Rivastigmine Bioequivalence Trial With Multiple Application of Transdermal Patches (9.5mg/24h)

Open, Randomized, 2-period, 2-sequence, Cross-over Relative Bioavailability Study to Investigate the Pharmacokinetics and to Assess the Bioequivalence of a Rivastigmine Test Patch Formulation 9.5 mg/24 h (Twice Weekly Patch) Compared to the Reference Exelon® 9.5 mg/24 h (Once Daily Patch) Applied for 11 Days

The present clinical trial will be conducted in order to compare the bioavailability of rivastigmine and to assess bioequivalence at steady-state of the Test product RID-TDS 9.5 mg/24 h (Luye Pharma AG, Germany) and the marketed Reference product Exelon® 9.5 mg/24 h transdermales Pflaster (Novartis Pharma GmbH, Germany) after multiple patch application. Each of both treatments will last for 11 days with a washout period of 14 days between the treatments.

Study Overview

• Status: Completed
• Conditions: Bioequivalence
• Intervention / Treatment: Drug: RID-TDS 9.5 mg/24 h; Drug: Exelon® 9.5 mg/24 h

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Thüringen
    • Erfurt, Thüringen, Germany, 99084
      • SocraTec R&D GmbH, Clinical Pharmacology Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. sex: male
2. age: 18-55 years, inclusive
3. body-mass index2 (BMI): ≥18.5 kg/m² and ≤ 30.0 kg/m²
4. good state of health as determined by no clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination (including vital sign) and/or ECG, as determined by the investigator
5. non-smoker or ex-smoker for at least 1 month
6. written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in the clinical trial

Exclusion Criteria:

1. existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient (especially sick sinus syndrome or conduction defects such as sino-atrial block, atrio-ventricular block)
2. existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient (especially predisposition to urinary obstruction and seizures)
3. existing gastrointestinal diseases or pathological findings, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient (especially active gastric or duodenal ulcers or predisposition to these conditions)
4. history of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders
5. Subjects with chronic obstructive or other pulmonary diseases or bronchial asthma
6. known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparations or previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine patch
7. subjects with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
8. systolic blood pressure < 90 or >139 mmHg
9. diastolic blood pressure < 60 or >89 mmHg
10. heart rate < 50 bpm or > 90 bpm
11. body weight below 50 kg
12. QTc interval > 450 ms
13. laboratory values out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator
14. ASAT > 20% ULN, ALAT > 10% ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine > 0.1 mg/dL ULN (limit of > 0.1 mg/dL correspondents to of > 9 μmol/l ULN).
15. positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test or anti-HCV-test
16. Presence or history of acute or chronic diseases especially of the skin, which could affect dermal absorption or metabolism, which may interfere with the bioavailability and /or the pharmacokinetics of the IMP based on assessment of the investigator
17. Skin abnormality (e.g. tattoo or scar) at the application site
18. acute or chronic diseases which may interfere with the pharmacokinetics of the IMP
19. history of or current drug or alcohol dependence
20. positive alcohol or drug test at screening examination
21. regular intake of alcoholic food or beverages of ≥ 40 g pure ethanol per day
22. subjects who are on a diet which could affect the pharmacokinetics of the active ingredient
23. regular intake of caffeine containing food or beverages of ≥ 500 mg caffeine per day
24. blood donation or other blood loss of more than 400 ml within the last 2 months prior to individual enrolment of the subject
25. administration of any investigational medicinal product during the last 2 months prior to individual enrolment of the subject
26. regular treatment with any systemically available medication
27. subjects practising top-performance sports (more than 4 x 2 h per week)
28. subjects suspected or known not to follow instructions
29. subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RID-TDS 9.5 mg/24 h; 3 consecutive applications of 1 patch (1st patch for 4 days, 2nd patch for 3 days, 3rd patch for 4 days) covering an 11-day period	Drug: RID-TDS 9.5 mg/24 h; 3 consecutive applications of 1 patch (1st patch for 4 days, 2nd patch for 3 days, 3rd patch for 4 days) covering an 11-day period
Active Comparator: Exelon® 9.5 mg/24 h; 11 consecutive applications of 1 patch (each patch will be applied for 1 day) covering an 11-day period	Drug: Exelon® 9.5 mg/24 h; 11 consecutive applications of 1 patch (each patch will be applied for 1 day) covering an 11-day period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC96-264	partial area under the plasma concentration vs. time profile for the time interval 96-264 hours	from 96 to 264 hours after the first patch application
Cmax,96-264	maximum concentration in plasma during the nominal time interval 96-264 hours	from 96 to 264 hours after the first patch application
Cmin,96-264	absolute minimum concentration within the nominal time interval 96-264 hours	from 96 to 264 hours after the first patch application
Patch adhesion properties	lower one-sided 90% confidence limit for the mean of Test	at 96, 168 and 264 hours after the first Test patch application

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skin irritation	frequency of scores for quantification of skin irritation per treatment and time point	from first patch removal until last patch removal (approx. 9 to 13 days)
Adverse events	descriptive evaluation of frequency and intensity, relationship to the IMP, action taken, outcome, seriousness, period and treatment	approximately 7 to 12 weeks, through study completion in case of follow-up
inhibition of plasma butyrylcholinesterase (BuChE)	% inhibition of BuChE activity in plasma in comparison to baseline	from first patch application until 24 hours after the last patch removal

Collaborators and Investigators

• Sponsor: SocraTec R&D GmbH
• Collaborators: SocraMetrics GmbH

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2018
• Primary Completion (Actual): November 28, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: August 28, 2018
• First Submitted That Met QC Criteria: September 5, 2018
• First Posted (Actual): September 6, 2018

Study Record Updates

• Last Update Posted (Actual): September 19, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Cholinesterase Inhibitors; Rivastigmine
• Other Study ID Numbers: 1352riv18ct; 2018-001570-18 (EudraCT Number); C_30410_P1_05 (Other Identifier: Luye Pharma AG / Luye Supply AG)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No