Kidney Transplantation Cytomegalovirus (CMV) Negative Recipients
Conditions
Keywords
ASP0113, Cytomegalovirus (CMV), Kidney Transplantation
Brief summary
The purpose of this study was to evaluate the efficacy of ASP0113 compared to placebo in reducing the incidence of cytomegalovirus (CMV) viremia in CMV-seronegative subjects receiving a kidney from a CMV-seropositive donor. This study also evaluated the safety of ASP0113 in this patient population.
Detailed description
Participants were followed for one year after first study drug injection. This was the primary study period. Participants were followed for 4.5 years after completion of the primary study to assess long-term safety of the vaccine.
Interventions
BIOLOGICALASP0113
intramuscular injection
DRUGPlacebo
intramuscular injection
Sponsors
Vical
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
* CMV negative subject having received a CMV seropositive kidney (living or deceased) * Participant started valganciclovir or ganciclovir within 10 days of transplant and had received it through Randomization.
Exclusion criteria
* Participant underwent a course of CMV-specific prophylactic therapy with antiviral drugs with a duration of greater than 100 days. * Participant had received from one month prior to transplant or planned to receive CMV immunoglobulin. * Participant had CMV viremia or CMV disease from time of transplant until time of Randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection | From first study dose injection (day 1) up to one year post study drug injection (up to Day 380) | CMV viremia was defined as presence of cytomegalovirus as measured in plasma viral load of ≥ 1000 IU/mL by central laboratory assay. A participant who discontinued the study without a positive CMV viral load was imputed as having a CMV viremia. A participant who had more than one viral load ≥ 1000 IU/mL by central assay was counted once in this summary. CMV viral loads after first injection (Day 1) through Day 380 (scheduled or unscheduled) were included in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease (Primary Study Period) | From first study dose injection (day 1) up to one (up to Day 380) year post study drug injection | An independent panel of medical experts reviewed/adjudicated events of CMV-associated disease including CMV syndrome and tissue invasive disease, which were defined according to the American Society of Transplantation Recommendations for Screening, Monitoring and Reporting of Infectious Complications in Immunosuppression Trials in Recipients of Organ Transplantation 2006. |
| Percentage of Participants With Plasma Viral Load ≥ The Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory (Primary Study Period) | From first study dose injection (day 1) up to one year post study drug injection (up to Day 380) | The central laboratory had the LLOQ level for CMV viral load assessment. When the viral load was below the LLOQ the actual reading was not possible and was denoted as ≤LLOQ. If the participant had any CMV viral load assessments greater than the LLOQ, set up by the central laboratory, participant was classified as viremic and was included in the analysis. |
| Percentage of Participants Who Took Adjudicated CMV-specific Antiviral Therapy for the Treatment of CMV Viremia or Disease (Primary Study Period) | From first study dose injection (day 1) up to one year post study drug injection (up to Day 380) | An independent panel of medical experts reviewed/adjudicated events of CMV-specific AVT for treatment of CMV viremia or disease. |
| Percentage of Participants With Graft Survival (Primary Study Period) | From first study dose injection (day 1) up to one year post study drug injection (up to Day 380) | Graft survival was defined for any participant that did not fit the definition of graft loss. Graft loss was defined as participant death, re-transplant, nephrectomy, or return to permanent dialysis (i.e., for \> 30 days). Missing values for graft survival were not included in the denominator when making the proportion. The analysis population was the FAS. |
| Percentage of Participants With Graft Survival (Long-term Follow up) | Month 18, 30, 42, 54, and 66 | Graft survival was defined for any participant that did not fit the definition of graft loss. Graft loss was defined as participant death, re-transplant, nephrectomy, or return to permanent dialysis (i.e., for \> 30 days). Missing values for graft survival were not included in the denominator when making the proportion. |
Countries
Australia, Canada, France, Germany, Spain, United States
Participant flow
Recruitment details
A total of 150 participants were enrolled into the study from 6 countries. Eligible participants were ≥18 years of age, CMV-seronegative at the time of the transplant and had a kidney allograft from a CMV-seropositive living or deceased donor. After the primary period completion, 149 participants entered the long-term follow-up period.
Pre-assignment details
Screening assessments were performed from 14-30 days after the transplant. Participants were randomized at day 30 in relation to the day of the transplant, in a 1:1 ratio to ASP0113 or placebo. Participants were stratified by the use of antithymocyte globulin (ATG) prior to randomization and by the receipt of a kidney from a living or deceased donor.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 1 mL of 5 mg/mL of placebo via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0). | 74 |
| ASP0113 Participants received 1 mL of 5 mg/mL of ASP0113 via injection in the deltoid muscle alternating sides with each dose on days 30, 60, 90, 120 and 180 in relation to the day of transplant (Day 0). | 76 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Did Not Take Study Drug | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | ASP0113 |
|---|---|---|---|
| Age, Continuous | 47.9 Years STANDARD_DEVIATION 13.3 | 49.4 Years STANDARD_DEVIATION 13.5 | 50.8 Years STANDARD_DEVIATION 13.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 72 Participants | 70 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 78 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 25 Participants | 11 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 | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) White | 57 Participants | 118 Participants | 61 Participants |
| Randomization Strata Deceased Donor & ATG Use = No | 26 Participants | 53 Participants | 27 Participants |
| Randomization Strata Deceased Donor & ATG Use = Yes | 22 Participants | 44 Participants | 22 Participants |
| Randomization Strata Living Donor & ATG Use = No | 18 Participants | 34 Participants | 16 Participants |
| Randomization Strata Living Donor & ATG Use = Yes | 8 Participants | 18 Participants | 10 Participants |
| Randomization Strata Not Recorded | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 19 Participants | 40 Participants | 21 Participants |
| Sex: Female, Male Male | 55 Participants | 110 Participants | 55 Participants |
| Source of Current Transplant DECEASED DONOR | 48 Participants | 97 Participants | 49 Participants |
| Source of Current Transplant LIVING RELATED DONOR | 16 Participants | 25 Participants | 9 Participants |
| Source of Current Transplant LIVING UNRELATED DONOR | 10 Participants | 27 Participants | 17 Participants |
| Source of Current Transplant Not Recorded | 0 Participants | 1 Participants | 1 Participants |
| Use of ATG No | 44 Participants | 88 Participants | 44 Participants |
| Use of ATG Yes | 30 Participants | 62 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 74 | 7 / 75 |
| other Total, other adverse events | 72 / 74 | 75 / 75 |
| serious Total, serious adverse events | 36 / 74 | 44 / 75 |
Outcome results
Primary
Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection
CMV viremia was defined as presence of cytomegalovirus as measured in plasma viral load of ≥ 1000 IU/mL by central laboratory assay. A participant who discontinued the study without a positive CMV viral load was imputed as having a CMV viremia. A participant who had more than one viral load ≥ 1000 IU/mL by central assay was counted once in this summary. CMV viral loads after first injection (Day 1) through Day 380 (scheduled or unscheduled) were included in the analysis.
Time frame: From first study dose injection (day 1) up to one year post study drug injection (up to Day 380)
Population: The Full Analysis Set (FAS) consisted of all randomized patients who received at least 1 dose of randomized study drug and who had at least 1 post dose viral load assessment within 1 year post first injection by central laboratory.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection | Known CMV viremia | 35.6 Percentage of Paticipants |
| Placebo | Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection | Imputed CMV viremia due to discontinuation | 5.5 Percentage of Paticipants |
| ASP0113 5mg | Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection | Known CMV viremia | 35.6 Percentage of Paticipants |
| ASP0113 5mg | Percentage of Participants With CMV Viremia Through 1 Year Post First Study Drug Injection | Imputed CMV viremia due to discontinuation | 0 Percentage of Paticipants |
Comparison: The Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization strata, and the 90% CIs of the CMH odds ratio stratified by randomization group.p-value: 0.30790% CI: [0.43, 1.47]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Took Adjudicated CMV-specific Antiviral Therapy for the Treatment of CMV Viremia or Disease (Primary Study Period)
An independent panel of medical experts reviewed/adjudicated events of CMV-specific AVT for treatment of CMV viremia or disease.
Time frame: From first study dose injection (day 1) up to one year post study drug injection (up to Day 380)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Took Adjudicated CMV-specific Antiviral Therapy for the Treatment of CMV Viremia or Disease (Primary Study Period) | 45.21 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants Who Took Adjudicated CMV-specific Antiviral Therapy for the Treatment of CMV Viremia or Disease (Primary Study Period) | 42.47 Percentage of Participants |
Comparison: The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.p-value: 0.41990% CI: [0.48, 1.61]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease (Primary Study Period)
An independent panel of medical experts reviewed/adjudicated events of CMV-associated disease including CMV syndrome and tissue invasive disease, which were defined according to the American Society of Transplantation Recommendations for Screening, Monitoring and Reporting of Infectious Complications in Immunosuppression Trials in Recipients of Organ Transplantation 2006.
Time frame: From first study dose injection (day 1) up to one (up to Day 380) year post study drug injection
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease (Primary Study Period) | 19.18 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Adjudicated CMV-Associated Disease, Including CMV Syndrome and CMV Tissue-Invasive Disease (Primary Study Period) | 19.18 Percentage of Participants |
Comparison: The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.p-value: 0.57690% CI: [0.46, 2.15]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Graft Survival (Long-term Follow up)
Graft survival was defined for any participant that did not fit the definition of graft loss. Graft loss was defined as participant death, re-transplant, nephrectomy, or return to permanent dialysis (i.e., for \> 30 days). Missing values for graft survival were not included in the denominator when making the proportion.
Time frame: Month 18, 30, 42, 54, and 66
Population: All participants who entered long-term follow-up.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 30 | 83.8 Percentage of Participants |
| Placebo | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 54 | 78.4 Percentage of Participants |
| Placebo | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 42 | 85.1 Percentage of Participants |
| Placebo | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 66 | 82.4 Percentage of Participants |
| Placebo | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 18 | 91.9 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 66 | 84.2 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 18 | 94.7 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 30 | 81.6 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 42 | 80.3 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Long-term Follow up) | Long Term Follow Up Month 54 | 77.6 Percentage of Participants |
Secondary
Percentage of Participants With Graft Survival (Primary Study Period)
Graft survival was defined for any participant that did not fit the definition of graft loss. Graft loss was defined as participant death, re-transplant, nephrectomy, or return to permanent dialysis (i.e., for \> 30 days). Missing values for graft survival were not included in the denominator when making the proportion. The analysis population was the FAS.
Time frame: From first study dose injection (day 1) up to one year post study drug injection (up to Day 380)
Population: The analysis population was the FAS, with data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Graft Survival (Primary Study Period) | 98.53 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Graft Survival (Primary Study Period) | 100 Percentage of Participants |
Comparison: Exact Cochran-Mantel-Haenszel estimate of the common odds ratio could not be calculated as 100% of ASP0113 group showed graft survival, and this leads to having a value of 0 for the denominator for the ratio thus odds ratio is not estimable. The 90% CI (2-sided) values for the odds ratio are 0.11 to NA, where NA is an infinity value.p-value: 0.5Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Plasma Viral Load ≥ The Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory (Primary Study Period)
The central laboratory had the LLOQ level for CMV viral load assessment. When the viral load was below the LLOQ the actual reading was not possible and was denoted as ≤LLOQ. If the participant had any CMV viral load assessments greater than the LLOQ, set up by the central laboratory, participant was classified as viremic and was included in the analysis.
Time frame: From first study dose injection (day 1) up to one year post study drug injection (up to Day 380)
Population: The analysis population was the FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Plasma Viral Load ≥ The Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory (Primary Study Period) | 49.32 Percentage of Participants |
| ASP0113 5mg | Percentage of Participants With Plasma Viral Load ≥ The Lower Limit of Quantification (LLOQ) Assessed by Central Laboratory (Primary Study Period) | 46.58 Percentage of Participants |
Comparison: The exact Cochran-Mantel-Haenszel (CMH) estimate of the common odds ratio (ASP0113 vs placebo) stratified by randomization group, and the 90% CI of the exact CMH odds ratio stratified by randomization group.p-value: 0.40890% CI: [0.48, 1.59]Cochran-Mantel-Haenszel