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

NCT02943213 | Completed Phase 1 Results

• 2 other identifiers: CT-004PXL231486
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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%

Conditions

Anti-Psychotic; Management of Manifestations of Psychotic Disorders; Treatment of Schizophrenia; Control Nausea and Vomiting; Relief of Restlessness and Apprehension Before Surgery; Acute Intermittent Porphyria; Adjunct in the Treatment of Tetanus; Control Manifestations of the Manic Type of Mani-depressive Illness; Relief of Intractable Hiccups

Keywords

Chlorpromazine; Hydrochloride; Chlorpromazine Hydrochloride; Bioavailability; Variability; Variable; Absorption; USL Pharma; USL; Healthy; South Africa; Cycle; Anti-Psychotic

Outcome Measures

Primary Outcomes (6)

• Maximum Observed Plasma Concentration (Cmax) - Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Maximum Observed Plasma Concentration (Cmax) - 7-Hydroxy-Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Area Under the Plasma Concentration Versus Time Curve, From Time Zero to t, Where t is the Time of the Last Quantifiable Concentration (AUC(0-t)) - Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Area Under the Plasma Concentration Versus Time Curve, From Time Zero to t, Where t is the Time of the Last Quantifiable Concentration (AUC(0-t)) - 7-Hydroxy-Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞)) - Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Area Under the Plasma Concentration Versus Time Curve, With Extrapolation to Infinity (AUC(0-∞)) - 7-Hydroxy-Chlorpromazine

  Time Frame = sampling times.

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

Secondary Outcomes (6)

• Time to Maximum Observed Plasma Concentration (Tmax) - Chlorpromazine

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Time to Maximum Observed Plasma Concentration (Tmax) - 7-Hydroxy-Chlorpromazine

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Terminal Elimination Rate Constant (λz) - Chlorpromazine

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Terminal Elimination Rate Constant (λz) - 7-Hydroxy-Chlorpromazine

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

• Apparent Terminal Elimination Half-life (t1/2) - Chlorpromazine

  0, 0.5, 1, 1.3, 1.6, 2, 2.5, 3, 4, 5, 6, 9, 12, 16, 24, 36, 48, 72 and 96 hours

Study Arms (2)

Treatment Period 1

EXPERIMENTAL

First dosing period in which all enrolled subjects are administered a single dose of 25 mg Chlorpromazine Hydrochloride Tablet.

Drug: Chlorpromazine Hydrochloride

Treatment Period 2

EXPERIMENTAL

Second dosing period in which all enrolled subjects are administered a single dose of 25 mg Chlorpromazine Hydrochloride Tablet.

Drug: Chlorpromazine Hydrochloride

Interventions

Chlorpromazine Hydrochloride DRUG

Chlorpromazine Hydrochloride (25 mg Tablet) - Generic US Applicant holder is USL Pharma Inc.

Also known as: Trade name: Chlorpromazine Hydrochloride 25 mg Tablets, USP

Treatment Period 1; Treatment Period 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy males and females, 18 to 65 years (both inclusive) at signing of informed consent.
• Body Mass Index (BMI) between 18.5 and 30 kg/m2 (both inclusive).
• Body mass not less than 50 kg.
• 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.
• Non-smokers.
• 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.
• 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.
• Written consent given for participation in the study.

You may not qualify if:

• 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.
• Current alcohol use \> 21 units of alcohol per week for males and \> 14 units of alcohol per week for females.
• Consumption of more than 5 cups of coffee (or equivalent amounts of caffeine) per day.
• Regular exposure to substances of abuse (other than alcohol) within the past year.
• 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.
• 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.
• 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.
• A major illness during the 3 months before commencement of the screening period.
• History of hypersensitivity or allergy to the IMP or its excipients or any related medication including phenothiazines or other anti-psychotics or anti-emetics.
• History of extrapyramidal symptoms.
• History of liver or renal dysfunction, epilepsy, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostate hypertrophy.
• Familial history of deep vein thrombosis.
• Hereditary problems of galactose intolerance, Lapp lactase deficiency.
• History of QT prolongation or signs of QT prolongation on ECG.

Sponsors & Collaborators

• Cycle Pharmaceuticals Ltd.: lead
• Parexel: collaborator

Study Sites (1)

Farmovs Parexel

Bloemfontein, Kampuslaan Suid, 9300, South Africa

Location

MeSH Terms

Conditions

Vomiting; Porphyria, Acute Intermittent

Interventions

Chlorpromazine; Tablets

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Porphyrias, Hepatic; Liver Diseases; Digestive System Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases; Skin and Connective Tissue Diseases; Porphyrias; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: James Price
• Organization: Cycle Pharmaceuticals Ltd

james.price@cyclepharma.com

+44 1223 803638

Study Officials

• Dr. Yolandi Swart, FCPHM(SA)

  Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2016
• First Posted: October 24, 2016
• Study Start: November 1, 2016
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: November 14, 2017
• Results First Posted: October 13, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)