Abatacept for Kidney Transplant Recipients

Recruiting at 20 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Calcineurin inhibitors, Mycophenolic acid, Steroids

Must not be taking: Immunomodulatory agents, Investigational drugs

Disqualifiers: HIV, Active Hepatitis B, COPD, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

800 Participants Needed

Trial Summary

What is the purpose of this trial?

800 adult first time kidney transplant recipients will be enrolled in the Observational Study and followed to evaluate their Human Leukocyte Antigen (HLA)-DR/DQ molecular mismatch (mMM) score as a risk-stratifying prognostic biomarker. Six months after transplant the study will identify those who meet the eligibility criteria for the Nested Randomized Control Trial (RCT). 300 eligible subjects will be randomized 2:1 to abatacept or Standard of care (SOC) in the randomization and followed for 18 months monitoring for safety and improvement in renal function, neurocognitive function, and a life participation patient reported outcome measure (PROM). The primary objective of the Observational Study is to test the validity of the HLA-DR/DQ mMM score as a prognostic biomarker for stratification of post-transplant alloimmune risk. Whereas the objective of the Nested RCT is to test whether a superior outcome in kidney function (primary endpoint), as well as secondary endpoints (neurocognitive function, and life participation PROM), will be achieved in patients who are transitioned from Tacrolimus (TAC) to abatacept, while maintaining efficacy (freedom from biopsy proven acute rejection).

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that participants will transition from Tacrolimus to abatacept. This suggests you may need to change some medications, but it's best to discuss with the study team for specific guidance.

What data supports the effectiveness of the drug abatacept for kidney transplant recipients?

A study involving kidney transplant recipients who could not tolerate standard immunosuppressive drugs showed that switching to abatacept helped maintain kidney function and patient survival over a long period. This suggests abatacept could be a promising option for these patients. ^{1 2 3 4 5}

Is abatacept generally safe for humans?

Abatacept (Orencia) has been studied for rheumatoid arthritis and is generally considered safe, but it may increase the risk of infections and allergic reactions. Patient alert cards are used to inform patients and healthcare professionals about these risks. ^{1 2 4 6 7}

How does the drug abatacept differ from other treatments for kidney transplant recipients?

Abatacept is unique because it is a selective costimulation modulator that inhibits the full activation of T cells, which are part of the immune system. This mechanism is different from other treatments that may not specifically target T cell activation, making it potentially beneficial for preventing immune-related complications in kidney transplant recipients. ^{1 2 4 5 8}

Research Team

Peter S Heeger, M.D.

Principal Investigator

Cedars Sinai Medical Center: Transplantation

Peter Nickerson, M.D.

Principal Investigator

University of Manitoba Max Rady College of Medicine - Transplantation

Eligibility Criteria

This trial is for adult kidney transplant recipients who are on a stable medication regimen, have good kidney function (eGFRCKD-EPI 30-90 ml/min/1.73m^2) at 6 months post-transplant, and no acute rejection or significant infections. They must agree to use effective contraception and be able to consent. Exclusions include severe lung disease, certain viral infections like HIV or active hepatitis B, recent other vaccine or drug trials participation.

Inclusion Criteria

I am of childbearing age and have a negative pregnancy test.

I am eligible for or have received a compatible kidney transplant recently.

Vaccines up to date as per Division of Allergy, Immunology, and Transplantation (DAIT) guidance for patients in transplant trials

Exclusion Criteria

I am currently using drugs that affect my immune system.

I have not been exposed to the Epstein-Barr virus and have received a kidney transplant.

Inability or unwillingness of a participant to give written informed consent or comply with study protocol including a mandated 6-mo kidney transplant biopsy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

0-6 months

Multiple visits during initial hospitalization

Observational Study

Participants are followed observationally to evaluate HLA-DR/DQ molecular mismatch (mMM) as a risk-stratifying prognostic biomarker

24 months

Regular follow-up visits

Nested RCT Randomization

Eligible participants are randomized to abatacept or Standard of Care (SOC) and followed for safety and improvement in renal function, neurocognitive function, and life participation

18 months

Regular follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Abatacept
• Standard of Care

Trial Overview The study first observes 800 patients to see if their HLA-DR/DQ mismatch score can predict immune system risk after a transplant. Then it randomly assigns 300 eligible patients either to continue standard care or switch from Tacrolimus to Abatacept treatment, monitoring kidney function improvement and quality of life for 18 months.

Participant Groups

Group I: Nested RCT - Treatment Group (Abatacept) Experimental Treatment 1 Intervention

Eligible subjects will be re-consented and randomized to the investigational (abatacept/Mycophenolate mofetil (MMF)/Pred) Arm. Starting with abatacept at a fixed dose (125 mg s.c. weekly) and eliminate Calcineurin Inhibitor (CNI) over \~3 months using serial Tacrolimus (TAC) C0 level targets to taper the dose. 2200 subjects will be followed for 18 months post-randomization, monitoring for safety and improvement in renal function, neurocognitive function, and a life participation patient reported outcome measure (PROM). Subjects who develop Biopsy Proven Acute Rejection (BPAR) will have concurrent serum/urine/tissue samples collected and stored.

Group II: Nested RCT - Control Group (SOC) Active Control 1 Intervention

Eligible subjects will be re-consented and randomized to the control group (tacrolimus/Mycophenolate mofetil (MMF)/Pred) . 100 subjects will be and followed for 18 months post-randomization, monitoring for safety and improvement in renal function, neurocognitive function, and a life participation patient reported outcome measure (PROM). Subjects who develop Biopsy Proven Acute Rejection (BPAR) will have concurrent serum/urine/tissue samples collected and stored.

Group III: Observational Study - Full Cohort Active Control 1 Intervention

800 adults first kidney transplant recipients will be followed observationally to evaluate HLA-DR/DQ molecular mismatch (mMM) as a risk-stratifying prognostic biomarker. Donor-recipient HLA-DR/DQ mMM score will be determined at enrollment and recipients will be followed over 24-months post-kidney transplant for primary alloimmune events (i.e., TCMR, DSA, and ABMR). Standard of care (SOC) therapy will be used to satisfy the FDA requirement to prospectively evaluate the HLA-DR/DQ mMM score as a prognostic biomarker for post-kidney transplant outcomes.

Abatacept is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in United States as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis

Approved in Canada as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Approved in Japan as Orencia for:

• Rheumatoid arthritis
• Polyarticular juvenile idiopathic arthritis

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

Abatacept significantly improves health outcomes in patients with rheumatoid arthritis, showing higher likelihoods of achieving American College of Rheumatology (ACR) response rates compared to placebo and other treatments, based on a meta-analysis of 13 randomized control trials involving 5978 patients.

Patients treated with abatacept experienced fewer adverse events compared to those receiving other biologic disease-modifying anti-rheumatic drugs, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of efficacy and safety of abatacept for rheumatoid arthritis: systematic review and meta-analysis. Mohamed Ahamada, M., Wu, X.[2023]

The study found that 60% of rheumatoid arthritis patients were aware of the patient alert cards (PACs) for abatacept, and those who received the PACs had significantly better knowledge about the risk of infections compared to those who did not (64% vs 46%).

Among healthcare professionals, 90% were aware of the PACs, and those who accessed the cards had a higher understanding of infection risks (91% vs 73%), indicating that PACs effectively enhance safety knowledge for both patients and healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linking process indicators and clinical/safety outcomes to assess the effectiveness of abatacept (ORENCIA) patient alert cards in patients with rheumatoid arthritis. Artime, E., Kahlon, R., Méndez, I., et al.[2021]

In a study of 9 kidney transplant recipients who could not tolerate calcineurin inhibitors, switching to abatacept as a rescue immunosuppressive therapy resulted in 100% patient and graft survival over a median follow-up of 115 months.

Patients maintained stable renal function while on abatacept for a median of 82 months, with only one episode of cellular rejection, suggesting that abatacept could be a viable alternative for patients intolerant to traditional immunosuppressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. Badell, IR., Karadkhele, GM., Vasanth, P., et al.[2023]

In a 2-year observational study of 100 patients with moderate to severe rheumatoid arthritis in Austria, abatacept showed a high overall retention rate of 60.5%, with better retention in biologic-naïve patients (65.1%) compared to those with prior biologic failures (58.0%).

The study found that good/moderate EULAR response rates were notably high, reaching 100% in biologic-failure patients, indicating that abatacept can be particularly effective for those who have not responded to previous biologic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept retention and clinical outcomes in Austrian patients with rheumatoid arthritis: real-world data from the 2-year ACTION study. Peichl, P., Alten, R., Galeazzi, M., et al.[2020]

Abatacept (Orencia) significantly improves symptoms of active rheumatoid arthritis and slows joint damage progression in patients who have previously been treated with other therapies, based on results from two phase III trials involving multiple centers over 6 to 12 months.

The treatment is generally well tolerated, with similar rates of serious adverse events between abatacept and placebo, although it may be less well tolerated when combined with other biologic DMARDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept. Hervey, PS., Keam, SJ.[2018]

In a study of 137 rheumatoid arthritis patients treated with abatacept for 24 weeks, significant improvements in disease activity were observed, with SDAI scores decreasing from 24.6 to 12.9 and DAS28-ESR scores from 5.2 to 3.9, indicating effective management of the disease.

The retention rate of abatacept was high at 79.6%, and structural remission was achieved in 63.4% of patients, suggesting that abatacept is a safe and effective first-line biologic treatment for rheumatoid arthritis, particularly in biologic-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of abatacept in routine care of patients with rheumatoid arthritis: Orencia(®) as Biological Intensive Treatment for RA (ORBIT) study. Tanaka, Y., Kubo, S., Yamanaka, H., et al.[2016]

In a study of 2350 patients with moderate-to-severe rheumatoid arthritis, abatacept showed a 2-year retention rate of 47.9%, with higher rates in biologic-naive patients (54.5%) compared to those with prior biologic failures (45.2%).

The main reasons for discontinuation were lack of efficacy (61.4% in biologic-naive vs 67.7% in biologic-failure patients) and safety concerns, while seropositivity for rheumatoid factor and anti-CCP was associated with better retention rates, suggesting these factors could help predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study. Alten, R., Mariette, X., Lorenz, HM., et al.[2021]

In the ACTION study, which included 677 patients with rheumatoid arthritis in Germany, the retention rate of abatacept at 2 years was 39.9%, with biologic-naïve patients showing a significantly lower retention rate compared to those from other countries (42.1% vs. 58.7%).

Despite similar retention rates between biologic-naïve and biologic-failure patients in Germany, the EULAR response rates for biologic-naïve patients were lower in Germany (85.5%) compared to other countries (92.1%), suggesting potential differences in treatment effectiveness or patient management across regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept retention and clinical outcomes in rheumatoid arthritis: real-world data from the German cohort of the ACTION study and a comparison with other participating countries. Alten, R., Feist, E., Lorenz, HM., et al.[2020]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Analysis of efficacy and safety of abatacept for rheumatoid arthritis: systematic review and meta-analysis. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Linking process indicators and clinical/safety outcomes to assess the effectiveness of abatacept (ORENCIA) patient alert cards in patients with rheumatoid arthritis. [2021]

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

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. [2023]

4. Austria pubmed.ncbi.nlm.nih.gov

Abatacept retention and clinical outcomes in Austrian patients with rheumatoid arthritis: real-world data from the 2-year ACTION study. [2020]

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

Abatacept. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of abatacept in routine care of patients with rheumatoid arthritis: Orencia(®) as Biological Intensive Treatment for RA (ORBIT) study. [2016]

7. Germany pubmed.ncbi.nlm.nih.gov

Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study. [2021]

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

Abatacept retention and clinical outcomes in rheumatoid arthritis: real-world data from the German cohort of the ACTION study and a comparison with other participating countries. [2020]