Clinical trial NCT04818229: A Study to Investigate the Effects of CBP-307 on the Heart Rate-corrected QT Interval (QTc) in Healthy Subjects
Official title: A Phase I, Multicenter, Randomized, Double-blind, Double-dummy, Placebo- and Positive-Controlled Study to Investigate the Effects of CBP-307 on the QTc Interval in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Autoimmune Diseases
Lead sponsor: Connect Biopharm LLC
Sponsor class: INDUSTRY
First posted: 2021-03-26
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This study will investigate the effects of therapeutic and supratherapeutic oral doses of CBP-307 on the QTc interval in healthy subjects.

Detailed description: This will be a Phase I, randomized, double-blind, double-dummy, placebo-controlled, positive-controlled, multi-site, 3-arm study to investigate the effects of therapeutic and supratherapeutic oral doses of CBP-307 on the QTc interval in healthy male and female subjects.

Eligibility criteria: Inclusion Criteria:

1. Males or females, of any race, between 18 and 60 years of age, inclusive.
2. Body mass index between 18.0 and 30.0 kg/mE2, inclusive.
3. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia \[eg, suspicion of Gilbert's syndrome based on total and direct bilirubin\] is not acceptable) at screening and confirmed at check-in as assessed by the investigator (or designee).
4. Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception. Negative pregnancy test for females of childbearing potential at screening (blood test) and check-in (urine test).
5. Supine diastolic blood pressure between 60 and 90 mmHg and systolic blood pressure between 90 and 140 mmHg (inclusive) at screening on a single measurement (confirmed by a single repeat, if necessary) following at least 5 minutes of rest.
6. No clinically significant history or presence of ECG findings as judged by the investigator at screening and check-in, including each criterion as listed below:

   1. Normal sinus rhythm (HR between 55 bpm and 100 bpm inclusive);
   2. QTcF interval ≤450 msec for males and females;
   3. QRS interval ≤110 msec; and confirmed by manual over-read if \>110 msec;
   4. PR interval ≤200 msec.
7. Has serum potassium, calcium, and magnesium levels within the normal reference range at screening, as judged by the investigator.
8. Able to swallow multiple tablets (based on subject's verbal confirmation).
9. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.

Exclusion Criteria:

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Subjects will be excluded from the study if they satisfy any of the following criteria at the screening visit unless otherwise stated:

1. Subject is mentally or legally incapacitated or has had significant history of recent mental health issues requiring medication and/or hospitalization at the time of the screening visit or expected during the conduct of the study.
2. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or designee). Note: Childhood asthma that is considered recovered or seasonal allergies that are not currently active or requiring treatment are allowed.
3. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee).
4. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs, related compounds, or inactive ingredients.
5. History of significant multiple and/or severe allergies (eg, latex allergy, band-aids, adhesive dressing, or medical tape), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs.
6. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs within 6 months prior to the first dose of study drug (uncomplicated appendectomy and hernia repair will be allowed).
7. History or presence of:

   1. Hypokalemia, in the opinion of the investigator (or designee);
   2. Risk factors for Torsades de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome);
   3. Sick sinus syndrome, second, or third degree atrioventricular block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged QT interval, or conduction abnormalities;
   4. Repeated or frequent syncope or vasovagal episodes;
   5. Hypertension, angina, bradycardia, or severe peripheral arterial circulatory disorders.
8. Clinically significant abnormalities (as judged by the investigator in laboratory tests results \[out-of-range results confirmed on repeat\]), including but not limited to the following parameters:

   1. alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or total bilirubin greater than 1.5 × upper limit of normal;
   2. hemoglobin \<10 g/dL, WBC \<3.0 ×10E9/L, neutrophils \<1.5 ×10E9/L, lymphocytes \<0.8 ×10E9/L and platelets \<100 ×10E9/L or \>1200 × 10E9/L;
9. History or evidence of alcoholism or drug/chemical abuse within 2 years prior to check-in.
10. Alcohol consumption of \>10 units per week for males and females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits.
11. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at screening or check-in.
12. Positive hepatitis panel, positive syphilis test, and/or positive human immunodeficiency virus test.
13. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 28 days prior to the first dose of study treatment on Day 1. The 28-day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study.
14. Participation in a previous clinical study where subjects received CBP-307.
15. Administration of a Coronavirus Disease 2019 (COVID-19) vaccine in the past 28 days prior to first dose of study treatment on Day 1.
16. Use or intend to use any prescription medications/products within 14 days prior to first dose of study drug (Day 1) and throughout the study, unless deemed acceptable by the investigator (or designee). Note: For females only, the use hormonal contraception, hormone replacement therapy or oral, implantable, transdermal, injectable, or intrauterine hormonal contraceptives within 14 days prior to Day 1 is not acceptable, except for Mirena®.
17. Use or intend to use any drugs known to be significant inhibitors or inducers of CYP enzymes and/or P-gp, including St. John's Wort, for days prior to the first dose of study drug and throughout the study. Appropriate sources will be consulted by the investigator or designee to confirm the lack of PK/PD interaction with the study drug.
18. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to check-in, unless deemed acceptable by the investigator (or designee).
19. Use or intend to use any nonprescription medications/products including antacids, vitamins (especially those containing magnesium, aluminum, iron, or zinc), minerals, and phytotherapeutic/herbal/plant-derived preparations within 14 days prior to check-in, unless deemed acceptable by the investigator (or designee).
20. Use of tobacco- or nicotine-containing products within 3 months prior to check-in, or positive cotinine at screening or check-in.
21. Has been on a diet incompatible with the on-study diet (including an extreme diet which resulted in a significant weight change for whatever reason), in the opinion of the investigator, within the 28 days prior to the first dose of study treatment, and throughout the study.
22. Consumption of caffeine/xanthine-containing foods or beverages within 48 hours prior to check-in until discharge.
23. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to check-in.
24. Receipt of blood products within 2 months prior to check-in.
25. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening.
26. Poor peripheral venous access.
27. Subjects who, in the opinion of the investigator (or designee), should not participate in this study.

Primary outcomes:
measure: Change-from-baseline QT Interval Corrected for Heart Rate Using Fridericia's Method (QTcF)
timeFrame: From Baseline to Day 16
Secondary outcomes:
measure: Change-from-baseline Heart Rate (HR)
timeFrame: From Baseline at Day 16
measure: Change-from-baseline PR
timeFrame: From Baseline at Day 16
measure: Change-from-baseline QRS
timeFrame: From Baseline at Day 16
measure: Placebo-corrected Change-from-baseline HR
timeFrame: From Baseline to Day 16
measure: Placebo-corrected Change-from-baseline QTcF
timeFrame: From Baseline to Day 16
measure: Placebo-corrected Change-from-baseline PR
timeFrame: From Baseline to Day 16
measure: Placebo-corrected Change-from-baseline QRS
timeFrame: From Baseline to Day 16
measure: Categorical Outliers for QTcF
timeFrame: From Baseline to Day 16
measure: Categorical Outliers for HR
timeFrame: From Baseline to Day 16
measure: Categorical Outliers for PR
timeFrame: From Baseline to Day 16
measure: Categorical Outliers for QRS
timeFrame: From Baseline to Day 16
measure: Frequency of Treatment-emergent Changes of T-wave Morphology
timeFrame: From Baseline to Day 16
measure: Frequency of Treatment-emergent Changes of U-wave Presence
timeFrame: From Baseline to Day 16
measure: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf)
timeFrame: From Baseline to Day 29 ± 2
measure: Area Under the Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24)
timeFrame: From Baseline to Day 29 ± 2
measure: Maximum Observed Concentration (Cmax)
timeFrame: From Baseline to Day 29 ± 2
measure: Time of the Maximum Observed Concentration (Tmax)
timeFrame: From Baseline to Day 29 ± 2
measure: Incidence and Severity of Adverse Event (AE)
timeFrame: From Baseline to Day 29 ± 2
Other outcomes:
Locations:
city: Hialeah
country: United States
facility: Clinical Pharmacology of Miami (CPMI), LLC
state: Florida
city: Adelaide
country: Australia
facility: CMAX
state: South Australia
Study officials:
affiliation: Connect Biopharma Australia Pty Ltd
name: Australia Connect
role: STUDY_DIRECTOR
affiliation: Connect Biopharm LLC
name: Suzhou Connect
role: STUDY_DIRECTOR
References: