Safety, Tolerability and Pharmacokinetics of CBP-174 in Healthy Adults

• ClinicalTrials.gov Identifier: NCT04811469
• Recruitment Status: Completed
• First Posted: March 23, 2021
• Last Update Posted: August 10, 2022
• Sponsor: Connect Biopharma Australia Pty Ltd
• Information provided by (Responsible Party): Suzhou Connect Biopharmaceuticals, Ltd. ( Connect Biopharma Australia Pty Ltd )

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of CBP-174 after a single oral dose in healthy adult subjects.

Condition or disease	Intervention/treatment	Phase
Healthy Adult Subjects	Drug: CBP-174; Drug: Placebo	Phase 1

Detailed Description:

This is a randomized, double-blind, placebo-controlled, single ascending dose study in healthy subjects to evaluate the safety, tolerability and pharmacokinetics of CBP-174 compared to placebo. The study plans to set 6 dose escalation cohorts with single oral dose. Each subject will receive only one dose regimen in this study and the total duration to participate the study is approximately 1 to 4-week.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Healthy Subjects to Evaluate the Safety, Tolerability, and Pharmacokinetics of CBP-174 After Oral Administration
• Actual Study Start Date: May 24, 2021
• Actual Primary Completion Date: May 14, 2022
• Actual Study Completion Date: May 21, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: CBP-174; CBP-174 oral solution	Drug: CBP-174; CBP-174 oral solution, given once
Experimental: Placebo; placebo oral solution	Drug: Placebo; Placebo oral solution, given once

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events and serious adverse events [ Time Frame: Up to 7 days post dosing ]
   Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Dictionary.
2. Severity of adverse events and serious adverse events [ Time Frame: Up to 7 days post dosing ]
   The investigator may use the CTCAE V5.0 to assist in the determination of severity and clinical significance.
3. Change in blood pressure [ Time Frame: Up to 7 days post dosing ]
   Blood pressure measured in mmHg
4. Change in pulse rate [ Time Frame: Up to 7 days post dosing ]
   Pulse rate measured per minute
5. Change in respiratory rate [ Time Frame: Up to 7 days post dosing ]
   respiratory rate measured in breaths per minute
6. Change in tympanic temperature [ Time Frame: Up to 7 days post dosing ]
   tympanic temperature measured in celsius
7. Clinically significant abnormality in physical examinations [ Time Frame: Up to 7 days post dosing ]
   Physical examinations includes examination in cutaneous, lymph node, head (especially of eyes) and neck, chest, abdomen, musculoskeletal and nervous systems.
8. Clinically significant change in heart rate [ Time Frame: Up to 7 days post dosing ]
   Heart rate in beats per minute (Bpm) through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
9. Clinically significant change in RR interval [ Time Frame: Up to 7 days post dosing ]
   R-R interval measured in millisecond through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
10. Clinically significant change in PR interval [ Time Frame: Up to 7 days post dosing ]
    P-R interval measured in millisecond through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
11. Clinically significant change in QRS complex [ Time Frame: Up to 7 days post dosing ]
    QRS complex measured in millisecond through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
12. Clinically significant change in QT interval [ Time Frame: Up to 7 days post dosing ]
    QT interval measured in millisecond through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
13. Clinically significant change in Fridericia's Correction QT (QTcF) interval [ Time Frame: Up to 7 days post dosing ]
    QTcF interval measured in millisecond through 12-lead ECG assessment. The Investigator or designee will be responsible for review and interpretation of safety ECGs on site.
14. Clinically significant abnormal laboratory value in Total Protein (TB) [ Time Frame: Up to 7 days post dosing ]
    Measured in g/dL. The physician will judge whether an abnormality is clinically significant.
15. Clinically significant abnormal laboratory value in Albumin (ALB) [ Time Frame: Up to 7 days post dosing ]
    Measured in g/dL. The physician will judge whether an abnormality is clinically significant.
16. Clinically significant abnormal laboratory value in Alanine aminotransferase (ALT) [ Time Frame: Up to 7 days post dosing ]
    Measured in IU/L. The physician will judge whether an abnormality is clinically significant.
17. Clinically significant abnormal laboratory value in Aspartate aminotransferase (AST) [ Time Frame: Up to 7 days post dosing ]
    Measured in IU/L. The physician will judge whether an abnormality is clinically significant.
18. Clinically significant abnormal laboratory value in Alkaline phosphatase (ALP/AKP) [ Time Frame: Up to 7 days post dosing ]
    Measured in IU/L. The physician will judge whether an abnormality is clinically significant.
19. Clinically significant abnormal laboratory value in Glutamyl transpeptidase [ Time Frame: Up to 7 days post dosing ]
    Measured in U/L. The physician will judge whether an abnormality is clinically significant.
20. Clinically significant abnormal laboratory value in Total bilirubin [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
21. Clinically significant abnormal laboratory value in Direct Bilirubin [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
22. Clinically significant abnormal laboratory value in Indirect Bilirubin [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
23. Clinically significant abnormal laboratory value in Blood Glucose [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
24. Clinically significant abnormal laboratory value in Blood Urea [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
25. Clinically significant abnormal laboratory value in Blood Uric Acid [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
26. Clinically significant abnormal laboratory value in Blood Creatinine [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
27. Clinically significant abnormal laboratory value in Blood Creatine Kinase [ Time Frame: Up to 7 days post dosing ]
    Measured in IU/L. The physician will judge whether an abnormality is clinically significant.
28. Clinically significant abnormal laboratory value in Blood Potassium [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/dL. The physician will judge whether an abnormality is clinically significant.
29. Clinically significant abnormal laboratory value in Blood Sodium [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/dL. The physician will judge whether an abnormality is clinically significant.
30. Clinically significant abnormal laboratory value in Blood Chloride [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/dL. The physician will judge whether an abnormality is clinically significant.
31. Clinically significant abnormal laboratory value in Blood Calcium [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/dL. The physician will judge whether an abnormality is clinically significant.
32. Clinically significant abnormal laboratory value in Blood Total Cholesterol [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/L. The physician will judge whether an abnormality is clinically significant.
33. Clinically significant abnormal laboratory value in Blood Triglycerides [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/L. The physician will judge whether an abnormality is clinically significant.
34. Clinically significant abnormal change in Leukocyte Count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
35. Clinically significant abnormal change in Neutrophil count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
36. Clinically significant abnormal change in Lymphocyte count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
37. Clinically significant abnormal change in Monocytes count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
38. Clinically significant abnormal change in Eosinophils count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
39. Clinically significant abnormal change in Basophil count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
40. Clinically significant abnormal change in percentage of Neutrophil [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
41. Clinically significant abnormal change in percentage of Lymphocyte [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
42. Clinically significant abnormal change in percentage of Monocytes [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
43. Clinically significant abnormal change in percentage of Eosinophils [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
44. Clinically significant abnormal change in percentage of Basophils [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
45. Clinically significant abnormal change in Erythrocyte count [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
46. Clinically significant abnormal change in Hemoglobin [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
47. Clinically significant abnormal change in Hematocrit [ Time Frame: Up to 7 days post dosing ]
    Measured in %. The physician will judge whether an abnormality is clinically significant.
48. Clinically significant abnormal change in Platelets [ Time Frame: Up to 7 days post dosing ]
    Counted in K/uL. The physician will judge whether an abnormality is clinically significant.
49. Clinically significant abnormal finding in Urine Occult Blood [ Time Frame: Up to 7 days post dosing ]
    Urine Occult Blood will be record as positive or negative. The physician will judge whether an abnormality is clinically significant.
50. Clinically significant abnormal change in Urine Bilirubin [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
51. Clinically significant abnormal change in Urine pH [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
52. Clinically significant abnormal change in Urine Protein [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
53. Clinically significant abnormal change in Urine Glucose [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
54. Clinically significant abnormal change in Urine Specific gravity [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
55. Clinically significant abnormal change in Urine Ketones [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
56. Clinically significant abnormal change in Urobilinogen [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
57. Clinically significant abnormal change in Urinary leukocyte [ Time Frame: Up to 7 days post dosing ]
    Urinary leukocyte will be counted in K/uL. The physician will judge whether an abnormality is clinically significant.
58. Clinically significant abnormal change in Urine erythrocytes [ Time Frame: Up to 7 days post dosing ]
    Urine erythrocytes will be counted in K/uL. The physician will judge whether an abnormality is clinically significant.
59. Clinically significant abnormal change in Urine Nitrites [ Time Frame: Up to 7 days post dosing ]
    Measured in mg/dL. The physician will judge whether an abnormality is clinically significant.
60. Clinically significant abnormal change in Prothrombin time (PT) [ Time Frame: Up to 7 days post dosing ]
    Measured in seconds by coagulation tests. The physician will judge whether an abnormality is clinically significant.
61. Clinically significant abnormal change in Activated partial thromboplastin time (APTT) [ Time Frame: Up to 7 days post dosing ]
    Measured in seconds by coagulation tests. The physician will judge whether an abnormality is clinically significant.
62. Clinically significant abnormal change in International normalized ratio (INR) [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
63. Clinically significant abnormal change in Fibrinogen (FIB) [ Time Frame: Up to 7 days post dosing ]
    Measured in mmol/L. The physician will judge whether an abnormality is clinically significant.
64. Clinically significant abnormal change in Thrombin time (TT) [ Time Frame: Up to 7 days post dosing ]
    Measured in seconds by coagulation tests. The physician will judge whether an abnormality is clinically significant.
65. Clinically significant abnormal in Feces colour [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
66. Clinically significant abnormal in Feces properties [ Time Frame: Up to 7 days post dosing ]
    The physician will judge whether an abnormality is clinically significant.
67. Clinically significant abnormal in Fecal Red blood cell [ Time Frame: Up to 7 days post dosing ]
    Measured in Units. The physician will judge whether an abnormality is clinically significant.
68. Clinically significant abnormal in Fecal White blood cell [ Time Frame: Up to 7 days post dosing ]
    Measured in Units. The physician will judge whether an abnormality is clinically significant.
69. Clinically significant abnormal in Fecal Occult blood [ Time Frame: Up to 7 days post dosing ]
    Recorded as positive or negative. The physician will judge whether an abnormality is clinically significant.

Secondary Outcome Measures :

1. AUC0-72 h: Area under the plasma concentration-time curve of CBP-174 from time 0 to 72h [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
2. AUC0-∞: Area under the plasma concentration-time curve of CBP-174 from time 0 to infinity [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
3. Cmax: Maximum observed concentration [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
4. Tmax: Time to maximum concentration; [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
5. T1/2: Elimination half-life; [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
6. λz: Terminal phase rate constant; [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
7. CL/F: Apparent clearance; [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
8. V/F: Apparent Volume; [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)
9. %AUCex: Percentage of AUC0-∞ obtained by extrapolation [ Time Frame: Up to 72 hours post dosing ]
   Calculated by non-compartmental analysis with WinNonlin (Version 8.3.1 or above)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Subjects will be enrolled into the study only if they meet ALL of the following inclusion criteria:

1. Subjects are fully informed of the study, and are willing to participate in the study and sign the informed consent document prior to any procedure
2. Healthy male and female subjects, aged 18 to 55 years (both inclusive)
3. Body mass index is between 18 and 32 kg/m2 (both inclusive), the weight of male subjects ≥ 50 kg, the weight of female subjects ≥ 45 kg
4. Considered generally normal or abnormal with no clinical significance upon medical history, physical examination, vital signs, ECG, and clinical laboratory tests, as judged by the Investigator
5. Female subjects of child-bearing potential must agree to use highly effective contraceptive methods 1 month before the screening, during the entire study, and within 3 months after the end of this study, and have no egg donation plan within 3 months of study end. The male partner of a female subject must agree to use condoms during the screening, entire study, and within 3 months after the end of this study. Male subjects considered fertile must agree to not plan to father a child, donate sperm, and take effective contraceptive methods during the screening, entire study, and within 3 months after the end of this study. The female partner of male subjects must agree to use a highly effective method of female contraception (Section 9.8.3.2) during the screening, entire study, and within 3 months after the end of this study. Contraceptive requirements applies to subjects in same sex relationships for male and female subjects, female subjects of non child bearing potential or male subjects with female partners of non-childbearing potential.
6. Subjects who are able to communicate well with Investigators, as well as understand and adhere to the requirements of this study

Exclusion Criteria:

Subjects will be excluded from the study, if they meet ANY of the following criteria:

Subjects will be excluded from the study, if they meet ANY of the following criteria:

1. Subjects who have difficulties in venous blood collection or history of dizziness with blood or needles
2. Female subjects who have a positive pregnancy test or are breastfeeding
3. Subjects who have allergy/hypersensitivity history to any excipient of CBP-174 solution, or hypersensitivity to antihistamines, or severe allergies at the discretion of Investigator
4. Exposure to any other investigational medicinal product or any other clinical trial within 30 days or 5 times half-lives (whichever is longer) before dosing current study medication
5. Subjects who have a history of gastrointestinal (such as duodenal ulcer, alimentary tract hemorrhage, etc.), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs
6. Subjects who have a history of significant eye diseases (such as keratitis, and scleritis, etc.) or clinical significant eye signs (conjunctiva hyperemia, etc.)
7. Subjects who have a history of attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD)

8. Subjects who have a history of sleep disorders within 2 years before the screening visit or score highly on the PSQI or ISI questionaire; or have a history of epilepsy or other seizure disorder

   *Pittsburgh Sleep Quality Index (PSQI) ≥ 8 or Insomnia Severity Index (ISI) ≥ 8

9. Subjects who have the medical history of other significant diseases (including but not limited to pulmonary, cardiovascular, gastrointestinal, hematological endocrinological, immunological, dermatological, malignant diseases, mental and nervous systems, and other related diseases) or any other disease/ailment at the discretion of the Investigator

10. Subjects with any of the following clinical laboratory tests results at screening:

    a Aspartate aminotransferase (AST) > 1.5 × the upper limit of normal (ULN)

    b Alanine aminotransferase (ALT) > 1.5 × ULN

    c Serum creatinine > 1.2 × ULN; or creatinine clearance < 60 mL/min (calculated by the Cockcroft-Gault)

    *The clinical laboratory tests of hematology, blood biochemistry, or urinalysis could be allowed repeat once if Investigator considers it necessary

11. Subjects whose QTcF interval prolongation at screening (male: QTcF interval ≥ 450 ms, female: QTcF interval ≥ 470 ms)
12. Blood donation or blood loss more than 400 mL within 3 months before the screening visit
13. Subjects with a known history of drug abuse within 2 years before the screening visit; or positive drug abuse at screening
14. Weekly alcohol consumption of more than 14 units of alcohol (1 unit of alcohol = 360 mL of beer or 45 mL of spirit with the alcohol content of 40% or 150 mL of wine) in any week within the past 3 months before the screening visit; or intake of alcohol-containing products within 48 hours before the first dose, or cannot abstain from any alcohol product during the study, or positive breath alcohol test at screening or check-in (Day -1）
15. Smoking history (> 5 cigarettes per day) within 3 months before the screening visit, or cannot abstain from any tobacco products during the study, or positive urine nicotine test before randomization
16. Excessive drinking of tea, coffee, or caffeine-containing beverage (at least 8 cups per day, 1 cup = 250 mL) any day within 3 months before screening; intake of rich caffeine- or xanthine-containing food or drinks that may produce caffeine or xanthine after being metabolized (eg, coffee, tea, chocolate, cola drinks) within 48 hours before the first dose
17. Any marketed medication (prescription and nonprescription drugs) within 14 days before the first dose or within 5 times the elimination half-life or pharmacodynamic half-life of the medication (excluding oral contraceptives and low dose paracetamol at the discretion of the Investigator, or topical ointments at the discretion of the Investigator)
18. Administration of a Coronavirus Disease 2019 (COVID-19) vaccine in the past 14 days prior to dosing
19. Use of herbal medicines, dietary supplements and vitamin within 14 days before the first dose(permissible at the discretion of the Investigator)
20. Subjects who have a major surgery within 3 months before the first dose or who plan to undergo surgery during the study
21. Positive screening test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody
22. Subjects who are determined as not eligible to participate in this study by the Investigator

Contacts and Locations

Locations

Australia, Victoria

Nucleus Network Pty Ltd

Melbourne, Victoria, Australia, 3004

Sponsors and Collaborators

Connect Biopharma Australia Pty Ltd

Investigators

• Study Director: Australia Connect; Connect Biopharma Australia Pty Ltd
• Study Director: Suzhou Connect; Suzhou Connect Biopharmaceuticals, Ltd.

More Information

• Responsible Party: Connect Biopharma Australia Pty Ltd
• ClinicalTrials.gov Identifier: NCT04811469
• Other Study ID Numbers: CBP-174AU001
• First Posted: March 23, 2021
• Last Update Posted: August 10, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No