Comparison of the Bioavailability of Diclofenac in a Combination Product (Diclofenac 2% + Capsaicin 0.075% Topical Gel) With Two Diclofenac Only Products, Diclofenac Mono Gel 2% and Voltarol® 12 Hour Emulgel 2.32% Gel, in Healthy Volunteers

• ClinicalTrials.gov Identifier: NCT03074162
• Recruitment Status: Completed
• First Posted: March 8, 2017
• Results First Posted: March 1, 2019
• Last Update Posted: March 1, 2019
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

The main objective of this study is to assess the relative systemic bioavailability of diclofenac in the presence and absence of capsaicin by comparing the systemic bioavailability of diclofenac from a combination product (Diclofenac 2% + Capsaicin 0.075% Topical Gel) with two diclofenac only products, Diclofenac Mono Gel 2% and Voltarol® 12 Hour Emulgel 2.32% Gel, following topical administration.

In order to examine potential racial differences in pharmacokinetics (PK), the study population will be stratified 50:50, Caucasian versus Black people. With respect to the main objective, additionally a supportive analysis will be performed to investigate the influence of race on the intra-individual bioavailability ratios.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Diclofenac Sodium; Drug: Diclofenac & Capsaicin; Drug: Diclofenac Sodium Topical Gel	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A SINGLE CENTER, MULTIPLE DOSE, OPEN-LABEL, RANDOMIZED, THREE-PERIOD CROSSOVER STUDY TO DETERMINE THE RELATIVE BIOAVAILABILITY OF DICLOFENAC IN THE TOPICAL GEL COMBINATION PRODUCT (DICLOFENAC 2% + CAPSAICIN 0.075%) COMPARED TO DICLOFENAC MONO GEL 2% AND VOLTAROL® 12 HOUR EMULGEL 2.32% GEL IN AT LEAST 42 HEALTHY MALES AND FEMALES
• Actual Study Start Date: April 20, 2017
• Actual Primary Completion Date: June 29, 2017
• Actual Study Completion Date: June 29, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Diclofenac Sodium (A)	Drug: Diclofenac Sodium; twice daily
Experimental: Diclofenac & Capsaicin (B)	Drug: Diclofenac & Capsaicin; twice daily
Active Comparator: Diclofenac Sodium Topical Gel	Drug: Diclofenac Sodium Topical Gel; twice daily

Outcome Measures

Primary Outcome Measures :

1. Area Under the Plasma Concentration-time Curve (AUC) Over One Dosing Interval for Diclofenac at Steady State (AUC0-τ,ss) (τ = 12 Hours) (Day 7) [ Time Frame: Pharmacokinetic samples were collected on Day 7 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the drug administration ]
   AUC0-τ,ss, Area under the plasma concentration-time curve (AUC) over one dosing interval at steady state for diclofenac at day 7 (τ = 12 hours). Stratification by race was analysed using a supportive Analysis of Variance (ANOVA) yielding point estimates for each underlying pairwise comparison analog to the main analysis. As the resulting two Least Square Means and Geometric Means (gMeans) per treatment and race are very similar, only gMeans per treatment and race are presented.
2. Maximum Plasma Concentration During a Dosage Interval (Cmax,ss) Obtained Directly From the Concentration-time Data for Diclofenac at Steady State (Day 7) [ Time Frame: Pharmacokinetic samples were collected on Day 7 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the drug administration ]
   Cmax,ss, Maximum plasma of diclofenac concentration during a dosage interval obtained directly from the concentration-time data at steady state for diclofenac on day 7. Stratification by race was analysed using a supportive Analysis of Variance (ANOVA) yielding point estimates for each underlying pairwise comparison analog to the main analysis. As the resulting two Least Square Means and gMeans per treatment and race are very similar, only gMeans per treatment and race are presented.

Secondary Outcome Measures :

1. Time to Maximum Observed Plasma Concentration at Steady State for Diclofenac at Steady State (Tmax,ss) (Day 7) [ Time Frame: Pharmacokinetic samples were collected on Day 7 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the drug administration ]
   tmax,ss, Time to maximum observed plasma concentration at steady state for diclofenac at day 7 (tmax,ss). Descriptive statistics by race are reported in addition.
2. Average Plasma Concentration (Cav,ss) for Diclofenac at Steady State [ Time Frame: Pharmacokinetic samples were collected on Day 7 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the drug administration ]
   Average plasma concentration (Cav,ss) calculated as AUC0-t,ss divided by τ=12 hours (τ is the duration of the dosing interval). Descriptive statistics by race are reported in addition.
3. Percentage Peak-trough Fluctuation (%PTF), Calculated as [100*(Cmax,ss - Cpre,ss)/Cav,ss] [ Time Frame: Pharmacokinetic samples were collected on Day 7 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours after the drug administration ]
   Percentage peak-trough fluctuation (%PTF) which was calculated as [100*(Cmax,ss - Cpre,ss)/Cav,ss] for Diclofenac. Descriptive statistics by race are reported in addition.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Healthy males and females, 18 to 50 years (inclusive) at time of screening.
• Body mass index (BMI) between 18.5 and 29.9 kg/m2 (inclusive).
• Body mass not less than 50 kg for males and females.
• Findings for medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations must be normal or within laboratory reference ranges for the relevant laboratory tests, unless the PI considers the deviation to be not clinically significant for the purpose of the study.
• Non-smokers.

• Females, if:

  • Not of childbearing potential,

  • Of childbearing potential, the following conditions are to be met:

    • Negative pregnancy test.
    • Not lactating.
    • Abstaining from sexual activity (if this is the usual lifestyle of the subject) or must agree to use an accepted method of contraception, and agree to continue with the same method throughout the study.
• Written informed consent given for participation in the study.
• Further inclusion criteria apply.

Exclusion Criteria:

• Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements.
• Current alcohol use > 21 units of alcohol per week for males and > 14 units of alcohol per week for females. One unit (10 g alcohol) is equal to beer (330 mL), wine (200 mL), or distilled spirits (25 mL) per day.
• Regular exposure to substances of abuse (other than alcohol) within the past year.
• Use of any medication, prescribed or over-the-counter (especially products containing diclofenac or use of other oral nonsteroidal anti-inflammatory drugs [NSAIDS]) or herbal remedies, within 2 weeks before the first administration of Investigational medicinal product (IMP) except if this will not affect the outcome of the study in the opinion of the PI (Principal Investigator) (in collaboration with the Sponsor). In this study the concomitant use of hormonal contraceptives is allowed.
• Participation in another study with an experimental drug, where the last administration of the previous IMP was within 8 weeks (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for anti-bodies or insulin), whichever is the longer before administration of IMP in this study, at the discretion of the PI.
• Treatment within the previous 3 months before the first administration of IMP with any drug with a well-defined potential for adversely affecting a major organ or system.
• A major illness during the 3 months before commencement of the screening period.
• History of hypersensitivity or allergy (acute rhinitis, angioedema, urticaria or bronchial asthma) to the IMP or its excipients or any related medication (Aspirin or any other NSAID).
• History of hypersensitivity or allergy to cayenne pepper or other capsaicinoids (paprika plants).
• History of bronchospasm or bronchial asthma, arterial hypertension, myocardial infarction, thrombotic events, stroke, congestive heart failure, impaired renal function or liver disease.
• History or current diagnosis of gastrointestinal bleeding or peptic ulcer disease.
• Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome.
• Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of IMP (Investigational medicinal product) .
• Bruises, damaged skin, eczema or wounds on the application site, or the application site inappropriate for applying the IMP in the opinion of the PI (Principal Investigator).
• Further exclusion criteria apply.

Contacts and Locations

Locations

South Africa

Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)

Bloemfontein, South Africa, 9301

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:

Study Protocol  [PDF] February 13, 2017

Statistical Analysis Plan  [PDF] November 22, 2017

More Information

Additional Information:

Related Info 

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03074162
• Other Study ID Numbers: 1358.2
• First Posted: March 8, 2017
• Results First Posted: March 1, 2019
• Last Update Posted: March 1, 2019
• Last Verified: February 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diclofenac; Capsaicin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antipruritics; Dermatologic Agents