Thymoglobulin Induction Therapy for Heart Transplant Recipients

Enrolling by invitation at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Cedars-Sinai Medical Center

Must not be taking: Investigational drugs

Disqualifiers: Previous transplants, BMI > 35, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests Thymoglobulin, an immunosuppressive therapy, to determine its effectiveness in preventing CAV, a condition affecting heart transplant patients. Thymoglobulin is administered alongside standard medications such as Mycophenolate Mofetil, tacrolimus, and steroids. Participants will be randomly assigned to receive either Thymoglobulin or no additional treatment after the transplant. This trial targets individuals undergoing their first heart transplant, who do not have certain infections, and have kidney function within a specific range. As a Phase 2 trial, this research measures Thymoglobulin's effectiveness in an initial, smaller group, allowing participants to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that Thymoglobulin induction therapy is likely to be safe for humans?

Research has shown that Thymoglobulin, a treatment for heart transplant patients, has generally been well-tolerated in past studies. It can help reduce episodes of acute rejection, where the body attacks the new heart. However, it does not appear to improve overall survival rates for these patients.

Regarding safety, Thymoglobulin has been linked to some side effects, including low white blood cell counts and infections, common with treatments that lower immune system activity. Despite this, many patients have used Thymoglobulin without serious problems, suggesting it is safe for many people.

Thymoglobulin has also been used in other medical situations, providing some reassurance about its safety. However, potential participants should still consult their doctor about any concerns to better understand the risks and benefits. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for heart transplant recipients focus on suppressing the immune system to prevent rejection. However, Thymoglobulin is unique because it uses rabbit-derived antibodies that specifically target and eliminate human T-lymphocytes, which are key players in the body's rejection of transplanted organs. This targeted approach may provide more precise and effective immunosuppression compared to standard treatments, potentially reducing the risk of rejection and improving transplant outcomes. Researchers are excited about Thymoglobulin because it represents a more refined method of preventing organ rejection, possibly leading to better long-term success for heart transplant patients.

What evidence suggests that Thymoglobulin might be an effective treatment for preventing CAV in heart transplant recipients?

In this trial, participants will be randomized to receive either Thymoglobulin, also known as rabbit anti-thymocyte globulin, or no induction therapy. Research has shown that Thymoglobulin is often used in heart transplant patients to help prevent rejection of the new heart. Some studies suggest it might allow for lower doses of steroids early on, reducing side effects. However, evidence is mixed on its impact on the long-term success of heart transplants. Specifically, one study found no major improvement in overall success but noted it might help manage early steroid use. Thymoglobulin targets specific immune cells that could cause rejection. While it is a promising option, its benefits can vary from person to person. ^{1 2 6 7 8}

Who Is on the Research Team?

Jon Kobashigawa, MD

Principal Investigator

Director

Are You a Good Fit for This Trial?

This trial is for first-time heart transplant recipients aged 18-70 with functioning kidneys (Creatinine < 2.0 mg/dl). Women must test negative for pregnancy and use two forms of contraception, as should men with childbearing partners. Exclusions include allergies to Thymoglobulin or rabbit proteins, active infections, peptic ulcers, previous transplants, BMI over 35, certain viral infections like HIV or Hepatitis B/C, blood disorders, recent investigational drugs usage except those listed in the study details.

Inclusion Criteria

My creatinine level is below 2.0 mg/dl before a transplant.

I am using two reliable birth control methods during and 4 months after the study.

I understand the study's risks and have signed the consent form.

Exclusion Criteria

My BMI is over 35.

I will need a heart pump after my transplant surgery.

I might have an untreated infection before surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Thymoglobulin® induction therapy with Mycophenolate Mofetil, tacrolimus, and steroids. Thymoglobulin is administered for 5 consecutive days post-operation.

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness, including mechanistic assays and standard care protocols for heart transplant recipients.

12 months

Regular visits as per standard care

What Are the Treatments Tested in This Trial?

Interventions

• Thymoglobulin

Trial Overview The trial tests if Thymoglobulin induction therapy combined with Mycophenolate Mofetil, tacrolimus and steroids can prevent chronic allograft vasculopathy (CAV) post-heart transplant. Participants are randomly assigned to receive either Thymoglobulin or not alongside standard care; their immune cell levels and cytokines will be monitored at intervals.

How Is the Trial Designed?

Group I: Thymoglobulin® Active Control 5 Interventions

Thymoglobulin® (Genzyme) \[rabbit anti-thymocyte globulin (ATG)\] is a purified pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains polyclonal cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. Approximately half of the patients will be randomized to receive a total of 5 doses of Thymoglobulin during the study. The first dose of Thymoglobulin will be administered at 1.5 mg/kg via intravenous infusion over 6 hours immediately upon arrival to the ICU post-operation (day 1). Subsequent doses of 1.5 mg/kg will be administered on days 2, 3, 4, and 5 via IV infusion over 4 hours. In addition, there will be maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and cumulative dose of corticosteroids at 12 months post-transplantation

Group II: No induction therapy Active Control 1 Intervention

Patients qualifying for the study will be randomized before the transplantation surgery in a 1:1 ratio to either Thymoglobulin® or no treatment.

Thymoglobulin is already approved in United States, European Union for the following indications:

Approved in United States as Thymoglobulin for:

• Prophylaxis and treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression
• Severe aplastic anemia

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute cellular rejection after renal transplantation
• Severe aplastic anemia

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

Genzyme, a Sanofi Company

Industry Sponsor

Trials

528

Recruited

186,000+

David Meeker

Genzyme, a Sanofi Company

Chief Executive Officer since 2011

MD from the University of Vermont Medical School, Advanced Management Program at Harvard Business School

Jean-Paul Kress

Genzyme, a Sanofi Company

Chief Medical Officer since 2015

MD from Faculte Necker-Enfants Malades, Paris

Published Research Related to This Trial

The study found that mATG effectively depletes T cells in the blood, spleen, lymph nodes, and bone marrow within one day at doses as low as 1 mg/kg, indicating its strong immunosuppressive capability.

Despite its effectiveness in depleting T cells, mATG does not deplete thymocytes in vivo, suggesting limited access to the thymus, and it preferentially depletes naïve T cells while sparing other immune cell types like B cells and macrophages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. Ruzek, MC., Neff, KS., Luong, M., et al.[2021]

Rabbit-derived antithymocyte globulin (ATG) can induce a strong immune response in patients, leading to the production of antibodies against specific rabbit glycoprotein epitopes, which may compromise its effectiveness in treating conditions like type 1 diabetes.

The study found that patients developed significant levels of antibodies against these rabbit-specific epitopes after ATG treatment, suggesting that using IgGs without these xenoantigens could enhance the safety and efficacy of ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Salama, A., Evanno, G., Lim, N., et al.[2022]

In a study involving 163 renal transplant patients, Thymoglobulin was more effective than Atgam in reversing acute rejection, achieving an 88% rejection reversal rate compared to 76% for Atgam.

Thymoglobulin also demonstrated a lower rate of recurrent rejection at 90 days (17% vs. 36% for Atgam), while both treatments had similar safety profiles and long-term survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation. Gaber, AO., First, MR., Tesi, RJ., et al.[2019]

A serious anaphylactic reaction occurred in a patient during renal transplantation after the first injection of Thymoglobulin, highlighting the potential risk even though such reactions are rare.

The case emphasizes the need for thorough allergy screening for rabbit allergens in patients before administering Thymoglobulin, as it is contraindicated in individuals with a history of hypersensitivity to rabbit proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An avoidable cause of thymoglobulin anaphylaxis. Brabant, S., Facon, A., Provôt, F., et al.[2020]

Thymoglobulin treatment in adult renal transplant recipients resulted in significantly lower rates of acute rejection (4%) compared to Atgam (25%) after one year, indicating better efficacy for Thymoglobulin.

While Thymoglobulin was associated with more frequent early leukopenia, it led to fewer serious adverse events and better overall event-free survival (94% vs. 63% for Atgam), suggesting a safer profile despite the lymphocyte count reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Brennan, DC., Flavin, K., Lowell, JA., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6248055/

Outcomes of Induction Therapy with Rabbit Anti-Thymocyte ... A retrospective cohort study was conducted from 2005 to 2009 and data of consecutive 268 heart transplant recipients were reviewed. Results. The data of 144 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8238107/

Rabbit Antithymocyte Globulin Induction in Heart ... Conclusion: These results suggest that while rATG induction does not improve heart allograft outcomes, it may enable reducing early corticosteroid exposure in ...

3. jhltonline.org jhltonline.org/article/S1053-2498(21)00432-0/abstract

The Optimal Cumulative Dose of Rabbit Antithymocyte ... A cumulative rATG dose of 1.2 mg/kg may be effective in achieving CD3+ counts < 50 cells/mm 3. However, beware of leukopenia or thrombocytopenia.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1053249804000889

A comparison of anti-thymocyte globulin and daclizumab in ... We compared the safety and efficacy of daclizumab and anti-thymocyte globulin (ATG) with respect to the frequency and severity of acute cardiac allograft ...

5. journals.lww.com journals.lww.com/transplantationdirect/fulltext/2016/06000/a_proposal_for_early_dosing_regimens_in_heart.1.aspx

A Proposal for Early Dosing Regimens in Heart Transplant... Rabbit antithymocyte globulin (rATG) is widely used for induction therapy in adult and pediatric heart transplant recipients. Despite the fact that rATG has ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2950133425001867

Cumulative Weight-based Rabbit Anti-thymocyte Globulin ... We retrospectively analyzed a total of 340 primary HTx patients (1983-2018) receiving a fixed rATG dose (125 mg daily for 3 days).

7. journals.lww.com journals.lww.com/transplantationdirect/fulltext/2022/06000/retrospective_evaluation_of_rabbit_antithymocyte.11.aspx

Retrospective Evaluation of Rabbit Antithymocyte Globulin... These recommendations are supported by limited data showing reduced rejection rates but no mortality benefit in rATG-treated patients within the first 6 mo of ...

8. ectrx.org ectrx.org/detail/archive/2022/20/8/0/762/0

FULL TEXT Conclusions: Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the ...