A Four Way Crossover Thorough QT/QTc Study to Evaluate the Electrocardiographic Effects of Therapeutic and Supratherapeutic Doses of Cytisinicline in Healthy Smokers

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Achieve Life Sciences Inc.

Participant type

Healthy volunteers

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

17 Oct 2022 → 6 Jan 2023

Decision date (initial)

2022-10-03

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: Dose response, Safety

Assess the effects of cytisinicline at therapeutic and supratherapeutic doses on cardiac repolarization relative to placebo in healthy adult subjects who are smokers.

Secondary objectives 1

1. Assess the effects of cytisinicline at therapeutic and supratherapeutic dose on other ECG parameters relative to placebo in healthy adult subjects who are smokers.

Conditions and MedDRA coding

Nicotine addiction

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Regular moderate cigarette smokers (minimum 10 cigarettes per day).
2. Healthy males and females 18-45 years of age.
3. If woman, she meets one of the following criteria: a. is of non-childbearing potential or b. is of childbearing potential and agrees to use an accepted contraceptive method from at least 4 weeks prior to admission to period 1 until at least the last study drug administration.
4. No clinically significant abnormal serum chemistry or hematology values at Screening.
5. Body mass index (BMI) within 18-30 kg/m2 at Screening.
6. Subject must be willing to communicate with the investigator and site staff and comply with all study procedures and requirements.
7. Subject must be able to provide written, informed consent including compliance with the requirements listed in the consent form.
8. Subject must be able and willing to swallow whole tablets without breaking, cutting, or chewing.

Exclusion criteria 29

1. History or presence of a systemic disease, which as judged by the investigator, may affect the subject’s ability to participate in the study or in the outcome of the study.
2. Evidence of infection with Hepatitis B or C, or human immunodeficiency virus HIV-1 or HIV-2, as determined by results of testing at Screening.
3. Female subjects who are pregnant or lactating.
4. Family history of QTc prolongation or of unexplainable sudden death at <50 years of age.
5. History of QTc prolongation or knowledge of any kind of cardiovascular disorder/condition known to increase the possibility of QT prolongation or history of additional risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders.
6. History of myocardial infarction, unstable angina pectoris, cerebrovascular disease, atherosclerosis or arterial hypertension.
7. History of rare hereditary problem of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
8. History of glucose 6-phosphate dehydrogenase deficiency or myasthenia gravis.
9. Use of any medication that might interfere with the PK of cytisinicline.
10. Resting supine pulse rate less than 50 beats per minute or greater than 100 beats per minute at Screening.
11. Resting supine systolic blood pressure less than 90 mmHg or greater than 140 mmHg; resting supine diastolic blood pressure less than 50 mmHg or greater than 90 mmHg at Screening.
12. Clinically significant ECG abnormalities at Screening, including: a. QTcF >450 ms b. QRS >110 ms c. PR >200 ms d. Second or third-degree AV block e. Any rhythm other than sinus rhythm, which is interpreted by the investigator to be clinically significant
13. Renal impairment defined as a creatinine clearance (CrCl) <90 mL/min, based on creatinine clearance calculation by the Cockcroft-Gault formula and normalized to an average surface area of 1.73 m2, at Screening.
14. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) above the ULN (upper limit of the reference range) at Screening.
15. Positive urine drug and alcohol screen at Screening or Day -1 for each Treatment Period.
16. Positive pregnancy test for WOCBP at Screening or Day-1 to each Treatment Period.
17. History of significant alcohol abuse, drug abuse, or use of illicit drugs within one year prior to Screening.
18. Average weekly alcohol consumption of >14 units for males and >7 units for females within the previous 6 months.
19. Average daily consumption of methylxanthines-containing beverages or food (e.g., coffee, tea, cola, sodas, chocolate) equivalent to >500 mg of methylxanthines.
20. Subject has donated or lost ≥450 mL of blood within the previous 2 months prior to study drug administration or has donated plasma within 7 days prior to study drug administration.
21. Known hypersensitivity/allergy reaction to moxifloxacin or other fluoroquinolones.
22. Use of prescription medication within 14 days or 5 half-lives (whichever is longer) or over-the-counter products (including natural food supplements) within 7 days prior to admission to Treatment Period 1, unless in the investigator’s opinion the medication does not interfere with the pharmacokinetics of study drug or compromise subject safety. Exceptions include topical products without systemic absorption, hormonal contraceptives, hormone replacement therapy, and acetaminophen (≤2 g/day).
23. Any allergy, intolerance, restriction or special diet that, in the opinion of the investigator, could contraindicate the subject’s participation in this study.
24. History of unexplained loss of consciousness, unexplained syncope, unexplained irregular heartbeats or palpitations or near drowning with hospital admission.
25. Subjects who received any investigational drug 30 days or 5 half-lives (whichever is longer) prior to first study drug administration.
26. Use of other forms of nicotine (e-cigarettes, smokeless tobacco) or are planning to use these products during study.
27. Known hypersensitivity/allergy reaction to varenicline, cytisinicline or other cytisinicline-derivatives.
28. Positive SARS-CoV-2 test, prior to admission to each study period.
29. Any reason which, in the opinion of the investigator, would prevent the subject from participating in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Concentration effect modeling: change from baseline in QTc, corrected for HR based on the Fridericia QT correction method (ΔQTcF) compared with matched timepoint cytisinicline concentration. This is used to calculate a predicted placebo-adjusted change from baseline in the QTcF interval (ΔΔQTcF). In the event of an effect on HR of ≥10 bpm, the individual QT correction method (QTcI) will be utilized as the primary QT correction method.

Secondary endpoints 5

1. Time-point change from baseline in QTc, placebo-adjusted and corrected for HR based on the Fridericia QT correction (QTcF) method (ΔΔQTcF). In the event of an effect on HR of ≥10 bpm, the individual QT correction method (QTcI) will be utilized as the primary QT correction method.
2. Time-point change from baseline, placebo-adjusted, for HR, PR interval (PR), and QRS duration (QRS).
3. Evaluation of the relationship between the plasma concentration of cytisinicline and the placebo-adjusted change from baseline in HR, PR, and QRS
4. Evaluation of the effects of cytisinicline on ECG morphology (including T wave and U wave).
5. Central tendency and categorical outlier analyses based on uncorrected QT, PR, QRS, and HR.

Investigational products

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

Test 1

Comparator 1

Placebo 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

1 EU/EEA country · 1 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 2 files

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

Application history

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