Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients

Hereditary Angioedema Clinical Trial

Official title:

A Phase 1, Randomized, Placebo-Controlled, Double Blind Single Ascending Dose Study in Healthy Volunteers and an Expansion Cohort in Patients With Hereditary Angioedema to Evaluate the Safety, Tolerability, PK and PD of ADX-324

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05691361
• Other study ID #: ADX-324-101
• Status: Recruiting
• Phase: Phase 1
• Start date: December 14, 2022
• Est. completion date: December 26, 2025

Study information

• Verified date: March 2024
• Source: ADARx Pharmaceuticals, Inc.
• Contact: CMAX Reception
• Phone: +610870887900
• Email: Jane.kelly[@]cmax.com.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The first-in-human Phase 1 study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ADX-324 in healthy volunteers (HV) and in patients with Hereditary Angioedema (HAE).

Description:

The clinical study described in this protocol is a Phase 1, single-center study evaluating safety, tolerability, PK, and PD of ADX-324.

The study consists of 2 parts:

• Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HV with up to 6 dose cohorts. For SAD cohorts and planned dosing; and,

• Expansion cohort in participants with Hereditary Angioedema (HAE) at selected dose from Part A and will be open label.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 53
• Est. completion date: December 26, 2025
• Est. primary completion date: January 2, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Part A - HV

Inclusion Criteria:

1. Male and female adults 18 to 55 years old

2. Body mass index (BMI) between 18 and 30 kg/m2

3. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

4. Willing and able to provide informed consent and comply with all study visits

Exclusion Criteria:

1. Any significant medical history

2. Active malignancy and/or history of malignancy in the past 5 years

3. History of liver disease, Gilbert's syndrome, or abnormal liver function test

4. Estimated creatinine clearance <60 mL/min or serum creatinine > 1.5-fold upper limit of normal.

5. Any active infection or acute illness

6. Major surgery or significant traumatic injury occurring within 3 months

7. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study.

8. Positive serology tests (HepB, Hep C, HIV)

9. Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication

10. Treatment with another investigational product within 30 days prior to the first study drug administration

11. Known any clinically significant allergic reactions which, in the opinion of the Investigator, would interfere with the volunteer's ability to participate in the study

12. Known hypersensitivity to any of the study drug ingredients.

13. Pregnancy, intent to become pregnant during the course of the study, or lactating women

Part B - HAE

Inclusion Criteria:

1. Male and female =18 years old, inclusive, at the time of signing the PICF

2. Confirmed diagnosis of HAE Types I or II

3. Evidence of an average of (at least) one HAE attack per month

4. Participants must have access to, and the ability to use, acute medication(s) to treat angioedema attacks.

5. Body mass index (BMI) between 18 and 30 kg/m2

6. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

7. Willing and able to provide informed consent and comply with all study visits

Exclusion Criteria:

1. Concurrent diagnosis of any other type of chronic angioedema

2. History of clinically significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk.

3. Any significant medical history

4. Active malignancy and/or history of malignancy in the past 5 years

5. Any active infection or acute illness, inclusive of cold/flu or COVID-19, within 30 days prior to the first study drug administration.

6. Major surgery or significant traumatic injury occurring within 3 months prior to signature of the PICF

7. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study.

8. Positive serology tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).

9. Use of C1-INH products, androgens, antifibrinolytics or other small molecule medications for routine prophylaxis within four half-lives prior to screening

10. Must have documented evidence of medical history of HAE attacks

11. Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication (with the exception of oral contraceptives) within 7 days prior to the first study drug administration.

12. Treatment with another investigational product or biologic agent within 30 days prior to the study drug administration

13. History or presence of alcohol abuse or drug use within 30 days prior to the first study drug administration and throughout the study.

14. Blood donation of 50 to 499 mL within 30 days prior to the first study drug administration or of >499 mL within 60 days prior to the first study drug administration.

15. Pregnancy, intent to become pregnant during the course of the study, or lactating women.

Related Conditions & MeSH terms

• Angioedema
• Hereditary Angioedema

Intervention

Drug:
• ADX-324
siRNA duplex oligonucleotide
• Placebo
saline

Locations

Country	Name	City	State
Australia	CMAX Clinical Research	Adelaide	South Australia

Sponsors (1)

Lead Sponsor	Collaborator
ADARx Pharmaceuticals, Inc.

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety in Healthy Volunteers	To evaluate the safety and tolerability of ADX-324 in HVs by incidence, relationship, and severity of adverse events and serious adverse events	365 days
Primary	Safety in Healthy Volunteers	To evaluate the safety and tolerability of ADX-324 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals)	365 days
Primary	Safety in Hereditary Angioedema	To evaluate the safety and tolerability of ADX-324 in HAE by incidence, relationship, and severity of adverse events and serious adverse events	365 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Maximum observed concentration (Cmax)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Time to Cmax (Tmax)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-8)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Apparent terminal half-life (t½)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Terminal elimination rate constant (?z)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Total apparent body clearance (CL/F)	8 days
Secondary	Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-324 in HVs by measuring the Apparent volume of distribution (Vz/F)	8 days
Secondary	Pharmacodynamics in Healthy Volunteers	To characterize the PD of ADX-324 in HVs by the Change from base in plasma concentrations over time of pre Kallikrein (PKK)	365 days
Secondary	Pharmacodynamics in Healthy Volunteers	To characterize the PD of ADX-324 in HVs by the Change from base in plasma concentrations over time of Kallikrein (KK)	365 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Maximum observed concentration (Cmax) of ADX-324	365 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Time to Cmax (Tmax) of ADX-324	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last) of ADX-324	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Area under the concentration-time curve from 0 to infinity (AUC0-8) of ADX-324	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Apparent terminal half-life (t½)	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Terminal elimination rate constant (?z)	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Total apparent body clearance (CL/F)	8 days
Secondary	Pharmacokinetics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Apparent volume of distribution (Vz/F)	8 days
Secondary	Pharmacodynamics in Hereditary Angioedema	To characterize the PD of ADX-324 in HV by Change from base in plasma concentrations over time pre-kallikrein (PKK)	365 days
Secondary	Pharmacodynamics in Hereditary Angioedema	To characterize the PD of ADX-324 in HAE by Change from base in plasma concentrations over time kallikren (KK)	365 days