A Phase I, Open-Label Study to Evaluate the Effect of Renal Impairment and Dialysis Treatment on the Pharmacokinetics of a Single 3 mg Cytisinicline Dose

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Achieve Life Sciences Inc.

Participant type

Patients, Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04]

Trial duration

13 Dec 2022 → 6 Sep 2023

Decision date (initial)

2022-10-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Achieve Life Sciences, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic

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

Secondary objectives 1

1. To assess the safety and tolerability of cytisinicline in subjects with impaired renal function

Conditions and MedDRA coding

Nicotine addiction

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Free written informed consent prior to any procedure required by the study.
2. 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.
3. Willingness to accept and comply with all study procedures and restrictions.
4. Male or female subject between 18 and 75 years, inclusive, at Screening.
5. Body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive, at Screening.
6. A female subject is eligible if she meets one of the following criteria: a. 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 b. 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).
7. 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).
8. Stable concomitant medications for at least 7 days prior to dose administration (first dose administration for Group 5) and up to the EOS.
9. eGFR at Screening 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) determined by the Cockcroft-Gault equation
10. Subjects with ESRD are on dialysis for at least 3 months prior to Screening
11. Systolic blood pressure (SBP) 100-180 mmHg, diastolic blood pressure (DBP) 50-105 mmHg, and pulse rate 50–100 bpm (inclusive), at Screening and Admission.
12. eGFR ≥90 mL/min at Screening, determined by the Cockcroft-Gault equation.
13. No clinically relevant abnormalities on clinical laboratory tests at Screening.
14. Blood pressure and pulse rate at Screening within the following ranges: • SBP 90-140 mmHg, DBP 60-90mmHg, 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 23

1. Known hypersensitivity/allergy reaction to cytisinicline substance or any of the excipients.
2. History of renal, heart, and/or liver transplant.
3. 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.
4. Symptoms of an acute clinically relevant infection in the 4-week period preceding Screening (e.g., bacterial, viral, or fungal infection).
5. History or clinical evidence of alcohol use disorder or substance use disorder according to DSM-5 classification, within the 3-year period prior to Screening.
6. Clinically relevant abnormalities on a 12-lead electrocardiogram (ECG), recorded after 5 min in the supine position at Screening.
7. Currently using any creatine supplement.
8. Nicotine consumption (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) from 48 hours prior to Admission.
9. Excessive caffeine consumption, defined as ≥800 mg per day at Screening.
10. Positive result in drugs-of-abuse or ethanol tests at Screening or Admission.
11. 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).
12. Participation in any clinical trial within the previous 2 months.
13. Loss of 250 mL or more blood within 3 months prior to screening.
14. If female, positive pregnancy test in serum at Screening or positive pregnancy test in urine at Admission.
15. If female, she is breast-feeding.
16. Presence of severe cardiac disease.
17. History of severe renal artery stenosis.
18. Presence of unstable diabetes mellitus.
19. Acute, ongoing, recurrent, or chronic systemic disease other than renal function impairment that could interfere with the evaluation of the study results.
20. Presence of any organ disorder, except for renal function impairment, which might interfere with the PK of cytisinicline.
21. Use of any medication which might interfere with the PK of cytisinicline.
22. Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis), except for those related to renal impairment, at Screening.
23. Blood hemoglobin <10g/dL at Screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Determination of cytisinicline plasma concentrations. Pharmacokinetic parameters: • Cmax • Tmax • Area under the plasma concentration versus time curve (AUC) from pre-dose (time zero) to the last sampling time with quantifiable concentrations (AUC0-t); • AUC0-∞ • Apparent terminal elimination rate constant (λz); • Apparent terminal elimination half-life (t1/2), • Fraction unbound (fu) • Apparent clearance (CL/F) • Apparent volume of distribution (V/F)
2. Determination of cytisinicline urine concentrations. Pharmacokinetic parameters: • Amount of drug excreted in urine (Ae) • Fraction of unchanged drug excreted in urine (fe) • Area under the urine excretion rate curve from time zero to last measurable observed excretion rate (AURC) • Renal clearance (CLR) • Apparent nonrenal clearance (CLNR/F)
3. Dialysate samples for determination of cytisinicline. Pharmacokinetic parameters: • Amount of drug recovered from each dialysate collection (AD) • Cumulative amount of drug recovered from the dialysate (AD, total) • Partial area under the curve estimated from predialyzer samples collected from start of dialysis (t0) to end of dialysis (t1) (AUCt0-t1) • Dialysis clearance (CLD) • Fraction of the administered dose that is recovered in the dialysate (Frem)

Secondary endpoints 1

1. Safety will be evaluated through the assessment of adverse events (AEs), ECG, vital signs, and clinical laboratory tests.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Achieve Life Sciences Inc.

Sponsor organisation

Achieve Life Sciences Inc.

Address

19820 North Creek Parkway Suite 201

City

Bothell

Postcode

98011-8227

Country

United States

Scientific contact point

Organisation

Achieve Life Sciences Inc.

Contact name

Daniel Cain

Public contact point

Organisation

Achieve Life Sciences Inc.

Contact name

Daniel Cain

Third parties 1

Locations

2 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications