Thymoglobulin Induction Therapy for Heart Transplant Recipients

Recruiting 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

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, controlled, single center study to evaluate the efficacy of Thymoglobulin induction therapy in combination with Mycophenolate Mofetil, tacrolimus, and steroids in the prevention of CAV. 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. Mechanistic assays (T-reg cells, Lym subsets, B cell subsets, IL-1b, cytokines, TGFb, IL-21 to be drawn at Pre-transplant, 3, 6, 12 months post-transplant) will also be performed. All patients will be followed and monitored according to standard of care protocols for heart transplant recipients at our center.

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.

What data supports the effectiveness of the drug Thymoglobulin for heart transplant recipients?

Research shows that Thymoglobulin, a rabbit-derived drug, is effective in preventing organ rejection in heart transplant patients. It has been used successfully for over 10 years, showing favorable results compared to other treatments, with high survival rates and reduced rejection and infection rates. ^{1 2 3 4 5}

Is Thymoglobulin safe for use in humans?

Thymoglobulin is generally safe for use in humans, but it can cause rare allergic reactions and is associated with a higher risk of cytomegalovirus infections. It may also induce serum sickness, a type of immune reaction, if not used with other immunosuppressive drugs. ^{1 2 6 7 8}

What makes Thymoglobulin unique as a drug for heart transplant recipients?

Thymoglobulin is unique because it is a rabbit-derived polyclonal antibody used for immunosuppression, which can prevent the production of circulating antibodies after heart transplantation. However, it may lead to a higher incidence of cytomegalovirus infections compared to other similar treatments. ^{1 2 3 9 10}

Research Team

Jon Kobashigawa, MD

Principal Investigator

Director

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

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

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. [2022]

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

Midterm results of a prospective randomized comparison of two different rabbit-antithymocyte globulin induction therapies after heart transplantation. [2022]

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

Anti-thymocyte gamma-globulin may prevent antibody production after heart transplantation. [2018]

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

In Vitro Effects of Thymoglobulin in Human Embryonic Kidney Cell Line (HEK293) in Culture. [2021]

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

Rabbit antithymocyte globulin. A 10-year experience in cardiac transplantation. [2019]

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

An avoidable cause of thymoglobulin anaphylaxis. [2020]

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

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. [2022]

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

Differential depletion of total T cells and regulatory T cells and prolonged allotransplant survival in CD3Ɛ humanized mice treated with polyclonal anti human thymocyte globulin. [2019]

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

In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin. [2021]

10. United States 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. [2019]