Evaluate the Ability of dOFM for BE Testing of Topically Applied Diclofenac Sodium Products in Healthy Subjects

A Single Center, Open-label, Clinical Study to Evaluate the Ability of Dermal Open Flow Microperfusion (dOFM) for Bioequivalence Testing of Topically Applied Diclofenac Sodium Products in Healthy Subjects

This will be a single center, open label, exploratory research study to assess the dermal pharmacokinetic (PK) profile of three marketed diclofenac products in 26 healthy volunteers using dermal open flow microperfusion (dOFM).

This clinical study aims to assess bioequivalence (BE) of three different diclofenac products.

The clinical study is divided into a pilot and a pivotal study. The pilot study will involve 6 healthy adult volunteers. The pilot study aims to develop the optimal study design for the pivotal study by defining the dose of the reference product (diclofenac sodium gel 1%) and by evaluating the absence of significant systemic cross-talk (systemic redistribution) and lateral diffusion (cross-talk between adjacent treatment sites), which could increase background drug levels in the dermis that might confound the discrimination of dermal PK profiles between different products. Additionally, the suitability of a non-equivalent test product to serve as negative control for BE relative to the reference product will be evaluated.

The pivotal study will involve 20 healthy adult volunteers. In each volunteer the dermal PK profile of three different diclofenac products will be assessed in 6 topical treatment sites using dermal open flow microperfusion (dOFM), where the diclofenac penetration will be measured from baseline to 12 h post-dose. BE of the reference product against a generic test product (positive control) and against a non-equivalent test product (negative control) will be evaluated.

Inclusion Criteria:

1. Healthy, adult volunteers of age 18 to 65 years (both inclusive).
2. Males or non-pregnant, non-breast feeding females using adequate contraceptive methods or abstinence.
3. Able to read, understand and sign the written informed consent form.
4. Willing to follow the protocol requirements and comply with protocol restrictions.

Exclusion Criteria:

1. Social habits

   1. Smoker who is not willing to refrain from smoking during the in-house visit.
   2. History of drug and/or alcohol abuse within one year of start of study as judged by the investigator.

2. Medications: Use of any medications other than hormonal contraceptive, hormone replacement therapy or routine vitamins within the 7 days or 5 half-life periods whichever is longer prior to the initial dose of study medication.

3. Diseases: Presence of any clinically relevant acute or chronic disease, which in the investigator´s opinion might jeopardise subject's safety, evaluation of results or compliance with the protocol.

4. Any reason, which in the opinion of the investigator, would prevent the subject from safely participating in the study.

5. Any abnormalities found during physical examination or vital signs, unless deemed not clinically significant by the investigator.

6. Clinically significant abnormal laboratory evaluation results, as deemed by the investigator.

7. Clinically significant abnormal 12-lead ECG at screening, as deemed by the investigator.

8. Positive results to the test for hepatitis B antigen or hepatitis C antibodies.

9. Positive HIV test.

10. Positive alcohol breath test.

11. Blood donation within 30 days or significant loss of blood or plasma (more than 550 ml) within 90 days prior to screening.

12. Subjects who have received an investigational drug within 30 days prior to the initial dose of study medication.

13. Known hypersensitivity to diclofenac or any components of the drugs.

14. Tattoos or broken and/or damaged skin and/or scarring at the application areas.

15. Active skin diseases like psoriasis or atopic dermatitis, as judged by the investigator.

16. Subjects prone to keloid or hypertrophic scar formation or any known wound healing disorder.

17. Recent and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.), as judged by the investigator.

18. Not willing to avoid excessive sun exposure, steam baths, sauna, swimming and other strenuous activities for 14 days after Visit 2 to ensure good tissue regeneration.

19. Not willing to refrain from shaving the planned treatment sites or using skin care products on the planned treatment sites for at least 5 days prior to start of Visit 2.

20. Pronounced hairiness on the planned treatment sites that may negatively affect BE testing.

21. Known allergy/hypersensitivity to any of the materials/supplies used during the study.

22. Presence of needle phobia.

23. Increased risk of thrombosis, e.g. personal or first degree relative(s) history of deep vein thrombosis.

24. Not enough space on the thighs for the dOFM probe set-up (minimum length of 24 cm, 3 treatment sites with 4 dOFM probes).