Bronchiectasis, Chronic Obstructive Pulmonary, Cystic Fibrosis, Idiopathic Pulmonary Fibrosis, Pulmonary Vascular Disease
Conditions
Keywords
pulmonary transplantation, Pulmonary Allograft Rejection
Brief summary
The purpose of this study is to assess the efficacy and safety of the study drug, known as ATG Fresenius S, which is sometimes called EZ-2053, to prevent a lung transplant patient's body from rejecting a transplanted lung or lungs.
Detailed description
Patients are generally consented for the study once they go on the lung transplant waiting list and then are re-consented periodically thereafter until they undergo the lung transplant surgery. A pre-surgical assessment consisting of medical history, physical exam, ECG, chest X-Ray, and blood tests are conducted. After lung transplant surgery, patients are assessed for continued eligibility. Within 6-24 hours after the end of surgery, patients are randomized to receive one infusion of study drug or placebo through a central venous catheter. Each day for 5 days following transplant surgery, patients are monitored for transplant rejection, infections, adverse events and laboratory test changes. On post-randomization Days 14, 30, 60, 90, 180, 270 and 365, patients will be monitored for acute transplant rejection, infections and cancer, pulmonary function tests and adverse experiences. Pulmonary biopsies will be performed on post-randomization Days 30, 60, 90, 180 and 365. Blood samples will be drawn during each visit.
Interventions
BIOLOGICALPlacebo
placebo infusion, single
BIOLOGICALEZ-2053
single IV infusion, 9 mg/kg
BIOLOGICALEZ-2053 5mg/kg
single IV infusion, 5mg/kg
Sponsors
Neovii Biotech
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Recipient of a primary single or double pulmonary allograft * Capable of understanding the purposes and risks of the study and has given written informed consent, and agrees to comply with the study requirements * Women of childbearing potential must have a negative serum pregnancy test within 4 days prior to randomization.
Exclusion criteria
* Undergoing second or living donor transplant * Prior treatment with T-cell depleting agents within the previous 5 years for the purpose of immunosuppression * Prior plasma exchange and/or treatment with IVIg within the past 5 years * Pulmonary infection with pan-resistant Pseudomonas or any Burkholderia species * Known positive blood cultures * Donor lung ischemia time \> 8 hours for first lung and \> 8 hours for the second lung * Previously received or is receiving a multi-organ transplant * Pregnant women, nursing mothers or women of child-bearing potential who are unwilling to use reliable contraception. Effective contraception must be used BEFORE beginning study drug therapy, for the duration of the study and for 6 months following completion of the study * Active, extra-pulmonary systemic infection requiring the prolonged or chronic use of antimicrobial agents or the presence of a chronic active hepatitis B or C * Active liver disease (liver function tests greater than or equal to 2 times the upper limit of normal) * Severe anemia (hemoglobin, \< 6 g/dL), leukopenia (WBC \< 2500/mm3), thrombocytopenia (platelet count \< 80,000/mm3), polycythemia (Hct \> 54% \[male\], Hct \> 49% \[female\]) or clinically significant coagulopathy * Recipient or donor is seropositive for HIV * Previous exposure or known contraindication to administration of the study drug or to rabbit proteins * Current malignancy or a history of malignancy (within the previous 5 years), except non-metastatic basal cell or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix that has been treated successfully * Unstable cardiovascular disease, or a myocardial infarction within the previous 6 months * Currently participating in another clinical trial with an investigational agent and/or is taking or has been taking an investigational agent in the 30 days prior to transplant and/or has not recovered from any reversible side effects of prior investigational drug * Unlikely to comply with visits schedule in the protocol * Any current history of substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the Investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With the Event Death, Graft Loss, Acute Rejection and/or Loss to Follow-up (Whichever Occurred First) | 12 months |
Secondary
| Measure | Time frame |
|---|---|
| Pulmonary Function Test, Forced Expiratory Flow 25-75 | 12 months |
| Number of Participants With Death or Graft Loss Post-transplant | 12 months |
| Number of Participants With Acute Rejection | 12 months |
| Pulmonary Function Test, Forced Expiratory Volume in 1 Second | 12 months |
| Number of Participants With Severe Adverse Events | 12 months |
| Pulmonary Function Tests, Total Distance Walked 6 Minute Walk Test | 12 months |
| Pulmonary Function Test, Forced Vital Capacity | 12 months |
| Number of Participants With Infections and Infestations | 12 months |
Countries
Australia, Austria, Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EZ-2053 9mg/kg Anti-human-T-lymphocyte Immune Globulin, Rabbit (EZ-2053) | 82 |
| Placebo USP 0.9% sodium chloride solution | 79 |
| EZ-2053 5mg/kg Anti-human-T-Lymphocyte Immune Globulin, Rabbit | 62 |
| Total | 223 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 19 | 13 | 15 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Other reason | 1 | 2 | 0 |
| Overall Study | Physician Decision | 1 | 2 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | EZ-2053 9mg/kg | Placebo | EZ-2053 5mg/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 11 Participants | 4 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 68 Participants | 58 Participants | 204 Participants |
| Region of Enrollment Australia | 14 participants | 15 participants | 7 participants | 36 participants |
| Region of Enrollment Austria | 18 participants | 18 participants | 14 participants | 50 participants |
| Region of Enrollment Canada | 5 participants | 5 participants | 5 participants | 15 participants |
| Region of Enrollment United States | 45 participants | 41 participants | 36 participants | 122 participants |
| Sex: Female, Male Female | 36 Participants | 36 Participants | 27 Participants | 99 Participants |
| Sex: Female, Male Male | 46 Participants | 43 Participants | 35 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 82 / 82 | 78 / 78 | 61 / 61 |
| serious Total, serious adverse events | 65 / 82 | 52 / 78 | 44 / 61 |
Outcome results
Primary
Number of Participants With the Event Death, Graft Loss, Acute Rejection and/or Loss to Follow-up (Whichever Occurred First)
Time frame: 12 months
Population: ITT. During the interim analysis the 5 mg/kg arm was dropped and it was showed that the study was insufficiently powered so the main focus of study shifted to safety endpoints. Data is based on local lung biopsy readings for efficacy failure instead of central readings
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ-2053 9mg/kg | Number of Participants With the Event Death, Graft Loss, Acute Rejection and/or Loss to Follow-up (Whichever Occurred First) | 33 participants |
| Placebo | Number of Participants With the Event Death, Graft Loss, Acute Rejection and/or Loss to Follow-up (Whichever Occurred First) | 29 participants |
| EZ-2053 5mg/kg | Number of Participants With the Event Death, Graft Loss, Acute Rejection and/or Loss to Follow-up (Whichever Occurred First) | 30 participants |
Secondary
Number of Participants With Acute Rejection
Time frame: 12 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ-2053 9mg/kg | Number of Participants With Acute Rejection | 22 participants |
| Placebo | Number of Participants With Acute Rejection | 20 participants |
| EZ-2053 5mg/kg | Number of Participants With Acute Rejection | 22 participants |
Secondary
Number of Participants With Death or Graft Loss Post-transplant
Time frame: 12 months
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ-2053 9mg/kg | Number of Participants With Death or Graft Loss Post-transplant | 13 participants |
| Placebo | Number of Participants With Death or Graft Loss Post-transplant | 8 participants |
| EZ-2053 5mg/kg | Number of Participants With Death or Graft Loss Post-transplant | 7 participants |
Secondary
Number of Participants With Infections and Infestations
Time frame: 12 months
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ-2053 9mg/kg | Number of Participants With Infections and Infestations | 75 participants |
| Placebo | Number of Participants With Infections and Infestations | 70 participants |
| EZ-2053 5mg/kg | Number of Participants With Infections and Infestations | 57 participants |
Secondary
Number of Participants With Severe Adverse Events
Time frame: 12 months
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EZ-2053 9mg/kg | Number of Participants With Severe Adverse Events | 18 participants |
| Placebo | Number of Participants With Severe Adverse Events | 14 participants |
| EZ-2053 5mg/kg | Number of Participants With Severe Adverse Events | 9 participants |
Secondary
Pulmonary Function Test, Forced Expiratory Flow 25-75
Time frame: 12 months
Population: Pulmonary Function Tests (PFTs) are reported for all participants of the ITT population, who were alive at 12 months after transplantation and for whom PFT results were reported for the 12-month visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EZ-2053 9mg/kg | Pulmonary Function Test, Forced Expiratory Flow 25-75 | 2.7 Liters/second |
| Placebo | Pulmonary Function Test, Forced Expiratory Flow 25-75 | 2.2 Liters/second |
| EZ-2053 5mg/kg | Pulmonary Function Test, Forced Expiratory Flow 25-75 | 2.6 Liters/second |
Secondary
Pulmonary Function Test, Forced Expiratory Volume in 1 Second
Time frame: 12 months
Population: Pulmonary Function Tests (PFTs) are reported for all participants of the ITT population, who were alive at 12 months after transplantation and for whom PFT results were reported for the 12-month visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EZ-2053 9mg/kg | Pulmonary Function Test, Forced Expiratory Volume in 1 Second | 2.3 Liters |
| Placebo | Pulmonary Function Test, Forced Expiratory Volume in 1 Second | 2.3 Liters |
| EZ-2053 5mg/kg | Pulmonary Function Test, Forced Expiratory Volume in 1 Second | 2.5 Liters |
Secondary
Pulmonary Function Test, Forced Vital Capacity
Time frame: 12 months
Population: Pulmonary Function Tests (PFTs) are reported for all participants of the ITT population, who were alive at 12 months after transplantation and for whom PFT results were reported for the 12-month visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EZ-2053 9mg/kg | Pulmonary Function Test, Forced Vital Capacity | 3.0 Liters |
| Placebo | Pulmonary Function Test, Forced Vital Capacity | 2.9 Liters |
| EZ-2053 5mg/kg | Pulmonary Function Test, Forced Vital Capacity | 3.3 Liters |
Secondary
Pulmonary Function Tests, Total Distance Walked 6 Minute Walk Test
Time frame: 12 months
Population: Pulmonary Function Tests (PFTs) are reported for all participants of the ITT population, who were alive at 12 months after transplantation and for whom PFT results were reported for the 12-month visit
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EZ-2053 9mg/kg | Pulmonary Function Tests, Total Distance Walked 6 Minute Walk Test | 457.0 Meters |
| Placebo | Pulmonary Function Tests, Total Distance Walked 6 Minute Walk Test | 448.0 Meters |
| EZ-2053 5mg/kg | Pulmonary Function Tests, Total Distance Walked 6 Minute Walk Test | 427.0 Meters |