Study Evaluating the Bioequivalence of Brincidofovir Form H and Form II Tablets in Healthy Adults

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate whether both Form H and Form II, 100mg brincidofovir tablets are bioequivalent, when given under fasting conditions in healthy adults. Participants will be randomized to each receive one tablet of Form H and one tablet of Form II,14 days apart and undergo pharmacokinetic testing pre-dose and post-dose to evaluate safety. This is an open-label, single-dose, randomized, two-period, crossover study.

Detailed Description
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Primary Objectives: To evaluate the bioequivalence (BE) of brincidofovir (BCV) hydrate (Form H) tablet and the Form II tablet when administered under fasting conditions in healthy adult participants. To characterize plasma BCV pharmacokinetics (PK) following single doses of BCV when administered in healthy adult participants. Safety Objective: - To evaluate the safety of BCV following administration of single dose of 100 mg BCV Form H and BCV Form II tablet in healthy adult participants.

Official Title
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A Phase 1, Open-label, Single-dose, Randomized, Two-period, Crossover Study Evaluating the Bioequivalence of Brincidofovir Form H and Form II Tablets in Healthy Adult Participants

Conditions
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Smallpox

Intervention / Treatment
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* Drug: Brincidofovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide informed consent voluntarily signed by participant. Male or female between 18 to 70 years of age, inclusive at screening. Body mass index (BMI) from 18 to 32 kg/m² with a minimum body weight of ≥ 50 kg, inclusive at screening. Women must be of nonchildbearing potential, i.e., postmenopausal woman (defined as spontaneous amenorrhea for 1-year prior to Period 1 Day 1) with a confirmed follicle stimulating hormone (FSH) level in laboratory's postmenopausal reference range; or a premenopausal woman documented as surgically sterile following either a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, tubal ligation. Males must be surgically sterilized (confirmed by documented azoospermia at least 90 days after procedure). Overtly healthy as determined by medical evaluation and judgment of the investigator including medical history, physical examination (PE), laboratory tests, vital signs (VS), and eletrocardiogram (ECG) at screening and Day -1. [Note: hematology, serum chemistry, and urinalysis parameters must fall within the laboratory's normal reference ranges or have been determined by the investigator to have no clinical significance in the context of this study.] Except: Alanine transaminase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) x ≤1.5 upper limit of normal reference range (ULN) Total Bilirubin x ≤1.5 ULN Hemoglobin (Hb) ≥10.5 g/dL for females or ≥12 g/dL for males Able to comply with the dosing instructions and available to complete the study schedule of assessments. Exclusion Criteria: History or current symptoms of any serious psychiatric illness, including addiction, which could interfere with participant treatment, assessment, or compliance with the protocol. History of chronic liver disease or hepatic impairment, including but not limited to alcoholic liver disease, chronic viral hepatitis, autoimmune hepatitis, steatosis, or hemochromatosis. Note: A remote (≥12 months prior to screening) history of hepatitis A infection will not be cause for exclusion. History of Gilbert's syndrome or current evidence of the disease based on laboratory information at screening visit or Day -1. History of hematological disorders, including disorders such as a bleeding disorder or a risk of gastrointestinal bleeding. Clinically significant history of difficulty with blood donation, including vasovagal syncope (fainting), and/or poor venous access for the purposes of phlebotomy. Positive (reactive) serological test result at the screening evaluation consistent with possible infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human immunodeficiency virus type 1 or 2 (HIV). Positive test for drugs of abuse and/or alcohol at either screening or check-in days. Clinically significant infection (e.g., COVID-19, cold, flu, or febrile illness) within 14 days prior to Period 1 Day 1. Donated a unit of blood or had clinically significant blood loss within 30 days prior to Period 1 Day 1 or donated plasma within 14 days prior to Period 1 Day 1. Received any investigational drug, agent, or device within 30 days prior to Period 1 Day 1, or current participation in another interventional study. Consumed any fruit juice including grapefruit juice, pomegranate juice, cranberry juice, orange juice, and Seville orange juice (also known as sour, bitter or bigarade orange) within 3 days prior to Period 1 Day 1 and throughout the study, unless prior approval is granted by both the investigator and the medical monitor. Received any medication or herbal product (e.g., St. John's wort) known to induce or inhibit hepatic metabolizing enzymes and/or transporters within 30 days or 5 half-lives of the compound, whichever is longer, prior to Period 1 Day 1 and throughout the study, unless approval is granted by both the investigator and the medical monitor. Received any vaccines (including COVID-19 vaccine) within 14 days prior to Period 1 Day 1 and throughout the study, unless approval is granted by both the investigator and the medical monitor. Any condition or set of circumstances that, in the judgment of the investigator, could interfere with the participant's ability to comply with the dosing schedule and completion of the study evaluations (e.g., participants who are unable to communicate or cooperate with the investigator).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is an open-label, single-dose, randomized, two-period, crossover study to evaluate BE of BCV plasma PK parameters after administration of single 100 mg doses of BCV using the Form H (test tablet) and Form II (reference tablet) under fasting conditions in normal healthy adults. The study will also evaluate the safety of BCV following administration of two 100 mg single doses of BCV. Eligible participants will be randomized in a 1:1 ratio to one of two treatment sequences, Treatment AB or Treatment BA.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment AB - Form H (test tablet) first<br>Treatment AB: Participants assigned to Treatment AB in Period 1, will be given a single 100 mg tablet of Form H (test tablet). In Period 2, participants will be given a single 100 mg tablet of Form II (reference tablet) after a 14 day washout period. | Drug: Brincidofovir<br>* 100 mg tablet of Form H and 100 mg tablet of Form II<br>* Other names: CMX001-129;|
| Active Comparator: Treatment BA - Form II (reference tablet) first<br>Treatment BA: Participants assigned to Treatment BA in Period 1, will be given a single 100 mg tablet of Form II (reference tablet). In Period 2, participants will be given a single 100 mg tablet of Form H (test tablet) after a 14 day washout period. | Drug: Brincidofovir<br>* 100 mg tablet of Form H and 100 mg tablet of Form II<br>* Other names: CMX001-129;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK endpoint - Peak Plasma Concentration (Cmax) | Assess maximum observed plasma concentration of Brincidofovir | Through 96 hours post-dose | 
| PK endpoint - AUClast | Assess area under the plasma concentration-time curve from time 0 to time of the last measurable concentration (AUC 0 - last) of Brincidofovir | Through 96 hours post-dose | 
| PK endpoint - AUCinf | Assess area under the plasma concentration-time curve from time 0 to infinity (AUC 0 - inf) of Brincidofovir | Through 96 hours post-dose | 
| Incidence of treatment adverse events (AEs) | Incidence of treatment-emergent AEs, treatment-related AEs, severe AEs, AEs leading to withdrawal and serious adverse events | Through end of study visit (within 14 days after 2nd dose) | 
| Descriptive statistical summary abnormal Heart Rate | Descriptive statistical summary (summarized by treatment, study day, and time) of abnormal heart rate | Through end of study visit (within 14 days after 2nd dose) | 
| Descriptive statistical summary abnormal Respiratory Rate | Descriptive statistical summary (summarized by treatment, study day, and time) of abnormal respiratory rate | Through end of study visit (within 14 days after 2nd dose) | 
| Descriptive statistical summary abnormal Systolic Blood Pressure and Diastolic Blood Pressure (mmHg) | Descriptive statistical summary (summarized by treatment, study day, and time) of abnormal Systolic Blood Pressure | Through end of study visit (within 14 days after 2nd dose) | 
| Descriptive statistical summary abnormal Body Temperature (Celsius) | Descriptive statistical summary (summarized by treatment, study day, and time) of abnormal body temperature | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameters: Total Protein, Albumin, Globulin (g/dL) | Descriptive statistical summary (summarized by treatment, study day, and time) of Total Protein, Albumin, Globulin | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameter: Albumin/Globulin ratio | Descriptive statistical summary (summarized by treatment, study day, and time) of albumin/globulin ratio | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameters: alkaline phosphatase, ALT, AST, GGT and Creatine phosphokinase (U/L) | Descriptive statistical summary (summarized by treatment, study day, and time) of alkaline phosphatase, ALT, AST, GGT and Creatine phosphokinase | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameters: bilirubin (total and direct), BUN, serum calcium, glucose (random), serum phosphate, serum uric acid and serum magnesium (mg/dL) | Descriptive statistical summary (summarized by treatment, study day, and time) of bilirubin (total and direct), BUN, serum calcium, glucose (random), serum phosphate, serum uric acid and serum magnesium | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameters: serum chloride, CO2, serum sodium and serum potassium (mmol/L) | Descriptive statistical summary (summarized by treatment, study day, and time) of serum chloride, CO2, serum sodium and serum potassium | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameter: Creatinine (g/24h) | Descriptive statistical summary (summarized by treatment, study day, and time) of creatinine | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameter: eGFR (ml/min) | Descriptive statistical summary (summarized by treatment, study day, and time) of eGFR | Through end of study visit (within 14 days after 2nd dose) | 
| Chemistry parameter: LDH (units/L) | Descriptive statistical summary (summarized by treatment, study day, and time) of LDH | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameters: basophils, eosinophils, lymphocytes, monocytes and neutrophils (cells/uL) | Descriptive statistical summary (summarized by treatment, study day, and time) of basophils, eosinophils lymphocytes, monocytes and neutrophils | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameters: leukocytes and platelets (thousand/uL) | Descriptive statistical summary (summarized by treatment, study day, and time) of leukocytes and platelets | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameters: proportion of basophils, eosinophils, lymphocytes, monocytes and neutrophils | Descriptive statistical summary (summarized by treatment, study day, and time) of basophils/leukocytes, eosinophils//leukocytes, lymphocytes//leukocytes, monocytes//leukocytes and neutrophils//leukocytes | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameter: erythrocytes (million/uL) | Descriptive statistical summary (summarized by treatment, study day, and time) of erythrocytes | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameter: erythrocytes mean corpuscular volume (MCV) (fL) | Descriptive statistical summary (summarized by treatment, study day, and time) of erythrocytes MCV | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameter: hematocrit (%) | Descriptive statistical summary (summarized by treatment, study day, and time) of hematocrit | Through end of study visit (within 14 days after 2nd dose) | 
| Hematology parameter: hemoglobin (g/dL) | Descriptive statistical summary (summarized by treatment, study day, and time) of hemoglobin | Through end of study visit (within 14 days after 2nd dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smallpox, Pharmacokinetics (PK), Bioequivalence (BE), Orthopox, CMX001-129