Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618002011268p
Ethics application status
Submitted, not yet approved
Date submitted
29/11/2018
Date registered
14/12/2018
Date last updated
14/12/2018
Date data sharing statement initially provided
14/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study comparing Brincidofovir administered as an oral suspension versus Intravenous Formulation in Japanese and Non-Japanese Adult Volunteers
Scientific title
An Open-Label, Single-Dose, Randomized, Two-Period, Crossover Study Evaluating the Absolute Bioavailability of Brincidofovir Administered as CMX001-P-SUS-HPI-010 Suspension Formulation Compared to CMX001-P-IVS-PPS-003 BCV Intravenous formulation in Healthy Japanese and Non-Japanese Adult Subjects
Secondary ID [1] 296734 0
CMX-127
Universal Trial Number (UTN)
U1111-1223-8206
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Viral Infection - orthopoxviruses 310599 0
Viral Infection - polyomaviruses 310807 0
Viral Infection - human herpesviruses (HHV)
 310808 0
Viral Infection - human papillomaviruses (HPV), 310809 0
Viral Infection - adenoviruses (AdV). 310810 0
Condition category
Condition code
Infection 309315 309315 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label, single-dose, randomized, two-period, crossover study to evaluate absolute bioavailability of Brincidofovir (BCV) after administration of either:
PART A (Non-Japanese) : a single, 200 mg dose of BCV suspension formulation (20 mls to be drunk) compared to a single, 20 mg dose of BCV IV formulation.
PART B: (Japanese) a single 100 mg dose of BCV suspension formulation (10 mls to be drunk) compared to a single 10 mg dose of BCV IV formulation.

All doses will be administered while resident in a phase 1 unit. Volunteers will need to stay 2 nights in the unit for each dose.

A wash out of at least 21 days will occur between the two treatments.
Intervention code [1] 313041 0
Treatment: Drugs
Comparator / control treatment
Cross Over study design. Volunteers acting as their own controls.
Control group
Active

Outcomes
Primary outcome [1] 308273 0
To evaluate the absolute bioavailability of suspension formulation relative to the IV formulation of brincidofovir (BCV) in healthy non-Japanese and Japanese subjects.
Timepoint [1] 308273 0
Blood Sampling:
Plasma BCV and Cidofovir (CDV) AUCinf, AUClast, Cmax, Tmax, Tlag, Tlast, Clast, t1/2,%AUCextrap, CL (BCV IV), CL/F (BCV oral), Vss and Vz (BCV IV), and Vz/F (BCV oral)
Samples taken at the following timepoints:
In Part A and Part B, subjects receiving IV BCV administered over a 2-hour infusion, blood
samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes prior to start of infusion) and at 0.5, 1, 2 (end of infusion) and at 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose (post start of
infusion).
In Part A and Part B, subjects receiving oral BCV, blood samples for analysis of plasma BCV and CDV oncentrations will be collected as follows:
• Predose (up to 15 minutes prior) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.
Primary outcome [2] 308274 0
To characterize composite plasma BCV and cidofovir (CDV) pharmacokinetics (PK) and intracellular (peripheral blood mononuclear cells [PBMCs]) CDV-PP PK, following single doses of BCV when administered in healthy non-Japanese subjects. (Part A)
PK parameters examined:Plasma BCV and CDV AUCinf, AUClast, Cmax, Tmax, Tlag, Tlast, Clast, t1/2, %AUCextrap, CL (BCV IV), CL/F (BCV oral), Vss and Vz (BCV IV), and Vz/F
(BCV oral).
Timepoint [2] 308274 0
Blood Sampling:
:- subjects receiving IV BCV administered over a 2-hour infusion, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes prior to start of infusion) and at 0.5, 1, 2 (end of infusion) and at 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose (post start of infusion).
-subjects receiving oral BCV, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.
- blood samples for analysis of intracellular CDV-PP concentrations in PBMCs will be collected from all subjects in each period as follows:
• Predose (within 1 hour) and at 24, 48, 72, 168, and 312 hours postdose (post start of infusion).
Primary outcome [3] 308277 0
To characterize composite plasma BCV and CDV pharmacokinetics (PK) following single doses of BCV when administered in
healthy Japanese subjects (Part B).
PK parameters examined: Plasma BCV and CDV AUCinf, AUClast, Cmax, Tmax, Tlag, Tlast, Clast, t1/2, %AUCextrap, CL (BCV IV), CL/F (BCV oral), Vss and Vz (BCV IV), and Vz/F
(BCV oral)
Timepoint [3] 308277 0
Blood Sampling:
subjects receiving IV BCV administered over a 2-hour infusion, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes prior to start of infusion) and at 0.5, 1, 2 (end of infusion) and at 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose (post start of infusion).
- subjects receiving oral BCV, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.
Secondary outcome [1] 354495 0
To evaluate the safety of BCV following administration as a single 200 mg dose (part A) or 100mg dose (Part B) of the suspension formulation and a
single 20 mg dose (part A) or 10 mg dose (Part B) of the IV formulation administered over 2 hours in healthy non-Japanese subjects (Part A) or Japanese subjects (Part B).
Timepoint [1] 354495 0
Demographic/Medical History - Screening visit
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be measured at screening, on Days -1, 1, and 3 in each dose period, and at the FU visit on Period 2 Day 14.
Weight, Height, Total Body Fat Percentage, and Body Mass Index - Screening visit. Body weight will additionally be measured on Day -1 in each dose period, and at the FU visit on Period 2 Day 14.

Physical Examination: - A standard PE will be performed at screening to confirm study eligibility. An abbreviated (brief)
PE, targeted to new signs and symptoms, will be performed on Day -1 in both study periods and at the FU visit on Period 2 Day 14 (+ 2 days).
Electrocardiogram (ECG) - Screening visit
Blood Sampling: Blood will be drawn and urine will be collected for routine clinical laboratory testing (standard
haematology, serum chemistry and urinalysis panels) at screening, on Days -1, 3, 5, 8, 11 and 14 in each period.
Virus Serology - Screening
Alcohol and Drug Screen - An alcohol screen (breath, urine, or blood based test, will be performed at the screening evaluation, and on Day -1, 5, 8, 11, and 14 of each period..
Follicle-stimulating Hormone and Pregnancy Testing-
FSH will be measured in all female subjects as part of the screening evaluation.
A serum or urine pregnancy test will be performed in female subjects at the screening evaluation, on Day -1 in each period, and at the FU visit on Period 2
Exploratory Hepatic Biomarker GLDH - Blood will be collected predose (Day -1) and on days 3, 5, 8, 11 and 14 in both periods for exploratory hepatic biomarker GLDH analysis.
Adverse Events - For all study participants, all AEs will be recorded from the time of first admission to the clinical
study unit on Period 1 Day -1 until the subject has completed the study,
Secondary outcome [2] 354496 0
To evaluate the composite effect of CYP4F2 and OATP1B1 polymorphisms on plasma BCV PK (Part A and Part B).
Timepoint [2] 354496 0
Blood Sample Collection for Genotyping -
A blood sample for CYP4F2 and OATP1B1 genotyping will be collected on any day following BCV administration.
Secondary outcome [3] 354497 0
To characterize the potential differences in composite plasma BCV and CDV in healthy non-Japanese subjects (Part A) compared to healthy Japanese subjects (Part B).
Timepoint [3] 354497 0
subjects receiving IV BCV administered over a 2-hour infusion, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows:
• Predose (within 15 minutes prior to start of infusion) and at 0.5, 1, 2 (end of infusion) and at 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose (post star of infusion).
- subjects receiving oral BCV, blood samples for analysis of plasma BCV and CDV concentrations will be collected as follows::
• Predose (within 15 minutes) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hours postdose.

Eligibility
Key inclusion criteria
1. Male or female between 18 to 70 years of age.
2. Born in Japan, have both parents and grandparents of Japanese origin, and lived for < 10
years outside of Japan (Part B only).
3. Non-Japanese (Part A only)
4. Female must be of non-childbearing potential, i.e., postmenopausal woman or a premenopausal woman documented as surgically sterile following either a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, tubal ligation or placement of bilateral fallopian tube occlusion or with medically documented ovarian failure.
5. . Males must be surgically-sterilized or agree to use two contraception methods during
heterosexual intercourse with a female partner capable of becoming pregnant.
6.Willing and able to provide written informed consent.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
. Have a positive pregnancy test at screening or Day -1.
2. Have received any investigational drug,or device within 30 days prior to study start
3. Have received BCV in a previous clinical trial.
4. Have a positive test result at the screening consistent infection with HBV, HCV, or HIV.
5. Have a positive test for drugs of abuse, cotinine, and/or alcohol .
6. History of tobacco/nicotine use (Part A only). [Note: Former tobacco/nicotine users are
eligible, provided the subject has not used a tobacco- or nicotine-containing product for a
minimum of 6 months prior to Period 1 Day 1.]
7. Have any serious or active medical or psychiatric illness,
8. Have a history of a gastrointestinal condition or disorder
9. Have a history or symptoms of cardiovascular disease,
10. Have a history of haematological disorders such as a bleeding disorder.
11. Have a history of chronic liver disease or hepatic impairment,
12. History of Gilbert’s syndrome or a total bilirubin greater than the upper limit of the
normal reference range
13.Have symptoms of infection (such as those experienced with a cold or flu,)
14. Have a history of difficulty with blood donation, including vasovagal syncope (fainting),
15. Have a clinically significant abnormal haemoglobin.
16. Have donated blood or had clinically significant blood loss within 30 days prior to study start
17. Have received any medication or herbal product known to induce or inhibit hepatic metabolizing enzymes
18. Have received any prescription medication within 14 days prior to Day 1,
19. Have received any non-prescription medication within 3 days prior to Day 1,
20. Have a history of clinically relevant drug or alcohol dependence within the past 2 years
21. Have consumed fruit juice within 3 days prior to Period 1 Day 1,
22. Any condition or set of circumstances that, in the judgment of the investigator, could
interfere with the subject’s ability to comply with completion of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
NA
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Part A
The largest observed within-subject CVs for single dose BCV PK parameters for a suspension formulation were 19% for AUClast and 26% for Cmax (Study CMX001-124). Based on the larger of these estimates (26%), the lower and upper limit of the 90% confidence interval (CI) for the ratio of the geometric mean for the test treatment (BCV suspension) to the geometric mean for the reference treatment (BCV IV) for a sample of size of 24 will be obtained by dividing/multiplying the point estimates of the ratio by a factor of 1.14 (or the half-width of the 90% CI for the ratio of geometric means should be no more than 14% of the point estimate of the ratio). Hence if the estimate of the ratio is 1, the 90% CI will be from 0.88 to 1.14.
Part B
The primary objectives for Part B are to characterize the absolute bioavailability of suspension formulate

Safety Analysis
The safety analyses described below will be done separately for each part of the study.
Extent of Exposure - Dosing information for individual subjects will be listed.
Demographic Data/Baseline Characteristics - Demographic data and baseline measurements (i.e., age, gender, race, ethnicity, height, body weight, body fat %, BMI, etc.) will be listed for individual subjects and summarized using standard descriptive statistics Disposition of subjects will be summarized, including the number and percentage of subjects randomized to each treatment sequence, the number and percentage of subjects who completed and discontinued the study, and the number and percentage of subjects by reason for discontinuing the study.
Listings will be provided for subject disposition and medical/surgical history.
Adverse Events - AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) dictionary. System Organ Class (SOC) and Preferred Term will be included in the clinical database. AEs will be summarized on the basis of the date of onset of the AE.
or any AE that existed pre-dose that worsens on or after BCV administration.
Laboratory Evaluations - results will be evaluated using the relevant laboratory’s
reference ranges. Selected laboratory data including change from baseline (baseline defined as the Day -1 measurement in each period) will be summarized (n, mean, SD, median, first and third quartiles, minimum, and maximum) by treatment and study day.
Other Safety Evaluations - Vital signs measurements along with the change from baseline (baseline defined as measurement taken pre-dose at each period) will be listed for individual subjects by study day and may be summarized either by incidence (frequencies) or descriptive statistics (e.g., n, mean, SD, median, first and third quartiles, minimum and maximum) by treatment and study day.

Pharmacokinetics
The following analyses will be done separately for each part of the study.
Plasma concentrations of each analyte will be listed by subject and treatment.. Concentrations for each analyte will be displayed as individual concentration vs. time profiles using actual time points,.
Plasma BCV and CDV PK parameters will be determined using standard non compartmental methods and actual sampling times utilizing a PK data analysis program
• Plasma BCV and CDV parameters will be listed by subject. Summary statistics of PK
parameters for each analyte and will be tabulated.
The assessments described above will also be performed for intracellular (PBMC) CDV-PP data collected in Part A of the study.
Plasma BCV PK parameters will also be summarized and plotted by treatment and by CYP4F2 and OATP1B1 genotype. Plasma BCV PK parameters may be summarized by treatment and combinations of genotypes (e.g. CYP4F2 and OATP1B1).
For the assessment of absolute bioavailability in Part A, plasma BCV dose normalized AUC will be log transformed and compared between treatments by using an analysis of variance (ANOVA) with a mixed effects model, with treatment and period as fixed effects and subject as a random effect. Point estimates and their associated 90% confidence intervals (CIs) will be constructed for the differences in means (suspension formulation (Test [Treatment A]) - BCV IV formulation (Reference [Treatment B])). The point estimates and associated CIs will be exponentiated to provide point estimates and 90% CIs for the ratios of geometric means between the suspension and IV formulations.
The above statistical analysis will be repeated for Part B, with Treatment C as the test treatment and Treatment D as the reference treatment.
Exploratory analyses will be performed to compare the dose-normalized plasma BCV and CDV in healthy Japanese subjects (Part B) and healthy non-Japanese subjects (Part A).
Other exploratory analysis, such as correlation of PK to demographics (e.g. age, body weight, body composition), correlation of PK to safety end points (e.g. plasma GLDH) may also be performed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/01/2019
Actual
Date of last participant enrolment
Anticipated
29/03/2019
Actual
Date of last data collection
Anticipated
26/04/2019
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment outside Australia
Country [1] 21087 0
New Zealand
State/province [1] 21087 0
Auckland & Christchurch

Funding & Sponsors
Funding source category [1] 301314 0
Commercial sector/Industry
Name [1] 301314 0
Chimerix
Country [1] 301314 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Chimerix Inc.
Address
Chimerix, Inc.
2505 Meridian Parkway, Suite 100
Durham, North Carolina 27713
USA
Country
United States of America
Secondary sponsor category [1] 300980 0
None
Name [1] 300980 0
Address [1] 300980 0
Country [1] 300980 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 302056 0
New Zealand Health & Disability Committee
Ethics committee address [1] 302056 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Street address:
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 302056 0
New Zealand
Date submitted for ethics approval [1] 302056 0
19/11/2018
Approval date [1] 302056 0
Ethics approval number [1] 302056 0

Summary
Brief summary
This is an open-label, single-dose, randomized, two-period, crossover study to evaluate absolute bioavailability of Brincidofovir (BCV) after administration of either:
PART A (Non-Japanese) : a single, 200 mg dose of BCV suspension formulation compared to a single, 20 mg dose of BCV IV formulation.
PART B: (Japanese) a single 100 mg dose of BCV suspension formulation compared to a single 10 mg dose of BCV IV formulation.
A screening evaluation will be performed no more than 28 days prior to the first BCV dose (Period 1 Day 1) to identify subjects who are eligible to participate in the study. Eligible subjects will be randomized in a 1:1 ratio.
In each period, BCV will be administered on Day 1. Subjects will be admitted to the clinic on Day -1, the day prior to dosing. Subjects will remain in the clinic until the morning of Day 3. A follow visit will occur following the last visit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88974 0
Dr Chris Wynne
Address 88974 0
Christchurch Clinical Studies Trust
4/264 Antigua Street
Christchurch 8011
Country 88974 0
New Zealand
Phone 88974 0
+6433729477
Fax 88974 0
Email 88974 0
chris@ccst.co.nz
Contact person for public queries
Name 88975 0
Dr Chris Wynne
Address 88975 0
Christchurch Clinical Studies Trust
4/264 Antigua Street
Christchurch 8011
Country 88975 0
New Zealand
Phone 88975 0
+6433729477
Fax 88975 0
Email 88975 0
chris@ccst.co.nz
Contact person for scientific queries
Name 88976 0
Dr Chris Wynne
Address 88976 0
Christchurch Clinical Studies Trust
4/264 Antigua Street
Christchurch 8011
Country 88976 0
New Zealand
Phone 88976 0
+6433729477
Fax 88976 0
Email 88976 0
chris@ccst.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD data will be not be publicly available. Data will be anonymised and documented in a study report. A summary of the data will be available to the volunteers.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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