Trial Outcomes & Findings for Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation (NCT NCT01278745)

Last Updated: 2020-08-25

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

362 participants

Primary outcome timeframe

Baseline, 1 year

Results posted on

2020-08-25

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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 After 6 months, prednisone was withdrawn at the discretion of the investigator.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.	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 After 6 months, prednisone was withdrawn at the discretion of the investigator.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.	Discontinued Pre-Transplant Subjects that enrolled, but withdrew from the study prior to their transplant.	Discontinued Pre-Randomization Subjects that were enrolled and transplanted on study, but withdrew from the study prior to randomization.
Overall Study STARTED	89	74	121	78
Overall Study COMPLETED	84	68	0	0
Overall Study NOT COMPLETED	5	6	121	78

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	Discontinued Pre-Transplant Subjects that enrolled, but withdrew from the study prior to their transplant.	Discontinued Pre-Randomization Subjects that were enrolled and transplanted on study, but withdrew from the study prior to randomization.
Overall Study Death	2	5	7	0
Overall Study Physician Decision	1	0	0	9
Overall Study Withdrawal by Subject	1	1	5	1
Overall Study Sponsor Decision	1	0	62	6
Overall Study Ineligible	0	0	42	61
Overall Study Moves,enrollment in mx studies, et al.	0	0	5	1

Baseline Characteristics

Prevention of Cardiac Allograft Vasculopathy Using Rituximab (Rituxan) Therapy in Cardiac Transplantation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.	Total n=163 Participants Total of all reporting groups
Age, Continuous	54.6 years STANDARD_DEVIATION 11.80 • n=93 Participants	54.8 years STANDARD_DEVIATION 11.76 • n=4 Participants	54.7 years STANDARD_DEVIATION 11.75 • n=27 Participants
Sex: Female, Male Female	16 Participants n=93 Participants	8 Participants n=4 Participants	24 Participants n=27 Participants
Sex: Female, Male Male	73 Participants n=93 Participants	66 Participants n=4 Participants	139 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=93 Participants	7 Participants n=4 Participants	16 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	72 Participants n=93 Participants	62 Participants n=4 Participants	134 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=93 Participants	5 Participants n=4 Participants	13 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Asian	5 Participants n=93 Participants	1 Participants n=4 Participants	6 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants	12 Participants n=4 Participants	19 Participants n=27 Participants
Race (NIH/OMB) White	70 Participants n=93 Participants	57 Participants n=4 Participants	127 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	7 Participants n=93 Participants	3 Participants n=4 Participants	10 Participants n=27 Participants
Region of Enrollment United States	89 Participants n=93 Participants	74 Participants n=4 Participants	163 Participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline, 1 year

Population: Randomized participants with available data at year one

Outcome measures

Outcome measures
Measure	Rituximab n=49 Participants 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.	Placebo n=37 Participants 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.
Change in Percent Atheroma Volume (PAV)	6.8 percent Standard Deviation 8.21	1.9 percent Standard Deviation 4.38

SECONDARY outcome

Timeframe: 12 months

Population: Randomized subjects

Participants who died within 12 months post-transplant

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Death	3 Participants	5 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Re-transplantation or Re-listed for Transplantation	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants with at least one centrally read heart biopsy

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.

Outcome measures

Outcome measures
Measure	Rituximab n=86 Participants 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.	Placebo n=70 Participants 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.
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant 0 Episodes of BPAR	45 Participants	18 Participants
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant 1 Episode of BPAR	13 Participants	28 Participants
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant 2 Episodes of BPAR	17 Participants	14 Participants
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant 3 Episodes of BPAR	9 Participants	8 Participants
Number of Episodes of Biopsy Proven Acute Rejection (BPAR) of Any Grade Per Participant 4 Episodes of BPAR	2 Participants	2 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants with at least one centrally read heart biopsy

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.

Outcome measures

Outcome measures
Measure	Rituximab n=86 Participants 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.	Placebo n=70 Participants 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.
Incidence of BPAR (Any Grade)	41 Participants	52 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Incidence of AMR	8 Participants	11 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants with at least one centrally read heart biopsy

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

Outcome measures

Outcome measures
Measure	Rituximab n=86 Participants 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.	Placebo n=70 Participants 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.
Incidence of Cellular Rejection	41 Participants	52 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Incidence of Any Treated Rejection	22 Participants	24 Participants

SECONDARY outcome

Timeframe: 6 to 12 months

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Number of Participants With Episodes of Rejection Associated With Hemodynamic Compromise (HDC)	2 Participants	1 Participants

SECONDARY outcome

Timeframe: 1 year

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Number of Participants With Development of Angiographically Evident Cardiac Allograft Vasculopathy	19 Participants	7 Participants

SECONDARY outcome

Timeframe: Transplantation through end of study, up to 1 year post transplantation.

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Number of Participants With Post-transplant Serious Infections Requiring Intravenous Antimicrobial Therapy	16 Participants	13 Participants

SECONDARY outcome

Timeframe: Transplantation through end of study, up to 1 year post transplantation.

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Number of Participants With Post-transplant Incidence of PTLD	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Transplantation through end of study, up to 1 year post transplantation

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Rituximab n=89 Participants 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.	Placebo n=74 Participants 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.
Post-transplant Safety Outcomes Among Participants: Safety and Tolerability of Rituximab	26 Participants	26 Participants

Adverse Events

Rituximab

Serious events: 55 serious events

Other events: 29 other events

Deaths: 0 deaths

Placebo

Serious events: 45 serious events

Other events: 26 other events

Deaths: 0 deaths

Discontinued Pre-Transplant

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Discontinued Pre-Randomization

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Rituximab n=89 participants at risk 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.	Placebo n=74 participants at risk 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.	Discontinued Pre-Transplant n=121 participants at risk Subjects that enrolled, but withdrew from the study prior to their transplant.	Discontinued Pre-Randomization n=78 participants at risk Subjects that were enrolled and transplanted on study, but withdrew from the study prior to randomization.
Blood and lymphatic system disorders Anaemia	9.0% 8/89 • Number of events 8 • From enrollment through end of study (up to one year post randomization)	9.5% 7/74 • Number of events 7 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Blood and lymphatic system disorders Leukopenia	7.9% 7/89 • Number of events 7 • From enrollment through end of study (up to one year post randomization)	8.1% 6/74 • Number of events 7 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Cardiac disorders Atrial fibrillation	1.1% 1/89 • Number of events 1 • From enrollment through end of study (up to one year post randomization)	5.4% 4/74 • Number of events 4 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Gastrointestinal disorders Diarrhoea	5.6% 5/89 • Number of events 5 • From enrollment through end of study (up to one year post randomization)	5.4% 4/74 • Number of events 4 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Infections and infestations Urinary tract infection	7.9% 7/89 • Number of events 7 • From enrollment through end of study (up to one year post randomization)	5.4% 4/74 • Number of events 5 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Nervous system disorders Headache	2.2% 2/89 • Number of events 5 • From enrollment through end of study (up to one year post randomization)	5.4% 4/74 • Number of events 4 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Renal and urinary disorders Renal failure acute	7.9% 7/89 • Number of events 7 • From enrollment through end of study (up to one year post randomization)	8.1% 6/74 • Number of events 6 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)
Respiratory, thoracic and mediastinal disorders Pleural effusion	6.7% 6/89 • Number of events 6 • From enrollment through end of study (up to one year post randomization)	2.7% 2/74 • Number of events 2 • From enrollment through end of study (up to one year post randomization)	0.00% 0/121 • From enrollment through end of study (up to one year post randomization)	0.00% 0/78 • From enrollment through end of study (up to one year post randomization)

Additional Information

Director, Clinical Research Operations Program

DAIT/NIAID

Phone: 301-594-7669

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place