A Randomised, Double Blinded, Placebo-controlled Single and Multiple Ascending Dose Study of Orally Administered RV299 to Evaluate Safety, Tolerability, Pharmacokinetics and Food Effect in Healthy Adult Participants
Overview
- Phase
- Phase 1
- Intervention
- RV299
- Conditions
- Respiratory Syncytial Virus Infections
- Sponsor
- Pfizer
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- Evaluate safety and tolerability of RV299 by assessing changes from baseline in blood pressure (BP) (vital sign parameters).
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The main aims of the study are to assess the safety, tolerability, pharmacokinetics and food effects of RV299 compared to Placebo in healthy adult participants.
The study consists of three parts: single ascending dose (Part A), multiple ascending doses (Part B) and food effect (Part C) in Caucasian participants.
Detailed Description
This is a randomised, double blind, placebo-controlled Phase I study to assess the safety, tolerability, pharmacokinetics and food effect of RV299 in healthy participants aged ≥ 20 to ≤ 40 years. The clinical study consists of 3 parts (Parts A - C): Part A: single ascending doses (SAD) of RV299 in healthy adult Caucasian participants (up to 3 dose levels of RV299 in 3 cohorts; 6 participants/cohort) Part B: multiple ascending doses (MAD) of RV299 in healthy adult Caucasian participants (up to 2 dose levels of RV299 in 2 cohorts of 8 participants dosed for 5 consecutive days). Part B will incorporate a drug-drug interaction (DDI) design to investigate interaction between RV299 and midazolam in one cohort (Cohort 3) of 8 participants. Part C: food effect (FE) in healthy adult Caucasian participants (one cohort of 8 participants to be randomised to receive either RV299 in the first treatment period fasted and in the second treatment period fed, or vice versa) The study will be conducted as an adaptive integrated design since various study parts can be triggered at appropriate times during the conduct of other parts of the study. Dose escalation to the following scheduled dose or progression to a consecutive part of the study will only occur after satisfactory review of all safety, tolerability and pharmacokinetic (PK) data.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or Female, Caucasian, aged greater than or equal to 20 to less than or equal to 40 years at the date of signing informed consent.
- •Participants in Caucasian cohorts should be distinguished by very light to brown skin pigmentation and straight to wavy or curly hair, and should be indigenous to Europe, northern Africa, western Asia, India. This includes Caucasian participants from North America, Australia and South Africa.
- •Healthy as defined by: a) the absence of clinically significant illness and surgery within four weeks prior to dosing; b) the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, haematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.
- •Participants must agree to use contraceptive requirements as described in the study protocol for the applicable duration.
- •Participants must agree not to donate sperm or ova from the time of the first administration of trial medication until 3 months after three months after the last follow-up visit.
- •Participants must have a body mass index (BMI) between 18.0-25.0 kg/m² inclusive at screening.
- •Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluation that is reasonably likely to interfere with the participant's participation in or ability to complete the trial as assessed by the Investigator.
- •Ability to provide written, personally signed, and dated informed consent.
- •An understanding, ability, and willingness to fully comply with trial procedures and restrictions.
Exclusion Criteria
- •Current or recurrent disease (e.g., cardiovascular, haematological, neurological, endocrine, immunological, renal, hepatic or gastrointestinal or other conditions) that could affect the action, absorption, or disposition of RV299, or could affect clinical assessments or clinical laboratory evaluations.
- •Current or relevant history of physical or psychiatric illness that are not stable or may require a change in treatment, use of prohibited therapies during the trial or make the participant unlikely to fully comply with the requirements of the trial or complete the trial, or any condition that presents undue risk from the investigational product or trial procedures.
- •Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial may influence the result of the trial, or the participant's ability to participate in the trial.
- •Use or intention to use any medications/products that are known inhibitors of the CYP3A4 enzymes or substrates of Aldehyde oxidase (AO), Pglycoprotein (PgP) or Breast Cancer Resistance Protein (BCRP) for 2 weeks prior to Day 1 of the dosing period up to the follow-up visit. (The Indiana University (2016) "Cytochrome P450 Drug Interaction Table" should be utilized to determine inhibitors of CYP3A) (http://medicine.iupui.edu/clinpharm/ddis/table.aspx).
- •The history or presence of any of the following cardiac conditions known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events.
- •Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QTc interval changes. (Participants with borderline abnormalities may be included if the deviations do not pose a safety risk, and if agreed between the appointed Cardiologist and the PI.)
- •Has vital signs outside of the following normal range at screening or Day -1/Day-
- •Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening;
- •Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or monocyte count less than lower limit of normal (LLN) (up to two repeats may be taken).
- •Has total bilirubin, ALT or AST consistently greater than ULN at Screening (up to two repeats may be taken).
Arms & Interventions
Part A Single Ascending Dose (SAD) - RV299/Placebo
Participants will receive RV299 or placebo as a single dose on Day 1. Sentinel dosing will be used (one on RV299 and one on placebo) before the rest of the cohort are dosed together.
Intervention: RV299
Part A Single Ascending Dose (SAD) - RV299/Placebo
Participants will receive RV299 or placebo as a single dose on Day 1. Sentinel dosing will be used (one on RV299 and one on placebo) before the rest of the cohort are dosed together.
Intervention: Placebo
Part B Multiple Ascending Dose (MAD) - RV299/Placebo
Participants will receive RV299 or placebo twice daily on Day 1-4 and a single dose on Day 5. Participants in each cohort will receive ascending doses of RV299, depending on emerging safety and PK data. Part B, Cohort 3 will investigate interaction between midazolam and RV299. Participants will receive a single dose of midazolam on Day 1 and Day 7, and receive RV299 twice daily on Days 2 - 6
Intervention: RV299
Part B Multiple Ascending Dose (MAD) - RV299/Placebo
Participants will receive RV299 or placebo twice daily on Day 1-4 and a single dose on Day 5. Participants in each cohort will receive ascending doses of RV299, depending on emerging safety and PK data. Part B, Cohort 3 will investigate interaction between midazolam and RV299. Participants will receive a single dose of midazolam on Day 1 and Day 7, and receive RV299 twice daily on Days 2 - 6
Intervention: Placebo
Part B Multiple Ascending Dose (MAD) - RV299/Placebo
Participants will receive RV299 or placebo twice daily on Day 1-4 and a single dose on Day 5. Participants in each cohort will receive ascending doses of RV299, depending on emerging safety and PK data. Part B, Cohort 3 will investigate interaction between midazolam and RV299. Participants will receive a single dose of midazolam on Day 1 and Day 7, and receive RV299 twice daily on Days 2 - 6
Intervention: Midazolam
Part C Food Effect (FE)- RV299
Participants will receive RV299 as a single dose on Day 1 and Day 5; treatment will be administered in the first treatment period fasted and the second treatment period fed (or vice versa).
Intervention: RV299
Outcomes
Primary Outcomes
Evaluate safety and tolerability of RV299 by assessing changes from baseline in blood pressure (BP) (vital sign parameters).
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Blood pressure (systolic and diastolic) will be measure in mm Hg. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
Number of participants with treatment-emergent adverse events (TEAE) as assessed by CTCAE V5.0.
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Listings and summary tables of AEs will be based on TEAEs (defined as events starting, or worsening, after the first dose of RV299).
Evaluate the proportion of participants with clinically significant shifts in haematology/clinical chemistry/coagulation/urinalysis values from baseline following dosing with RV299
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Blood and urine tests will be conducted at a central laboratory. Results at each visit will be summarized using the statistics n, mean, standard deviation, median, minimum and maximum.
Assess terminal half life of (t1/2) of midazolam (as index substrate) before and after dosing with RV299.
Time Frame: Part B Cohort 3 only: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 13, 16, and 24 hours following administration of midazolam on Day 1 and Day 7.
Pharmacokinetic analysis will include listings and summaries of midazolam concentration by time point and analysis of relationship with dose and body weight
Evaluate the proportion of subjects with changes in ECG measurements from baseline following dosing with RV299
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Parameters collected will be: PR interval (msec); QRS interval (msec); QT interval (msec); QTcB interval (msec); QTcF interval (msec); Heart rate (bpm). Results at each visit will be summarized using the statistics n, mean, standard deviation, median, minimum and maximum.
Assess area under the plasma concentration versus time curve (AUC) of midazolam (as index substrate) from 0 to 24 hours post-dose (AUC0-24h) before and after dosing with RV299.
Time Frame: Part B Cohort 3 only: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 13, 16, and 24 hours following administration of midazolam on Day 1 and Day 7.
Pharmacokinetic analysis will include listings and summaries of midazolam concentration by time point and analysis of relationship with dose and body weight.
Evaluate safety and tolerability of RV299 by assessing changes from baseline in tympanic temperature (vital sign parameters)
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Tympanic temperature will be collected in degrees Celsius (°C). Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
Evaluate safety and tolerability of RV299 by assessing changes from baseline in heart rate (HR) (vital sign parameters).
Time Frame: PPart A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Heart rate will be measure in beats per minute (bpm). Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
Evaluate safety and tolerability of RV299 by assessing changes from baseline in respiratory rate (vital sign parameters).
Time Frame: Part A: 7 days after single dose; Part B: 28 days after final dose; Part C: 7 days after final dose
Respiratory rate will be measured in breaths per minute. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum.
Assess time to maximum plasma concentration (tmax) of midazolam (as index substrate) before and after dosing with RV299.
Time Frame: Part B Cohort 3 only: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 13, 16, and 24 hours following administration of midazolam on Day 1 and Day 7.
Pharmacokinetic analysis will include listings and summaries of midazolam concentration by time point and analysis of relationship with dose and body weight
Assess maximum plasma concentration (Cmax) of midazolam (as index substrate) before and after dosing with RV299.
Time Frame: Part B Cohort 3 only: pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 12, 13, 16, and 24 hours following administration of midazolam on Day 1 and Day 7.
Pharmacokinetic analysis will include listings and summaries of midazolam concentration by time point and analysis of relationship with dose and body weight
Secondary Outcomes
- Assess terminal half-life (t1/2) of RV299 following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess area under the plasma concentration-time curve of RV299 from time zero to infinity (AUC0-inf) following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess minimum blood plasma concentration (Cmin) of RV299 between administration of two doses of RV299.(Parts B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess apparent volume of distribution (VZ/F) of RV299 following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Characterise steady-state plasma pharmacokinetics (PK) of RV299 following multiple doses of RV299 by comparing AUC against dosing intervals.(Part B only: pre-dose (Day 1) to 7 days after final dose of RV299 (at Day 5).)
- Characterise plasma pharmacokinetics (PK) of RV299 by assessing time to maximum plasma concentration (tmax) following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess rate constant (λz) of RV299 following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess area under the plasma concentration versus time curve (AUC) from time zero to 24 hours post-dose (AUC0-24h) following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 24 hours after final dose of RV299)
- Assess area under the plasma concentration versus time curve (AUC) of RV299 from time zero to last quantifiable plasma concentration (AUC0-t) following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess accumulation ratio of RV299 based on AUC0-tau following multiple doses of RV299.(Part B only: pre-dose (Day 1) to 7 days after final dose of RV299 (at Day 5))
- Assess maximum plasma concentration (Cmax) of RV299 after dosing in the fed and fasted states.(Part C only: pre-dose (Day 1) to 7 days after second (final) dose (at Day 5).)
- Assess maximum plasma concentration (Cmax) of RV299 following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess plasma clearance (rate of removal of RV299 from plasma) (CL/F) following single and multiple doses of RV299.(Parts A, B and C: pre-dose (Day 1) to 7 days after final dose of RV299)
- Assess area under the plasma concentration versus time curve (AUC) of RV299 after dosing in the fed and fasted states.(Part C only: pre-dose (Day 1) to 7 days after second (final) dose (Day 5).)
- Assess area under the plasma concentration versus time curve from time zero to 12 hours post-dose (AUC0-12) following multiple doses of RV299.(Part B only: pre-dose to 12 hours following administration of first dose of RV299 (Day 1) and final dose (Day 5))