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Trial registered on ANZCTR


Registration number
ACTRN12622001391763
Ethics application status
Approved
Date submitted
13/10/2022
Date registered
31/10/2022
Date last updated
7/07/2023
Date data sharing statement initially provided
31/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparative Bioavailability of Smartech 2% Sodium Diclofenac Topical Solution and PENNSAID 2% Applied to the Knees of Healthy Male and Female Subjects
Scientific title
Comparative Bioavailability, Pharmacokinetics, Safety and Tolerability of Smartech 2% Sodium Diclofenac Topical Solution and PENNSAID 2% Applied to the Knees of Healthy Male and Female Subjects
Secondary ID [1] 308072 0
SMTPK001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthritis 327766 0
Condition category
Condition code
Musculoskeletal 324835 324835 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, open-label, multiple-dose, 2-period crossover study in up to 32 subjects to evaluate the Pharmacokinetics (PK) and bioavailability of Smartech (diclofenac sodium topical solution) compared to PENNSAID® (diclofenac sodium topical solution) 2% w/w in healthy males and females. Each treatment will be applied twice daily for 7.5 days over 2 separate treatment periods. Each treatment period will be separated by a 14 day (+ 3 days) washout period.

The overall expected duration is approximately 11 weeks.

Subjects will be randomised to one of two treatment sequences being either Smartech (diclofenac sodium topical solution) 2% w/w or PENNSAID® (diclofenac sodium topical solution) 2% w/w per the randomisation code after final qualification assessments have been completed for the first dosing period.

Smartech (diclofenac sodium topical solution) 2% w/w will be applied as a 40 mg dose to each knee. The dose will be dispensed as 2 pump actuations (20 mg [1mL] per actuation) from an airless container for each knee.

For Treatment Period 1, admission to clinic will occur on Day -1 with Day 1 beginning the first treatment day. Study drug will be administered twice daily on Day 1 through to the morning of Day 8, approximately 12 hours apart, for a total of 15 doses per Treatment Period. Actual dosing times will be recorded. Discharge from the clinic will occur on Day 9 followed by out patient visits on Day 11, 13 and Day 15.

A 14 day washout period will occur before Treatment Period 2 commences on Day 22 after last treatment on Day 8. Treatment Period 2 will follow the same treatment regime as Treatment Period 1. On Day 15 of Treatment Period 2, a final outpatient visit will occur (End of Treatment). Participants will have a final Follow-up phone call on Day 22 (End of Study) after last treatment period.

The Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w product containers will be weighed before and after each application by the clinical staff and the weight recorded.
Intervention code [1] 324522 0
Treatment: Drugs
Comparator / control treatment
PENNSAID® (diclofenac sodium topical solution) 2% w/w will be applied as a 40 mg dose to each knee. The dose will be dispensed as 2 pump actuations (20 mg [1mL] per actuation) which is the recommended dose, from an airless container for each knee.

The dose will be applied twice daily (in the morning and in the evening, 12 hours apart) from Days 1 to 7. On Day 8, a morning dose only will be applied. The dose should be applied at the same time each day.
Control group
Active

Outcomes
Primary outcome [1] 332651 0
To compare the bioavailability of Smartech (diclofenac sodium topical solution) 2% w/w to PENNSAID® (diclofenac sodium topical solution) 2% w/w in healthy volunteers across 2 treatment periods of 15 days.

Pharmacokinetic (PK) endpoints of diclofenac are used to evaluate bioavailability. Whole blood samples will be collected for each blood draw to yield plasma collected for bioanalytical analysis;
AUC (Area under the plasma concentration-time curve from time 0 to 12 hours),
Cmax (Maximum observed plasma concentration),
Tmax (Time to maximum concentration obtained directly from the observed concentration versus time data),
Tlag (Time to quantifiable concentration (lag-time)),
Cmin (Minimum plasma concentration over the dosing interval),
Cavg (Average concentration over the dosing interval),
degree of fluctuation and swing,
lambda z (Apparent Terminal Elimination Phase Rate Constant),
t½ (Terminal phase half-life).
Timepoint [1] 332651 0
Plasma samples for diclofenac PK will be collected: Pre-first dose and at 0.5, 1, 2, 3, 4, 6, 8, 10 hours and 12 hours post-first dose only on Days 1 and on Day 8 (noting that only one dose is given on Day 8), pre-morning dose on Days 2 to 7 (±15 minutes), and in the morning on Days 9 (Discharge), 11, 13 and 15 (End of Treatment), (24, (± 60 min), 72, 120 and 168 hours (± 120 min) post-dosing on Day 8, respectively) in each treatment period. Actual time of collection must be recorded. An allowable ±5 minute window applies to samples at 0.5, 1, 2 and 3 hours post completion of investigational product administration, and ±15 minutes for 4, 6, 8, 10 hours and 12 hours (pre-second dose). On Day 9 a ±60 minute window applies, and, pre first dose, Day 11, 13 and 15 a ±120 minute window applies.
Primary outcome [2] 332652 0
To evaluate the safety and tolerability of Smartech (diclofenac sodium topical solution) 2% w/w across 2 treatment periods of 15 days.

Safety endpoints include:
- adverse events (AEs),
- vital signs,
- physical examination,
- electrocardiogram (ECG),
- clinical labs,
- local tolerability assessment for skin irritation
Timepoint [2] 332652 0
Treatment Period 1: Adverse events will be assessed by participant self-report in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0) and assessed on Check-in (Day -1), once daily Days 1 to 9 (Discharge), Day 11, Day 13, Day 15 post-treatment commencement.

Treatment Period 2: Adverse events will be assessed by participant self-report in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0) and assessed on Check-in (Day -1), once daily on Days 1 to 9 (Discharge), Day 11, Day 13, Day 15 End of Treatment) and Day 22 post-treatment commencement (End of Study).

Vital Signs include tympanic temperature (thermometer), respiration (counting breaths per minute), blood pressure (sphygmomanometer), and pulse rate (pulse oximeter) and should be collected at Screening, Check-in (Day -1), pre-morning dose and at 2 and 6 hours post-morning dose on Days 1-8 (± 30 mins), pre-afternoon dose on Days 1-8 (± 30 mins), prior to the PK blood sample collection on Days 9 (Discharge), 13 and 15 post-treatment commencement. The exact time of collection should be recorded. Vitals may be performed with an allowable window of ± 30 mins of the scheduled timepoint.

The full physical examination should include evaluation of physical exam of General Appearance, head, eyes, ears, nose, throat (HEENT), Mouth/Dental (if required), Neck (incl Thyroid & Nodes), Cardiovascular, Respiratory, Gastrointestinal, Renal, Neurological, Musculoskeletal, Skin at Screening and Day 15 (End of Treatment) of Treatment Period 2.

Triplicate 12-lead electrocardiogram (ECG) taken when Supine or semi-supine for at least 5 minutes at Screening, followed by single 12-lead ECG at Day -1 (Admission), Day 1 - 6hrs post first-dose (±15 minute window), Day 8 post first-dose (±15 minute window), Day 15 post final dose of Treatment Period 1 and Day 15 post final dose (End of Treatment) of Treatment Period 2.

Clinical Laboratory blood and urine samples collected for serum chemistry, haematology, and urinalysis at Screening, on Day -1 (first treatment period only), and on Day 15 post final dose (last treatment period only). The exact time of collection should be recorded.

Skin irritation will be assessed pre-morning dose on Days 1 - 8 and 6 hours post-morning dose on an ordinal scale ranging from 0 to 4 whereby: 0=none, 1=slight/minimal erythema, 2 = mild, erythema only, 3 = moderate erythema or mild erythema plus oedema/ papules, 4 = severe erythema or at least moderate erythema plus oedema/ papules.
Secondary outcome [1] 414251 0
Assessments of skin irritation of Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w using a simple ordinal scale.

To assess skin irritation of Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w using a simple ordinal scale .
Timepoint [1] 414251 0
Skin irritation will be assessed pre-morning dose and 6 hours post-morning dose on Days 1-8 post-treatment commencement during each treatment period using an ordinal scale ranging from 0 to 4 whereby: 0=none, 1=slight/minimal erythema, 2 = mild, erythema only, 3 = moderate erythema or mild erythema plus oedema/ papules, 4 = severe erythema or at least moderate erythema plus oedema/ papules.
Secondary outcome [2] 414252 0
Collection of aesthetic descriptions for Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w.

Formulation aesthetics will be assessed by the staff applying the formulation using a rating ranging from 1-10.
Timepoint [2] 414252 0
Staff will complete a questionnaire addressing the aesthetics of the formulation following application on the morning of Days 1 and 8. The staff that apply the study drug will rate immediately following application and will provide a rating from 1-10 at 10 minutes after application using the following evaluation:

Rate the formulation using a scale of 1-10 for:
A. Sensory attributes, describe the sensations during application (staff applying solution to rate)
1- Doesn’t spread easily - very oily, greasy and/or sticky
10 - Easy to spread over entire application area - not oily, greasy or sticky
Secondary outcome [3] 414811 0
Assessments of skin dryness of Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w using a simple ordinal scale.

To assess skin dryness of Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w using a simple ordinal scale .
Timepoint [3] 414811 0
Skin dryness will be assessed pre-morning dose and 6 hours post-morning dose on Days 1-8 post-treatment commencement during each treatment period using an ordinal scale ranging from 0 to 4 whereby 0=normal, 1=slight/minimal skin dryness, 2 = mild skin dryness, 3 = moderate dryness plus scaling, 4 = severe dryness and/or cracked flaky skin
Secondary outcome [4] 414812 0
Collection of aesthetic descriptions for Smartech (diclofenac sodium topical solution) 2% w/w and PENNSAID® (diclofenac sodium topical solution) 2% w/w.

Formulation aesthetics will be assessed by the participant using a rating ranging from 1-10.
Timepoint [4] 414812 0
The participant will complete a questionnaire addressing the aesthetics of the formulation following application on the morning of Days 1 and 8. The participant will provide a rating from 1-10 at 10 minutes after application using the following evaluation:

Rate the formulation using a scale of 1-10 for:

B. Final impression due to feeling on the skin following application (participant to rate 10 minutes after application):
1- Undesirable sensation such as stinging or drying
10- Pleasant sensation such as soothing and moisturising

Eligibility
Key inclusion criteria
1. Is between 18 – 55 years of age (inclusive) at clinical research unit (CRU) admission and a Human Research Ethical committee (HREC)-approved informed consent has been signed and dated.
2. Has a body mass index between 19 to 32 kg/ m2.
3. Be non-smokers (including tobacco, e-cigarettes and marijuana) for at least 1 month prior to first study drug administration and have a negative test for nicotine at the screening visit and at check-in on Day -1.
4. Medically healthy without clinically significant (in the opinion of the Investigator) abnormalities at screening and prior to dosing at the timepoints indicated in the Schedule of Assessments (SoA), including:
• Physical examination without any clinically relevant findings at the discretion of the investigator;
• Systolic blood pressure in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after at least 5 minutes in a supine or semi-supine position;
• Heart rate (HR) in the range of 45 to 100 bpm after at least 5 minutes rest in a supine or semi-supine position;
• Body temperature (tympanic), between 35.5°C and 37.7°C;
• No clinically significant findings at the discretion of the investigator in serum chemistry, haematology, coagulation and urinalysis tests;
• Triplicate 12-lead ECG, taken after at least 5 minutes in a supine or semi-supine position, with a QT interval corrected using the Fridericia method (QTcF) less than or equal to 450 msec for males and less than or equal to 470 msec for females and no clinically significant abnormalities
5. Female volunteers must:
a. Be of nonchildbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause, and a follicle-stimulating hormone level >30 IU/L at the screening visit), or
b. If of childbearing potential, must agree not to donate ova, not to attempt to become pregnant and, if engaging in sexual intercourse with a male partner, must agree to use an acceptable method of contraception from signing the consent form until at least 30 days after the last dose of the study drug
6. Male volunteers must agree not to donate sperm and, if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use an acceptable method of contraception from signing the consent form until at least 90 days after the last dose of study drug.
7. All lab values at Screening and CRU admission fall within local laboratory reference ranges or are designated by the Investigator to be not clinically significant. Repeat tests allowable at discretion of Investigator.
8. Agree to abstain from:
a. Prescription medication (including herbal products, diet aids and hormone supplements), or dietary supplements and over the counter medications, from 14 days prior to CRU admission through to study completion, except contraception prevention medications
9. Agrees to abstain from alcohol 3 days prior to each CRU admission and during the confinement period.
10. Agrees to abstain from shaving, waxing or any hair removal technique from the knee area within 7 days of each CRU admission. (laser hair removal 90 days). The use of a hair clipper with guard allowable at any time up to and including check-in Day -1 of each treatment period.
11. Agrees to avoid exposure to natural or artificial sunlight on treated knees during each CRU admission period and for the 4 days following discharge. .
12. Has the ability to understand the requirements of the study and is willing to comply with all study procedures.
13. Is considered healthy, with no clinically significant illnesses or conditions that would prevent inclusion within the study as determined by the Principal Investigator (PI).
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Has a known hypersensitivity to diclofenac sodium, salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs).
2. History of asthma (childhood asthma acceptable), urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
3. Has risk factors for cardiovascular thrombotic events; known cardiovascular disease or risk factors for cardiovascular disease.
4. Has had a coronary artery bypass graft surgery within the past 12 months.
5. In the opinion of the Investigator, a history of and/or risk factors for serious gastrointestinal events (cholecystectomy and Gilbert’s Syndrome acceptable).
6. History of gastric bypass surgery.
7. Has any skin condition in the opinion of the Investigator that would prohibit topical application of the IP to the skin around the knee, or impair assessment of the skin, this includes tanning product use within 14 days, tattoos or any permanent cosmetic visual alteration (i.e. cosmetic scarification) in the area of application, current or recent unresolved sunburn.
8. Has any open wounds on the knee area, or any irregularities of the skin on the knee area (i.e. post-surgical or excessive scarring), or amount of hair, which in the opinion of the Investigator would:
a. impact absorption of the investigational product and/or,
b. prevent any AE from being noticed and/or
c. in the instance of hair around the knee that the Investigator deems may impact conditions a. and/or b., they may choose to allow the use of a hair clipper with guard at any time up to and including check-in Day -1 of each treatment period.
9. Has participated in an investigational research study within the last 30 days, or less than five (5) half-lives of the investigational drug have elapsed prior to CRU admission.
10. Donation of blood or plasma within 30 days prior to first study drug administration, or loss of whole blood of more than 500 mL within 30 days prior to first study drug administration, or receipt of a blood transfusion within 1 year of first study drug administration
11. Has human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen. . (Note that a sustained hepatitis C virologic response is allowable).
12. History of substance abuse or alcohol abuse (defined as more than 10 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; 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], 30 mL spirit [40% Alc./Vol]) within 12 weeks prior to the screening visit.
13. Positive drugs of abuse or alcohol breath test results at the screening visit or at check-in (Day -1). Retest allowable at discretion of Investigator.
14. Is a current smoker or uses tobacco products, or has a positive nicotine test upon screening or admission to the CRU.
15. Creatinine clearance (CrCl) < 80 mL/min calculated using the Cockcroft-Gault formula or serum creatinine more than 1.5-fold above the upper limit of normal (ULN).
16. Liver function test results elevated more than 1.5-fold above the ULN for gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Volunteers with ALP and/or ALT/AST above the limits specified may be included, at the discretion of the Investigator, if the levels are unaccompanied by clinical signs and are determined to be normal variants.
17. Liver function tests outside the normal range for bilirubin (total, direct and indirect).
18. Positive test results for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit. (Note that a sustained hepatitis C virologic response is allowable).
19. Known hypersensitivity to any of the study drug ingredients.
20. Use of any vaccinations within 14 days prior to the first study drug administration.
21. For women of childbearing potential (WOCBP), a positive serum pregnancy test at the screening visit or a positive urine pregnancy test (with confirmatory serum pregnancy test) at check-in (Day -1).
22. Females who are breastfeeding or planning to breast feed at any time during the study.
23. Participation in another clinical trial of an investigational drug within 30 days or 5 half-lives of the investigational agent (whichever is longer) prior to the first study drug administration.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a randomised open-label crossover study. Subjects will be randomised to one of two treatment sequences per the randomisation code after final qualification assessments have been completed for the first dosing period.
Simple randomisation using a randomisation distribution created by computer software (i.e. PROC PLAN procedure in Statistical Analysis System[SAS]).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
This study will compare the bioavailability of the Smartech (diclofenac sodium topical solution) 2% w/w to PENNSAID 2%.
The sample size (32 participants) allows for a powered comparison of Smartech (diclofenac sodium topical solution) 2% w/w to PENNSAID 2% using the parameters: Cmax and AUC.
All data used in analyses and/or collected during the study will be provided in listings.
Data analysis for continuous variables (e.g., age) will be summarized using the number of
observations (n), mean, SD, median, minimum, and maximum, while categorical variables (e.g., sex, race) will be summarized using the number of observations (n) and percentage in each category.

Relative bioavailability assessment will be performed by using a linear, repeated-measures, mixed-effect model appropriate for a 2-period, 2-sequence design.
In this model, the log-transformed PK parameters (AUC0-12 and Cmax) will be set as the outcome variable assessed, while the treatment, sequence, and period will be set as fixed effects and subject within sequence as a random effect, separately for Day 1 and Day 8.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
31/10/2022
Date of last participant enrolment
Anticipated
12/01/2023
Actual
18/01/2023
Date of last data collection
Anticipated
25/02/2023
Actual
3/03/2023
Sample size
Target
32
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23266 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 38635 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 312327 0
Commercial sector/Industry
Name [1] 312327 0
Smartech Topical Au Pty Ltd
Country [1] 312327 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Avance Clinical Pty Ltd
Address
Level 1, 2 Ann Nelson Drive, Thebarton, South Australia 5031
Country
Australia
Secondary sponsor category [1] 313882 0
None
Name [1] 313882 0
Address [1] 313882 0
Country [1] 313882 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311694 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [1] 311694 0
Ethics committee country [1] 311694 0
Australia
Date submitted for ethics approval [1] 311694 0
23/08/2022
Approval date [1] 311694 0
29/09/2022
Ethics approval number [1] 311694 0
2022-02-141

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

Contacts
Principal investigator
Name 122026 0
Dr Jonathan Newchurch
Address 122026 0
CMAX
Level 5, 18a North Terrace
Adelaide South Australia 5000
Country 122026 0
Australia
Phone 122026 0
+61 0423 223 756
Fax 122026 0
Email 122026 0
jnewchurch@gmail.com
Contact person for public queries
Name 122027 0
Jonathan Newchurch
Address 122027 0
CMAX
Level 5, 18a North Terrace
Adelaide South Australia 5000
Country 122027 0
Australia
Phone 122027 0
+61 0423 223 756
Fax 122027 0
Email 122027 0
jnewchurch@gmail.com
Contact person for scientific queries
Name 122028 0
Jonathan Newchurch
Address 122028 0
CMAX
Level 5, 18a North Terrace
Adelaide South Australia 5000
Country 122028 0
Australia
Phone 122028 0
+61 0423 223 756
Fax 122028 0
Email 122028 0
jnewchurch@gmail.com

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


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.