Study of CMX001 to Prevent/Control Cytomegalovirus Infection in R+ Hematopoietic Stem Cell Transplant Recipients

Cytomegalovirus Infection Clinical Trial

Official title:

A Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study of the Safety, Tolerability and Ability of CMX001 to Prevent or Control CMV Infection in R+ Hematopoietic Stem Cell Transplant Recipients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00942305
• Other study ID #: CMX001-201
• Status: Completed
• Phase: Phase 2
• Start date: October 2009
• Est. completion date: January 2012

Study information

• Verified date: June 2021
• Source: Chimerix
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study of brincidofovir (BCV) administered orally once or twice weekly for up to 11 weeks. Dosing was initiated immediately following engraftment (between Days 14-30 post-transplant) to prevent/control cytomegalovirus (CMV) infection or prevent disease in R+ hematopoietic stem cell transplant (HCT) recipients.

Description:

This was to be a 2-part study. Part 1 was a randomized, double-blind, placebo-controlled, dose-escalation study of multiple doses of oral brincidofovir (BCV) in R+ hematopoietic stem cell transplant (HCT) recipients. In Part 2, one of the dose levels administered in Part 1 was to be tested against placebo to evaluate the statistical significance of BCV as a therapy for preventing progression of cytomegalovirus (CMV) infection or preventing CMV disease. The first 3 dose-escalating cohorts in Part 1 were to include 32 subjects within each cohort (24 randomized to receive oral BCV and 8 randomized to receive placebo in a 3:1 ratio) for a total of 96 planned subjects. Following completion of the first 3 cohorts and subsequent safety review of the data, up to an additional 3 cohorts of 32 subjects each could have been enrolled. Two additional cohorts (labeled Cohort 4 and Cohort 4A) beyond the initial 3 cohorts were actually enrolled in Part 1 of the study. Following the safety and antiviral activity analyses of the 5 cohorts in Part 1 and the number of subjects enrolled in each of those cohorts, Part 2 of the study was not conducted.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 239
• Est. completion date: January 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria For inclusion into the study, all prospective subjects were required to fulfill all of the

following criteria (as applicable):

1. Were aged =18 years. Males must have been able and willing to use adequate contraceptive methods throughout the treatment and follow-up phases of the study.

2. Were cytomegalovirus (CMV) seropositive before allogeneic hematopoietic stem cell transplantation (HCT) (i.e., R+ subjects).

3. Were less than 30 days post qualifying transplant.

4. Had evidence of engraftment before randomization and receiving their first dose of study drug.

5. Were able to ingest and absorb oral medication (in the judgment of the investigator and based on lack of significant gastrointestinal [GI] events).

6. Were willing and able to understand and provide written informed consent.

7. To the best of his or her knowledge, were willing and able to participate in all required study activities for the duration of the study. Exclusion Criteria Subjects meeting any of the following exclusion criteria were to be excluded from

participation in the study:

1. Females who were pregnant or currently nursing.

2. Had a body mass index >35 kg/m2. [Note: This criterion was removed per Protocol Amendment 2 dated 27 August 2010.]

3. Had hypersensitivity to cidofovir (CDV) or brincidofovir.

4. Recipients for whom the current, predose clinical course of CMV infection suggested that the investigator would not be able to withhold treatment for CMV for a minimum of 5, but preferably 7 days following the subject's first dose of study drug.

5. Received any of the following:

• Ganciclovir, valganciclovir, foscarnet or CDV within 14 days prior to enrollment;
• Any anti-CMV therapy following transplantation (including Cytogam®1);
• Any CMV vaccine;
• Any investigational drug with antiviral activity against double-stranded DNA (dsDNA) viruses within 14 days prior to enrollment. [Note: An investigational drug was defined as a drug that was not approved for any indication by the Food and Drug Administration.]; or
• Any other investigational drug (i.e., those without any "anti-dsDNA virus" activity; e.g., anti-influenza compounds) within 14 days prior to enrollment without the prior written consent of the medical monitor. The use of investigational drugs in certain circumstances was added per Protocol Amendment 1 dated 15 January 2010.

6. Received high dose acyclovir (>2000 mg total oral daily dose or >5 mg/kg intravenously 3 times daily) or valacyclovir (Valtrex; >3000 mg total daily dose) at the time of dosing.

7. Were diagnosed with active CMV disease within 6 months prior to enrollment; patients with CMV DNAemia requiring intervention with antiviral therapy at the time of enrollment.

8. Were HIV positive; patients with active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection as evidenced by plasma levels of HCV RNA or HBV DNA, respectively.

9. Received another allogeneic HCT within the past 2 years, other than the qualifying HCT.

10. Had renal insufficiency as evidenced by glomerular filtration rate (GFR) <30 mL/min.

11. Had a current diagnosis of hypotony, uveitis, or retinitis or any intraocular pathology that would predispose the subject to any one of these conditions.

12. Had hepatic dysfunction as evidenced by alanine aminotransferase or aspartate aminotransferase >5 x the upper limit of normal (ULN) or direct bilirubin >2.5 x the ULN.

13. Had any of the following active autoimmune disorders: myasthenia gravis, Addison's disease, Wegener's granulomatosis, primary biliary cirrhosis, bullous pemphigoid, autoimmune hemolytic anemia, autoimmune hepatitis, multiple sclerosis, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, lupus erythematosus, dermatomyositis, polymyositis, or vasculitis.

14. Had active solid tumor malignancies with the exception of basal cell carcinoma or the condition under treatment (e.g., lymphomas).

15. Had 1 or more episode of hyperglycemic coma or diabetic ketoacidosis within the 6 months prior to enrollment.

16. Had cardiovascular disease which, in the opinion of the investigator, would interfere with the conduct of the study.

17. Had Grade 3 or 4 graft versus host disease of the GI tract; subjects with any GI disease that would, in the judgment of the investigator, preclude the subject from taking or absorbing oral medication (e.g. clinically active Crohn's disease, ischemic colitis, moderate or severe ulcerative colitis, or any condition expected to require abdominal surgery during the course of study participation).

18. Any other condition including abnormal laboratory values that would have, in the judgment of the investigator, put the subject at increased risk for participating in the trial, or interferes with the conduct of the trial.

Related Conditions & MeSH terms

• Communicable Diseases
• Cytomegalovirus Infection
• Cytomegalovirus Infections
• Infection

Intervention

Drug:
• Brincidofovir
Subjects received their first dose of study drug of brincidofovir (BCV) within 30 (+5) days post-transplant and were treated through Week 13 post-transplant.
• Placebo
Subjects received their first dose of study drug within 30 (+5) days post-transplant and were treated through Week 13 post-transplant. Matching placebo administered for each cohort.

Locations

Country	Name	City	State
United States	University of Michigan Medical School	Ann Arbor	Michigan
United States	Winship Cancer Institute at Emory University	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Womens Hospital, Division of Infectious Disease	Boston	Massachusetts
United States	Montefiore Medical Center Oncology	Bronx	New York
United States	UNC Health Care Center	Chapel Hill	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	The Cleveland Clinic	Cleveland	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	UT Southwestern Medical Center at Dallas	Dallas	Texas
United States	Harper University Hospital	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	Moores UCSD Cancer Center	La Jolla	California
United States	UCLA Medical Center	Los Angeles	California
United States	University of Minnesota Medical Center	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mt. Sinai School of Medicine	New York	New York
United States	Nebraska Medical Center	Omaha	Nebraska
United States	Oregon Health and Science University	Portland	Oregon
United States	University of Rochester Medical Center	Rochester	New York
United States	Utah Cancer Specialists - Intermountain Healthcare	Salt Lake City	Utah
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Wake Forest University School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Chimerix

Country where clinical trial is conducted

United States, 

References & Publications (2)

Lanier ER, Foster S, Brundage T, Chou S, Prichard MN, Kleiboeker S, Wilson C, Colville D, Mommeja-Marin H. Analysis of Mutations in the Gene Encoding Cytomegalovirus DNA Polymerase in a Phase 2 Clinical Trial of Brincidofovir Prophylaxis. J Infect Dis. 2016 Jul 1;214(1):32-5. doi: 10.1093/infdis/jiw073. Epub 2016 Mar 3. — View Citation

Marty FM, Winston DJ, Rowley SD, Vance E, Papanicolaou GA, Mullane KM, Brundage TM, Robertson AT, Godkin S, Momméja-Marin H, Boeckh M; CMX001-201 Clinical Study Group. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Clinically Significant CMV Infection	The primary efficacy endpoint was a binomial outcome of failure to prevent cytomegalovirus (CMV) infection defined as CMV DNAemia >200 copies/mL obtained at the time of the last treatment with study drug or diagnosis of CMV disease at some point during the treatment phase.	Randomization to Week 8 post-treatment (~19 weeks)

External Links

•   Analysis of Mutations in Gene Encoding Cytomegalovirus DNA Polymerase in a Phase 2 Clinical Trial of Brincidofovir Prophylaxis
•   CMX001 to Prevent Cytomegalovirus Disease in Hematopoietic-Cell Transplantation