Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624001134516p
Ethics application status
Submitted, not yet approved
Date submitted
3/09/2024
Date registered
19/09/2024
Date last updated
19/09/2024
Date data sharing statement initially provided
19/09/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
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
Scientific title
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
Secondary ID [1] 312642 0
MRX-4TZT-04
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spasticity 334608 0
Condition category
Condition code
Neurological 331194 331194 0 0
Other neurological disorders
Musculoskeletal 331527 331527 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 329161 0
Treatment: Drugs
Comparator / control treatment
Tizanidine hydrochloride (HCl) capsules (Zanaflex® or generic equivalent) will be administered to all study participants (Cohorts 1 and 2) in Period 1 at the following dose levels:
3 x 2 mg (1 capsule x 2 mg) oral tizanidine (total dose of 6 mg) will be administered on Day 1
3 x 8 mg (2 capsules x 4 mg) oral tizanidine (total dose of 24 mg/day) will be administered on Day 2
Control group
Dose comparison

Outcomes
Primary outcome [1] 338959 0
To investigate the PK parameters of tizanidine administered as 2 dose levels of oral tizanidine (reference regimen) in healthy adult volunteers. (Period 1)
Timepoint [1] 338959 0
Blood plasma will be assessed in Period 1 on Day 1 pre-dose, 0.5, 1, 1.5, 2 and 3 hrs post-dose, pre-second dose, 0.5, 1, 1.5, 2 and 3 hrs post-second dose, pre-third dose, 0.5, 1, 1.5, 2 and 3 hrs post-third dose, Day 2 pre-dose, 0.5, 1, 1.5, 2 and 3 hrs post-dose, pre-second dose, 0.5, 1, 1.5, 2 and 3 hrs post-second dose, pre-third dose, 0.5, 1, 1.5, 2 and 3 hrs post-third dose.
Primary outcome [2] 339162 0
To investigate the Pharmacokinetic (PK) parameters of tizanidine administered as MRX-4TZT TDS (60 cm2 and 90 cm2 containing 24 mg and 36 mg of tizanidine as the drug adhesive layer, respectively) following once daily 24 hour application for 3 days (test regimens) in healthy adult volunteers. (Period 2)
Timepoint [2] 339162 0
Blood plasma will be assessed in Period 2 on Day 1 pre-dose, 6, 12 and 18 hrs post-dose, Day 2 pre-second dose, 6, 12 and 18 hrs post-second dose, Day 2 pre-third dose, 6, 12 and 18 hrs post-third dose, Day 4 pre-TDS Removal, 6, 12 and 18 hrs post-TDS Removal, Day 5 24 hrs post-TDS Removal.
Secondary outcome [1] 438030 0
To monitor dermal irritancy of MRX-4TZT TDS in healthy adult subjects.
Timepoint [1] 438030 0
Assessments as per the FDA Draft Guidance for Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs (FDA 2023) will be conducted at 30 minutes and 24 hours after removal of the TDS.
Secondary outcome [2] 438031 0
To assess the dermal adhesion of MRX-4TZT TDS in healthy adult subjects.
Timepoint [2] 438031 0
Adhesion of the TDS as per FDA Draft Guidance “Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs Guidance for Industry” 2023 are to be evaluated at 4, 8, 12, 16, 20, 24 hours post MRX-4TZT TDS application on Days 1, 2 and 3 in Period 2. A photograph is to be taken at each assessment timepoint.
Secondary outcome [3] 438032 0
Composite Outcome:
To evaluate the safety and tolerability of 2 TDS sizes of MRX-4TZT TDS following once daily 24-hour application for 3 days (test regimens) and 2 dose levels of oral tizanidine capsules (reference regimen) in healthy adult volunteers.
Timepoint [3] 438032 0
Composite Outcome Timepoint:
Adverse events will be graded using 'mild', 'moderate' and 'severe' categories and assessed continuously as they are reported or observed and reviewed daily from Day -1 until Day 10 End of Study/Early Termination Visit (EoS/ETV).

Local Tolerability will be assessed as per the FDA Draft Guidance for Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs (FDA 2023) will be conducted at 30 minutes and 24 hours after removal of the TDS in Period 2.

Physical examinations will include, at a minimum, assessment of the following: general appearance, head, ears, eyes, nose and throat, neck (including thyroid and lymph nodes) respiratory system, cardiovascular system, gastrointestinal system, renal system, neurological condition, musculoskeletal system, skin and assessed at Screening, Day -1, then conducted as necessary in the presence of specific symptoms on Day 1 to Day 10 End of Study/Early Termination Visit (EoS/ETV).

Clinical laboratory evaluations - blood and urine samples will be collected from Screening, Day -1, pre-first dose Day 2, Day 3 in Period 1, then Period 2 -24 hrs pre-dose Day 1, pre-dose Day 2, pre-dose Day 3, Day 4, Day 5 and Day 10 End of Study/Early Termination Visit (EoS/ETV).

Vital signs - Blood pressure and heart rate is measured using sphygmomanometer, respiratory rate by manual breath count, oxygen saturation by oximeter and temperature by thermometer. Period 1 assessed at Screening, Day -1, pre-dose Day 1 post-dose, pre-second dose Day 2 post-second dose, Day 3. Period 2 pre and post MRX-4TZT TDS application on Day -1, Day 1, 2 and 3, Day 4, Day 5 and Day 10 End of Study/Early Termination Visit (EoS/ETV).

ECG completed at Period 1 Screening, Day -1, pre-dose Day 1, pre-second dose Day 2, Day 3. Period 2 Day -1, pre and post MRX-4TZT TDS application on Day -1, Day 1, 2 and 3, Day 5 and Day 10 End of Study/Early Termination Visit (EoS/ETV).

Sedation will be assessed with the 7 point Stanford Sleepiness Scale a self reporting questionnaire and is to be assessed pre-dose and at 2, 6, 10, 12, 24 hours after the first dose of study drugs each day (Period 1: Day 1 and Day 2; Period 2: Day 1, Day 2, Day 3).

Suicidal thoughts and behaviours will be captured using the Columbia Suicide Severity Rating Scale (C-SSRS) and is to be administered at Screening, check-in (Day -1; Period 1 and 2), and prior to discharge from the clinical site on Day 3 (Period 1) and Day 5 (Period 2).

Eligibility
Key inclusion criteria
1. 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.
2. 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.
3. Adult males and females, 18 to 55 years of age (inclusive) at screening.
4. 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.
5. 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.
6. 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.
7. 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.
8. Have suitable bilateral venous access for blood sampling.
9. Willing and able to comply with all study assessments and adhere to the protocol schedule and restrictions.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known hypersensitivity to the study drug or any of the study drug ingredients.
2. 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.
3. Previous history of unexplained syncope or orthostatic hypotension.
4. 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).
5. History of passive or active suicidal ideation as judged by the PI (or delegate) using the Columbia-Suicide Severity Rating Scale (C-SSRS).
6. 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.
7. History of major surgery or hospitalization within 3 months prior to screening, or surgery planned during the study.
8. Any history of malignant disease in the last 10 years (excludes surgically resected skin squamous cell or basal cell carcinoma).
9. Presence of clinically relevant immunosuppression from, but not limited to, immunodeficiency conditions such as common variable hypogammaglobulinemia.
10. History of risk factors for torsade de pointes (including a family history of long QT syndrome or sudden cardiac death) or a known arrythmia.
11. 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.
12. 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.
13. 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.
14. 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).
15. 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.
16. History of substance use disorder.
17. 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.
18. 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]).
19. Females who are breastfeeding or planning to breastfeed.
20. Females who are using hormonal forms of contraception in form of oral or implant (hormonal intrauterine device [IUD] is permitted).
21. 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.
22. 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.
23. Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medication within 10 days prior to study drug administration.
24. Unwillingness or inability to refrain from receiving a vaccine both 28 days prior to and 28 days after study drug administration.
25. 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.
26. 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.
27. History of suspected or confirmed diagnosis of sleep apnoea.
28. History of contact dermatitis to adhesives, tapes, bandages or patches.
29. 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All study subjects who sign an informed consent form (ICF) will receive a unique sequential number (i.e., a screening number). Subjects who meet the study eligibility criteria will be assigned a randomization number pre-dose on Day 1, which corresponds to a study treatment (Cohort 1: 24 mg MRX-4TZT TDS or Cohort 2: 36 mg MRX-4TZT TDS).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation to Cohort 1: 24 mg MRX-4TZT TDS or Cohort 2: 36 mg MRX-4TZT TDS will be performed using a block randomization algorithm and will be documented in the study randomization schedule.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Given the nature of Phase I trials and the absence of formal statistical comparison between treatment groups, the sample size was selected to ensure adequate representation to support the analysis of PK parameters, safety and tolerability of the tizanidine oral administration compared to MRX-4TZT TDS administration. The planned sample size of 24 subjects (with 12 assigned to each treatment cohort) is considered adequate to evaluate all study endpoints.

The Full Analysis Set (FAS) will include all randomized subjects, where subjects will be categorized according to the treatment they were randomized to, regardless of which treatment the subjects actually received.

The Safety Analysis Set (SAS) will include all subjects who receive at least 1 dose of study drug (MRX-4TZT TDS or oral tizanidine). Subjects will be analysed according to treatment received.

The PK Analysis Set (PKAS) will include all subjects in the Safety Analysis Set (SAS) who have sufficient post-dose data to be able to reliably determine at least one PK parameter. Subjects will be analysed according to treatment received. Refer to the SAP for rules of exclusion of subjects from the PK analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/09/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 27045 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 43114 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 317075 0
Commercial sector/Industry
Name [1] 317075 0
MEDRx Australia Pty Ltd
Country [1] 317075 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
MEDRx Australia Pty Ltd
Address
Country
Australia
Secondary sponsor category [1] 319326 0
None
Name [1] 319326 0
Address [1] 319326 0
Country [1] 319326 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315826 0
Bellberry Human Research Ethics Committee A
Ethics committee address [1] 315826 0
Ethics committee country [1] 315826 0
Australia
Date submitted for ethics approval [1] 315826 0
07/08/2024
Approval date [1] 315826 0
Ethics approval number [1] 315826 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135922 0
Dr Tony Le
Address 135922 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 135922 0
Australia
Phone 135922 0
+61 0449 044 697
Fax 135922 0
Email 135922 0
[email protected]
Contact person for public queries
Name 135923 0
Tony Le
Address 135923 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 135923 0
Australia
Phone 135923 0
+61 0449 044 697
Fax 135923 0
Email 135923 0
[email protected]
Contact person for scientific queries
Name 135924 0
Tony Le
Address 135924 0
CMAX Clinical Research Pty Ltd, Ground Floor, 21-24 North Terrace, Adelaide, South Australia, 5000
Country 135924 0
Australia
Phone 135924 0
+61 0449 044 697
Fax 135924 0
Email 135924 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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