Phase 2 Study to Evaluate Brincidofovir for the Prevention of Adenovirus Disease

A Randomized, Placebo-controlled, Multi-site Phase 2 Study Evaluating the Safety and Efficacy of Preemptive Treatment With CMX001 for the Prevention of Adenovirus Disease Following Hematopoietic Stem Cell Transplantation

This study was designed to assess the safety and efficacy of preemptive treatment with oral brincidofovir (BCV), as compared to placebo, for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia.

Study Overview

• Status: Completed
• Conditions: Adenovirus Disease
• Intervention / Treatment: Drug: Brincidofovir; Other: Placebo

Detailed Description

This was a Phase 2, randomized, multicenter, placebo-controlled study for pediatric and adult subjects who had undergone hematopoietic stem cell transplantation (HCT) and who had been identified as having asymptomatic adenovirus (AdV) viremia [i.e., had detectable AdV DNA in plasma based on polymerase chain reaction testing performed at the local laboratory with no AdV disease symptoms]. The primary objectives of the study were to assess the safety and tolerability of oral brincidofovir (BCV), and to estimate the treatment failure rate based on an efficacy endpoint with 2 different dosing regimens of oral BCV versus placebo.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Pheonix Children's Hospital
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • Los Angeles, California, United States, 90033
      • Childrens Hospital of LA
    • Orange, California, United States, 92868
      • CHOC Children's Hospital
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • Stanford, California, United States, 94304
      • Lucile Packard Childrens hopsital at Stanford
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital-Denver
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • LSU Health Sciences Center New Orleans Childrens Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Harvard-Children's Hospital Boston
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Univeristy of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hosptial
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Childrens Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Judes Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine, Texas Childrens Hospital
    • San Antonio, Texas, United States, 78229
      • Methodist Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical of Utah
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

For inclusion into the study, subjects were required to fulfill all of the following criteria:

1. Were males or female aged ≥3 months to ≤75 years.
2. Received an allogeneic hematopoietic stem cell transplant (HCT).
3. Had positive serum adenovirus (AdV) PCR (>100 copies/mL) as measured by the central laboratory (unless the subject developed AdV disease while participating in the prescreening activities and after concurrence from the Chimerix medical monitor or designee).
4. Was on dialysis during treatment if he/she had an estimated glomerular filtration rate (eGFR) ≤30 mL/minute.
5. Subject or guardian(s) were willing to comply with the protocol.
6. Subject or guardian(s) were willing and able to understand the informed consent/assent.
7. Female subjects of child-bearing potential must have had a negative pregnancy test and must have agreed to use 2 acceptable methods of birth control throughout the study with at least 1 being a barrier method. Sexually active males of procreation potential must have been able and willing to se a reliable and medically approved contraceptive method throughout the study. At least 1 barrier method of contraception must have been used.

Exclusion Criteria

Subjects meeting any of the following exclusion criteria were excluded from participation in the study:

1. Had possible, probable, or definitive AdV disease (unless the subject developed probable or definitive AdV disease while participating in prescreening activities and after concurrence from he Chimerix medical monitor or designee).
2. Had suspected gut graft versus host disease that was not biopsy-proven (subjects with a biopsy performed were included in the study).
3. Had an eGFR ≤30 mL/minute and was not currently on dialysis.
4. Had an alanine aminotransferase or aspartate aminotransferase >5 x the upper limit of normal (ULN), total bilirubin ≥2 x the ULN, or conjugated (direct) bilirubin ≥1.5 x the ULN.
5. Had a condition that prevented oral dosing of study drug.
6. Was HIV antibody positive, based upon available medical records.
7. Had ocular hypotony, uveitis, or retinitis or any other intraocular pathology that would have predisposed the subject to 1 of these conditions.
8. Had participated in another clinical study of an investigational drug/biologic or was exposed to an investigational drug/biologic within 30 days of enrollment without the prior written approval of the Chimerix medical monitor or designee. For subjects who were participating in any clinical study involving non-investigational drugs and/or biologics, the investigator must have obtained approval from the Chimerix medical monitor or designee prior to enrolling the subject.
9. Was pregnant or breast-feeding or intended to conceive during the course of the study, including the follow-up period after drug discontinuation.
10. Had known immunologic hypersensitivity to cidofovir (CDV) or brincidofovir (BCV) drug or any of its excipients.
11. Had a history of illicit drug use or alcohol abuse within the previous 6 months.
12. Had any medical condition that, in the opinion of the investigator, might have interfered with the subject's participation in the study, posed an added risk for the subject, or confounded the assessment of the subject (e.g. severe cardiovascular, central nervous system or pulmonary disease).
13. Received BCV, CDV, ribavirin, or leflunomide within the previous 14 days.
14. Was receiving or was anticipated to need treatment with digoxin that could not have been withheld for the duration of BCV therapy.

Any exemptions to the protocol inclusion or exclusion criteria, as applicable, for subjects who developed probably or definitive AdV disease while participating in prescreening activities must have been discussed with and approved by the Chimerix medical monitor or designee before the subject was allowed to receive open-label BCV therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Brincidofovir; Adult subjects: 200mg BCV administered as 50mg tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets).; Pediatric subjects: 4mg/kg BCV (not to exceed a total single dose of 200mg) administered using a 10 mg/mL liquid formulation taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).	Drug: Brincidofovir; Adult subjects: 200mg BCV administered as 50mg tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets).; Pediatric subjects: 4mg/kg BCV (not to exceed a total single dose of 200mg) administered using a 10 mg/mL liquid formulation taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).; Other Names: BCV; CMX001
Placebo Comparator: Placebo; Adult subjects: Matching placebo tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets).; Pediatric subjects: Matching liquid placebo taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).	Other: Placebo; Adult subjects: Matching placebo tablets taken orally either once weekly (QW; 4 tablets) or twice weekly (BIW; 2 tablets). • Pediatric subjects: Matching liquid placebo taken orally either QW (as 4 mg/kg) or BIW (as 2 mg/kg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinically Significant AdV Infection	The primary objective of this study was to evaluate the safety and efficacy of preemptive treatment with brincidofovir (BCV) versus placebo for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia. The outcome measure for the primary endpoint was treatment failure, a composite endpoint that consisted of the following: Progression to probable AdV disease (other positive causes/agents have been ruled out and subject has disease-targeted organ-specific signs or symptoms) or definitive AdV disease (AdV detected in disease-targeted organ/system biopsy via antigen/immunohistochemistry, culture, and/or polymerase chain reaction and has at least 1 disease-targeted organ-specific sign or symptom); or; Increasing AdV viremia (defined as an increase from baseline in AdV viremia by ≥1 log10, confirmed on a second measurement, at least 1 week apart) and requiring discontinuation from blinded therapy.	12 weeks

Collaborators and Investigators

• Sponsor: Chimerix

Publications and helpful links

General Publications

• Tippin TK, Morrison ME, Brundage TM, Mommeja-Marin H. Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies. Ther Drug Monit. 2016 Dec;38(6):777-786. doi: 10.1097/FTD.0000000000000353.
• Grimley MS, Chemaly RF, Englund JA, Kurtzberg J, Chittick G, Brundage TM, Bae A, Morrison ME, Prasad VK. Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial. Biol Blood Marrow Transplant. 2017 Mar;23(3):512-521. doi: 10.1016/j.bbmt.2016.12.621. Epub 2017 Jan 5.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2010
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: November 12, 2010
• First Submitted That Met QC Criteria: November 15, 2010
• First Posted (Estimate): November 16, 2010

Study Record Updates

• Last Update Posted (Actual): July 21, 2021
• Last Update Submitted That Met QC Criteria: July 19, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: HSCT; AdV; Hematopoeitic Stem Cell Transplant
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Adenoviridae Infections; Anti-Infective Agents; Antiviral Agents; Brincidofovir
• Other Study ID Numbers: CMX001-202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No