A Phase 1, Single and Multiple Ascending Dose, Food Effect, and Drug-Drug Interaction Study with Itraconazole, Midazolam and Fexofenadine of Orally Administered AV078 in Healthy Adults
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 89
- Locations
- 2
- Primary Endpoint
- Occurrence of clinically significant changes in physical examination (including neurological assessment).
Study Overview
Brief Summary
This Phase 1 study in healthy adult volunteers is planned to evaluate the safety, tolerability, and pharmacokinetics (PK) of AV078, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1).
The study will begin with a standard exploration of safety and tolerability in sequential single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. Subsequent cohorts will collect PK data to evaluate food effects and potential drug-drug interactions relevant to AV078.
Detailed Description
This Phase 1 study in healthy adult volunteers is planned to evaluate the safety, tolerability, and pharmacokinetics (PK) of AV078, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1). The study will additionally explore the relationship between AV078 and pharmacodynamic biomarkers related to mTOR.
The study will begin with a standard exploration of safety and tolerability in sequential single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, incorporating reviews by a dedicated Safety Review Group to guide dose escalation decisions. The study will also include a cohort using a 2-way crossover design to evaluate food effects on the PK of AV078. The study will additionally include cohorts evaluating potential drug-drug-interactions (DDIs) using coadministration of index substrates and index perpetrators typically used in DDI studies of the relevant enzymes. Specifically, one DDI cohort will assess the effects of administration of itraconazole (a strong inhibitor of CYP3A4) on the PK of AV078, and an additional DDI cohort will assess the effects of administration of AV078 on the PK of midazolam (a sensitive probe substrate for CYP3A4) and fexofenadine (a probe substrate for P-gp).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Masking Description
Parts A and B of the study comparing AV078 to placebo will be a double-blind design (participant and investigator) Parts C, D and E are open label.
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy male or female as determined by medical evaluation including medical history, psychiatric history, and no clinically significant findings on physical examination, laboratory tests, and cardiac monitoring. Slight excursions outside of normal limits may be allowed provided they are considered not clinically significant by the investigator.
- •Ages 18-65 years (inclusive), at the time of consent.
- •At least 45 kg with a body mass index (BMI; Quetelet index) in the range 18.0-32.0, at screening.
- •Sufficient intelligence to understand the nature of the trial and any hazards of participating in it. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire trial.
- •Willingness to give written consent to participate after reading the information and consent form, and after having the opportunity to discuss the trial with the investigator or their delegate.
- •Agree not to donate blood or blood products during the study and for up to 3 months after the last administration of the trial medication.
- •Have received at least 2 doses of the COVID vaccine (1 dose of the Janssen-Cilag vaccine is acceptable).
Exclusion Criteria
- •Current, or past history of any clinically significant mental or physical illness or condition that the Investigator concludes would create significant concern for participation in the study.
- •Surgery (eg stomach bypass) or medical condition that might affect absorption of medicines (cholecystectomy is allowed).
- •Presence or history of severe adverse reaction to any drug or a history of sensitivity to midazolam (Part E only), fexofenadine (Part E only) and itraconazole (Part D only), or any excipients in the tablets/solutions.
- •History of relevant atopy including any confirmed significant allergic reactions against any drug, or multiple drug allergies (non-active hay fever is acceptable)
- •History of suicidal behaviour or express or have any suicidal ideation on the C-SSRS at screening or admission.
- •Employee of the Sponsor, the CRO and/or study site or their relatives.
- •Unable or unwilling to eat a high-fat breakfast per study requirements (Part C only).
Arms & Interventions
AV078
In part A, a single ascending doses of AV078 oral solution will be investigated in separate cohorts. The starting dose will be 0.5 mg and ascending doses will be determined based on data from previous cohorts.
In Part B, multiple ascending doses of AV078 oral solution will be administered once daily for 14 days. Dose levels will be determined based on data from the single ascending dose study and previous cohorts in the multiple ascending dose study.
In Part C the effect of food (fasting or high calorie) on the pharmacokinetics of a single dose of AV078 will be investigated. The dose will be determined from Part A of the study.
Intervention: AV078 (Drug)
Placebo
In Part A, placebo oral solution (containing no active ingredient) will be administered once.
In Part B, placebo oral solution (containing no active ingredient) will be administered once daily for 14 days.
Intervention: Placebo (Drug)
Itraconazole
In Part D, 200 mg itraconazole will be administered as an oral capsule once daily for 9 days, to investigate the effect of itraconazole on the pharmacokinetics of AV078.
Intervention: Itraconazole (Drug)
Midazolam and fexofenadine
In Part E, 2.5 mg midazolam will be administered as an oromucosal solution and 120 mg fexofenadine will be administered as an oral tablet on day 1 and day 18, to investigate the effect of AV078 on the pharmacokinetics of midazolam and fexofenadine.
Intervention: Midazolam (Drug)
Midazolam and fexofenadine
In Part E, 2.5 mg midazolam will be administered as an oromucosal solution and 120 mg fexofenadine will be administered as an oral tablet on day 1 and day 18, to investigate the effect of AV078 on the pharmacokinetics of midazolam and fexofenadine.
Intervention: Fexofenadine (Drug)
Outcomes
Primary Outcomes
Occurrence of clinically significant changes in physical examination (including neurological assessment).
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Abnormal physical examination findings will be listed.
Change in lipid panel values.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Lipid panel data will be summarised by treatment
Pharmacokinetics measured by area under the concentration-time curve in fasted and fed state.
Time Frame: Day 1 to Day 7 post-dose and final follow-up visit (Day 14)
To determine the effect of food on the pharmacokinetic profile of AV078.
Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by the maximum plasma concentration (Cmax).
Time Frame: Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine)
Clinically significant ECG findings.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Occurrence of clinically significant ECG findings will be listed.
Pharmacokinetics measured by the maximum plasma concentration (Cmax) in fasted and fed state.
Time Frame: Day 1 to Day 7 post-dose and final follow-up visit (Day 14)
To determine the effect of food on the pharmacokinetic profile of AV078.
Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by area under the concentration-time curve.
Time Frame: Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine)
Change in urinalysis values.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Urinalysis data will be summarised by treatment
Effects of itraconazole on the pharmacokinetics of AV078 measured by area under the concentration-time curve.
Time Frame: Day 1 to Day 15 post-dose and final follow-up visit (Day 23)
Effects of itraconazole on the pharmacokinetics of AV078 measured by the maximum plasma concentration (Cmax).
Time Frame: Day 1 to Day 15 post-dose and final follow-up visit (Day 23)
Incidence and severity of treatment emergent adverse events (TEAEs).
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Change in blood haematology values.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Haematology data will be summarised by treatment
Change in blood biochemisty values.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Biochemistry data will be summarised by treatment
Change in blood coagulation values.
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
Blood coagulation data will be summarised by treatment
Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS).
Time Frame: From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).
C-SSRS will be listed and summarised for each visit.
Secondary Outcomes
- Occurrence of clinically significant changes in physical examination (including neurological assessment).(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Change in blood haematology values(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Change in lipid panel values(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Pharmacokinetics of AV078 measured by the maximum plasma concentration (Cmax).(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Pharmacokinetics of AV078 measured by fraction of drug excreted in urine.(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Change from baseline and placebo-corrected change from baseline in ECG parameter - QRS interval(Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)])
- Pharmacokinetics of AV078 measured by renal clearance from plasma/whole blood.(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Change from baseline and placebo-corrected change from baseline in ECG parameter - heart rate (HR)(Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)])
- Change from baseline and placebo-corrected change from baseline in ECG parameter - PR interval(Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)])
- Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS)(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Pharmacokinetics of AV078 measured by the area under the concentration-time curve.(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Pharmacokinetics of AV078 measured by time of maximum plasma/whole blood concentration.(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Pharmacokinetics of AV078 measured by terminal elimination half-life.(Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B).)
- Change from baseline and placebo-corrected change from baseline in ECG parameter, QTcF including exposure response.(Part A: Screening (Day -42) to Day 5 post-dose, and final follow-up visit (Day 14). Part B: Screening (Day -42) to Day 2 post-dose, then Day 4, 7, 10, 14, 15 and 18 post-dose, and final follow-up visit (Day 42)])
- Incidence and severity of treatment emergent adverse events (TEAEs)(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Change in blood biochemistry values(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Change in urinalysis values(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))
- Change in blood coagulation values(From screening (Day -42) to final visit post-treatment (Day 14 for Part C, Day 23 for Part D and Day 26 for Part E))