TerminatedPhase 1ACTRN12624001134516

Comparative, Multiple-Dose, Fixed Sequence, Pharmacokinetic Study of 2 Sizes of Daily MRX-4TZT TDS (Tizanidine Transdermal Delivery System) Applied for 3 Days and 2 Dose Levels of Oral Tizanidine in Healthy Adult Subjects

Sponsor

MEDRx Australia Pty Ltd

Enrollment

24 participants

Start Date

Oct 18, 2024

Study Type

Interventional

Conditions

Spasticity

Summary

In this project, we will be exploring the safety, tolerability and Pharmacokinetics of Tizanidine, comparing the oral capsule with a transdermal patch. Oral Tizanidine is currently approved for use for the management of spasticity in the United States, it is not approved for use in Australia by the Australian TGA. Oral Tizanidine is a short-acting muscle relaxant and is rapidly metabolised by the liver requiring daily dosing. The sponsor company has developed a transdermal patch to deliver Tizanidine in an attempt to improve patient compliance and reduce side effects of the medication. Who is it for? You may be eligible for this study if you are aged 18 to 55 years and are in good general health without a clinically significant medical history. Study details All healthy volunteer participants who choose to enrol in this study will be assigned by chance to receive 2 of the 3 treatments in a fixed sequence (reference regimen for 2 days in Period 1 then 1 of 2 test regimens for 3 days in Period 2). All participants will have their vital signs checked (heart rate, blood pressure, temperature, etc), and will provide blood and urine samples for testing. It is hoped this research will determine that doses of MRX-4TZT can be administered continuously and consistently via a transdermal patch safely without causing severe reactions.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 55 Yearss

Inclusion Criteria28

Must have given written informed consent before any study-related activities are performed and must be able to understand the full nature and purpose of the study, including possible risks and adverse effects.
Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dose and throughout the study, based on subject self-reporting.
Adult males and females, 18 to 55 years of age (inclusive) at screening.
Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 32.0 kg/m2, with a body weight greater than 50 kg and less than 120 kg at screening.
Medically healthy (in the opinion of the PI or delegate), as determined by pre-study medical history, and without clinically significant (CS) abnormalities including the following:
a. Physical examination without any CS findings.
b. Systolic blood pressure (BP) in the range of 100 to 160 mmHg and diastolic BP in the range of 50 to 95 mmHg after resting for 5 minutes in a seated position.
c. Pulse rate in the range of 45 to 100 bpm after 5 minutes resting in a seated position.
d. No evidence of positive orthostatic vital signs, within 3 minutes of standing from a seated position; positive orthostatic vital signs are indicated by:
i. Decrease in systolic BP greater than or equal to 20 mmHg; or
ii. Decrease in diastolic BP greater than or equal to 10 mmHg; or
iii. Increase in pulse rate greater than or equal to 30 bpm; or
iv. positive symptoms with position change including light headedness, dizziness, blurred vision, weakness, nausea, palpitations, and syncope.
e. Body temperature (tympanic or infrared), between 35.5°C and 37.7°C.
f. Electrocardiogram (ECG) without CS abnormalities including QT interval corrected using Fridericia’s formula (QTcF) <450 msec for male subjects and <470 msec for female subjects.
g. No CS findings in clinical chemistry, haematology, coagulation, and urinalysis tests.
Female volunteers:
a. Must be of non-child-bearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy) at least 6 weeks before the screening visit or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or
b. If of child-bearing potential, must:
i. Have a negative pregnancy test at the screening visit and on admission to the study site on Day-1.
ii. Agree not to attempt to become pregnant or donate ova from signing the consent form until at 30 days after the last dose of study drug.
iii. Agree to use adequate contraception (defined as use of a condom by the male partner combined with use of a highly effective method of contraception, noting that hormonal contraception in the form of oral or implant is not permitted as a form of birth control for this study) from one month prior to screening until at least 30 days after the last dose of study drug, if not exclusively in a same-sex relationship or abstinent as a committed lifestyle.
Male volunteers, must:
a. Agree not to donate sperm from signing the consent form until at least 90 days after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, agree to use adequate contraception (defined as use of a condom combined with use of a highly effective method of contraception) from signing the consent form until at least 90 days after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, agree to use a condom from signing the consent form until at least 90 days after the last dose of study drug.
Have suitable bilateral venous access for blood sampling.
Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.

Exclusion Criteria33

Known hypersensitivity to the study drug or any of the study drug ingredients.
History of anaphylaxis or other significant allergy which, in the opinion of the PI (or delegate), would interfere with the volunteer’s ability to participate in the study.
Previous history of unexplained syncope or orthostatic hypotension.
Current or past history of mental illness such as anxiety, depression, schizophrenia or other psychotic disorders. Subjects with a history of mild anxiety or depression, not requiring medication or hospitalization, and not within the past 5 years, may be included at the discretion of the PI (or delegate).
History of passive or active suicidal ideation as judged by the PI (or delegate) using the Columbia-Suicide Severity Rating Scale (C-SSRS).
History or presence of CS cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal (GI), endocrine, immunologic, dermatologic, psychiatric, or neurological disease/disorder, including any acute illness, within the past 3 months determined by the PI (or delegate) to be clinically relevant. Note: history of childhood asthma (resolved) and occasional migraine are permitted.
History of major surgery or hospitalization within 3 months prior to screening, or surgery planned during the study.
Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
Presence or having sequelae of GI, liver (including Gilbert’s syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Note: history of cholecystectomy is permitted.
Liver function test results elevated >1.5-fold above the ULN for gamma glutamyl transferase, bilirubin (total), ALP, AST or ALT at screening or Day -1. Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the PI (or delegate), if the levels are unaccompanied by clinical signs and are determined to be normal variants.
Haemoglobin <115 g/L for females and <125 g/L for males or haematocrit outside the upper or lower limits of the normal range per reference laboratory at both Screening and Day -1.
Subjects with history or pre-existing renal disease, as defined below:
a. Estimated glomerular filtration rate (eGFR) <80 mL/min/1.73 m2 at Screening and Day -1 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula). Note: one retest of the exclusionary eGFR value is allowed at the discretion of the PI (or delegate).
A history of, or positive test results for human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
History of substance use disorder.
Positive drugs of abuse test, cotinine test or alcohol breath test results at the screening visit and/or on admission to the study site on Day -1.
Regular consumption of more than 10 standard alcoholic drinks/week, where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], or 30 mL spirit [40% Alc/Vol]).
Females who are breastfeeding or planning to breastfeed.
Females who are using hormonal forms of contraception in form of oral or implant (hormonal intrauterine device [IUD] is permitted).
Presence or evidence of a skin condition, excessive hair at the application sites, scar tissue, tattoos, open sores, recent sunburn, or body piercing that in the opinion of the PI (or delegate) would interfere with the placement of the TDS or evaluation of the subject’s response to the study drug/TDS.
Unable to refrain from or anticipates the use of:
a. Any drug, including prescription and non-prescription medications, herbal remedies, vitamin supplements, or dietary supplements, beginning 7 days prior to the first dose and throughout the study. Exceptions during the screening period include the use of paracetamol (up to 2 g per day) for no more than 3 consecutive days, use of ibuprofen (up to 1.2 g per day) for no more than 3 consecutive days and the use of contraceptives for female subjects of childbearing potential (noting oral/implant hormonal contraceptives are not permitted).
b. Any drugs known to be significant inhibitors of CYP1A2 enzymes and/or P glycoprotein (P gp) and/or organic anion transporting polypeptide for 14 days prior to the first dose and throughout the study. Appropriate sources (e.g., Flockhart Table) will be consulted to confirm lack of potential PK/PD interaction with study drug.
c. Any drugs known to be significant inducers of CYP1A2 enzymes and/or P gp, including St. John’s Wort, for 28 days prior to the first dose and throughout the study. Appropriate sources (e.g., Flockhart Table) will be consulted to confirm lack of PK/PD interaction with study drug.
Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to study drug administration.
Unwillingness or inability to refrain from receiving a vaccine both 28 days prior to and 28 days after study drug administration.
Donation of blood or plasma within 30 days prior to study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to study drug administration, or receipt of a blood transfusion within 1 year of study drug administration.
Participation in another clinical study of an investigational drug or investigational device within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to screening.
History of suspected or confirmed diagnosis of sleep apnoea.
History of contact dermatitis to adhesives, tapes, bandages or patches.
Any other condition or prior therapy that in the opinion of the PI (or delegate) would make the volunteer unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

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Interventions

This is an open-label, fixed-sequence, 2-period, 3-treatment, adhesion and PK study. to be conducted at a single site. Healthy adult volunteers will be enrolled and randomized to 2 cohorts in which they will receive 2 of the 3 treatments in a fixed sequence, consisting of reference regimen for 2 days in Period 1 followed by 1 of 2 test regimens for 3 days in Period 2. In Period 1 (reference regimen), all healthy volunteers (Cohorts 1 and 2) will receive multiple oral doses of tizanidine capsules 2 mg administered 3 times daily (at 4 hourly intervals; total dose 6mg/day) on Day 1, and 8 mg administered 3 times daily (at 4 hourly intervals; total dose 24 mg/day) on Day 2. There will be a washout period of at least 5 days between the last study drug administration in Period 1 (oral tizanidine) and first study drug administration in Period 2 (MRX-4TZT TDS). In Period 2 (test regimens), healthy volunteers will be randomised to receive 1 of the 2 test regimens as multiple 24-hour applications of MRX-4TZT transdermal delivery system (TDS). The TDS will be applied daily (24 hourly intervals) for 3 days on Days 1 to 3. The TDS will be applied to intact skin on the upper arm or upper back and will be administered at the following dose levels: Cohort 1: 24 mg tizanidine (60 cm2 TDS containing 24 mg of tizanidine as the drug adhesive layer)) Cohort 2: 36 mg tizanidine (90 cm2 TDS containing 36 mg of tizanidine as the drug adhesive layer) Study site staff will administer the study drug only to healthy volunteers enrolled and randomised in this study and will be verified by a second staff member and recorded in the appropriate drug accountability records and the subjects eCRF.