A Phase 3 Study of Brincidofovir Versus Valganciclovir for the Prevention of Cytomegalovirus Disease

To compare the efficacy of oral brincidofovir (BCV) to valganciclovir (vGCV) for the prevention of cytomegalovirus (CMV) disease in kidney transplant allograft recipients who are CMV seronegative pretransplant and received a kidney from a CMV seropositive donor

This was a randomized, double-blind, double-dummy, parallel-group, multicenter study of the efficacy, safety, and tolerability of oral BCV versus vGCV for the prevention of CMV disease in high-risk kidney transplant allograft recipients, defined as CMV-seronegative recipients (R-) receiving a CMV-seropositive graft (D+). The study comprised a screening evaluation period (up to 14 days posttransplant), a treatment period (up to 28 weeks posttransplant), and a posttreatment follow-up period (24 weeks, through Week 52 posttransplant).

Eligibility Criteria:
Inclusion Criteria

Subjects must have met all of the following criteria, as applicable, to be eligible to participate in this study:

1. Were male or female kidney transplant recipients who were ≥18 years of age (subject to local law/practice for clinical trial participation) and ≤14 days following their first or second renal allograft.
2. Were at high risk of cytomegalovirus (CMV) infection defined as CMV-seronegative recipients who have received an allograft from a CMV-seropositive donor.
3. Had an estimated glomerular filtration rate of \>10 mL/min (Cockcraft-Gault equation) at screening based on local laboratory results.
4. Were CMV viremia negative (i.e., "not detected") as measured by the desginated central virology laboratory using the Roche COBAS® AmpliPrep/COBAS® TaqMan® CMV Test no more than 5 days prior to subject randomization, and at all prior assessments performed since transplant under local standard of care.
5. Were able to ingest, absorb, and tolerate tablets.
6. If male, was willing to use an acceptable contraceptive method(s) throughout the duration of his participation in the study, i.e., through Week 52.
7. If female of childbearing potential, i.e., not post menopausal or surgically sterile, was willing to use 2 acceptable contraceptive methods, 1 of which must have been a barrier method, throughout the duration of her participation in the study, i.e., through Week 52.
8. Were willing and able to provide informed consent.
9. Were willing and able to participate in all required study activities for the entire duration of the study (i.e., through Week 52).

Exclusion Criteria

Subjects who met any of the following criteria were not eligible to participate in this study:

1. Weighed ≤50 kg (110 lbs) or ≥120 kg (265 lbs).
2. Were pregnant or breastfeeding or intended to conceive during the study period (i.e., through Week 52).
3. Received a stem cell transplant or a solid organ transplant other than a kidney transplant.
4. Had suspected CMV disease (either syndrome or tissue-invasive disease) or detectable CMV viremia by the central virology laboratory prior to the first dose of study drug.
5. Had a history of CMV disease (either syndrome or tissue-invasive disease) within 6 months prior to the first dose of study drug.
6. Had an absolute neutrophil count of \<500 cells/μL, platelet count of \<25,000/μL, or hemoglobin of \<8 g/dL at screening.
7. Had hypersensitivity (not including renal dysfunction or an eye disorder) to valganciclovir (vGCV), ganciclovir (GCV), cidofovir (CDV) or to brincidofovir (BCV) or their excipients.
8. Received (or were anticipated to need treatment with) any of the following:

   * GCV, vGCV, foscarnet, intravenous CDV, or any other anti-CMV therapy (including CMV immune globulin, cell-based therapies, and investigational anti-CMV drugs, e.g., leflunomide, letermovir \[previously AIC246\], or maribavir) at any time posttransplant;
   * Any anti-CMV vaccine at any time;
   * Any other investigational drug within 14 days prior to the first dose of study drug (unless prior approval had been received from the Chimerix Medical Monitor or designee); or
   * Prior treatment with BCV at any time. \[Note: An "investigational drug" was defined as any drug that is not approved for any indication by the FDA (or appropriate regulatory authority).\]
9. Received acyclovir orally at \>2000 mg total daily dose (TDD) or intravenously at \>15 mg/kg TDD, valacyclovir at \>3000 mg TDD on the first dose of study drug or were anticipated to receive any of these drugs at the doses described after the the first dose of study drug.
10. Were infected with HIV, hepatitis B virus (HBV), and/or hepatitis C virus (HCV), had evidence of active viral replication within 6 months prior to screening, as demonstrated by detectable HIV or HCV RNA, or detectable HBV DNA in blood, plasma or serum.
11. Had severe vomiting, diarrhea, or malabsorption syndrome on or prior to the first dose of study drug.
12. Had gastrointestinal (GI) disease that would have, in the judgement of the investigator, precluded the subject form taking or absorbing oral medication (e.g., gastroparesis, diabetic autonomic neuropathy affecting the GI tract, clinically active Crohn's disease, ischemic colitis, moderate or severe ulcerative colitis, small bowel resection, ileus, or any condition that was expected to require abdominal surgery during the course of study participation).
13. Had serum alanine aminotransferase or aspartate aminotransferase concentrations \>5 x the upper limit of normal (ULN).
14. Had total serum bilirubin \>2 x the ULN and direct bilirubin \>1.5x the ULN.
15. Had moderate (Class B) to severe (Class C) hepatic dysfunction according to the Child-Pugh Turcotte scoring system.
16. Were receiving or would require digoxin or ketoconazole therapy (other than topical formulations) during the treatment phase of the study.
17. Had active malignancies (with the exception of basal cell carcinoma).
18. Had a serious psychiatric, medical disorder, including abnormal laboratory values, that would have, in the judgement of the investigator, put the subject at increased risk by participating in the study, or would have interfered with the conduct of the study.