Cytomegalovirus Infection
Conditions
Keywords
CMV, cytomegalovirus infections, ganciclovir, liver transplant, preemptive therapy, prophylaxis, valganciclovir
Brief summary
This is a trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in R-D+ liver transplant patients. Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir, 900 mg orally once daily or preemptive therapy (weekly monitoring for CMV viremia by plasma PCR) for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia and continued until plasma PCR is negative on two consecutive weekly PCR tests). A minimum of 176 subjects will be enrolled in the study. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients.
Detailed description
This is a prospective, randomized, multicenter trial of preemptive therapy vs. prophylaxis for prevention of Cytomegalovirus (CMV) disease in seronegative recipient- seropositive donor (R-D+) liver transplant patients.Subjects will be randomized within 10 days of transplant to receive in an open label design, either antiviral prophylaxis with valganciclovir 900 mg orally once daily or preemptive therapy for 100 days post-randomization with initiation of oral valganciclovir 900mg orally twice daily at onset of CMV viremia (monitored weekly) and continued until plasma PCR is negative on two consecutive weekly PCR tests. Study participants will be followed during the intervention period (100 days post randomization) and until 12 months post-transplant for CMV disease, toxicity, and clinical outcomes (opportunistic infections, rejection, graft loss and mortality). Drug safety labs will be assessed and recorded for the entire treatment period in both the prophylaxis and preemptive group. Re-transplantation and all-cause mortality will also be assessed at study closure and no longer than 5 years after enrollment. Additionally, the impact of the two CMV prevention strategies on CMV-specific cellular and humoral immune responses will be evaluated at 100 days after randomization, and 6 and 12 months post-transplant. A minimum of 176 subjects will be enrolled in the study. Allowing for over-enrollment to replace dropouts, up to 205 subjects may be enrolled to achieve the target enrollment of 176. Subjects will be randomized into one of the two groups in 1:1 ratio. The study duration is 7 years. The primary objective of this study is to compare prophylaxis versus preemptive therapy using valganciclovir for the prevention of CMV disease in R-/D+ liver transplant recipients. The secondary objectives are:1) to assess the two preventive strategies for clinical outcomes (major bacterial, fungal and non-CMV viral infections, rejection, graft loss and mortality) at one year post transplantation; 2) to assess the two preventive strategies for hematologic toxicity (assessment of neutropenia and receipt of hematopoietic growth factor during study days 1-107).
Interventions
DRUGValganciclovir
Valganciclovir, 900 mg given orally once daily to all Prophylaxis group subjects for 100 days post transplantation as prophylaxis. Valganciclovir, 900 mg given orally twice daily to Preemptive Therapy group subjects as a PET only after a positive CMV PCR test and stopped after PCR is negative for 2 consecutive weeks.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Be \> / = 18 years of age. 2. Have negative Cytomegalovirus (CMV) serology (confirmed within 6 months of transplant) and receive a liver from a donor with positive CMV serology (R-/D+). 3. Have received their first orthotopic liver transplant (the transplanted liver may be deceased donor or live donor graft) within 10 days prior. 4. Have absolute neutrophil count \> 1000/µL at randomization. 5. \- If female, and not postmenopausal or surgically sterile, must have negative pregnancy test (serum or urine) within 48 hours prior to randomization and must also agree to use medically approved method of contraception. Acceptable methods include: barrier method, intrauterine device (hormonal or non-hormonal), oral hormonal contraceptives, abstinence for 100 days after randomization and 3 months after valganciclovir cessation. \-- If male, and has not had a vasectomy, he must agree to practice barrier method of contraception for 100 days after randomization and 3 months after valganciclovir cessation. 6. Subject or legally authorized representative has provided written informed consent.
Exclusion criteria
1. Currently enrolled in any interventional trial of an investigational therapeutic agent unless co-enrollment has been approved by study Principal Investigators (PIs) and the DMID prior to enrollment. 2. Have hypersensitivity to acyclovir, ganciclovir or valganciclovir. 3. Be breast-feeding mother. 4. Have known Human immunodeficiency virus (HIV) infection (based on testing performed during the transplant evaluation process). 5. Be undergoing multi organ transplant or have undergone prior organ transplant. 6. Have expected life expectancy of less than 72 hours.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Cytomegalovirus (CMV) Disease. | 365 days post-transplant | CMV disease as verified by an independent end point committee |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Allograft Rejection | Up to 365 days post-transplant | Number of subjects with allograft rejection |
| Graft Loss | Up to 365 days post-transplant | Incidence of graft loss (re-transplantation) |
| Late-onset CMV Disease | Up to 365 days post-transplant | Incidence of late-onset CMV disease (occurring after 100 days post-randomization) as adjudicated by end point committee |
| Bacterial Infections | Up to 365 days post-transplant | Incidence of bacterial opportunistic infections |
| All-cause Mortality | Up to 365 days post-transplant | Survival probability at 1 year |
| Major Non-CMV Viral Infections | Up to 365 days post-transplant | Incidence of non-CMV viral infections |
| Neutropenia | Day 1 through Day 107 | Incidence of neutropenia less than 1000/µL while on valganciclovir treatment |
| Neutropenia Less Than 500 | prior to day 107 | ANC less than 500 while on valganciclovir |
| Hematopoietic Growth Factors | Day 1 through Day 107 | Hematopoietic growth factor receipt for ANC less than 500 during valganciclovir treatment. |
| Major Fungal Infections | Up to 365 days post-transplant | Opportunistic fungal infections |
Countries
United States
Participant flow
Pre-assignment details
538 liver transplant candidates or recipients were screened. 333 were not eligible. 229 did not meet inclusion criteria. 29 met at least 1 exclusion criteria. 75 unable to give, or refused consent. No study procedures were conducted on these 333 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Preemptive Therapy 900 mg of Valganciclovir given orally twice daily to Preemptive Therapy subjects upon detection of CMV viremia until plasma PCR is negative on two consecutive weekly PCR test. All dosages adjusted for renal dysfunction. n=100 | 100 |
| Prophylaxis 900 mg of Valganciclovir given orally once daily to subjects for 100 days post transplantation. All dosages adjusted for renal dysfunction. n=105 | 105 |
| Total | 205 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not consent to extended follow up | 8 | 9 |
Baseline characteristics
| Characteristic | Preemptive Therapy | Prophylaxis | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 58 years | 58 years |
| Baseline absolute neutrophil count(ANC) | 6888 Count per 1000 cells/µL | 7409 Count per 1000 cells/µL | 7160 Count per 1000 cells/µL |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 11 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 94 Participants | 186 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 3 Participants | 9 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 | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 90 Participants | 99 Participants | 189 Participants |
| Region of Enrollment United States | 100 participants | 105 participants | 205 participants |
| Sex: Female, Male Female | 35 Participants | 27 Participants | 62 Participants |
| Sex: Female, Male Male | 65 Participants | 78 Participants | 143 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 100 | 7 / 105 |
| other Total, other adverse events | 1 / 100 | 1 / 105 |
| serious Total, serious adverse events | 2 / 100 | 0 / 105 |
Outcome results
Primary
Incidence of Cytomegalovirus (CMV) Disease.
CMV disease as verified by an independent end point committee
Time frame: 365 days post-transplant
Population: All randomized subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preemptive Therapy | Incidence of Cytomegalovirus (CMV) Disease. | 9 participants |
| Prophylaxis | Incidence of Cytomegalovirus (CMV) Disease. | 20 participants |
p-value: 0.0396Mantel Haenszel
p-value: 0.04895% CI: [1.01, 7.3]Competing risk regression
Secondary
All-cause Mortality
Survival probability at 1 year
Time frame: Up to 365 days post-transplant
Population: Intent to treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Preemptive Therapy | All-cause Mortality | .880 survivor probabillity |
| Prophylaxis | All-cause Mortality | .933 survivor probabillity |
p-value: 0.19Log Rank
Secondary
Bacterial Infections
Incidence of bacterial opportunistic infections
Time frame: Up to 365 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Bacterial Infections | 22 Participants |
| Prophylaxis | Bacterial Infections | 26 Participants |
p-value: 0.6495% CI: [0.61, 2.23]Mantel Haenszel
Secondary
Graft Loss
Incidence of graft loss (re-transplantation)
Time frame: Up to 365 days post-transplant
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Graft Loss | 2 Participants |
| Prophylaxis | Graft Loss | 2 Participants |
p-value: 0.9695% CI: [0.13, 6.92]Mantel Haenszel
Secondary
Hematopoietic Growth Factors
Hematopoietic growth factor receipt for ANC less than 500 during valganciclovir treatment.
Time frame: Day 1 through Day 107
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Hematopoietic Growth Factors | 5 Participants |
| Prophylaxis | Hematopoietic Growth Factors | 7 Participants |
p-value: 0.61Chi-squared
Secondary
Incidence of Allograft Rejection
Number of subjects with allograft rejection
Time frame: Up to 365 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Incidence of Allograft Rejection | 28 Participants |
| Prophylaxis | Incidence of Allograft Rejection | 26 Participants |
p-value: 0.695% CI: [0.45, 1.58]Mantel Haenszel
Secondary
Late-onset CMV Disease
Incidence of late-onset CMV disease (occurring after 100 days post-randomization) as adjudicated by end point committee
Time frame: Up to 365 days post-transplant
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Late-onset CMV Disease | 6 Participants |
| Prophylaxis | Late-onset CMV Disease | 18 Participants |
p-value: 0.01495% CI: [1.21, 8.69]Mantel Haenszel
Secondary
Major Fungal Infections
Opportunistic fungal infections
Time frame: Up to 365 days post-transplant
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Major Fungal Infections | 4 Participants |
| Prophylaxis | Major Fungal Infections | 9 Participants |
p-value: 0.1895% CI: [0.66, 7.62]Mantel Haenszel
Secondary
Major Non-CMV Viral Infections
Incidence of non-CMV viral infections
Time frame: Up to 365 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Major Non-CMV Viral Infections | 2 Participants |
| Prophylaxis | Major Non-CMV Viral Infections | 0 Participants |
p-value: 0.24Fisher Exact
Secondary
Neutropenia
Incidence of neutropenia less than 1000/µL while on valganciclovir treatment
Time frame: Day 1 through Day 107
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Neutropenia | 36 Participants |
| Prophylaxis | Neutropenia | 35 Participants |
p-value: 0.69Chi-squared
Secondary
Neutropenia Less Than 500
ANC less than 500 while on valganciclovir
Time frame: prior to day 107
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preemptive Therapy | Neutropenia Less Than 500 | 12 Participants |
| Prophylaxis | Neutropenia Less Than 500 | 10 Participants |
p-value: 0.57Chi-squared