Trial Outcomes & Findings for To Investigate Primary Irritation Potential of Four Skin Serum Products on Human Subjects Assessed by 24 Hour Patch Test (NCT NCT03233009)

NCT ID: NCT03233009

Last Updated: 2019-01-16

Results Overview

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 48 hours following patch removal on Day 4 post 72 hours of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

43 participants

Primary outcome timeframe

At Day 4 (48 hours post patch removal)

Results posted on

2019-01-16

Participant Flow

All the participants were enrolled at one center in Brazil.

A total of 46 participants were screened, out of which 3 participants did not meet study criteria, 43 participants were enrolled in the study out of which 3 participants withdrew their consent. Remaining 40 participants were randomized to the study.

Participant milestones

Participant milestones
Measure
Overall Participants
All participants enrolled in the study received all the study products. Test and control products were applied to a paper disc (or cell) contained within an adhesive patch in a randomized manner. The number of cells available on the patch test tape is 6 (but only 5 cells were used, 4 test and 1 reference products). The patch was then applied onto the dorsum (scapula region) of each participant for a period of 24 ± 2 hours, the sequence of the product application to the cells was as per the randomization schedule.
Overall Study
STARTED
40
Overall Study
Test Product 1
39
Overall Study
Test Product 2
39
Overall Study
Test Product 3
39
Overall Study
Test Product 4
39
Overall Study
Reference Product
39
Overall Study
COMPLETED
39
Overall Study
NOT COMPLETED
1

Reasons for withdrawal

Reasons for withdrawal
Measure
Overall Participants
All participants enrolled in the study received all the study products. Test and control products were applied to a paper disc (or cell) contained within an adhesive patch in a randomized manner. The number of cells available on the patch test tape is 6 (but only 5 cells were used, 4 test and 1 reference products). The patch was then applied onto the dorsum (scapula region) of each participant for a period of 24 ± 2 hours, the sequence of the product application to the cells was as per the randomization schedule.
Overall Study
Lost to Follow-up
1

Baseline Characteristics

To Investigate Primary Irritation Potential of Four Skin Serum Products on Human Subjects Assessed by 24 Hour Patch Test

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Overall Participants
n=40 Participants
All participants randomized to the study. Test and control products were applied to a paper disc (or cell) contained within an adhesive patch. The number of cells available on the patch test tape is 6 (but only 5 cells were used, 4 test and 1 reference products). The patch was then applied onto the dorsum (scapula region) of each participant for a period of 24 ± 2 hours, the sequence of the product application to the cells was as per the randomization schedule.
Age, Continuous
35.7 Years
STANDARD_DEVIATION 11.65 • n=5 Participants
Sex: Female, Male
Female
33 Participants
n=5 Participants
Sex: Female, Male
Male
7 Participants
n=5 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=5 Participants
Race (NIH/OMB)
Asian
0 Participants
n=5 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=5 Participants
Race (NIH/OMB)
Black or African American
11 Participants
n=5 Participants
Race (NIH/OMB)
White
29 Participants
n=5 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=5 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=5 Participants

PRIMARY outcome

Timeframe: At Day 2 (15-30 minutes post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 15-30 minutes following patch removal on Day 2 post 24 hrs of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
6
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
4
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
5
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
7
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
0
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 15-30 Minutes Post Patch Removal
3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants

PRIMARY outcome

Timeframe: At Day 3 (24 hours post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 24 hours following patch removal on Day 3 post 48 hrs of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
0
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
4
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
5
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
6
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 24 Hours Post Patch Removal
7
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants

PRIMARY outcome

Timeframe: At Day 4 (48 hours post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 48 hours following patch removal on Day 4 post 72 hours of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
0
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
4
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
5
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
6
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Frequency of Dermal Response Score at 48 Hours Post Patch Removal
7
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants

PRIMARY outcome

Timeframe: At Day 2 (15-30 minutes post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 15-30 minutes following patch removal on Day 2 post 24 hours of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Average Dermal Response Score at 30 Minutes Post Patch Removal
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0

PRIMARY outcome

Timeframe: At Day 3 (24 hours post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 24 hours following patch removal on Day 3 post 48 hours of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Average Dermal Response Score at 24 Hours Post Patch Removal
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0
0 Score on Scale
Standard Deviation 0

PRIMARY outcome

Timeframe: At Day 4 (48 hours post patch removal)

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

Product tolerability was assessed by Dermal Response Score. Test sites were evaluated 48 hours following patch removal on Day 4 post 72 hours of patch application. Response score from 0 to 7; 0= No evidence of irritation, 1= Minimal erythema, barely perceptible, 2= Definite erythema, readily visible; minimal edema or minimal papular response, 3= Erythema and papules, 4= Definite edema, 5= Erythema, edema and papules, 6= Vesicular eruption, 7= Strong reaction spreading beyond test site.

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Average Dermal Response Score at 48 Hours Post Patch Removal
0 Score on scale
Standard Deviation 0
0 Score on scale
Standard Deviation 0
0 Score on scale
Standard Deviation 0
0 Score on scale
Standard Deviation 0
0 Score on scale
Standard Deviation 0

SECONDARY outcome

Timeframe: At Day 2 (15-30 minutes), Day 3 (24 hours) and Day 4 (48 hours) post patch removal

Population: The ITT (N= 39) population included all participants who were randomized into the study and have skin irritation scores from at least one of the test sites available.

A trained assessor assessed all patch sites.Following scores were used to express response observed at time of examination:0=No evidence of irritation,1=Minimal erythema;barely perceptible,2=Definite erythema,readily visible;or minimal edema; or minimal papular response,3=Erythema and papules,4=Definite edema,5=Erythema, edema,and papules,6=Vesicular eruption,7=Strong reaction spreading beyond test site.Other features indicative irritation (Superficial irritation) scores were:GradeA/Score0=Slight glazed appearance,GradeB/Score1=Marked glazing,GradeC/Score2=Glazing with peeling and cracking,GradeF/Score3=Glazing with fissures,Grade G/Score 3=Film of dried serous exudate covering all or portion of patch,Grade H/Score3=Small petechial erosions and/or scabs.The letter grades were converted to scores.Superficial irritation scores were only provided if there was a dermal response score \>0.No effect is 0 score(i.e. no evidence).Full Range 0-10.Lower score indicates better product tolerabily

Outcome measures

Outcome measures
Measure
Test Product 1
n=39 Participants
This arm includes data from the test sites where test product 1 was applied.
Test Product 2
n=39 Participants
This arm includes data from the test sites where test product 2 was applied.
Test Product 3
n=39 Participants
This arm includes data from the test sites where test product 3 was applied.
Test Product 4
n=39 Participants
This arm includes data from the test sites where test product 4 was applied.
Reference Product
n=39 Participants
This arm includes data from the test sites where reference product was applied.
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · No effect
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade A/Score 0
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade B/Score 1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade C/Score 2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade F/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade G/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 2 (15-30 minutes) · Grade H/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · No effect
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade A/Score 0
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade B/Score 1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade C/Score 2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade F/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade G/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 3 (24 hours) · Grade H/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · No effect
39 Participants
39 Participants
39 Participants
39 Participants
39 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Missing
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade A/Score 0
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade B/Score 1
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade C/Score 2
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade F/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade G/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants
Number of Participants With Combined Skin Irritation (Dermal Response) Scores at 30 Minutes, 24 Hours and 48 Hours Post Patch Removal
Day 4 (48 hours) · Grade H/Score 3
0 Participants
0 Participants
0 Participants
0 Participants
0 Participants

Adverse Events

Test Product 1

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Test Product 2

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Test Product 3

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Test Product 4

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Reference Product

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Overall Participants

Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

  • 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.
  • Publication restrictions are in place

Restriction type: OTHER