Bioequivalence and Adhesion of a Rotigotine Patch in Healthy Subjects

Single Dose Bioequivalence and Adhesion Study of Rotigotina B7 TDS (2 mg/24h) (Rotigotine Transdermal Patch 2 mg/24 Hours) and 'NEUPRO®' (Rotigotine) 2 mg/24 Hours Transdermal Patch in Healthy Adult Human Participants.

This study was intended to demonstrate bioequivalence of the Amarin's Rotigotine patch respect to Neupro, (RLD), as well as non-inferiority in adhesion, when tested at a dose of 2 mg/24h in healthy subjects of both sexes. Local and systemic adverse events were also monitored and reported. Worn patches were recovered and analysed to compare residual drug.

Objectives:

• To evaluate the bioequivalence and the non-inferiority in the adhesion of Rotigotina B7 TDS (2 mg/24h) (Rotigotine Transdermal Patch 2 mg/24 hours) respect to 'NEUPRO®' (Rotigotine) 2 mg/24 hours Transdermal Patch in healthy, adult human participants.
• To compare the residual drug content, cold flow properties and to monitor the safety and tolerability of the participants.

Methodology:

This evaluator-blinded, randomized, two-period, two-treatment, four-sequence, crossover, balanced, single dose bioequivalence and adhesion study in healthy adult human participants was conducted to evaluate the bioequivalence and the non-inferiority in the adhesion of test formulation respect to reference formulation. The study was conducted with 36 (32 Male + 04 Female) participants and 35 participants (31 Male + 04 Female) completed the study in accordance with protocol. A single patch of either the test product Rotigotina B7 TDS (2mg/24h) (Rotigotine Transdermal Patch 2 mg/24 hours) (T) or the reference product (R). Neupro® 2 mg/24 h Transdermal Patch Rotigotin (e) was applied for 24 hours on the healthy skin (that was clean, dry, hairless and free of redness, irritation, burns or cuts) on left or right side of upper arm according to the randomization schedule of each participant in each study period (on Day 0 for Period 1 and Day 3 for Period 2) at ambient temperature.

Blood samples were collected at pre-dose (0.0 hour) and at 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 22.0, 24.0 (prior to removal), 26.0, 28.0, 32.0, 36.0, 42.0 and 48.0 hours post dose in each period. The plasma samples were shipped to the Bioanalytical facility for analysis.

Statistical analysis was performed on pharmacokinetic parameters to compare and evaluate the bioequivalence and statistical analysis was performed on adhesion score data to evaluate the non-inferiority in the adhesion of test formulation to the reference formulation. Bioequivalence was determined by a statistical comparison of Cmax, AUCt and AUCi for the test and reference products for Rotigotine. To demonstrate adhesiveness, the 90% confidence interval of mean adherence for the test product at the end of the dosing interval was to be lie above 90%.

Inclusion Criteria:

1. Age: 18 to 55 years old, both inclusive.

2. Gender: Male and/or non-pregnant, non-lactating female. A. Female of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test performed within 28 days prior to first patch application. They must be using an acceptable form of contraception.

   B. For female of childbearing potential, acceptable forms of contraception include the following:

   i. Non hormonal intrauterine device in place for at least 3 months prior to the start of the study and remaining in place during the study period, or ii. Barrier methods containing or used in conjunction with a spermicidal agent, or iii. Surgical sterilization or iv. Practicing sexual abstinence throughout the course of the study.

   C. Female will not be considered of childbearing potential if one of the following is reported and documented on the medical history:

   i. Postmenopausal with spontaneous amenorrhea for at least one year, or ii. Spontaneous amenorrhea for more than 6 months and less than one year with Serum Follicular Stimulating Hormone (FSH) level > 40 mIU/mL, or iii. Bilateral oophorectomy with or without a hysterectomy and an absence of bleeding for at least 6 months, or iv. Total hysterectomy and an absence of bleeding for at least 3 months.

3. BMI: 18.5 to 30.0 weight in kg/(height in meter)2 both inclusive; BMI value should be rounded off to one significant digit after decimal point (e.g. 30.04 rounds down to 30.0, while 18.45 rounds up to 18.5).

4. Non-alcoholic (i.e. having no past history of alcohol consumption for at least one year prior to study).

5. Non-smokers and non-tobacco user (i.e. having no past history of smoking and tobacco consuming for at least one year prior to study).

6. Able to communicate effectively with study personnel.

7. Willing to provide written informed consent to participate in the study.

8. All participants must be judged by the principal or sub-investigator or physician as normal and healthy during a pre-study safety assessment performed within 28 days of the first patch application of study which will include:

   1. A physical examination (clinical examination) with no clinically significant finding.
   2. Results within normal limits or clinically non-significant for the following tests:

Hematology Hemoglobin Total RBC count Total WBC count Platelet count

Differential leukocyte count:

Neutrophils Lymphocytes Eosinophils Monocytes Basophils Blood indices: HCT Biochemistry BUN Serum creatinine Random glucose SGPT & SGOT Alkaline phosphatase Uric acid Serum bilirubin Serum total protein: Total proteins, Albumin Serum electrolytes: Serum sodium, serum chloride, serum potassium, serum phosphorous, serum calcium Urinalysis Color, quantity, specific gravity, odour, appearance, reaction, albumin, bilirubin, ketone bodies, sugar, urobilinogen and microscopical examination (performed based on clinical judgment) Immunological Tests HIV-I & II HbsAg Anti HCV Serum (β-HCG) pregnancy test (for female of child-bearing potential) Serum Follicular Stimulating Hormone (FSH) (if required)

• Additional tests and/or examinations (apart from mentioned in protocol) may be performed, if necessary, based on principal investigators recommendation.
• All results will be assessed against the current laboratory normal ranges at the time of testing and a copy of the normal ranges used will be included in the study documentation.

Exclusion Criteria:

Participants must not be enrolled in the study if they meet any one of the following criteria:

1. History of allergic responses to Rotigotine, or any other components of the formulations (Test and/or Reference ones) or other related drugs and/or history of allergy to any adhesive materials.
2. Have significant diseases or clinically significant abnormal findings during screening [medical history, physical examination (clinical examination), laboratory evaluations, ECG, gynaecological history and examination (including pelvic examination and routine breast examination) (for female participants)].
3. Any disease or condition like diabetes, psychosis or others, which might compromise the haemopoietic, gastrointestinal, renal, hepatic, cardiovascular, respiratory, central nervous system or any other body system.
4. History or presence of bronchial asthma.
5. Use of any hormone replacement therapy within 3 months prior to the first patch application.
6. A depot injection or implant of any drug within 3 months prior to the first patch application.
7. Use of CYP enzyme inhibitors or inducers within 30 days prior to the first patch application (see https://drug-interactions.medicine.iu.edu/MainTable.aspx).
8. History or evidence of narcotic abuse, drug dependence.
9. History of difficulty with donating blood or difficulty in accessibility of veins.
10. A positive hepatitis screen (includes subtypes B & C).
11. A positive test result for HIV antibody.
12. Participants who have received a known investigational drug within seven elimination half-life of the administered drug prior to the first patch application.
13. Participants who have donated blood or loss of blood 50 ml to 100 ml within 30 days or 101 ml to 200 ml within 60 days or >200 ml within 90 days (excluding volume drawn at screening for this study) prior to first patch application, whichever is greater.
14. Intolerance to venipuncture
15. Any food allergy, intolerance, restriction or special diet that, in the opinion of the principal investigator or sub-investigator, could contraindicate the participant's participation in this study.
16. Institutionalized participants.
17. Participant has an obvious difference in skin color at the application site or the presence of a skin condition, excessive hair at the application sites, scar tissue, tattoos, open sores, a recent sunburn, or body piercing that would interfere with the placement of the investigational products, the skin assessment, or the participant's reactions to the study patch.
18. Presence of open sores, or other skin abnormalities at the application site.
19. Use of creams, make up, lotions, powders and gels, etc. or other topical products at application sites within 24 hours prior to first patch application.
20. Use of soap and/or solvents (e.g.: alcohol) at the patch application site within 12 hours prior to first patch application.
21. Medical history of significant dermatological diseases or conditions, such as atopy, psoriasis, eczema, atopic dermatitis, vitiligo or conditions known to alter skin appearance or physiologic response (e.g. diabetes, porphyria).
22. Medical history of condition that would significantly influence the immune response (e.g., primary or acquired immunodeficiencies such as human immunodeficiency virus (HIV) positive or AIDS, allergic disease such as anaphylaxis, asthma or generalized drug reaction, neoplasms such as lymphoma or leukemia, rheumatoid arthritis or systemic lupus erythematosus).
23. Medical history of significant dermatological cancers (e.g. melanoma, squamous cell carcinoma), except basal cell carcinomas that were superficial and did not involve the investigative site.
24. Use of any antihistamines (except steroid nose drops and/or eye drops) or used any topical drugs at application site within 72 hours prior to first patch application.
25. Use of medications or treatments that would significantly influence or exaggerate responses to the investigational product or that would alter inflammatory or immune response to the product [e.g. cyclosporine, tacrolimus, cytotoxic drugs, immunoglobulins, Bacillus Calmette-Guerin (BCG), monoclonal antibodies, radiation therapy] within 3 weeks prior to first patch application.
26. Use of any systemic or topical corticosteroids at the application site within 3 weeks prior to first patch application.
27. Participant who has a condition or is taking or has taken a medication that, in the investigator's judgment, makes the participant ineligible or places the participant at undue risk.
28. Participation in any transdermal/topical patch with active drug study or any patch study at the same application site within the last four weeks prior to the initial application of study patch.
29. Use of any prescribed medications within 14 days prior to the first patch application.
30. Use of any over-the-counter medications, including topical or systemic analgesics, herbal medications, vitamins, etc. 07 days prior to the first patch application.
31. Use of grapefruit and grapefruit containing products within 7 days prior to the first patch application.
32. Use of sunbath or steam baths within 7 days prior to first patch application
33. Ingestion of any caffeine or xanthine products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) within 72 hours prior to the first patch application.
34. Ingestion of any recreational drugs within 14 days prior to the first patch application.
35. Ingestion of any unusual diet, for whatever reason (e.g.: low sodium) for three weeks prior to the first patch application.
36. History of sulfite sensitivity
37. Medical history of asthma, orthostatic hypotension, dizziness, syncope, or dyskinesia
38. History of hyper or hypotension
39. Use of any monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase inhibitors, dopamine agonists, dopamine antagonists, reserpine, methyldopa, antipsychotics, neuroleptics, clozapine, olanzapine, quetiapine, metoclopramide, flunarizine, cinnarizine, risperidone within 3 months prior to first patch application. Use of any other medication that could alter the analysis of Rotigotine in plasma.
40. Medical history of somnolence and/or having fallen asleep without warning.
41. Medical history or presence of psychotic disorder.
42. History of suicide attempt or suicide-leading thinking within 6 months prior to patch application.
43. Clinically relevant findings in screening 12-lead ECG, such as second-or third-degree atrioventricular block or complete bundle branch block or arrhythmias.
44. The participant shows a QTc interval (corrected according Bazett formula) ≥ 430 ms for men and ≥ 450 ms for women.
45. History of narrow angle glaucoma.
46. Participant that recently or currently have (had) pain, irritation and/or other sensory disturbances at or adjacent to the area of application that could hamper assessment of the safety and tolerability