Study to Evaluate the Effect of Renal Impairment and Dialysis Treatment on the Pharmacokinetics of a Single 3 mg Cytisinicline Dose

Achieve Life Sciences

Status and phase: Completed; Phase 1

Conditions: Renal Impairment

Treatments: Drug: cytisinicline

Study type: Interventional

Funder types: Industry

Identifiers

NCT05631938

ACH-CYT-05

Details and patient eligibility

About

The primary objectives of this study are:

1. To obtain information on the pharmacokinetics of cytisinicline following a single oral dose in subjects with varying degrees of renal impairment relative to matched controls with normal renal function.
2. To investigate the extent of cytisinicline removal by hemodialysis.

Enrollment: 44 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Free written informed consent prior to any procedure required by the study.

• Ability to communicate well with the investigator, in a language understandable to the subject, and to understand and comply with the requirements of the study.

• Willingness to accept and comply with all study procedures and restrictions.

• Male or female subject between 18 and 75 years, inclusive, at Screening.

• Body mass index (BMI) of 18.0 to 35.0 kg/m^2, inclusive, at Screening.

• A female subject is eligible if she meets one of the following criteria:

  1. is of non-childbearing potential (underwent a permanent sterilization method [e.g., hysterectomy, bilateral salpingectomy and bilateral oophorectomy], is clinically diagnosed infertile, or is in a post-menopausal state); or
  2. is of childbearing potential and agrees to use an accepted contraceptive method from at least 28 days prior to dose administration (prior to first dose administration for Group 5) until at least 1 month after the end of study (EOS).

• Negative test results for anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus antibodies (anti-HCVAb).

• Stable concomitant medications for at least 7 days prior to dose administration (first dose administration for Group 5) and up to the EOS.

Additional Inclusion Criteria for Subjects with Renal Impairment (Groups 2 to 5)

• eGFR at Screening, determined by the Cockcroft-Gault equation, within:

  • 60-89 mL/min for Group 2 (mild renal impairment subjects).
  • 30-59 mL/min for Group 3 (moderate renal impairment subjects).
  • 15-29 mL/min for Group 4 (severe renal impairment subjects).
  • <15 mL/min for Group 5 (ESRD subjects)

• Subjects with ESRD are on dialysis for at least 3 months prior to Screening.

• Systolic blood pressure (SBP) 100-180mmHg, diastolic blood pressure (DBP) 50-105 mmHg, and pulse rate 50-100 bpm (inclusive), at Screening and Admission.

Additional Inclusion Criteria for Subjects with Normal Renal Function (Group 1)

• Estimated glomerular filtration rate (eGFR) ≥90 mL/min at Screening, determined by the Cockcroft-Gault equation.

• No clinically relevant abnormalities on clinical laboratory tests at Screening.

• Blood pressure and pulse rate at Screening within the following ranges:

  • SBP 90-140 mmHg, DBP 60-90 mmHg, and pulse rate 60-100 bpm (inclusive) for subjects <65 years of age.
  • SBP 95-160mmHg, DBP 65-95 mmHg, and pulse rate 60-100 bpm (inclusive) for subjects ≥65 years of age.

Exclusion criteria

• Known hypersensitivity/allergy reaction to cytisinicline substance or any of the excipients.
• History of renal, heart, and/or liver transplant.
• History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere in a relevant manner with the absorption, distribution, metabolism, or excretion of the study treatment except for renal disease.
• Symptoms of an acute clinically relevant infection in the 4-week period preceding Screening (e.g., bacterial, viral, or fungal infection).
• History or clinical evidence of alcohol use disorder or substance use disorder according to Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) classification, within the 3-year period prior to Screening.
• Clinically relevant abnormalities on a 12-lead electrocardiogram (ECG), recorded after 5 min in the supine position at Screening.
• Currently using any creatine supplement.
• Nicotine consumption (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) from 48 hours prior to Admission.
• Excessive caffeine consumption, defined as ≥800 mg per day at Screening.
• Positive result in drugs-of-abuse or ethanol tests at Screening or Admission. NOTE: Subjects receiving stable treatment of methadone and benzodiazepines will be allowed to be enrolled in the study even if the urine drug screen test is positive.
• Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access or puncture; veins with a tendency to rupture during or after puncture).
• Participation in any clinical trial within the previous 2 months.
• Loss of 250 mL or more blood within 3 months prior to screening.
• If female, positive pregnancy test in serum at Screening or positive pregnancy test in urine at Admission.
• If female, she is breast-feeding.

Additional Exclusion Criteria for subjects with Renal Impairment (Group 2 to 5)

• Presence of severe cardiac disease.
• History of severe renal artery stenosis.
• Presence of unstable diabetes mellitus.
• Acute, ongoing, recurrent, or chronic systemic disease other than renal function impairment that could interfere with the evaluation of the study results.
• Presence of any organ disorder, except for renal function impairment, which might interfere with the PK of cytisinicline.
• Use of any medication which might interfere with the PK of cytisinicline.
• Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis), except for those related to renal impairment, at Screening.

Additional Exclusion Criteria for Subjects with ESRD (Group 5)

• Blood hemoglobin <10 g/dL at Screening.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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44 participants in 5 patient groups

Group 1: Normal Renal Function

Experimental group

Description:

Participants with normal renal function receive a 3 mg single dose of cytisinicline.

Treatment:

Drug: cytisinicline

Group 2: Mild Renal Impairment

Experimental group

Description:

Participants with mild renal impairment receive a 3 mg single dose of cytisinicline.

Treatment:

Drug: cytisinicline

Group 3: Moderate Renal Impairment

Experimental group

Description:

Participants with moderate renal impairment receive a 3 mg single dose of cytisinicline.

Treatment:

Drug: cytisinicline

Group 4: Severe Renal Impairment

Experimental group

Description:

Participants with severe renal impairment receive a 3 mg single dose of cytisinicline.

Treatment:

Drug: cytisinicline

Group 5: ESRD Participants Undergoing Dialysis

Experimental group

Description:

Participants with ESRD undergoing dialysis receive a 3 mg single dose of cytisinicline on 2 occasions: after and prior to a dialysis session.

Treatment:

Drug: cytisinicline