Safety, Tolerability and Pharmacokinetics of AZD1613 in Adults With Autosomal Dominant Polycystic Kidney Disease

Official title

A Phase I Randomised, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD1613 Following Multiple Ascending Dose Administration in Participants With Autosomal Dominant Polycystic Kidney Disease

Overview

A study to investigate safety, tolerability, and pharmacokinetics of AZD1613 following subcutaneous or intravenous administration in participants with autosomal dominant polycystic kidney disease (ADPKD).

Detailed description

This Phase I, randomised, single-blind, placebo-controlled study will assess the safety and tolerability of AZD1613 and characterise the pharmacokinetics (PK) of AZD1613 in participants with autosomal dominant polycystic kidney disease (ADPKD), following subcutaneous (SC) or intravenous (IV) administration. Inclusion of participants receiving placebo is appropriate for benchmarking the safety and tolerability of AZD1613. Furthermore, the safety and PK profile will be evaluated in Chinese participants with ADPKD to assess any potential race effect in this population.

Interventions

• Drug AZD1613 - Part A
  Part A - Participants will be administered doses of AZD1613 on days 1, 29, 57, and 85 according to randomization in IRT.
• Drug Placebo - Part A
  Part A - Participants will be administered doses of placebo on days 1, 29, 57, and 85 according to randomization in IRT.
• Drug AZD1613 - Part B
  Part B - Participants will be administered doses of AZD1613 on days 1, 29, 57, and 85 according to randomization in IRT.
• Drug Placebo - Part B
  Part B - Participants will be administered doses of placebo on days 1, 29, 57, and 85 according to randomization in IRT.

Primary outcome measures

• Incidence of Treatment-Emergent Adverse Events (TEAEs) [Time frame: From randomization (Day 1) through end of follow-up (up to Day 189 ±3 days)]
• Change From Baseline in Safety 12-Lead ECG QTcF [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Safety 12-Lead ECG PR Interval [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Safety 12-Lead ECG QRS Duration [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Heart Rate (12-Lead Safety ECG) [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in ALT [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in AST [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Total Bilirubin [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Serum Creatinine [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]
• Change From Baseline in Estimated Glomerular Filtration Rate (eGFR; CKD-EPI 2021) [Time frame: Baseline (Day -1) and post-dose at scheduled visits through Day 189 ±3 days]

Secondary outcome measures (9)

• Maximum Observed Serum Concentration (Cmax) of AZD1613 [Time frame: Intensive PK sampling from Day 1 through Day 189 per protocol schedule]
• Area Under the Concentration-Time Curve to Last Quantifiable Concentration (AUClast) of AZD1613 [Time frame: Intensive PK sampling from Day 1 through Day 189 per protocol schedule]
• Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of AZD1613 [Time frame: Intensive PK sampling from Day 1 through Day 189 per protocol schedule]
• Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau) of AZD1613 [Time frame: Over the dosing interval (τ = 28 days) at steady state; sampling through Day 189]
• Time to Maximum Observed Serum Concentration (Tmax) of AZD1613 [Time frame: Intensive PK sampling from Day 1 through Day 189 per protocol schedule]
• Terminal Elimination Half-Life (t½) of AZD1613 [Time frame: Intensive PK sampling from Day 1 through Day 189 per protocol schedule]
• Incidence of Anti-Drug Antibodies (ADA) to AZD1613 [Time frame: Predose on dosing days and during follow-up through Day 189 ±3 days]
• ADA Titer to AZD1613 [Time frame: Predose on dosing days and during follow-up through Day 189 ±3 days]
• Change From Baseline in PD Markers of PAPPA-1 Inhibition [Time frame: Baseline to scheduled post-dose time points through Day 189 ±3 days]

Eligibility criteria

Inclusion criteria

• Patients with ADPKD Mayo Class (IB-IE), as per clinical diagnosis (MIC) assessed centrally. Genetic testing results will not be used for eligibility purposes
• eGFR = 45 to 90 mL/min /1.73m2
• Body weight ≥ 45 kg and body mass index within the range 18 to 35 kg/m2 (inclusive).
• Females are to be of non-childbearing potential

Exclusion criteria

• As judged by the investigator, any evidence of cardiac, vascular, and other renal conditions which in the investigator's opinion makes it undesirable for the participant to participate in the study.
• Positive hepatitis C antibody, hepatitis B virus surface antigen, or human immunodeficiency virus test, at screening.
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• Congenital long QT syndrome.
• History of ventricular arrhythmia requiring treatment. Patients with atrial fibrillation/flutter and controlled ventricular rate HR < 100 bpm can be eligible as judged by the investigator.
• Haemoglobin below the lower limit of the normal range or any other clinically significant haematological abnormality as judged by the investigator.
• Any clinically important abnormalities in clinical chemistry, haematology, coagulation, or urinalysis results other than those specifically described as exclusion criteria herein, as judged by the investigator.
• Systolic BP > 160 mmHg or diastolic BP > 100mmHg or HR < 50 bpm or > 100 bpm at screening. Patients taking anti-hypertensive medication should be on a stable treatment regimen of antihypertensive therapy for at least 30 days prior to the screening visit.
• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG and any abnormalities in the 12-lead ECG that, as considered by the investigator, may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.
• Kidney cyst interventions such as cyst aspiration or cyst fenestration within 12 weeks prior to screening and during the screening period, or such interventions planned or anticipated within the follow-up period.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 8 centers

• Research Site — Birmingham
• Research Site — Loma Linda
• Research Site — Jacksonville
• Research Site — Orlando
• Research Site — Lenexa
• Research Site — Baltimore
• Research Site — Rochester
• Research Site — San Antonio

China · 6 centers

• Research Site — Chengdu
• Research Site — Hangzhou
• Research Site — Nanjing
• Research Site — Shanghai
• Research Site — Wuhan
• Research Site — Xiamen

United Kingdom · 1 center

• Research Site — London

Identifiers

NCT: NCT07228364 · D9050C00002 · Identifier Number

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗