating kidney failure?

CSL300, also known as Clazakizumab, is unique because it targets interleukin-6 (a protein involved in inflammation) and is being tested specifically for kidney failure, which may offer a new approach compared to existing treatments that focus on other mechanisms or conditions like lupus nephritis. ^{6 7 8 9 10}

Research Team

Study Director

Principal Investigator

CSL Behring LLC

Eligibility Criteria

Adults with end-stage kidney disease (ESKD) on dialysis for at least 12 weeks can join this trial. They must also have diabetes or atherosclerotic cardiovascular disease (ASCVD), and signs of inflammation shown by high hs-CRP levels. People who were in the earlier part of the study, have certain gastrointestinal conditions, use strong immune system drugs, or have abnormal liver tests cannot participate.

Inclusion Criteria

I have been on dialysis for my kidney failure for at least 12 weeks.

I am 18 years old or older.

I have been diagnosed with diabetes or heart and blood vessel disease.

Exclusion Criteria

Subjects who participated in Part 1 (phase 2b) are not eligible to participate in Part 2 (phase 3)

I have had GI perforation, inflammatory bowel disease, or peptic ulcer disease.

I am currently taking drugs that suppress my immune system.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Finding (Phase 2b)

Participants receive varying doses of CSL300 or placebo to determine optimal dosing

12 weeks

Cardiovascular Outcomes Assessment (Phase 3)

Assessment of the efficacy of CSL300 on cardiovascular outcomes and safety in subjects with systemic inflammation and ESKD

Duration not specified

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CSL300 (Monoclonal Antibodies)
• Placebo (Other)

Trial Overview The study is testing CSL300 against a placebo to find the right dose and see if it helps with heart-related outcomes in patients with ESKD undergoing dialysis. It's organized into two parts: first finding the correct dosage and then checking its effectiveness and safety.

Participant Groups

Group I: CSL300 (medium dose)(Phase 2b) Experimental Treatment 1 Intervention

IV administration

Group II: CSL300 (low dose)(Phase 2b) Experimental Treatment 1 Intervention

Intravenous (IV) administration

Group III: CSL300 (high dose)(Phase 2b) Experimental Treatment 1 Intervention

IV administration

Group IV: CSL300 (Phase 3) Experimental Treatment 1 Intervention

IV administration

Group V: Placebo (Phase 2b) Placebo Group 1 Intervention

IV administration

Group VI: Placebo (Phase 3) Placebo Group 1 Intervention

IV administration

Who Is Running the Clinical Trial?

CSL Behring

Lead Sponsor

Trials

204

Recruited

1,207,000+

Dr. Paul McKenzie

CSL Behring

Chief Executive Officer since 2023

PhD in Chemical Engineering from Carnegie Mellon University, B.S. in Chemical Engineering from the University of Pennsylvania

Dr. Bill Mezzanotte

CSL Behring

Chief Medical Officer since 2021

MD from Duke University

Findings from Research

A single dose of alemtuzumab (30 mg) was used in a prospective study to create a steroid and calcineurin inhibitor-free regimen for kidney transplants, showing promising results over a follow-up period of up to 48 months.

The study indicated that patients receiving sirolimus had a higher glomerular filtration rate and fewer acute rejection episodes compared to those on tacrolimus, suggesting that this regimen may improve kidney function and reduce the need for traditional immunosuppressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab preconditioning allows steroid-calcineurin inhibitor-free regimen in live-donor kidney transplant. Refaie, AF., Mahmoud, KM., Ismail, AM., et al.[2017]

In a study of 21 pediatric patients who received deceased donor kidney transplants, the use of a single dose of alemtuzumab for induction and a steroid-free immunosuppression protocol resulted in a 95% graft survival rate and 100% patient survival over an average follow-up of 32 months.

The approach was found to be safe, with no cases of serious infections like cytomegalovirus or polyoma BK viral nephropathy, although three patients experienced acute rejection due to non-adherence to the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: a seven-yr experience. Supe-Markovina, K., Melquist, JJ., Connolly, D., et al.[2019]

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]

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]

Alemtuzumab, a humanized monoclonal antibody, is being increasingly used in renal transplantation to provide intense immunosuppression while minimizing or avoiding the nephrotoxic effects of calcineurin inhibitors (CNIs) and the adverse effects of steroids.

The use of alemtuzumab allows for rapid and profound depletion of lymphocytes, which may improve long-term graft outcomes by reducing the need for traditional immunosuppressive agents that can harm kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of alemtuzumab (Campath-1H) in renal transplantation. Pham, PT., Lipshutz, GS., Pham, PT., et al.[2021]

The combination of rituximab and belimumab was found to be safe for patients with refractory lupus nephritis, showing no increase in adverse events compared to those receiving rituximab alone.

While the addition of belimumab did not improve clinical efficacy compared to rituximab and cyclophosphamide alone, it did lead to a greater reduction in certain B cell populations, suggesting a mechanism that enhances the negative selection of autoreactive B cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Atisha-Fregoso, Y., Malkiel, S., Harris, KM., et al.[2022]

In a study of 1355 patients with lupus nephritis treated with tacrolimus for 5 years, the treatment was found to be well tolerated, with serious adverse drug reactions occurring mainly in the first 28 weeks and no significant increase in risk over time.

Tacrolimus significantly improved key health markers related to lupus nephritis, such as urine protein levels and anti-dsDNA antibody levels, while maintaining a low cumulative rate of progression to renal failure (6.6% at Year 5) and manageable relapse rates (30.6% at Year 5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST). Takeuchi, T., Wakasugi, N., Uno, S., et al.[2021]

Eculizumab shows promising efficacy in improving renal function in patients with systemic lupus erythematosus (SLE) who have renal involvement, particularly in cases of thrombotic microangiopathy (TMA) and refractory lupus nephritis, based on a review of six publications.

All patients treated with eculizumab demonstrated sustained improvement in renal function and normalization of complement levels over a median follow-up of 9 months, indicating its potential as a therapeutic option for severe cases of SLE with renal complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence. Sciascia, S., Radin, M., Yazdany, J., et al.[2020]

In a study of 25 patients with active lupus nephritis, sirukumab did not show the expected efficacy in reducing proteinuria compared to placebo, with a median percent change of 0.0% in the sirukumab group versus a -43.3% increase in the placebo group at week 24.

The safety profile of sirukumab raised concerns, as 47.6% of patients experienced serious adverse events, primarily infections, indicating that while the treatment was not effective, it also posed significant safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis. Rovin, BH., van Vollenhoven, RF., Aranow, C., et al.[2019]

Rituximab has been found to be safe and effective for treating non-renal systemic lupus erythematosus (SLE), particularly in improving disease activity and reducing the need for steroids, based on a review of 26 studies involving 1,231 patients.

While rituximab showed positive effects on conditions like arthritis and thrombocytopenia, relapses of disease were noted, and further high-quality studies are necessary to evaluate the long-term effects of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: a systematic review. Cobo-Ibáñez, T., Loza-Santamaría, E., Pego-Reigosa, JM., et al.[2022]

References

1. Turkey pubmed.ncbi.nlm.nih.gov

Alemtuzumab preconditioning allows steroid-calcineurin inhibitor-free regimen in live-donor kidney transplant. [2017]

2. Denmark pubmed.ncbi.nlm.nih.gov

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: a seven-yr experience. [2019]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Clazakizumab for desensitization in highly sensitized patients awaiting transplantation. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

The evolving role of alemtuzumab (Campath-1H) in renal transplantation. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. [2022]

7. Canada pubmed.ncbi.nlm.nih.gov

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST). [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Expanding the therapeutic options for renal involvement in lupus: eculizumab, available evidence. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: a systematic review. [2022]