Allogeneic, Hematopoietic Cell Transplant (HCT), Cytomegalovirus (CMV)-Positive Recipients
Conditions
Keywords
ASP0113, Cytomegalovirus (CMV), Hematopoietic Cell Transplant (HCT)
Brief summary
The purpose of the study was to evaluate the efficacy of ASP0113 compared with placebo as measured by a primary composite endpoint of overall mortality and CMV end organ disease (EOD) through 1 year post-transplant. Safety of ASP0113 in participants undergoing allogeneic HCT will also be evaluated.
Detailed description
Participants will be followed for 5.5 years post-transplant for long-term safety via an annual telephone contact.
Interventions
BIOLOGICALASP0113
Intramuscular injection
DRUGPlacebo
Intramuscular injection
Sponsors
Astellas Pharma Global Development, Inc.
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
* Participant is a CMV-seropositive HCT recipient * Participant is planned to undergo either of the following: * Sibling Donor Transplant * Unrelated Donor Transplant * Participant has one of the following underlying diseases: * Acute myeloid leukemia (AML) * Acute lymphoblastic leukemia (ALL) * Acute undifferentiated leukemia (AUL) * Acute biphenotypic leukemia * Chronic myelogenous leukemia (CML) * Chronic lymphocytic leukemia (CLL). * A defined myelodysplastic syndrome(s) (MDS) * Primary or secondary myelofibrosis * Lymphoma (including Hodgkin's)
Exclusion criteria
* Participant has active CMV disease or infection or has received treatment for active CMV disease or infection within 3 months (90 days) prior to transplant * Participant has a modified hematopoietic cell transplant comorbidity index (HCT-CI) score ≥ 4 * Participant has received a prior HCT and has residual Chronic Graft-versus-host Disease (cGVHD) * Participant who is scheduled to have a cord blood transplant or a haploidentical transplant * Participant has a platelet count of less than 50,000 mm3 within 3 days prior to randomization (platelet transfusions are allowed) * Participant has aplastic anemia or multiple myeloma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | This was the composite of all-cause mortality and adjudicated CMV EOD through 1 year posttransplant, The CMV EOD was assessed by the independent and blinded adjudication committee, which counted events that were observed up to day 380 from transplantation. Deaths that occurred up to day 365 from transplant were also counted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | Protocol-defined CMV viremia was defined as a CMV plasma viral load ≥1000 IU/mL as assessed by the central laboratory. Rate was based on cumulative incidence function estimated at 1 year. The central laboratory had the lower limit of quantification \[LLOQ\] for CMV viral load assessment, so when the viral load was below the LLOQ the actual viral load reading was not possible and was denoted as ≤LLOQ. If participant had any CMV viral load assessments greater than the LLOQ it was classified as viremic. |
| Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | The CMV-specific AVT use was adjudicated by the independent and blinded committee. When the CMV-specific AVT was initiated, a central CMV viral load was obtained weekly until it was discontinued. Participants without any CMV-specific AVT events were censored on the last study evaluation. |
| Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | Protocol-defined CMV viremia was as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. The CMV-specific AVT was determined by the adjudication committee. Participants with no posttransplant viral load data were excluded from the analysis. |
| Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | Rate was based on cumulative incidence function estimate at 1 year. Time to first CMV-specific AVT was defined as time to the start of AVT for CMV viremia or CMV EOD. CMV-specific AVT and EOD were determined by the adjudication committee. This endpoint was a composite endpoint based on the independent adjudication committee assessments of CMV-specific AVT and CMV EOD. |
| All-Cause Mortality at 1 Year Posttransplant | From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365) | All-cause mortality through 1-year post-transplantation summary included all deaths and unknown survival status. For the known deaths, the adjudication committee assessed results and summarized them according to the following category: Mortality due to the participant's primary disease, and mortality due to causes unrelated to the participant's primary disease. Participants with unknown survival status at 1 year were considered dead for this analysis. |
Countries
Australia, Belgium, Canada, France, Germany, Japan, South Korea, Spain, Sweden, Taiwan, United States
Participant flow
Recruitment details
A total of 514 participants were enrolled across 11 countries. At least 30% of enrolled participants had cytomegalovirus (CMV) seronegative donor and underwent allogeneic hematopoietic cell transplant (HCT). After the primary study period (day 365) participants were monitored for 5.5 years post-transplant for long-term safety. After the primary period completion, 326 participants entered the long-term follow-up period.
Pre-assignment details
Screening assessment occurred from 30 to 5 days before transplant. Participants who met the inclusion and none of the exclusion criteria were randomly assigned in a 1:1 ratio to receive either ASP0113 or placebo. The randomization to treatment was stratified by donor-recipient relatedness and by donor CMV serostatus.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0). | 263 |
| ASP0113 Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0). | 251 |
| Total | 514 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 57 | 52 |
| Overall Study | Miscellaneous | 4 | 4 |
| Overall Study | Physician Decision | 11 | 10 |
| Overall Study | Randomized but Never Received Drug | 8 | 5 |
| Overall Study | Withdrawal by Subject | 18 | 26 |
Baseline characteristics
| Characteristic | ASP0113 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 51.8 Year STANDARD_DEVIATION 12.41 | 51.9 Year STANDARD_DEVIATION 12.78 | 52.0 Year STANDARD_DEVIATION 13.15 |
| Antithymocyte Globulin (ATG) Use No | 208 Participants | 426 Participants | 218 Participants |
| Antithymocyte Globulin (ATG) Use Yes | 43 Participants | 88 Participants | 45 Participants |
| Body Mass Index (BMI) | 26.0 kg/m^2 STANDARD_DEVIATION 5.05 | 26.5 kg/m^2 STANDARD_DEVIATION 5.06 | 27.0 kg/m^2 STANDARD_DEVIATION 5.02 |
| Conditioning Regimen Missing | 7 Participants | 17 Participants | 10 Participants |
| Conditioning Regimen Myeloablative | 120 Participants | 242 Participants | 122 Participants |
| Conditioning Regimen Non-Myeloablative | 124 Participants | 255 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 30 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 232 Participants | 484 Participants | 252 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 169.7 Centimeteres STANDARD_DEVIATION 9.88 | 170.2 Centimeteres STANDARD_DEVIATION 9.9 | 170.6 Centimeteres STANDARD_DEVIATION 9.91 |
| Primary Diagnosis Acute Biphenotypic Leukemia (ABL) | 2 Participants | 4 Participants | 2 Participants |
| Primary Diagnosis Acute Lymphoblastic Leukemia (ALL) | 34 Participants | 68 Participants | 34 Participants |
| Primary Diagnosis Acute Myeloid Leukemia (AML) | 97 Participants | 223 Participants | 126 Participants |
| Primary Diagnosis Acute Undifferentiated Leukemia (AUL) | 2 Participants | 3 Participants | 1 Participants |
| Primary Diagnosis Chronic Lymphocytic Leukemia (CLL) | 10 Participants | 17 Participants | 7 Participants |
| Primary Diagnosis Chronic Myelogenous Leukemia (CML) | 12 Participants | 18 Participants | 6 Participants |
| Primary Diagnosis Lymphoma | 31 Participants | 64 Participants | 33 Participants |
| Primary Diagnosis Missing | 1 Participants | 1 Participants | 0 Participants |
| Primary Diagnosis Myelodysplastic Syndrome | 51 Participants | 97 Participants | 46 Participants |
| Primary Diagnosis Primary or Secondary Myelofibrosis | 11 Participants | 19 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 50 Participants | 97 Participants | 47 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 13 Participants | 6 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 | 17 Participants | 38 Participants | 21 Participants |
| Race (NIH/OMB) White | 177 Participants | 366 Participants | 189 Participants |
| Sex: Female, Male Female | 110 Participants | 215 Participants | 105 Participants |
| Sex: Female, Male Male | 141 Participants | 299 Participants | 158 Participants |
| Strata Non-related Seronegative Donor | 79 Participants | 151 Participants | 72 Participants |
| Strata Non-related Seropositive Donor | 73 Participants | 169 Participants | 96 Participants |
| Strata Related Seronegative Donor | 26 Participants | 56 Participants | 30 Participants |
| Strata Related Seropositive Donor | 73 Participants | 138 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 100 / 255 | 105 / 246 |
| other Total, other adverse events | 254 / 255 | 244 / 246 |
| serious Total, serious adverse events | 221 / 255 | 221 / 246 |
Outcome results
Primary
Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant
This was the composite of all-cause mortality and adjudicated CMV EOD through 1 year posttransplant, The CMV EOD was assessed by the independent and blinded adjudication committee, which counted events that were observed up to day 380 from transplantation. Deaths that occurred up to day 365 from transplant were also counted.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the full analysis set (FAS), which consisted of all randomized participants who received at least one dose of randomized study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | Participants With Composite Endpoint | 30.20 Percentage of Participants |
| Placebo | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | All-Cause Mortality | 28.24 Percentage of Participants |
| Placebo | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | Adjudicated CMV EOD | 3.53 Percentage of Participants |
| ASP0113 | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | Participants With Composite Endpoint | 35.37 Percentage of Participants |
| ASP0113 | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | All-Cause Mortality | 31.71 Percentage of Participants |
| ASP0113 | Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant | Adjudicated CMV EOD | 6.10 Percentage of Participants |
Comparison: Analysis of all-cause mortality and adjudicated CMV EOD. Analysis was completed using the Cochran-Mantel-Haenszel (CMH) test at the 1-sided 5% level stratified by use of antithymocyte globulin (ATG) and by receipt of a kidney from a living or deceased donor.p-value: 0.20595% CI: [0.87, 1.85]Cochran-Mantel-Haenszel
Secondary
All-Cause Mortality at 1 Year Posttransplant
All-cause mortality through 1-year post-transplantation summary included all deaths and unknown survival status. For the known deaths, the adjudication committee assessed results and summarized them according to the following category: Mortality due to the participant's primary disease, and mortality due to causes unrelated to the participant's primary disease. Participants with unknown survival status at 1 year were considered dead for this analysis.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | All-Cause Mortality at 1 Year Posttransplant | 28.24 Percentage of Participants |
| ASP0113 | All-Cause Mortality at 1 Year Posttransplant | 31.71 Percentage of Participants |
Comparison: Analysis of all-cause mortality at 1 year. Participants with unknown survival status at 1 year were considered dead for this analysis.p-value: 0.39395% CI: [0.81, 1.73]Cox Proportional Hazards Model
Secondary
Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use
Protocol-defined CMV viremia was as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. The CMV-specific AVT was determined by the adjudication committee. Participants with no posttransplant viral load data were excluded from the analysis.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use | 60.78 Percentage of Participants |
| ASP0113 | Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use | 60.98 Percentage of Participants |
Comparison: Analysis of composite of CMV viremia and adjudicated CMV-AVT. The CMV viremia was defined by the protocol as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. CMV-specific AVT was determined by the adjudication committee. Participants with no posttransplant viral load data were excluded from the analysis.p-value: 0.80295% CI: [0.73, 1.51]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant
The CMV-specific AVT use was adjudicated by the independent and blinded committee. When the CMV-specific AVT was initiated, a central CMV viral load was obtained weekly until it was discontinued. Participants without any CMV-specific AVT events were censored on the last study evaluation.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant | 53.2 Percentage of Participants |
| ASP0113 | Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant | 54.6 Percentage of Participants |
Comparison: Analysis of CMV-specific antiviral therapy (AVT) through 1 year. Time to first adjudicated CMV-specific therapy was defined as time to the start of AVT for CMV viremia. CMV-specific AVT was determined by the adjudication committee. Rate was based on cumulative incidence function estimate at 1 year.p-value: 0.88895% CI: [0.8, 1.29]Cox Proportional Hazard Model
Secondary
Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant
Rate was based on cumulative incidence function estimate at 1 year. Time to first CMV-specific AVT was defined as time to the start of AVT for CMV viremia or CMV EOD. CMV-specific AVT and EOD were determined by the adjudication committee. This endpoint was a composite endpoint based on the independent adjudication committee assessments of CMV-specific AVT and CMV EOD.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant | 54.4 Percentage of Participants |
| ASP0113 | Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant | 55.4 Percentage of Participants |
Comparison: Analysis of rate of adjudicated CMV AVT or CMV EOD. Time to first CMV-specific AVT was defined as time to the start of AVT for CMV viremia or CMV EOD. CMV-specific AVT and EOD and were determined by the adjudication committee. Rate based on cumulative incidence function estimate at 1 year.p-value: 0.92895% CI: [0.8, 1.28]Cox Proportional Hazards Model
Secondary
Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant
Protocol-defined CMV viremia was defined as a CMV plasma viral load ≥1000 IU/mL as assessed by the central laboratory. Rate was based on cumulative incidence function estimated at 1 year. The central laboratory had the lower limit of quantification \[LLOQ\] for CMV viral load assessment, so when the viral load was below the LLOQ the actual viral load reading was not possible and was denoted as ≤LLOQ. If participant had any CMV viral load assessments greater than the LLOQ it was classified as viremic.
Time frame: From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant | 58.6 Percentage of Participants |
| ASP0113 | Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant | 56.7 Percentage of Participants |
Comparison: Analysis of CMV viremia through 1 year posttransplant. CMV viremia was defined by the protocol as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. The 95% CI was based on cumulative incidence function CMV viremia rate at 1 year.p-value: 0.74895% CI: [0.76, 1.22]Cox Proportional Hazard Model