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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AV078 | Experimental | 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. |
|
| Placebo | Placebo Comparator | 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. |
|
| Itraconazole | Other | 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. |
|
| Midazolam and fexofenadine | Other | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AV078 | Drug | Oral solution containing active ingredient, AV078 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence and severity of treatment emergent adverse events (TEAEs). | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). | |
| Occurrence of clinically significant changes in physical examination (including neurological assessment). | Abnormal physical examination findings will be listed. | 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. | Haematology data will be summarised by treatment | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Change in blood biochemisty values. | Biochemistry data will be summarised by treatment | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Change in urinalysis values. | Urinalysis data will be summarised by treatment | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Change in lipid panel values. | Lipid panel data will be summarised by treatment | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Change in blood coagulation values. | Blood coagulation data will be summarised by treatment |
| Measure | Description | Time Frame |
|---|---|---|
| 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 the maximum plasma concentration (Cmax). | Day 1 to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
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Key Inclusion Criteria:
Key Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Davis Ryman | Chief Medical Officer, Aeovian Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Q-Pharm | Herston | Queensland | 4006 | Australia | ||
| Nucleus Network Pty Ltd |
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| ID | Term |
|---|---|
| D017964 | Itraconazole |
| D008874 | Midazolam |
| C093230 | fexofenadine |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Part A will study single doses of AV078 in a double-blind randomized, placebo-controlled, parallel-group and dose-escalating design ("single ascending dose [SAD] study").
Part B will study repeated doses of AV078 (once daily for 14 days) in a double-blind, randomized, placebo-controlled, parallel-group and dose-escalating design ("multiple ascending dose [MAD] study").
Part C will study the effect of food on the PK of AV078 in an open-label, randomized sequence 2-way crossover design.
Part D will study the effect of itraconazole on the PK of AV078 in an open-label, fixed sequence design.
Part E will study the effect of AV078 on the PK of midazolam and fexofenadine in an open-label, fixed sequence design.
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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.
| Placebo |
| Drug |
Oral solution with no active ingredients |
|
| Itraconazole | Drug | Once daily oral dose of 200 mg itraconazole administered for 9 days |
|
| Midazolam | Drug | 2.5 mg midazolam administered orally on day 1 and day 18 |
|
| Fexofenadine | Drug | 120 mg fexofenadine administered orally on day 1 and day 18 |
|
| From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Clinically significant ECG findings. | Occurrence of clinically significant ECG findings will be listed. | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS). | C-SSRS will be listed and summarised for each visit. | From screening (Day -42) to final visit post-treatment (Day 14 for Part A and Day 42 for Part B). |
| Pharmacokinetics measured by area under the concentration-time curve in fasted and fed state. | To determine the effect of food on the pharmacokinetic profile of AV078. | Day 1 to Day 7 post-dose and final follow-up visit (Day 14) |
| Pharmacokinetics measured by the maximum plasma concentration (Cmax) in fasted and fed state. | To determine the effect of food on the pharmacokinetic profile of AV078. | Day 1 to Day 7 post-dose and final follow-up visit (Day 14) |
| Effects of itraconazole on the pharmacokinetics of AV078 measured by area under the concentration-time curve. | 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). | Day 1 to Day 15 post-dose and final follow-up visit (Day 23) |
| Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by area under the concentration-time curve. | Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine) |
| Effects of AV078 on the pharmacokinetics of midazolam and fexofenadine measured by the maximum plasma concentration (Cmax). | Day 1, 2, 18 and 19 post-dose (midazolam) or Day 1-3, 18 and 19 post-dose (fexofenadine) |
| 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). |
| 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). |
| 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, 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)] |
| Change from baseline and placebo-corrected change from baseline in ECG parameter - heart rate (HR) | ECG parameters will be descriptively summarised at each time point. | 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 | ECG parameters will be descriptively summarised at each time point. | 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 - QRS interval | ECG parameters will be descriptively summarised at each time point. | 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) | Assessed for single doses of AV078 taken fasted or after a high-fat breakfast and repeated oral doses of AV078 | 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) |
| Occurrence of clinically significant changes in physical examination (including neurological assessment). | Abnormal physical examination findings will be listed. | 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 | Haematology data will be summarised by treatment. | 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 | Biochemistry data will be summarised by treatment. | 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 | Urinalysis data will be summarised by treatment. | 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 | Lipid panel data will be summarised by treatment. | 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 | Coagulation data will be summarised by treatment. | 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) |
| Monitor for the emergence of suicidal ideation and behaviour using the Columbia-Suicide Severity Rating Scale (C-SSRS) | C-SSRS will be listed and summarised for each visit | 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) |
| Melbourne |
| Victoria |
| 3220 |
| Australia |
| D010879 |
| Piperazines |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |