Cytomegalovirus Infections
Conditions
Keywords
Acute rejection, Non-CMV infections, Resistance
Brief summary
The study evaluated the efficacy and safety of a prolonged, continuous course of Valganciclovir (Valgan) in the prevention of CMV by comparing 3 months of Vaglanciclovir, the standard of care upon initiation of the study, to 12 months of Valganciclovir.
Detailed description
A multi-center two phase, double-blind, placebo controlled, randomized prospective study of 130 lung transplant recipients. Patients will be screened and consented prior to transplant. All consented patients will receive IV ganciclovir within 24 hours of transplant for not more than 14 days. Patients will enroll in Phase I of the study is an open label safety and efficacy analysis of three months of oral valganciclovir in adult transplant recipients who are at risk for CMV. After completion of 3 months of open label therapy, patients that meet the criteria for Phase II of the study will be randomized to 9 months of blinded therapy (Placebo/Valgan). Phase II of the study is designed to assess the efficacy of short course sequential IV ganciclovir followed by oral valganciclovir as compared to the extended period of oral valganciclovir prophylaxis in the prevention of CMV disease in at risk lung transplant recipients
Interventions
DRUGvalganciclovir
valgan 900mg QD x 9 months post lung transplant
OTHERPlacebo
Sponsors
Roche Pharma AG
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Phase I: * Adult lung transplant recipients age 18 or older * At risk for CMV (donor or recipient serology must be positive for CMV) * Adequate hematological and renal function, * On intravenous (IV) ganciclovir within 24 hours of surgery * Agreement to use effective methods of contraception * Negative pregnancy * Tolerate oral medications within 2 weeks of transplant * Negative baseline CMV PCR * Able to understand and sign the informed consent
Exclusion criteria
for Phase 1: * Repeat transplantation * Mechanical ventilation at study entry * Oral or intravenous ganciclovir treatment outside the study protocol * Invasive fungal infection * Participation in another investigational study * Acute CMV infection or disease * Anti-CMV therapy within 30 days before enrollment * Uncontrolled diarrhea or malabsorption * Allergic reaction to study drug * Required use of prohibited medications * Lactating women * Pregnancy * Renal failure Inclusion Criteria for Phase II: * Negative serial post transplant PCRs at day 75 * Negative bronchial cultures for CMV * Adequate hematological and renal function at day 75 * IV ganciclovir for up to 2 weeks post operation and open label up to day 90 * Effective contraceptives * Negative pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of CMV End Organ Disease | over the course of 300 days after randomization | The primary study end point was CMV end-organ disease determined by positive tissue immunostain or characteristic histopathology assessed for within 300 days post randomization. |
| Incidence of CMV Syndrome | over the course of 300 days after randomization | CMV clinical syndrome, with either positive serum PCR or positive culture for CMV from bronchoalveolar lavage and at least 2 of the following: fever, leukopenia, thrombocytopenia, elevated liver function test results malaise, reduction in pulmonary function (FEV1) greater than 20percent of baseline, or radiographic infiltrate consistent with CMV (all in the absence of other causes) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-CMV Infection | over the course of 300 days after randomization | non cmv opportunistic infections |
| Any CMV Infection | over the course of 300 days post randomization | Inclusive of CMV syndrome, disease, or infection not meeting primary end point. |
| Ganciclovir Resistance | over the course of 300 days post randomization | UL97 genotyping was done on all positive samples for CMV DNA at 1000 copies/mL, with resistance defined by the presence of 1 or more mutations shown by marker transfer to confer phenotypic ganciclovir resistance |
| Severity of Viremia | over the course of 300 days after randomization | upon diagnosis of cmv disease, the number of CMV DNA copies/mL as measured by PCR |
| Biopsy Proven Acute Lung Rejection | over the course of 300 days of randomization | — |
Countries
United States
Participant flow
Recruitment details
Prospective subjects were screened and enrolled from July 2003 - January 2007 at 11 US lung transplant centers. 189 subjects were screened and 157 met inclusion criteria and were therefore enrolled in the study.
Pre-assignment details
Upon receipt of a lung transplant, enrolled subjects received 90 days of valganciclovir for CMV prophylaxis, per standard of care, and then were randomly assigned, 1:1, in a double blind fashion, to either the extended prophylaxis group (9 additional months of standard of care dosing Valganciclovir, adjusted for renal function) or placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Group Upon randomisation at 3 months, patients discontinued Valganciclovir and received no CMV prophylaxis | 66 |
| Treatment Group Upon randomisation at 3 months, patients remained on Valganciclovir for 9 additional months. | 70 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 11 |
| Overall Study | Death | 3 | 4 |
| Overall Study | Other reasons | 2 | 1 |
| Overall Study | Physician Decision | 9 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo Group | Treatment Group | Total |
|---|---|---|---|
| 6MWD, feet | 1168 feet | 1120 feet | 1155 feet |
| Age, Continuous Age | 50.6 years STANDARD_DEVIATION 13.8 | 51.9 years STANDARD_DEVIATION 12.2 | 51.3 years STANDARD_DEVIATION 13 |
| Daily Supplemental Oxygen Use No supplemental oxygen use | 13 subjects | 19 subjects | 32 subjects |
| Daily Supplemental Oxygen Use Supplemental Oxygen use | 53 subjects | 51 subjects | 104 subjects |
| FEV1, liters | 0.75 liters | 0.80 liters | 0.79 liters |
| FVC, liters | 2.02 liters | 1.89 liters | 1.95 liters |
| Indication for Lung Transplant COPD | 35 subjects | 33 subjects | 68 subjects |
| Indication for Lung Transplant Cystic Fibrosis | 11 subjects | 12 subjects | 23 subjects |
| Indication for Lung Transplant Idiopathic Pulmonary Fibrosis | 16 subjects | 16 subjects | 32 subjects |
| Indication for Lung Transplant Other | 2 subjects | 6 subjects | 8 subjects |
| Indication for Lung Transplant Sarcoid | 2 subjects | 3 subjects | 5 subjects |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 7 Participants | 13 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 60 Participants | 63 Participants | 123 Participants |
| Sex: Female, Male Female | 28 Participants | 41 Participants | 69 Participants |
| Sex: Female, Male Male | 38 Participants | 29 Participants | 67 Participants |
| Smoking History Current Smoking | 0 subjects | 0 subjects | 0 subjects |
| Smoking History No Smoking History/Never Smoked (past or present) | 22 subjects | 21 subjects | 43 subjects |
| Smoking History Past Smoking History: former smokers who quit | 44 subjects | 49 subjects | 93 subjects |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 66 | 70 / 70 |
| serious Total, serious adverse events | 35 / 66 | 38 / 70 |
Outcome results
Primary
Incidence of CMV End Organ Disease
The primary study end point was CMV end-organ disease determined by positive tissue immunostain or characteristic histopathology assessed for within 300 days post randomization.
Time frame: over the course of 300 days after randomization
Population: Intention to treat analysis was conducted.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Incidence of CMV End Organ Disease | 21 participants |
| Treatment Group | Incidence of CMV End Organ Disease | 1 participants |
Primary
Incidence of CMV Syndrome
CMV clinical syndrome, with either positive serum PCR or positive culture for CMV from bronchoalveolar lavage and at least 2 of the following: fever, leukopenia, thrombocytopenia, elevated liver function test results malaise, reduction in pulmonary function (FEV1) greater than 20percent of baseline, or radiographic infiltrate consistent with CMV (all in the absence of other causes)
Time frame: over the course of 300 days after randomization
Population: intention to treat analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Incidence of CMV Syndrome | 13 participants |
| Treatment Group | Incidence of CMV Syndrome | 0 participants |
Secondary
Any CMV Infection
Inclusive of CMV syndrome, disease, or infection not meeting primary end point.
Time frame: over the course of 300 days post randomization
Population: intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Any CMV Infection | 42 participants |
| Treatment Group | Any CMV Infection | 7 participants |
Secondary
Biopsy Proven Acute Lung Rejection
Time frame: over the course of 300 days of randomization
Population: intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Biopsy Proven Acute Lung Rejection | 22 participants |
| Treatment Group | Biopsy Proven Acute Lung Rejection | 15 participants |
Secondary
Ganciclovir Resistance
UL97 genotyping was done on all positive samples for CMV DNA at 1000 copies/mL, with resistance defined by the presence of 1 or more mutations shown by marker transfer to confer phenotypic ganciclovir resistance
Time frame: over the course of 300 days post randomization
Population: intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Ganciclovir Resistance | 1 participants |
| Treatment Group | Ganciclovir Resistance | 2 participants |
Secondary
Non-CMV Infection
non cmv opportunistic infections
Time frame: over the course of 300 days after randomization
Population: intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Group | Non-CMV Infection | 35 participants |
| Treatment Group | Non-CMV Infection | 38 participants |
Secondary
Severity of Viremia
upon diagnosis of cmv disease, the number of CMV DNA copies/mL as measured by PCR
Time frame: over the course of 300 days after randomization
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Group | Severity of Viremia | 110,000 CMV copies/mL |
| Treatment Group | Severity of Viremia | 3,200 CMV copies/mL |