Comparative Bioavailability of Smartech 2% Sodium Diclofenac Topical Solution and PENNSAID 2% Applied to the Knees of Healthy Male and Female Subjects
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
Avance Clinical Pty Ltd
32 participants
Oct 31, 2022
Interventional
Conditions
Summary
This is a randomised, open-label, multiple-dose, 2-period crossover study to evaluate the PK and bioavailability of Smartech (diclofenac sodium topical solution) 2% w/w compared to PENNSAID® (diclofenac sodium topical solution) 2% w/w, This trial is the first clinical study to evaluate Smartech (diclofenac sodium topical solution) 2% w/w. PENNSAID® (diclofenac sodium topical solution) 2% w/w is a marketed product. Smartech’s PK study is intended to confirm that the use of optimised Penetration Enhancer (PE) ingredient/s in the Smartech product will deliver a higher amount of drug through the skin and joint, and into the blood, such that the systemic exposure for the Smartech products would be higher than PENNSAID® (diclofenac sodium topical solution) 2% w/w. This study is a relative PK study planned to determine the PK parameters (Cmax and AUC) between a Smartech (diclofenac sodium topical solution) 2% w/w compared to PENNSAID® (diclofenac sodium topical solution) 2% w/w. Up to 32 healthy male and female participants will be screened within 28 days (Days -28 to -2) of the first treatment 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. PENNSAID® (diclofenac sodium topical solution) 2% w/w will be applied as a 40 mg dose (2 pump actuations, 20 mg [1mL] per actuation) to each knee, which is the recommended dose. For each product, 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 doses should be applied at the same time each day. Assessment of the safety and tolerability of Smartech (diclofenac sodium topical solution) 2% w/w is a primary objective of this study. Safety and tolerability will be determined by physical examination findings, vital signs, ECGs, clinical laboratory parameters, and AEs. Safety and tolerability assessments may also be performed at various unscheduled time points or different assessments may be performed, if deemed necessary for participant safety by the PI.
Eligibility
Inclusion Criteria22
- 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.
- Has a body mass index between 19 to 32 kg/ m2.
- 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.
- 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
- 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
- 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.
- 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.
- 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
- Agrees to abstain from alcohol 3 days prior to each CRU admission and during the confinement period.
- 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.
- Agrees to avoid exposure to natural or artificial sunlight on treated knees during each CRU admission period and for the 4 days following discharge. .
- Has the ability to understand the requirements of the study and is willing to comply with all study procedures.
- Is considered healthy, with no clinically significant illnesses or conditions that would prevent inclusion within the study as determined by the Principal Investigator (PI).
Exclusion Criteria26
- Has a known hypersensitivity to diclofenac sodium, salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs).
- History of asthma (childhood asthma acceptable), urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
- Has risk factors for cardiovascular thrombotic events; known cardiovascular disease or risk factors for cardiovascular disease.
- Has had a coronary artery bypass graft surgery within the past 12 months.
- In the opinion of the Investigator, a history of and/or risk factors for serious gastrointestinal events (cholecystectomy and Gilbert’s Syndrome acceptable).
- History of gastric bypass surgery.
- 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.
- 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.
- 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.
- 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
- Has human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen. . (Note that a sustained hepatitis C virologic response is allowable).
- 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.
- 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.
- Is a current smoker or uses tobacco products, or has a positive nicotine test upon screening or admission to the CRU.
- 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).
- 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.
- Liver function tests outside the normal range for bilirubin (total, direct and indirect).
- 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).
- Known hypersensitivity to any of the study drug ingredients.
- Use of any vaccinations within 14 days prior to the first study drug administration.
- 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).
- Females who are breastfeeding or planning to breast feed at any time during the study.
- 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.
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Interventions
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.
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ACTRN12622001391763