Cardiac Allograft Vasculopathy, Heart Transplant Recipients
Conditions
Keywords
cardiac allograft vasculopathy (CAV), prevention, cardiac transplantation, rituximab
Brief summary
All people who have a heart transplant are at risk for developing cardiac allograft vasculopathy (CAV). CAV means narrowing of the heart transplant vessels, which is associated with poor heart transplant function. People who develop antibodies after transplant have a higher risk of developing CAV. Infections, high cholesterol, and rejection also increase the risk of developing CAV. People who develop CAV usually have to receive another transplant.
Detailed description
The purpose of this research study is to see if a study drug called rituximab (Rituxan®) prevents CAV. Rituximab destroys certain types of white blood cells called B cells. B cells are important cells in the immune system that help the body fight infection by producing substances called antibodies. B cells and the antibodies they produce are also involved in some kinds of rejection after organ transplantation. Rituximab decreases the number of B cells in the blood and other tissues. The goal of this study is to determine if decreasing B cells with Rituximab can prevent injury to the transplanted heart.
Interventions
BIOLOGICALRituximab induction/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
DRUGRituximab placebo/conventional immunosuppression (tacrolimus, MMF, and steroid taper)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Trials in Organ Transplantation
Genentech, Inc.
Rho Federal Systems Division, Inc.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
for Initial Enrollment: * Subject must be able to understand and provide informed consent; * Male or Female, 18 to 75 years of age; * Candidate for a primary heart transplant (e.g., listed for heart transplant only); * Historical panel reactive antibodies (PRA) less than 30%; * Calculated GFR ≥ 40 mL/minute using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI); * Female and male subjects with reproductive potential, must agree to use FDA approved methods of birth control for the duration of the study Inclusion Criteria for Randomization / Post-transplant: --Negative PRA within 12 weeks prior to transplant (Local HLA Center Testing) using one of the following: * One Lambda's LABScreen® Mixed Class I & II (presence or absence), or * Less than 10% by One Lambda's LABScreen® PRA Class I and II with an MFI of \<2000, or * Calculated panel reactive antibodies (cPRA) less than 10% by LABScreen® Single Antigen testing (Anti-HLA-A, -B, -DR, -DQ). The antigens reported will include those with an MFI \>2000. The Luminex Gen-Probe beads are equivalent to the One Lambda and may be used as an alternative; * Calculated GFR ≥ 40mL/minute using the CKD-EPI at time of randomization; * Serum immunoglobulin G (IgG) level greater than 500mg/dL within 90 days prior to randomization; * Negative test for HIV, HBsAg, HBcAb, and HCV Ab within 12 months prior to transplant. If documentation is not present to support that the testing was performed in the past 12 months, then a blood sample will be collected prior to transplant and sent for local testing. Results may be available after randomization. If positive result, the oversight committee will review the case and provide further recommendations. * Female subjects of childbearing potential must have a negative pregnancy test.
Exclusion criteria
for Enrollment: * Prior history of organ transplantation; * Previous treatment with Rituximab (MabThera® / Rituxan ®); * Transplant physician intention to use any induction agents; * History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies; * History of severe reaction to previous therapy with IVIG; * Active systemic infection at time of enrollment; * Any history of serologic positivity to HIV, HBsAg, HBcAb, and HCV Ab; * History of less than 5 years remission of malignancy. Any history of adequately treated in-situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted; * Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements; * Use of other investigational drugs within 4 weeks of enrollment; * Currently breast-feeding or plans to become pregnant during the timeframe of the study follow-up period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent Atheroma Volume (PAV) | Baseline, 1 year | Nominal or noticeable change, bad or good, from baseline to 1 year in percent atheroma volume (PAV) which is a measure of the degree of coronary arterial obstruction due to host alloimmune processes measured by intravascular ultrasound (IVUS) in a target coronary artery. Thus a decrease in PAV would be an indicator of less obstruction and a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Re-transplantation or Re-listed for Transplantation | 6 to 12 months | Re-transplantation is defined as the receipt of a subsequent heart transplant and re-listed for transplantation is being listed back on the heart transplant list to be re-transplanted. |
| Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 6 to 12 months | The number of times a participant experienced biopsy proven acute rejection (BPAR). Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy that met the International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory. |
| Incidence of BPAR (Any Grade) | 6 to 12 months | The number of subjects who experienced any grade of biopsy proven acute rejection (BPAR) within the clinical trial. Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory. |
| Incidence of AMR | 6 to 12 months | The number of participants who experienced antibody- mediated rejection (AMR). Antibody-mediated rejection (AMR) occurs when the subject develops antibodies directed against the transplanted heart. This was assessed based on local pathology biopsy reads. |
| Incidence of Cellular Rejection | 6 to 12 months | Cellular Rejection refers to the organ recipient's immune system recognizing a transplanted organ as foreign and mounting a response to it via cellular mechanisms. Cellular rejection was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory |
| Death | 12 months | Participants who died within 12 months post-transplant |
| Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC) | 6 to 12 months | The number of participants that experienced at least one episode of rejection associated with hemodynamic compromise (HDC). Rejection associated with HDC is when there is insufficient blood flow to the transplanted heart in association with acute rejection found in a biopsy. Local biopsies were used for this outcome measure. |
| Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy | 1 year | Cardiac allograft vasculopathy is an aggressive form of atherosclerosis that is characterized by the development of fibrosis affecting cardiac arteries that result in concentric narrowing of the arteries and, ultimately allograft failure. Development of cardiac allograft vasculopathy can be diagnosed via an angiograph which is an X-ray of the cardiac arteries by injecting a radiopaque substance such as iodine. |
| Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy | Transplantation through end of study, up to 1 year post transplantation. | Number of participants experiencing at least one serious infection requiring intravenous antimicrobial therapy which is used to kill the growth of microorganisms such as bacteria, fungi, or protozoans. |
| Number of Participants With Post-transplant Incidence of PTLD | Transplantation through end of study, up to 1 year post transplantation. | The number of participants experiencing at least one post-transplant lymphoproliferative disorder (PTLD) occurrence during this trial. Post-transplant lymphoproliferative disorder is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein-Barr virus. |
| Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab | Transplantation through end of study, up to 1 year post transplantation | Defined as participants that experienced at least one adverse event that was possibly, probably, or definitely related to the study drug (i.e., Rituximab or Placebo). Serious adverse events were used to evaluate this endpoint and the attribution was based on the DAIT Medical Monitor's assessment. |
| Incidence of Any Treated Rejection | 6 to 12 months | The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection (AMR) of the transplanted heart regardless of the presence of a biopsy. |
Countries
United States
Participant flow
Recruitment details
Twenty three out of N=24 participating sites in the United States enrolled 362 participants into this trial. N=163 participants reached the randomization stage of the trial.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Induction: Rituximab was administered in 2 1000 mg doses on Day 0 and Day 12 (+/- 2 days). Maintenance: Mycophenolate Mofetil (MMF) was given at a starting dose of 2-3 g by mouth or intravenously per day in 2 or 3 divided doses. Investigator could choose an alternative treatment if needed. Methylprednisolone/Prednisone dosing was administered according to the local center standard. After 6 months, prednisone was withdrawn at the discretion of the investigator. The suggested oral prednisone taper was Day 14: 20 mg/day by mouth, Day 30: 15 mg/day by mouth, Day 90: 10 mg/day by mouth, Day 180: 5 mg/day by mouth, and greater than Day 180: 0-5 mg/day by mouth. Tacrolimus, was administered per site standards to attain target trough levels. The target whole blood tacrolimus concentrations were as follows: Day 1-30 post transplant 10-20 ng/mL and Day 31-Month 12 5-15 ng/mL. | 89 |
| Placebo Induction: Rituximab Placebo was administered in 2 1000 mg doses on Day 0 and Day 12 (+/- 2 days). Maintenance: Mycophenolate Mofetil (MMF) was given at a starting dose of 2-3 g by mouth or intravenously per day in 2 or 3 divided doses. Investigator could choose an alternative treatment if needed. Methylprednisolone/Prednisone dosing was administered according to the local center standard. After 6 months, prednisone was withdrawn at the discretion of the investigator. The suggested oral prednisone taper was Day 14: 20 mg/day by mouth, Day 30: 15 mg/day by mouth, Day 90: 10 mg/day by mouth, Day 180: 5 mg/day by mouth, and greater than Day 180: 0-5 mg/day by mouth. Tacrolimus, was administered per site standards to attain target trough levels. The target whole blood tacrolimus concentrations were as follows: Day 1-30 post transplant 10-20 ng/mL and Day 31-Month 12 5-15 ng/mL. | 74 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 2 | 5 | 7 | 0 |
| Overall Study | Ineligible | 0 | 0 | 42 | 61 |
| Overall Study | Moves,enrollment in mx studies, et al. | 0 | 0 | 5 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 9 |
| Overall Study | Sponsor Decision | 1 | 0 | 62 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 5 | 1 |
Baseline characteristics
| Characteristic | Total | Rituximab | Placebo |
|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 11.75 | 54.6 years STANDARD_DEVIATION 11.8 | 54.8 years STANDARD_DEVIATION 11.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 134 Participants | 72 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) White | 127 Participants | 70 Participants | 57 Participants |
| Region of Enrollment United States | 163 Participants | 89 Participants | 74 Participants |
| Sex: Female, Male Female | 24 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 139 Participants | 73 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 89 | 26 / 74 | 0 / 121 | 0 / 78 |
| serious Total, serious adverse events | 55 / 89 | 45 / 74 | 0 / 121 | 1 / 78 |
Outcome results
Primary
Change in Percent Atheroma Volume (PAV)
Nominal or noticeable change, bad or good, from baseline to 1 year in percent atheroma volume (PAV) which is a measure of the degree of coronary arterial obstruction due to host alloimmune processes measured by intravascular ultrasound (IVUS) in a target coronary artery. Thus a decrease in PAV would be an indicator of less obstruction and a better outcome.
Time frame: Baseline, 1 year
Population: Randomized participants with available data at year one
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Percent Atheroma Volume (PAV) | 6.8 percent | Standard Deviation 8.21 |
| Placebo | Change in Percent Atheroma Volume (PAV) | 1.9 percent | Standard Deviation 4.38 |
p-value: 0.0019ANCOVA
Secondary
Death
Participants who died within 12 months post-transplant
Time frame: 12 months
Population: Randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Death | 3 Participants |
| Placebo | Death | 5 Participants |
Secondary
Incidence of AMR
The number of participants who experienced antibody- mediated rejection (AMR). Antibody-mediated rejection (AMR) occurs when the subject develops antibodies directed against the transplanted heart. This was assessed based on local pathology biopsy reads.
Time frame: 6 to 12 months
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Incidence of AMR | 8 Participants |
| Placebo | Incidence of AMR | 11 Participants |
Secondary
Incidence of Any Treated Rejection
The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection (AMR) of the transplanted heart regardless of the presence of a biopsy.
Time frame: 6 to 12 months
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Incidence of Any Treated Rejection | 22 Participants |
| Placebo | Incidence of Any Treated Rejection | 24 Participants |
Secondary
Incidence of BPAR (Any Grade)
The number of subjects who experienced any grade of biopsy proven acute rejection (BPAR) within the clinical trial. Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory.
Time frame: 6 to 12 months
Population: Randomized participants with at least one centrally read heart biopsy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Incidence of BPAR (Any Grade) | 41 Participants |
| Placebo | Incidence of BPAR (Any Grade) | 52 Participants |
Secondary
Incidence of Cellular Rejection
Cellular Rejection refers to the organ recipient's immune system recognizing a transplanted organ as foreign and mounting a response to it via cellular mechanisms. Cellular rejection was defined as a biopsy which met The International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory
Time frame: 6 to 12 months
Population: Randomized participants with at least one centrally read heart biopsy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Incidence of Cellular Rejection | 41 Participants |
| Placebo | Incidence of Cellular Rejection | 52 Participants |
Secondary
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant
The number of times a participant experienced biopsy proven acute rejection (BPAR). Biopsy proven acute rejection is when an examination of tissue removed from the transplanted organ indicates that the subject's immune system is trying to reject the graft. BPAR was defined as a biopsy that met the International Society for Heart & Lung Transplantation (ISHLT) criteria to be graded as 1R or greater rejection and was determined by a single, central pathology laboratory.
Time frame: 6 to 12 months
Population: Randomized participants with at least one centrally read heart biopsy
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rituximab | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 1 Episode of BPAR | 13 Participants |
| Rituximab | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 3 Episodes of BPAR | 9 Participants |
| Rituximab | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 2 Episodes of BPAR | 17 Participants |
| Rituximab | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 4 Episodes of BPAR | 2 Participants |
| Rituximab | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 0 Episodes of BPAR | 45 Participants |
| Placebo | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 4 Episodes of BPAR | 2 Participants |
| Placebo | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 0 Episodes of BPAR | 18 Participants |
| Placebo | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 1 Episode of BPAR | 28 Participants |
| Placebo | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 2 Episodes of BPAR | 14 Participants |
| Placebo | Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant | 3 Episodes of BPAR | 8 Participants |
Secondary
Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy
Cardiac allograft vasculopathy is an aggressive form of atherosclerosis that is characterized by the development of fibrosis affecting cardiac arteries that result in concentric narrowing of the arteries and, ultimately allograft failure. Development of cardiac allograft vasculopathy can be diagnosed via an angiograph which is an X-ray of the cardiac arteries by injecting a radiopaque substance such as iodine.
Time frame: 1 year
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy | 19 Participants |
| Placebo | Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy | 7 Participants |
Secondary
Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC)
The number of participants that experienced at least one episode of rejection associated with hemodynamic compromise (HDC). Rejection associated with HDC is when there is insufficient blood flow to the transplanted heart in association with acute rejection found in a biopsy. Local biopsies were used for this outcome measure.
Time frame: 6 to 12 months
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC) | 2 Participants |
| Placebo | Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC) | 1 Participants |
Secondary
Number of Participants With Post-transplant Incidence of PTLD
The number of participants experiencing at least one post-transplant lymphoproliferative disorder (PTLD) occurrence during this trial. Post-transplant lymphoproliferative disorder is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein-Barr virus.
Time frame: Transplantation through end of study, up to 1 year post transplantation.
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Number of Participants With Post-transplant Incidence of PTLD | 0 Participants |
| Placebo | Number of Participants With Post-transplant Incidence of PTLD | 0 Participants |
Secondary
Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy
Number of participants experiencing at least one serious infection requiring intravenous antimicrobial therapy which is used to kill the growth of microorganisms such as bacteria, fungi, or protozoans.
Time frame: Transplantation through end of study, up to 1 year post transplantation.
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy | 16 Participants |
| Placebo | Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy | 13 Participants |
Secondary
Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab
Defined as participants that experienced at least one adverse event that was possibly, probably, or definitely related to the study drug (i.e., Rituximab or Placebo). Serious adverse events were used to evaluate this endpoint and the attribution was based on the DAIT Medical Monitor's assessment.
Time frame: Transplantation through end of study, up to 1 year post transplantation
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab | 26 Participants |
| Placebo | Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab | 26 Participants |
Secondary
Re-transplantation or Re-listed for Transplantation
Re-transplantation is defined as the receipt of a subsequent heart transplant and re-listed for transplantation is being listed back on the heart transplant list to be re-transplanted.
Time frame: 6 to 12 months
Population: Randomized participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Re-transplantation or Re-listed for Transplantation | 0 Participants |
| Placebo | Re-transplantation or Re-listed for Transplantation | 0 Participants |