Clinical trial NCT05517226: Pharmacokinetics of Cotadutide in Participants With Hepatic Impairment
Official title: A Phase I, Parallel-group, Multi-center, Open-label, Investigation of the Pharmacokinetics, Safety and Tolerability of a Single Subcutaneous Injection of Cotadutide in Participants With Mild, Moderate or Severe Hepatic Impairment Compared to Participants With Normal Hepatic Function
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: Cotadutide
Hepatic impairment
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2022-08-26
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the pharmacokinetics (PK), safety, and tolerability of a single subcutaneous injection of cotadutide in participants with mild, moderate or severe hepatic impairment compared to participants with normal hepatic function.

Detailed description: This study will consist of four cohorts (Cohort 1, Cohort 2, Cohort 3, and Cohort 4).

Participants will be assigned to each of the cohorts as per Child-Pugh classification:

* Cohort 1: Mild hepatic impairment (Child-Pugh A), cotadutide 50 μg
* Cohort 2: Moderate hepatic impairment (Child-Pugh B), cotadutide 50 μg
* Cohort 3: Severe hepatic impairment (Child-Pugh C), cotadutide 50 μg
* Cohort 4: Normal hepatic function, cotadutide 50 μg

Eligibility criteria: Inclusion Criteria:

* Participant must be ≥ 18 to ≤ 85 years of age at the time of signing the Informed Consent Form (ICF).
* Body mass index ≥ 18 kg/m2 to \< 40 kg/m2.
* Female participants of childbearing potential must use at least one highly effective form of birth control.
* Capable of giving signed informed consent.

Participants with hepatic impairment only

- Diagnosis of chronic (≥ 6 months) and stable hepatic impairment (eg, no clinically significant change in signs, symptoms, or laboratory parameters of hepatic disease status within 30 days prior to study Screening).

Exclusion Criteria:

All participants

* History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to cotadutide.
* Any clinically important abnormalities in rhythm, conduction or morphology of the 12-lead resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG as considered by the Investigator that may interfere with the interpretation of QT interval corrected for heart rate using Fridericia's formula (QTcF), including abnormal ST-T-wave morphology, or left ventricular hypertrophy

  1. Prolonged QTcF \> 470 ms or family history of long QT syndrome.
  2. PR (PQ) interval shortening \< 120 ms.
  3. PR (PQ) interval prolongation (\> 220 ms) intermittent or permanent second or third degree atrioventricular (AV) block, or AV dissociation.
  4. Persistent or intermittent complete bundle branch block, or intraventricular conduction delay with QRS \> 119 ms.
* Any evidence of additional severe or uncontrolled systemic disease or laboratory finding that makes it unsafe for the participant to participate in the study.
* Impaired renal function, defined as estimated glomerular filtration rate (eGFR) \< 30 mL/minute/1.73 m2 at Screening.
* Any positive result on Screening for serum hepatitis B surface antigen, anti-Core HBV antibody, hepatitis C antibody, or human immunodeficiency virus (HIV).
* Any sign and confirmation of coronavirus disease 2019 (COVID19) infection:
* Participants with concurrent or previous use of a glucagon-like peptide-1 (GLP1) receptor agonist.
* Use of prohibited prescribed or nonprescribed medication during the 2 weeks prior to the first administration of Investigational Medicinal Product (IMP) or longer if the medication has a long half-life.
* History of neoplastic disease within 5 years prior to Screening, except for adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer.
* Presence of hepatocellular carcinoma or acute liver disease caused by an infection or drug toxicity.

Participants with hepatic impairment only

* Severe portal hypertension or surgical porto-systemic shunts.
* Biliary obstruction or other causes of hepatic impairment not related to parenchymal disorder and/or disease of the liver.
* Clinically relevant hepatic encephalopathy.
* Severe ascites defined as ascites requiring paracentesis and albumin at 4-week intervals or less.
* Fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within the 28-day Screening period.
* Post liver transplantation.
* Platelet count \< 50 × 109/L and/or neutrophil count \< 1.2 × 109/L and/or hemoglobin \< 8.5 g/dL or INR \>2.3.

Participants with normal hepatic function only

* History or presence of hepatic disease or evidence of other known forms of known chronic liver disease.
* History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* Urinary albumin-to-creatinine ratio \> 3 mg/μmol.

Primary outcomes:
measure: Maximum observed plasma (peak) drug concentration [Cmax]
timeFrame: Day 1 to Day 3
measure: Area under plasma concentration time curve from zero to infinity (AUCinf)
timeFrame: Day 1 to Day 3
measure: Area under the plasma concentration-curve from time zero to last quantifiable concentration (AUClast)
timeFrame: Day 1 to Day 3
measure: Time to reach peak or maximum observed concentration or response following drug administration (tmax)
timeFrame: Day 1 to Day 3
measure: Terminal half-life (t½λz)
timeFrame: Day 1 to Day 3
measure: Apparent total body clearance (CL/F)
timeFrame: Day 1 to Day 3
measure: Apparent volume of distribution based on the terminal phase (Vz/F)
timeFrame: Day 1 to Day 3
Secondary outcomes:
measure: Number of participants with Adverse Events (AEs)
timeFrame: From time of first dose to the final follow-up visit (Day 29)
measure: Incidence of ADAs (anti-drug antibodies)
timeFrame: From time of first dose to the final follow-up visit (Day 29)
Other outcomes:
Locations:
city: Hialeah
country: United States
facility: Research Site
state: Florida
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
Study officials:
References: