Clinical trial NCT01769170: A Study of the Safety and Efficacy of CMX001 for the Prevention of CMV Infection in CMV-seropositive HCT Recipients
Official title: A Phase 3 Study of the Safety, Tolerability, and Efficacy of CMX001 for the Prevention of Cytomegalovirus (CMV) Infection in CMV-seropositive (R+) Hematopoietic Stem Cell Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: CMV
Keywords: CMV
Hematopoietic Stem Cell Transplant Recipients
Prevention
Lead sponsor: Chimerix
Sponsor class: INDUSTRY
First posted: 2013-01-16
Enrollment: 452
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized, double-blind, placebo-controlled, parallel group, multicenter study compared the effectiveness of oral brincidofovir (BCV) to placebo for the prevention of cytomegalovirus (CMV) infection in stem cell transplant patients who were CMV seropositive but negative for CMV viremia before starting treatment with BCV.

Detailed description: This was a randomized, double-blind, placebo-controlled, parallel group multicenter study of oral brincidofovir (BCV) in approximately 450 cytomegalovirus (CMV)-seropositive subjects who had undergone allogeneic hematopoietic stem cell transplantation (HCT). The study consisted of a screening evaluation and a treatment phase of 10 to 14 weeks. Dosing with the study drug (BCV or placebo) was initiated as soon as individual subjects could ingest tablets after transplant but no later than Day 28 post-transplant, and was continued through Week 14. All randomized subjects remained on study and followed the same scheduled study treatment. Study assessments were performed weekly from randomization through completion of the first post-treatment follow-up assessment at Week 15, and every 3 weeks thereafter through Week 24.

Eligibility criteria: Inclusion Criteria

Subjects were required to meet all of the following criteria, as applicable, to be eligible to participate in this study:

1. Were allogeneic hematopoietic stem cell transplant (HCT) recipients who had prior evidence of cytomegalovirus (CMV) exposure (CMV-seropositive) before transplantation and were CMV viremia negative at screening and at any other assessments performed prior to the first dose of study drug.
2. Were aged ≥18 years.
3. If male, were willing to use an acceptable contraceptive method(s) throughout the duration of his participation in the study, i.e., through Week 24, when engaging in sexual intercourse with a female subject of childbearing potential.
4. If female of childbearing potential, i.e., not postmenopausal or surgically sterile, were 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 24, when engaging in sexual intercourse with a nonsterile male partner.
5. Were able to begin study drug dosing within 28 days following the qualifying HCT.
6. Were able to comfortably ingest and absorb oral medication (in the judgment of the investigator and base don lack of significant gastrointestinal events/medical history).
7. Were willing and able to understand and provide written informed consent.
8. Were willing and able to participate in all required study activities for the entire duration of the study (i.e., through Week 24).

Exclusion Criteria

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

1. Was pregnant or planned to become pregnant during the anticipated duration of her participation in the study (i.e., through Week 24), or was nursing a child.
2. Had a positive CMV viremia test (at the designated central virology laboratory or a local virology laboratory) at any time between transplant and the first dose of study drug.
3. Weighed ≥120 kg (\~265 lbs).
4. Had hypersensitivity (not renal dysfunction or eye disorder) to cidofovir (CDV), brincidofovir (BCV), or its excipients.
5. Had received (or were anticipated to need treatment with) any of the following:

   * Ganciclovir, valganciclovir, 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, or maribavir) at any time post-transplant;
   * Any anti-CMV vaccine at any time;
   * Any other investigation 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.
6. Were receiving of the following drugs on the first dose of study drug or were anticipated to receive any of these drugs at the doses described after the first dose of study drug:

   * Acyclovir orally at \>2000 mg total daily dose (TDD) or intravenously at \>15 mg/kg TDD;
   * Valaciclovir at \>3000 mg TDD; or
   * Leflunomide at any dose.
7. Were receiving digoxin or ketoconazole (other than topical formulations) at the first dose of study drug or were anticipated to need treatment with either digoxin or ketoconazole during the treatment phase (through Week 14).
8. Had possible, probably, or definitive CMV disease diagnosed within 6 months prior to first dose of study drug.
9. Were infected with HIV (based on serology), or had an active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, as evidence by detectable plasma HCV RNA or HBV DNA, respectively.
10. Had received another allogeneic HCT (i.e., other than the qualifying HCT) within 2 years prior to the first dose of study drug.
11. Had renal insufficiency, as evidence by an estimated glomerular filtration rate (eGFR) \<15 mL/min or required renal dialysis.
12. Had hepatic abnormalities as evidence by a screening of alanine aminotransferase or aspartate aminotransferase \>5 x the upper limit of normal (ULN), as reported by the central safety laboratory.
13. Had a screening total bilirubin \>2 x the ULN and direct bilirubin \>1.5 x the ULN, as reported by the central safety laboratory.
14. Had active solid tumor malignancies with the exception of basal cell carcinoma or the underlying condition necessitating HCT (e.g., lymphomas).
15. Had Stage 2 or higher graft versus host disease of the gut or any other GI disease that would have, in the judgment of the investigator, precluded the subject from taking or absorbing oral medication (e.g., clinically active Crohn's disease, ischemic colitis, moderate or severe ulcerative colitis, small bowel resection, ileus, or any condition expected to require abdominal surgery during the course of study participation).
16. Had any other condition, 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 or planned analyses of the study.

Primary outcomes:
measure: Number of Participants With Clinically Significant CMV Infection Through Week 24 Post-Transplant
timeFrame: 24 weeks
Secondary outcomes:
measure: Incidence of Clinically Significant CMV Infection Through Week 14
timeFrame: 14 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego-Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute-Emory
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Iowa City
country: United States
facility: The Universit of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Beth Isreal Decaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College/NY Presbyterial Hospital
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute/Carolinas Health
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: The Jewish Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny-Singer Research Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Healthcare of San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain Healthcare
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Brüssel
country: Belgium
facility: Centre Hospitalier Universitaire Sart Tilman Liege
state: Liege
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire de Montreal, Hopital Maisonneuve-Rosemont
state: Quebec
Study officials:
References:
citation: Marty FM, Winston DJ, Chemaly RF, Mullane KM, Shore TB, Papanicolaou GA, Chittick G, Brundage TM, Wilson C, Morrison ME, Foster SA, Nichols WG, Boeckh MJ; SUPPRESS Trial Clinical Study Group. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2019 Feb;25(2):369-381. doi: 10.1016/j.bbmt.2018.09.038. Epub 2018 Oct 4.