Trial Outcomes & Findings for A Study to Characterize Diclofenac's Plasma and Knee Exposure After Application of Diclofenac Gel to the Knee of Subjects With Osteoarthritis That Have a Scheduled Arthroplasty (NCT NCT03497039)

Last Updated: 2020-02-24

Results Overview

Synovial tissue was collected during surgery (participant's scheduled arthroplasty of the target knee on which study treatment was applied). Samples were analyzed for diclofenac levels using a validated bio analytical method in compliance with the applicable standard operating procedures of the bioanalytical laboratory. Synovial tissue diclofenac concentration was summarized by treatment group. Number of participants with diclofenac concentration values that were below the limit of quantification (LOQ) were replaced by 0 for placebo group. The geometric mean was calculated with a two-sided 95% confidence interval assuming data on the logarithmic scale were normally distributed.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

47 participants

Primary outcome timeframe

At Day 8 (up to a maximum of Day 15 in case of surgery delay)

Results posted on

2020-02-24

Participant Flow

The study was conducted at 4 sites in the United Kingdom and 1 site in Germany.

A total of 47 participants with osteoarthritis were enrolled out of which 46 were randomly assigned in 2 arms either to receive Diclofenac Diethylamine (DDEA) 2.32 percent (%) gel treatment or placebo gel. 1 participant withdrew consent before starting treatment.

Participant milestones

Participant milestones
Measure	Diclofenac Diethylamine (DDEA) Gel Participants randomized to this group were instructed to apply DDEA 2.32% gel topically,4grams(g) for about 1minute over a region of approximately 400 square centimeter(cm\^2)per knee, every 12hours (hrs) twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days.If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol,500milligrams \[mg\] tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Overall Study STARTED	30	17
Overall Study Treated	29	17
Overall Study COMPLETED	29	16
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Diclofenac Diethylamine (DDEA) Gel Participants randomized to this group were instructed to apply DDEA 2.32% gel topically,4grams(g) for about 1minute over a region of approximately 400 square centimeter(cm\^2)per knee, every 12hours (hrs) twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days.If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol,500milligrams \[mg\] tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Overall Study Withdrawal by Subject	1	0
Overall Study Protocol Violation	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 Participants Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=17 Participants Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Total n=46 Participants Total of all reporting groups
Age, Continuous	70.9 years STANDARD_DEVIATION 7.59 • n=29 Participants	71.7 years STANDARD_DEVIATION 8.63 • n=17 Participants	71.2 years STANDARD_DEVIATION 7.91 • n=46 Participants
Sex: Female, Male Female	15 Participants n=29 Participants	9 Participants n=17 Participants	24 Participants n=46 Participants
Sex: Female, Male Male	14 Participants n=29 Participants	8 Participants n=17 Participants	22 Participants n=46 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.

PRIMARY outcome

Timeframe: At Day 8 (up to a maximum of Day 15 in case of surgery delay)

Population: Analyzable population consists of all participants who were randomized, received at least 1 dose of investigational product, completed surgery and had evaluable synovial tissue or synovial fluid sample. Here, number analyzed indicates participants with diclofenac tissue concentration values greater than LOQ.

Outcome measures

Outcome measures
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 Participants Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=16 Participants Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Diclofenac Concentration in Treated Knee Synovial Tissue After 7 Days Topical Application of Study Treatment to the Knee (12 Hours After Last Administration of Study Treatment)	1.573 nanograms per gram (ng/g) Interval 1.124 to 2.2	NA nanograms per gram (ng/g) Data could not be computed due to participants with zero values.

PRIMARY outcome

Timeframe: At Day 8 (up to a maximum of Day 15 in case of surgery delay)

Population: Analyzable population consists of all participants who were randomized,received at least 1 dose of investigational product,completed surgery and had evaluable synovial tissue or synovial fluid sample.Here,number analyzed indicates participants with diclofenac fluid concentration values greater than LOQ.

Synovial fluid was collected during surgery (participant's scheduled arthroplasty of the target knee on which study treatment was applied). Samples were analyzed for diclofenac levels using a validated bio analytical method in compliance with the applicable standard operating procedures of the bioanalytical laboratory. Synovial fluid diclofenac concentration was summarized by treatment group. Number of participants with diclofenac concentration values that were below the LOQ were replaced by 0 for placebo group. The geometric mean was calculated with a two-sided 95% confidence interval assuming data on the logarithmic scale were normally distributed.

Outcome measures

Outcome measures
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 Participants Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=16 Participants Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Diclofenac Concentration in Treated Knee Synovial Fluid After 7 Days Topical Application of Study Treatment to the Knee (12 Hours After Last Administration of Study Treatment)	2.274 nanograms per milliliter (ng/mL) Interval 1.874 to 2.759	NA nanograms per milliliter (ng/mL) Data could not be computed due to some participants with zero values.

SECONDARY outcome

Timeframe: At Day 8 (up to a maximum of Day 15 in case of surgery delay)

Synovial tissue was collected during surgery (participant's scheduled arthroplasty of the target knee on which study treatment was applied). Samples were analyzed for diclofenac levels using a validated bio analytical method in compliance with the applicable standard operating procedures of the bioanalytical laboratory. Diclofenac concentration values that were below the LOQ were replaced by 0 for placebo group. The ratio between diclofenac concentration in treated knee synovial tissue and plasma was calculated.

Outcome measures

Outcome measures
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 Participants Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=16 Participants Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Ratio Between Diclofenac Concentration in Treated Knee Synovial Tissue and Plasma After 7 Days Topical Application of Study Treatment to the Knee (12 Hours After Last Administration of Study Treatment)	0.320 (ng/g)/(ng/mL) Interval 0.228 to 0.45	NA (ng/g)/(ng/mL) Data could not be computed due to participants with zero values.

SECONDARY outcome

Timeframe: At Day 8 (up to a maximum of Day 15 in case of surgery delay)

Synovial fluid was collected during surgery (participant's scheduled arthroplasty of the target knee on which study treatment was applied). Samples were analyzed for diclofenac levels using a validated bio analytical method in compliance with the applicable standard operating procedures of the bioanalytical laboratory. Diclofenac concentration values that were below the limit of quantification (LOQ) were replaced by 0 for placebo group. The ratio between diclofenac concentration in treated knee synovial fluid and plasma was calculated.

Outcome measures

Outcome measures
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 Participants Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=16 Participants Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Ratio Between Diclofenac Concentration in Treated Knee Synovial Fluid and Plasma After 7 Days Topical Application of Study Treatment to the Knee (12 Hours After Last Administration of Study Treatment)	0.463 (ng/mL)/(ng/mL) Interval 0.397 to 0.539	NA (ng/mL)/(ng/mL) Data could not be computed due to some participants with zero values.

Adverse Events

Diclofenac Diethylamine (DDEA) Gel

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Placebo Gel

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Diclofenac Diethylamine (DDEA) Gel n=29 participants at risk Participants randomized to this group were instructed to apply DDEA 2.32% gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.	Placebo Gel n=17 participants at risk Participants randomized to this group were instructed to apply Placebo gel topically, 4 g for about 1minute over a region of approximately 400 cm\^2 per knee, every 12 hrs twice daily for 7days. First and last doses were applied by trained nurse at study site. Last dose of study treatment administered at study site 12hrs (-1/+3hrs) prior to arthroplasty surgery (Day 7). If surgery delayed by up to 7days dosing with DDEA gel twice daily continued up to 14days. If surgery delayed by more than 7days,participant withdrawn from study. Rescue medication (Paracetamol, 500 mg tablets) provided at screening visit and instructed to take only if needed 1or2 tablets repeated after at least 4hrs up to 4times daily, up to a maximum of 4g per day.
Infections and infestations Escherichia urinary tract infection	3.4% 1/29 • From start of treatment (Day 1) up to Day 10 (up to a maximum of Day 18 in case of surgery delay) Safety population included all participants who were randomized and received at least one dose of investigational product. All adverse events (AEs) were summarized by system organ class and preferred term. All treatment emergent AEs and serious AEs were collected and reported.	0.00% 0/17 • From start of treatment (Day 1) up to Day 10 (up to a maximum of Day 18 in case of surgery delay) Safety population included all participants who were randomized and received at least one dose of investigational product. All adverse events (AEs) were summarized by system organ class and preferred term. All treatment emergent AEs and serious AEs were collected and reported.
Vascular disorders Hypotension	3.4% 1/29 • From start of treatment (Day 1) up to Day 10 (up to a maximum of Day 18 in case of surgery delay) Safety population included all participants who were randomized and received at least one dose of investigational product. All adverse events (AEs) were summarized by system organ class and preferred term. All treatment emergent AEs and serious AEs were collected and reported.	0.00% 0/17 • From start of treatment (Day 1) up to Day 10 (up to a maximum of Day 18 in case of surgery delay) Safety population included all participants who were randomized and received at least one dose of investigational product. All adverse events (AEs) were summarized by system organ class and preferred term. All treatment emergent AEs and serious AEs were collected and reported.

Other adverse events

Additional Information

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Phone: 866-435-7343

Email: [email protected]

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Principal investigator is a sponsor employee GSK agreements may vary with individual investigators but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
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