Assessment of the Safety, Tolerability and Pharmacokinetics of AV078 in Healthy Volunteers

NCT06205381 | Completed Phase 1

• 1 other identifier: CL-078-101
• Study Type: interventional
• Target: 89
• Locations: 1 country
• Sites: 2

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.

Conditions

Healthy Participants

Keywords

mTOR

Outcome Measures

Primary Outcomes (15)

• 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

  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)

Secondary Outcomes (18)

• 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).

• 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).

Study Arms (4)

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.

Drug: AV078

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.

Drug: Placebo

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.

Drug: Itraconazole

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.

Drug: Midazolam; Drug: Fexofenadine

Interventions

AV078 DRUG

Oral solution containing active ingredient, AV078

AV078

Placebo DRUG

Oral solution with no active ingredients

Placebo

Itraconazole DRUG

Once daily oral dose of 200 mg itraconazole administered for 9 days

Itraconazole

Midazolam DRUG

2.5 mg midazolam administered orally on day 1 and day 18

Midazolam and fexofenadine

Fexofenadine DRUG

120 mg fexofenadine administered orally on day 1 and day 18

Midazolam and fexofenadine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• Aeovian Pharmaceuticals, Inc.: lead

Study Sites (2)

Q-Pharm

Herston, Queensland, 4006, Australia

Location

Nucleus Network Pty Ltd

Melbourne, Victoria, 3220, Australia

Location

MeSH Terms

Interventions

Itraconazole; Midazolam; fexofenadine

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Davis Ryman

  Chief Medical Officer, Aeovian Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: December 19, 2023
• First Posted: January 16, 2024
• Study Start: January 31, 2024
• Primary Completion: February 8, 2025
• Study Completion: February 8, 2025
• Last Updated: March 26, 2025

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)