Evaluation of Anti-inflammatory Steroids of Use in the Prevention of Tooth Sensitivity in Teeth Whitening Technique Office
Phase: NA
Conditions: Inflammation
Sponsor: Universidade Federal Fluminense

 
Anti-inflammatory Steroids in the Prevention of 
Tooth Sensitivity 
 
 
NCT02956070 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
September 20th, 2017 
 
 
 

Materials and Methods 
 
The scientific review committee and the committee for the protection of human participants of 
the local university (protocol number 1.376.881) approved this clinical investigation. It was registered 
in the clinical trials.gov registry under the identification number NCT02956070. We performed this 
study using the protocol that the Consolidated Standards of Reporting Trials (CONSORT) statement 
established. Based on pre-established criteria, we selected 70 volunteers for this study. The study was 
performed from February 15, 2016, to July 12, 2016. 
Two weeks before the bleaching procedures, each volunteer received a dental prophylaxis with 
pumice and water in a rubber cup and signed an informed consent form. 
Study design: This was a randomized, triple-blinded, parallel-group clinical trial in which the 
volunteer, operator, and evaluator were blinded to the group assignment. A third researcher, not 
involved in the evaluation process, was responsible for the administration of the drugs. The study was 
carried out in the clinics of the School of Dentistry of Fluminense Federal University (Nova Friburgo, 
RJ, Brazil). Patients were recruited as they seek for treatment in the clinics of Dentistry of both 
Universities. No advertisement was made for participant recruitment. Patients were recruited in the 
order in which they reported for the screening session, thus forming a sample of convenience. 
Inclusion and exclusion criteria: Volunteers included in this clinical trial were at least 18 years 
old, had good general and oral health, and did not report any type of TS. The volunteers were required 
to have 8 caries-free maxillary anterior teeth without restorations, be free of periodontal disease and 
review and sign the informed consent form. The central incisors had to be shade A1 or darker as 
judged by comparison with a value-oriented shade guide (VITA Classical, VITA Zahnfabrik). Despite 
the fact that the color shade A1 is one of the lightest colors measurable using VITA Classical, many 
volunteers with A1 shade teeth seek dental bleaching, as they are dissatisfied with the color of their 
teeth. 
Two calibrated investigators (SM and CG) independently performed the color evaluations with 
the shade guide. The 2 examiners, blinded to the allocation assignment, schedule the volunteers for 
bleaching and evaluated their teeth against the shade guide at baseline and 1 week after the procedure. 
The 2 examiners were required to have an agreement of at least 85% (Kappa statistic test) before 
beginning the study evaluation. 
Volunteers with anterior restorations or dental prostheses, with anterior orthodontic 
apparatuses or with severe internal tooth discoloration (tetracycline stains, fluorosis, pulpless teeth) 
were not included in the study. In addition, pregnant and lactating women, participants with any other 
pathology that could cause sensitivity (such as gingival recession, dentinal exposure, visible cracks in 
teeth), those taking anti-inflammatory or analgesic drugs, those who smoked or volunteers who had 
undergone tooth-whitening procedures were excluded. Those who reported past or present health 
problems in the stomach, heart, kidneys or liver; those who reported the continuous use of anti-

inflammatory or analgesic drugs; those patients with diabetes, hypertension or the use of 
antihypertensive drugs; or patients who reported allergies to dexamethasone and lactose were also 
excluded from the study. 
Sample size calculation: The primary outcome of this study was the absolute risk of TS. The 
absolute risk of TS (that is, the number of patients [percent] who reported pain at some point during 
dental bleaching) was reported to be approximately 90% for a similar 35% hydrogen peroxide 
bleaching product [20,21,36]. Thus, a minimum sample size of 70 participants was required to have a 
90% chance of detecting, as significant at the 2-sided 5% level, a decrease in the primary outcome 
measure from 90% in the control group to 60% in the experimental group.  
Random sequence generation and allocation concealment: The authors used blocked 
randomization (block sizes of 2 and 4) with an equal allocation ration, using a 3rd-party service 
(Sealed Envelope), which did not intervene in the study. Opaque and sealed envelopes containing the 
identification of the groups were prepared.  
Study intervention: We divided volunteers into the dexamethasone group, who received the 
anti-inflammatory (dexamethasone, capsule – 8 mg) and application of a placebo gel, and the control 
group, who received placebo capsules and the application of desensitizing gel containing 6% 
potassium nitrate and 0.10% fluoride sodium (Soothe, SDI, Victoria, Australia). All volunteers 
received the same bleaching treatment, which 4 experienced operators (LP, FC, WA, ED) performed. 
One week before the in-office bleaching session, volunteers received individual pots containing 6 
capsules in total, with the dexamethasone (Handled by Bem Viver laboratory Ltda), or placebo, in 
identical capsules depending on their allocation group, which contained the same components of the 
dexamethasone drug except for the active ingredient (Table 1).  
The control group received placebo capsules and the application of desensitizing gel containing 
6% potassium nitrate and 0.10% fluoride sodium, and the dexamethasone group received the anti-
inflammatory (dexamethasone, capsule - 8mg) and application of a placebo gel. Volunteers were 
treated in 2 clinical sessions with an interval of 7 days (one week) between them. The protocol for use 
of the product was as follows: The volunteers in the experimental group received 6 capsules of 
dexamethasone 8 mg each, which was administered orally, initially 2 days before the 1st bleaching 
query (8mg, 9 AM, 2 days before the bleaching session; 8mg, 9 AM, 1 day before the bleaching 
session; 8mg, 9 AM, on the day of the bleaching session) [40]. This same scheme was performed for 
the 2nd bleaching session, which was 7 days after the 1st. The operators instructed the volunteers to 
increase adherence to the protocol, and the researches made telephone calls and sent cell phone text 
messages to remind the volunteers of every capsule to be taken.  
Before the dental bleaching, gingival tissue was isolated from teeth using a light-cured resin 
(Gingival Barrier, SDI), and each tooth was light-cured for 10 seconds using a light curing unit with 
1200 mW/cm2 light intensity (Radii-cal, SDI). After the placement of a lip retractor (OptraGate – 
Ivoclar Vivadent), the operator used the 37.5% hydrogen peroxide gel (polaoffice+, SDI) in three 8-

minute applications for both groups in accordance with the manufacturer’s directions. The bleaching 
agent was refreshed every 8 minutes during the 24-minute application period. At the end of each 
session, a single researcher responsible for the blinding (MB) delivered a single syringe to the operator, 
which would contain desensitizing gel if the patient was in the control group, or placebo gel containing 
only carbopol (no active ingredient) if the patient was in the dexamethasone group. The gel was 
applied with a brush on the labial surface of the whitened teeth for 2 to 3 minutes as the manufacturer 
(Soothe SDI Dental Limited) directed.  Two bleaching sessions were performed 1 week apart.  
TS evaluation: TS was evaluated during bleaching and up to 1 hour, 24 hours and 48 hours 
postbleaching. The volunteer was asked to indicate the numeric value of the degree of sensitivity for 
each of the periods above, using a 5-point numeric rating scale (NRS) in which 0= none, 1= mild, 2= 
moderate, 3= considerable and 4= severe [2,4,5,7,23]. 
In addition, the volunteers were also instructed to record the pain intensity using the visual 
analogic scale (VAS) [3,6-9]. This scale is a 100-milimeter horizontal line with scores of 0 and 100 at 
their ends, in which 0 = no sensitivity and 100 = severe sensitivity. The volunteer had to mark with a 
vertical line across the horizontal line of the scale the intensity of the TS. Then, the distance in 
millimeters from the zero ends was measured with the aid of a millimeter ruler. 
The data from each bleaching session were evaluated separately and were merged. For this 
purpose, the worst score or numeric value obtained in both bleaching sessions was considered for 
statistical purposes and the determination of the overall risk and intensity of TS. 
If the volunteer scored 0 (no sensitivity) in all time assessments from both bleaching sessions, 
this volunteer was considered to be insensitive to the bleaching protocol. In all other circumstances, the 
volunteers were considered to have sensitivity stemming from the bleaching procedure. This 
dichotomization allowed us to calculate the absolute risk of TS, which represented the percentage of 
volunteers who reported TS at least once during treatment. We also calculated the overall TS intensity. 
Color evaluation: Shade evaluation was performed before 1 week after the 1st bleaching 
session, but before the 2nd session, and 1 week after the 2nd bleaching session. Color evaluation was 
not performed immediately after each bleaching session so that the effect of dehydration and 
demineralization on color measures could be avoided. We performed the color evaluation using the 
shade guides of VITA Classical and the VITA Bleachedguide 3D-MASTER. (VITA Zahnfabrik). 
For the color evaluation, the VITA Classical shade guide’s 16 tabs were arranged from highest 
(B1) to lowest (C4) value. Although this scale is not linear in the truest sense, we treated the changes 
as representing a continuous and approximately linear ranking for the purpose of analysis, as already 
performed in several published studies [2,3,5,8,9,15,23,25]. The VITA Bleachedguide 3D-MASTER 
contains lighter shade tabs and is already organized from the highest (0M1) to lowest (5M3) value 
[24]. The measurement area of interest for shade matching was the middle 1/3 of the facial surface of 
the central incisor, according to the American Dental Association guidelines [4,12,15]. 

The 2 examiners, masked to the allocation assignment, scheduled the volunteers for bleaching 
and evaluated their teeth against the shade guide at the different time assessments. Color changes were 
calculated from the beginning of the active phase up to and including recall times by calculating the 
change in the number of shade guide units (∆SGU), which occurred toward the lighter end of the 
value-oriented list of shade tabs. In the event of disagreements between the examiners during shade 
evaluation, a consensus was reached through discussion. 
 
 
Statistical analysis 
 
We performed the analysis after the intention-to-treat protocol, and we involved all participants who 
were randomly assigned [21]. In cases of missing data, the last observation was carried forward. The 
statistician was masked to the study groups. The absolute risk of TS and its intensity were evaluated by 
using Fischer’s exact test. (α = 0.05). The authors calculated the relative risk as the confidence interval 
for the effect size. 
Comparison of the TS intensity (NRS data) of the 2 groups at the 2 different assessment points 
were performed by using the Mann-Whitney U test, and comparisons between times within each group 
were performed using the Friedman test. The comparisons of the TS intensity obtained with the VAS 
scale were evaluated by using a 2-way repeated measures ANOVA and Tukey’s test.   
Color changes between groups (∆SGU between base line versus 1 week after the 2nd bleaching 
session) were compared by using a t test, and the shade changes were evaluated by using Student’s t 
test. In all statistical tests, the significance level was 0.05. We performed all analyses by using the 
software SPSS for windows version 20.0 (IBM). 
 
Results 
  
We screened 123 participants examined in the dental chair to check if they met the inclusion 
and exclusion criteria (Figure 1). The bleaching procedures were implemented exactly as planned and 
no modification was performed. 
Characteristics of included participants: The baseline color of the volunteers was similar 
(control group: 5.9 [1.9]; dexamethasone: 5.6 [2.1]); the mean age (SD) between volunteers was 
similar between the groups (control: 22.5 [2.1] and dexamethasone: 22.3 [2.7]), ranging from 19 to 29 
years. Thirty-four percent of the volunteers from the control group, and 23% of the volunteers from the 
dexamethasone group were men. 
Protocol adherence and dropouts: No discontinuity in both treatment groups was found in the 
clinical investigation. All volunteers attended the recall visit 1 week postbleaching. 

Tooth Sensitivity: Two volunteers, 1 from each group, took an analgesic to alleviate the 
bleaching-induced TS (Tylenol, Janssen Cilag Farmacêutica) in the period from 5 to 7 hours after the 
2nd and last clinical bleachings. 
Table 2 shows the number of participants who experienced TS during the bleaching regimen in 
the control group and dexamethasone group. In this table, it is shown that no significant difference was 
observed between groups (p = 0.075). The relative risk, along with the 95% confidence interval, is also 
evidence that the use of the experimental drug protocol had no effect on the reduction of TS. 
Tables 3 and 4 show that the TS was similar in both groups, at different assessment points, in 
both sessions, using both pain scales. It is also seen that the bleaching-induced TS did not last longer 
than 48 hours after the bleaching protocol (Tables 3 and 4). 
Color Evaluation: Significant whitening was observed in both groups (P < .001). The 
descriptive data from bleaching obtained after the 1st and 2nd bleaching sessions can be seen in Table 
5. At the end of the bleaching protocol, a whitening of approximately 3 shade guide units was detected 
for both groups. 
The results of the subjective shade evaluation (VITA Classical: P = 0.27; VITA Bleachedguide 
3D-MASTER: P = 0.68) matched the hypothesis of equality between the groups after bleaching. The 
effect size and the confidence interval for the overall mean difference is also shown in Table 5 and is 
evidence of no statistical difference between groups. 
Adverse effects: In this study, no reports of adverse effects by volunteers were received. 
 
TABLE 1 
PRODUCT 
INGREDIENTS 
Pola Office + SDI* 
• 
37.5% hydrogen peroxide  
• 
potassium nitrate 
Soothe SDI* 
• 
potassium nitrate 6.0% 
• 
fluoride ions 0.10% 
• 
water 89.60% 
• 
thickener 4.20% 
• 
sodium benzoate 0.10% 
Dexamethasone capsules** 
• 
dexamethasone base 8mg 
• 
starch 50% 
• 
lactose monohydrate 35% 
• 
dibasic calcium phosphate 14% 
• 
magnesium stearate 1% 
Placebo capsules** 
• 
starch 50% 
• 
lactose monohydrate 35% 
• 
dibasic calcium phosphate 14% 
• 
magnesium stearate 1% 
Placebo gel** 
• 
carbopol 
* SDI, Victoria, Australia 
** Handled by Bem Viver laboratory Ltda, registration number 09047030/0001-28, located at Santa 
Rosa street, Icarai- Niteroi, RJ, Brazil. Batch of the product: 189155. 
 

TABLE 2 
Participants who experienced tooth sensitivity during the bleaching regimen in the control group 
and dexamethasone group* 
TREATMENT 
TOOTH SENSITIVITY 
(Nº. OF 
PARTICIPANTS) 
ABSOLUTE RISK 
RISK RATIO (95% 
CONFIDENCE 
INTERVAL) 
Yes 
No 
Control 
33 
2 
0.94 
0.24 (0.05 – 1.26) 
Dexamethasone 
28 
7 
0.80 
* Fischer’s exact test (p= 0.075). 
 
 

TABLE 3 
Medians and interquartile (1 and 3 interquartile) ranges of the tooth sensitivity at different assessment points 
using the numeric rating scale (NRS). 
ASSESSMENT 
TIMES 
First Session 
Second Session 
Control 
Dexamethason
e 
Compariso
n group 
Control 
Dexamethason
e 
Comparison 
group 
During 
bleaching 
0 (0-1)A 
0 (0-1) A 
NS! 
0 (0-1) A 
0 (0-1) A 
NS 
Up to 1h after 
bleaching 
0 (0-1) A 
0 (0-1) A 
NS 
0 (0-1) A 
1 (0-1) A 
NS 
Up to 24h after 
bleaching 
0 (0-1) A 
0 (0-1) A 
NS 
0 (0-2) A 
0 (0-1) A 
NS 
Up to 48h after 
bleaching 
0 (0-0) B 
0 (0-0) B 
NS 
0 (0-0) B 
0 (0-0) B 
NS 
* Within each column, significant differences are represented by different uppercase letters. 
! NS: No significant difference between groups. 
 
 

TABLE 4 
Means (standard deviations) of the tooth sensitivity intensity at the different assessment points using visual 
analog scales.* 
ASSESSMENT 
TIMES 
First Session 
Second Session 
Control 
Dexamethasone 
Compariso
n group 
Control 
Dexamethason
e 
Comparison 
group 
During 
bleaching 
8.09 
(17.06)AB 
7.51 (15.46)A 
NS! 
14.03 
(21.39)A 
6.46 (6.34)AB 
NS! 
Up to 1h after 
bleaching 
11.14 
(20.08)A 
6.31 (12.78)A 
NS 
14.31 
(20.13)A 
7.57 (13.46)A 
NS 
Up to 24h after 
bleaching 
8.26 (13.48)A 
5.06 (9.86)A 
NS 
16.60 
(21.57)A 
9.77 (20.55)A 
NS 
Up to 48h after 
bleaching 
2.91 (9.14)B 
0.37 (1.54)B 
NS 
1.91 (5.46)B 
1.14 (4.46)B 
NS 
* Within each column, significant differences are represented by different uppercase letters. 
! NS: No significant difference between groups. 
 
 
 

TABLE 5 
Means (standard deviations) of the change in shade guide units obtained with the VITAL Classical* and 
VITA Bleachedguide 3D-Master* at baseline versus each bleaching session and 1 week post-bleaching. 
TIME 
INTERVAL 
COLOR 
EVALUATION 
TOOL 
GROUPS 
P 
VALUE 
MEAN 
DIFFERENCE 
(95% 
CONFIDENCE 
INTERVAL) 
Control 
Dexamethasone 
Baseline versus 1st 
Session 
VITA Classical 
2.14 (1.52) 
1.89 (1.37) 
0.46 
0.35 (-0.43-0.95) 
VITA 
Bleachedguide 
1.91 (0.95) 
1.86 (0.97) 
0.81 
0.06 (-0.40-0.52) 
2nd session versus 
1st Session 
VITA Classical 
0.74 (1.15) 
0.71 (1.49) 
0.93 
0.03 (-0.61-0.66) 
VITA 
Bleachedguide 
1.29 (0.52) 
1.23 (0.69) 
0.70 
0.06 (-0.23-0.35) 
Baseline versus 
2nd Session 
VITA Classical 
2.54 (2.39) 
2.91 (1.96) 
0.48 
-0.37 (-1.42-0.67) 
VITA 
Bleachedguide 
3.00 (1.19) 
3.2 (1.35) 
0.51 
-0.20 (-0.81 -0.41) 
Baseline versus 1 
week after 2nd 
session 
VITA Classical 
2.77 (1.96) 
2.26 (1.87) 
0.27 
0.51 (-0.40-1.43) 
VITA 
Bleachedguide 
3.20 (1.13) 
3.09 (1.17) 
0.68 
0.11 (-0.44 – 0.66) 
*Manufactured by VITA Zahnfabrik.