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Efficacy of Topical Indomethacin Patch Over Placebo in Ankle Sprain Pain Relief

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ClinicalTrials.gov Identifier: NCT01957215
Recruitment Status : Completed
First Posted : October 8, 2013
Results First Posted : June 15, 2015
Last Update Posted : June 15, 2015
Sponsor:
Collaborator:
Rundo International Pharmaceutical Research & Development Co.,Ltd.
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Ankle Sprain
Interventions Drug: Indomethacin
Drug: Placebo
Enrollment 270
Recruitment Details The study was conducted across multiple sites in China.
Pre-assignment Details  
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description 0.35% w/w Indomethacin patch was applied on the sprained ankle twice a day (BID). Placebo patch was applied on the sprained ankle BID.
Period Title: Overall Study
Started 135 135
Completed 122 123
Not Completed 13 12
Reason Not Completed
Adverse Event             2             2
Lost to Follow-up             3             3
Protocol Violation             1             2
Withdrawal by Subject             7             5
Arm/Group Title Indomethacin Patch Placebo Patch Total
Hide Arm/Group Description Indomethacin patch was applied on the sprained ankle BID Placebo patch was applied on the sprained ankle BID Total of all reporting groups
Overall Number of Baseline Participants 135 135 270
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 135 participants 135 participants 270 participants
37.7  (12.73) 35.6  (12.29) 36.6  (12.53)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 135 participants 135 participants 270 participants
Female
76
  56.3%
73
  54.1%
149
  55.2%
Male
59
  43.7%
62
  45.9%
121
  44.8%
1.Primary Outcome
Title Sum of Pain Intensity Difference (SPID)1-3 Days
Hide Description

SPID was calculated as sum of products of Pain Intensity Differences (PID) at a given time-point (t) with the time-interval from that time-point to the previous time-point (t-1). The time-intervals used were 0 hrs (Day 1, pre treatment), 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs and 48 hrs. Positive and higher scores indicate greater reduction in pain. SPIDt = ∑PID x (time t - time t-1).

Pain Intensity was assessed at baseline and at each time-point based on numerical rating scale (NRS) which is a horizontal line with a scale from 0-10, where 0 represents “No” and 10 represents the “worst possible pain”

Time Frame Baseline (Day 1) to Day 3
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on the Intent-to-Treat (ITT) population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Least Squares Mean (Standard Error)
Unit of Measure: Score on scale
3.981  (0.2163) 3.264  (0.2163)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Indomethacin Patch, Placebo Patch
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0201
Comments P- value was obtained from ANCOVA model with treatment and site as fixed effects and NRS Baseline value as a covariate
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value 0.72
Confidence Interval 95%
0.1134 to 1.3199
Estimation Comments ADJ DIFF is the Treatment difference defined as the Adjusted Mean of 0.35% Indomethacin Patches minus Adjusted Mean of Placebo Patches
2.Secondary Outcome
Title Pain Relief Score (PRS) on Movement Over Time
Hide Description

PRS was assessed for pain on movement (walking 5 steps on flat surface) at 30, 60 minutes and 2, 4, 8 and 12 hrs after the first dose of treatment (indomethacin or placebo patch) and twice daily during the period from 12 hours to 24 hr, 36 hr, 48 hr, 60 hr, 72 hr, 84 hr, 96 hr, 108 hr, 120 hr, 132 hr and 144 hr between treatment groups.

Participants were asked to choose a number on a scale of 0 to 4, where, 0- No pain relief; 1- A little or perceptible pain relief; 2- Meaningful pain relief; 3- A lot of relief; 4- Complete relief. The mean PRS scores were calculated on the basis of participant's response based on the above score.

Time Frame 30 minutes (mins) to 144 hours (hrs) post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement.
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Mean (Standard Deviation)
Unit of Measure: Score on scale
0.5 hours 0.24  (0.539) 0.21  (0.546)
1 hr 0.40  (0.665) 0.42  (0.775)
2 hr 0.58  (0.806) 0.53  (0.791)
4 hr 0.80  (0.862) 0.68  (0.942)
8 hr 0.84  (0.820) 0.68  (0.861)
12 hr 1.22  (0.900) 0.94  (1.006)
24 hr 1.64  (0.933) 1.29  (1.055)
36 hr 1.93  (0.950) 1.55  (1.093)
48 hr 1.94  (0.963) 1.63  (1.006)
60 hr 2.09  (0.965) 1.65  (0.988)
72 hr 2.18  (0.934) 1.69  (1.006)
84 hr 2.33  (0.886) 1.84  (0.995)
96 hr 2.37  (0.920) 1.84  (1.018)
108 hr 2.36  (0.856) 2.07  (0.989)
120 hr 2.46  (0.954) 1.97  (1.026)
132 hr 2.47  (0.928) 2.14  (1.072)
144 hr 2.56  (0.895) 2.16  (0.982)
3.Secondary Outcome
Title NRS for Pain on Movement Over Time
Hide Description

NRS was assessed for pain on movement (walking 5 steps on flat surface) at 30, 60 minutes and 2, 4, 8 and 12 hrs after the first dose of treatment (indomethacin or placebo patch) and twice daily during the period from 12 hours to 24 hr, 36 hr, 48 hr, 60 hr, 72 hr, 84 hr, 96 hr, 108 hr, 120 hr, 132 hr and 144 hr between treatment groups.

The NRS is a horizontal line with a scale from 0-10. After application of patch (indomethacin or reference patch), patients were asked to choose a number that relates to their pain intensity on the scale of 0 to 10, where 0 represents no pain and 10 represents the worst possible pain.

Time Frame 30 mins to 144 hr post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch to be applied on the sprained ankle BID
Placebo patch to be applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Mean (Standard Deviation)
Unit of Measure: Score on scale
0.5 hr 6.90  (1.558) 6.89  (1.329)
1 hr 6.85  (1.510) 6.86  (1.407)
2 hr 6.55  (1.505) 6.63  (1.485)
4 hr 6.26  (1.547) 6.44  (1.609)
8 hr 6.30  (1.501) 6.37  (1.667)
12 hr 5.88  (1.619) 6.18  (1.757)
24 hr 5.27  (1.743) 5.47  (1.876)
36 hr 4.62  (1.875) 5.12  (1.933)
48 hr 4.40  (1.735) 4.86  (1.805)
60 hr 4.08  (1.860) 4.67  (1.886)
72 hr 3.76  (1.911) 4.47  (1.825)
84 hr 3.48  (1.719) 4.13  (1.804)
96 hr 3.21  (1.667) 3.97  (1.902)
108 hr 3.22  (1.571) 3.66  (1.843)
120 hr 2.95  (1.627) 3.58  (1.814)
132 hr 2.84  (1.461) 3.35  (1.804)
144 hr 2.70  (1.366) 3.23  (1.713)
4.Secondary Outcome
Title Change From Baseline in NRS at Rest
Hide Description Mean changes in pain intensity at each time point at rest twice daily (in the morning and afternoon) from treatment day 1 to day 7 between treatment groups at time points 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 84 hrs, 96 hrs, 108 hrs, 120 hrs, 132 hrs and 144 hrs was measured using NRS. The NRS is a horizontal line with a scale from 0-10. After application of patch (indomethacin or reference patch), participants were asked to choose a number that relates to their pain intensity on the scale of 0 to 10, where 0 represents no pain and 10 represents the worst possible pain.
Time Frame Baseline (Day 1) to Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID.
Placebo patch was applied on the sprained ankle BID.
Overall Number of Participants Analyzed 135 135
Least Squares Mean (Standard Error)
Unit of Measure: Score on scale
-3.581  (0.1273) -3.194  (0.1228)
5.Secondary Outcome
Title Time to Onset of Pain Relief
Hide Description Time to onset of pain relief was measured by the time to reach a pain relief score of "1" (“A little or perceptible pain relief”).
Time Frame Baseline (Day 1) to Day 3
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Median (Full Range)
Unit of Measure: Days
0.168
(0.09 to 0.19)
0.208
(0.09 to 0.51)
6.Secondary Outcome
Title Assessment of Sum of Pain Intensity Difference (SPID) on Movement
Hide Description

SPID was calculated as sum of products of Pain Intensity Differences (PID) at a given time-point (t) with the time-interval from that time-point to the previous time-point (t-1). The time-intervals used were 0 hrs (Day 1, pre treatment), 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 84 hrs, 96 hrs, 108 hrs, 120 hrs, 132 hrs and 144 hrs. Positive and higher scores indicate greater reduction in pain. SPIDt = ∑PID x (time t - time t-1).

Pain Intensity was assessed at baseline and at each time-point based on numerical rating scale (NRS) which is a horizontal line with a scale from 0-10, where 0 represents “No” and 10 represents the “worst possible pain”.

Time Frame Baseline (Day 1) to Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch to be applied on the sprained ankle BID
Placebo patch to be applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Least Squares Mean (Standard Error)
Unit of Measure: Score on scale
SPID (1-2 day) 1.402  (0.0985) 1.169  (0.0985)
SPID (1-7 day) 17.62  (0.7113) 15.82  (0.7113)
7.Secondary Outcome
Title Sum of Pain Intensity Difference and Pain Relief (SPRID) on Movement
Hide Description

SPRID:Sum of Pain Intensity Difference (SPID) and Total Pain Relief (TOTPAR) at each post-dosing time-point.

SPRID score ranged from -5.8 (least pain relief) to 40.3 (highest pain relief). SPID and TOTPAR were calculated as weighted sums of Pain Intensity Differences (PID) and Pain Relief Scores (PRS) at each measurement time; 0 hr (Day 1, pre treatment), 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, 24 hr, 36 hr, 48 hr, 60 hr, 72 hr, 84 hr, 96 hr, 108 hr, 120 hr, 132 hr and 144 hr, respectively.

PID was derived by subtracting the pain severity score at a given post-dosing time-point from the baseline [based on NRS which is a horizontal line with a scale from 0-10. where 0 represents “No” and 10 represents the “worst possible pain”]. NR scores were converted into PID scores by subtracting them from baseline pain scores.

PRS was assessed on 5-point categorical pain relief rating scale [0-no relief, 1-little relief, 2-some relief, 3-a lot of relief, 4-complete relief]

Time Frame Baseline (Day 1) to Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch to be applied on the sprained ankle BID
Placebo patch to be applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Least Squares Mean (Standard Error)
Unit of Measure: Score on scale
SPRID (1-2 days) 2.594  (0.1608) 2.099  (0.1608)
SPRID (1-3 days) 7.025  (0.3409) 5.695  (0.3409)
SPRID (1-7 days) 28.85  (1.1045) 25.43  (1.1045)
8.Secondary Outcome
Title Total Pain Relief (TOTPAR) on Movement
Hide Description

TOTPAR was calculated as sum of products of pain relief (PR) at a given time-point (t) with the time-interval from that time-point to the previous time-point (t-1). The time-intervals used were 0 hrs (Day 1, baseline), 0.5 hrs, 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 84 hrs, 96 hrs, 108 hrs, 120 hrs, 132 hrs and 144 hrs. Higher score indicated greater pain relief.

TOTPARt = ∑PR x (time t – time t-1). PR score was assessed at each of the above time-points based on a 5-point categorical scale [0-no relief, 1-little relief, 2-meaningful relief, 3-a lot of relief, 4-complete relief].

Time Frame Baseline (Day 1) to Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch to be applied on the sprained ankle BID
Placebo patch to be applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Mean (Standard Error)
Unit of Measure: Score on scale
TOPTAR (1-2 days) 1.197  (0.0695) 0.935  (0.0692)
TOPTAR (1-3 days) 3.057  (1.389) 2.44  (0.1384)
TOPTAR (1-7 days) 11.27  (0.4234) 9.649  (0.4218)
9.Secondary Outcome
Title Patients' Global Assessment to Treatment
Hide Description Patients global assessment in response to treatment was measured at the end of the study on a scale of 0 to 4 where: 0- Poor; 1- Fair; 2- Good; 3- Very Good; 4- Excellent
Time Frame Baseline (Day 1) to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID.
Overall Number of Participants Analyzed 135 135
Least Squares Mean (Standard Error)
Unit of Measure: Score on scale
2.7  (0.88) 2.2  (0.08)
10.Secondary Outcome
Title Rate of Rescue Medication Use
Hide Description Rescue medication use was monitored throughout a period of 14 days.
Time Frame Baseline (Day 1) to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Measure Type: Number
Unit of Measure: Number of participants
4 7
11.Secondary Outcome
Title Time to First Dose of Rescue Medication Use
Hide Description Rescue medication use was monitored throughout a period of 14 days.
Time Frame Baseline (Day 1) to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID.
Overall Number of Participants Analyzed 135 135
Median (95% Confidence Interval)
Unit of Measure: Days
0.198
(0.06 to 0.25)
0.681
(0.21 to 2.07)
12.Secondary Outcome
Title Total Dose of Rescue Medication Use
Hide Description Rescue medication use was monitored throughout a period of 14 days.
Time Frame Baseline (Day 1) to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy analysis was conducted on ITT population, defined as those participants who received study treatment and had at least one post-baseline efficacy measurement
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description:
Indomethacin patch was applied on the sprained ankle BID
Placebo patch was applied on the sprained ankle BID
Overall Number of Participants Analyzed 135 135
Median (Full Range)
Unit of Measure: Dose
3
(1 to 4)
4
(1 to 10)
Time Frame 19 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Indomethacin Patch Placebo Patch
Hide Arm/Group Description Indomethacin patch to be applied on the sprained ankle twice a day (BID). Placebo patch to be applied on the sprained ankle BID.
All-Cause Mortality
Indomethacin Patch Placebo Patch
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Indomethacin Patch Placebo Patch
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/135 (0.00%)      0/135 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0.5%
Indomethacin Patch Placebo Patch
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/135 (7.41%)      5/135 (3.70%)    
Gastrointestinal disorders     
Gingival bleeding   1/135 (0.74%)  1 0/135 (0.00%)  0
General disorders     
Application site pruritis   1/135 (0.74%)  1 0/135 (0.00%)  0
Inflammation   1/135 (0.74%)  1 0/135 (0.00%)  0
Infections and infestations     
Upper respiratory tract infections   1/135 (0.74%)  1 1/135 (0.74%)  1
Nasopharyngitis   1/135 (0.74%)  1 0/135 (0.00%)  0
Injury, poisoning and procedural complications     
Ligament sprain   1/135 (0.74%)  1 0/135 (0.00%)  0
Skin and subcutaneous tissue disorders     
Pruritis   1/135 (0.74%)  1 2/135 (1.48%)  2
Rash   2/135 (1.48%)  2 1/135 (0.74%)  1
Dermatitis allergic   0/135 (0.00%)  0 1/135 (0.74%)  1
Drug eruption   1/135 (0.74%)  1 0/135 (0.00%)  0
Erythma   0/135 (0.00%)  0 1/135 (0.74%)  1
Vascular disorders     
Vascular rupture   1/135 (0.74%)  1 0/135 (0.00%)  0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01957215     History of Changes
Other Study ID Numbers: 202177
RH01778 ( Other Identifier: GSK )
First Submitted: October 4, 2013
First Posted: October 8, 2013
Results First Submitted: March 26, 2015
Results First Posted: June 15, 2015
Last Update Posted: June 15, 2015