Study With CIN-107 Following Multiple Oral Ascending Doses in Healthy Subjects

A Randomized, Double-Blind Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of CIN-107 Following Multiple Oral Doses in Healthy Subjects

This is a randomized, double-blind, study to assess the safety, tolerability, PK, and PD of multiple oral doses of CIN-107 when administered to healthy adult subjects.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: CIN-107; Drug: Matching Placebo

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45227
      • Medpace Clinical Pharmacology Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy subjects between the ages of 18 and 55 years, inclusive, in good health based on medical and psychiatric history, physical examination, ECG, orthostatic vital signs, and routine laboratory tests (blood chemistry, hematology, coagulation, and urinalysis).
2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive.
3. Nonsmokers who have not used nicotine-containing products for at least 6 months prior to the Screening Visit.

Exclusion Criteria:

1. Actively participating in an experimental therapy study; received experimental therapy with a small molecule within 30 days of Day 1, or 5 half-lives, whichever is longer; or received experimental therapy with a large molecule within 90 days of Day 1, or 5 half-lives, whichever is longer.
2. A personal or family history of long QT syndrome, Torsades de Pointes, or other complex ventricular arrhythmias, or family history of sudden death.
3. History of, or current, clinically significant arrhythmias as judged by the Investigator, including ventricular tachycardia, ventricular fibrillation, or atrial fibrillation.
4. Prolonged QTcF (>450 msec) based on the average of triplicate ECGs.
5. Seated blood pressure higher than 150/90 mmHg or lower than 90/50 mmHg.
6. Resting heart rate higher than 100 bpm or lower than 50 bpm , sinus node dysfunction, or clinically significant heart block.
7. Temperature (T) greater than 37.6o C (99.68o F, measured orally), and respiration rate less than 12 and greater than 20 breaths/minute.
8. Postural tachycardia (ie >30 bpm upon standing) or orthostatic hypotension (ie, a fall in systolic blood pressure (SBP) of ≥20 mm Hg or DBP of ≥ 10 mm Hg when a person assumes a standing position).
9. Serum potassium > upper limit of normal of the reference range (ULN) and serum sodium < lower limit of normal of the reference range (LLN).
10. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values > 1.2 ULN.
11. Positive for human immunodeficiency virus (HIV) antibody, hepatitis C virus (HCV) antibody, or Hepatitis B surface antigen (HBsAg).
12. A known history of porphyria, myopathy, or an active liver disease.
13. Positive drug or alcohol test result or a history of alcoholism or drug abuse within 2 years prior to the first dose of study drug as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition: DSM-IV.
14. Typical consumption of ≥14 alcoholic drinks weekly.
15. Surgical procedures within 4 weeks of check-in or planned elective surgery during the study period.
16. Currently undergoing treatment with weight loss medication or prior weight loss surgery (eg, gastric bypass surgery).
17. Pregnant, breastfeeding, or planning to become pregnant during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: 2.5 mg CIN-107; Subjects on a low salt diet	Drug: CIN-107; A repeat oral dose of CIN-107 once daily for 10 days.; Other Names: baxdrostat
Experimental: Cohort 2: 5.0 mg CIN-107; Subjects on a low salt diet	Drug: CIN-107; A repeat oral dose of CIN-107 once daily for 10 days.; Other Names: baxdrostat
Experimental: Cohort 3: 1.5 mg CIN-107; Subjects on a normal salt diet	Drug: CIN-107; A repeat oral dose of CIN-107 once daily for 10 days.; Other Names: baxdrostat
Experimental: Cohort 4: 2.5 mg CIN-107; Subjects on a normal salt diet	Drug: CIN-107; A repeat oral dose of CIN-107 once daily for 10 days.; Other Names: baxdrostat
Experimental: Cohort 5: 0.5 mg CIN-107; Subjects on a normal salt diet	Drug: CIN-107; A repeat oral dose of CIN-107 once daily for 10 days.; Other Names: baxdrostat
Placebo Comparator: Cohort 1: 2.5 mg matching placebo; Subjects on a low salt diet	Drug: Matching Placebo; A repeat oral dose of matching placebo once daily for 10 days.
Placebo Comparator: Cohort 2: 5.0 mg matching placebo; Subjects on a low salt diet	Drug: Matching Placebo; A repeat oral dose of matching placebo once daily for 10 days.
Placebo Comparator: Cohort 3: 1.5 mg matching placebo; Subjects on a normal salt diet	Drug: Matching Placebo; A repeat oral dose of matching placebo once daily for 10 days.
Placebo Comparator: Cohort 4: 2.5 mg matching placebo; Subjects on a normal salt diet	Drug: Matching Placebo; A repeat oral dose of matching placebo once daily for 10 days.
Placebo Comparator: Cohort 5: 0.5 mg matching placebo; Subjects on a normal salt diet	Drug: Matching Placebo; A repeat oral dose of matching placebo once daily for 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax)	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data and following the first and last doses of CIN-107, as the data permit.	up to Day 15
Time to maximum plasma concentration (Tmax)	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data and following the first and last doses of CIN-107, as the data permit.	up to Day 15
Area under the curve from time 0 to the time of last quantifiable plasma concentration (AUC[0-last])	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data following the final dose of CIN-107, as the data permit.	up to Day 15
Area under the curve from time 0 to infinity	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data following the final dose of CIN-107, as the data permit.	up to Day 15
Area under the curve over a dosing interval (tau)	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data following the final dose of CIN-107, as the data permit.	up to Day 15
Area under the plasma concentration-time curve (AUC) from time 0 to 24 hours	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data and following the first dose of CIN-107, as the data permit.	up to Day 2
Percent of AUC extrapolated	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data following the final dose of CIN-107, as the data permit.	up to Day 15
Terminal phase elimination half-life	This PK parameter will be determined for CIN-107, its primary metabolite (CIN-107-M), and any other measured metabolites using plasma concentration data following the final dose of CIN-107, as the data permit.	up to Day 15
Apparent plasma clearance	This PK parameter will be determined for CIN-107 using plasma concentration data.	up to Day 15
Apparent volume of distribution	This PK parameter will be determined for CIN-107 using plasma concentration data.	Up to Day 15
The cumulative amount of CIN-107 and CIN-107-M excreted in the urine (Ae)	This PK parameter will be calculated using the urine concentrations of CIN-107 and its primary metabolite (CIN-107-M)	up to Day 15
Renal clearance (CLR Calculated as Ae/AUC) of CIN-107 and CIN-107-M	This PK parameter will be calculated using the urine concentrations of CIN-107 and its primary metabolite (CIN-107-M)	up to Day 15
Fraction of the dose excreted renally (fe)	This PK parameter will be calculated using the urine concentrations of CIN-107	up to Day 15
Number of patients experiencing adverse events (AEs)		up to Day 15
Number of patients experiencing adverse drug reactions		up to Day 15
Number of patients experiencing serious adverse events (SAEs)		up to Day 15
Plasma concentration of aldosterone		up to Day 15
Plasma renin activity		up to Day 15
Plasma concentration of cortisol (free and total)		up to Day 15
Plasma concentration of ACTH (Adrenocorticotropic hormone)		up to Day 15

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Leela Vrishabhendra, MD, Medpace Clinical Pharmacology Unit

Publications and helpful links

General Publications

• Freeman MW, Bond M, Murphy B, Hui J, Isaacsohn J. Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers. Hypertens Res. 2023 Jan;46(1):108-118. doi: 10.1038/s41440-022-01070-4. Epub 2022 Oct 20.

Helpful Links

• Redacted CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2019
• Primary Completion (Actual): April 3, 2020
• Study Completion (Actual): April 3, 2020

Study Registration Dates

• First Submitted: August 12, 2022
• First Submitted That Met QC Criteria: August 12, 2022
• First Posted (Actual): August 15, 2022

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: pharmacokinetics (PK), metabolism, baxdrostat
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: CIN-107-111

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal

Vivli.org. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. "Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No