Assessment of Intra-subject Variability in the Bioavailability of Chlorpromazine Hydrochloride

A Single Center, Single Dose, Open-Label, Two-Period Replicate Pilot Study to Investigate Intra-subject Variability in the Bioavailability of a Formulation Containing Chlorpromazine Hydrochloride (25 mg Sugar Coated Tablets) in at Least 16 Healthy Males and Females Under Fasting Conditions

Cycle Pharmaceuticals Ltd. (Cycle) is developing an oral tablet formulation of Chlorpromazine Hydrochloride and intends to conduct bioequivalence trials to demonstrate its similarity to the RLD.

The aim of this pilot study is to investigate intrasubject variability in the bioavailability of Chlorpromazine Hydrochloride 25 mg sugar coated tablets.

Cycle aims to demonstrate that Chlorpromazine Hydrochloride has a shallow dose response curve and a wide safety margin. This will then allow for the modification of bioequivalence acceptance criteria in future pivotal studies which will reduce the number of participants required whilst still maintaining assurance of safety and efficacy.

Pilot Subjects (n): 20 Periods: 2 (2xR) Dosing: Single-dose Strength: 25 mg Test Product: N/A Reference: USL PHARMA Chlorpromazine Hydrochloride Analytes (in plasma): Chlorpromazine; 7-Hydroxychlorpromazine Bioequivalence based on 90% CI (Cmax, AUC): Standard; 80.00 - 125.00%

This will be a single-dose, open-label, two-period replicate pilot study with orally administered chlorpromazine hydrochloride 25 mg (sugar coated tablets) conducted under fasting conditions in at least 16 healthy male and female subjects at a single study center.

Up to 20 eligible subjects will be enrolled in the study with 16 evaluable subjects to complete the study.

Analytes to be measured will be Chlorpromazine and 7-hydroxy-Chlorpromazine (free) as stipulated by FDA Guidance for assessment of bioequivalence for Chlorpromazine.

Inclusion Criteria:

1. Healthy males and females, 18 to 65 years (both inclusive) at signing of informed consent.

2. Body Mass Index (BMI) between 18.5 and 30 kg/m2 (both inclusive).

3. Body mass not less than 50 kg.

4. Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations must be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the investigator considers the deviation to be irrelevant for the purpose of the study.

5. Non-smokers.

6. Females, if:

   • Not of childbearing potential, e.g., has been surgically sterilized, undergone a hysterectomy, amenorrhea for ≥ 12 months and considered post-menopausal, Note: In postmenopausal women, the value of the serum pregnancy test may be slightly increased. This test will be repeated to confirm the results. If there is no increase indicative of pregnancy, the female will be included in the study.

   OR

   • Of childbearing potential, the following conditions are to be met:
   • Negative pregnancy test
   • If this test is positive, the subject will be excluded from the study. In the rare circumstance that a pregnancy is discovered after the subject received IMP, every attempt must be made to follow her to term.
   • Not lactating
   • Abstaining from sexual activity (if this is the usual lifestyle of the subject) or must agree to use an accepted method of contraception, and agree to continue with the same method throughout the study. Examples of reliable methods of contraception include non-hormonal intrauterine device, and barrier methods combined with an additional contraceptive method.

   In this study the concomitant use of hormonal contraceptives is NOT allowed. Other methods, if considered by the investigator as reliable, will be accepted.

7. Written consent given for participation in the study.

Exclusion Criteria:

1. Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements.

2. Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol per week for females.

3. Consumption of more than 5 cups of coffee (or equivalent amounts of caffeine) per day.

4. Regular exposure to substances of abuse (other than alcohol) within the past year.

5. Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks before the first administration of IMP except if this will not affect the outcome of the study in the opinion of the investigator.

   In this study the concomitant use of hormonal contraceptives is NOT allowed.

6. Participation in another study with an experimental drug, where the last administration of the previous IMP was within 8 weeks (or within 10 elimination half-lives for chemical entities or 2 elimination half-lives for antibodies or insulin), whichever is the longer) before administration of IMP in this study, at the discretion of the investigator.

7. Treatment within the previous 3 months before the first administration of IMP with any drug with a well-defined potential for adversely affecting a major organ or system.

8. A major illness during the 3 months before commencement of the screening period.

9. History of hypersensitivity or allergy to the IMP or its excipients or any related medication including phenothiazines or other anti-psychotics or anti-emetics.

10. History of extrapyramidal symptoms.

11. History of liver or renal dysfunction, epilepsy, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostate hypertrophy.

12. Familial history of deep vein thrombosis.

13. Hereditary problems of galactose intolerance, Lapp lactase deficiency.

14. History of QT prolongation or signs of QT prolongation on ECG.

15. History of bronchial asthma or any other bronchospastic disease.

16. History of convulsions.

17. History of porphyria.

18. Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome.

19. Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of IMP.

20. Diagnosis of hypotension made during the screening period.

21. Diagnosis of hypertension made during the screening period or current diagnosis of hypertension.

22. Resting pulse of > 100 beats per minute or < 40 beats per minute during the screening period, either supine or standing.

23. Positive testing for HIV and Hepatitis B and Hepatitis C.

24. Positive urine screen for drugs of abuse. In case of a positive result the urine screen for drugs of abuse may be repeated once at the discretion of the investigator.

25. Positive urine screen for tobacco use.

26. Female subjects that are pregnant (positive pregnancy test) or breastfeeding.

27. Difficulty in swallowing.

28. Any specific investigational product safety concern.

29. Vulnerable subjects, e.g., persons in detention.