Clinical trial NCT03799484
Conditions: Forehead Rhytides Forehead Wrinkles
Keywords: Rhytides Forehead Wrinkles
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2019-01-04; Completion date: 2019-06-14
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether there is a difference in clinical effect, duration of effect, level of discomfort and patient satisfaction in patients receiving topical anesthesia on one side of the forehead and petrolatum ointment on the other prior to Botulinum Toxin Type A administration for the treatment of forehead rhytides.

Detailed description:
This is a prospective, randomized, double-masked, comparative study in patients who present at the Robert Cizik Eye Clinic with horizontal forehead rhytides requiring treatment with botulinum toxin Type A (Botox ®; Allergan, Irvine, CA, USA).

The objective of this study is to determine whether there is a difference in clinical effect (weakness/paralysis of the frontalis muscle), duration of effect, level of discomfort and patient satisfaction in patients receiving topical anesthesia (2.5% lidocaine/2.5 % prilocaine cream, Impax Laboratories, LLC) on one side of the forehead and petrolatum ointment on the other prior to BTX-A administration for the treatment of forehead rhytides.

* Primary outcome variable is change of eyebrow excursion on each side of the forehead from baseline to each follow-up visit.
* Secondary outcome variables

  * Duration of effect, defined as the elapsed time from injection to the end of botulinum, such that return of baseline frontalis function, i.e. within 2 mm of baseline value
  * Perception of pain immediately after injection at each side
  * Patient satisfaction for each side
  * Patient's perception of difference in efficacy

Arms: arm 1: 2.5% Lidocaine/2.5% Prilocaine Cream will be applied to one side of the forehead and Petrolatum Ointment to the other prior to administration of Botulinum Toxin Type A Injection arm 2: Petrolatum Ointment will be applied to one side of the forehead and 2.5% Lidocaine/2.5% Prilocaine Cream to the other side prior to administration of Botulinum Toxin Type A Injection
Interventions: intervention 1: Botulinum toxin type A intervention 2: 2.5% lidocaine/2.5% prilocaine intervention 3: petrolatum ointment
Intervention descriptions: intervention 1: Botulinum toxin type A will be administered to both sides intervention 2: 2.5% lidocaine/2.5% prilocaine will be applied to one side of the forehead intervention 3: petrolatum ointment will be applied to one side of the forehead

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title: Randomized, Single Center, Masked Study Comparing the Efficacy of Botulinum Toxin Type 
A Injection After Topical Anesthesia versus Petrolatum Ointment 
 
NCT03799484 
 
Version Date: 11/30/2018 
 
 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
Title: Randomized, Single Center, Masked Study Comparing the Efficacy of Botulinum 
Toxin Type A Injection After Topical Anesthesia versus Petrolatum Ointment 
 
Principal Investigator: Karina Richani-Reverol, MD 
Biostatistician:  Alice Z. Chuang, PhD 
Study Coordinator: Laura Baker, BS 
Population: Sample size ~14, male/female, 18 – 65 years of age, diagnosed with 
forehead rhytides electing for treatment with botulinum toxin Type A 
Number of sites: 1, Robert Cizik Eye Center 
Study Duration: Patient participation time will be approximately 16 weeks 
 
 
 
Background: 
Botulinum toxin type A (BTX-A) is a potent neurotoxin that blocks the presynaptic 
acetylcholine release at the neuromuscular junction, causing a dose-dependent 
weakness or paralysis of skeletal muscle. Recovery of muscle function occurs through 
proximal axonal sprouting and muscle re-innervation by formation of a new 
neuromuscular junction. Botulinum toxins are currently used for the treatment of a 
variety of medical disorders including spastic facial conditions (essential 
blepharospasms, hemifacial spasms), strabismus, sphincter dysfunction, 
hyperlacrimation, hyperhydrosis and headaches (1-4). In addition, botulinum toxin has 
been used in the treatment of facial rhytides such as crow’s feet, and glabellar lines with 
great aesthetic results (5, 6). More recently, the US Food and Drug Administration 
approved the use of Botox for the temporary improvement in the appearance of 
moderate to severe forehead lines associated with frontalis muscle activity in adults. 
 
A number of factors have been postulated that may affect the efficacy and duration of 
action of botulinum toxin type A including reconstitution process, dilution (units per 
volume), storage time after reconstitution and depth of administration (7,8). The use of 
topical anesthetic prior to administration of BTX-A for the treatment of facial cosmetic 
rythides and blepharospasm has been proposed to have a deleterious impact on BTX-A 
effect, but the data is very limited (7). Multiple studies have investigated the use of 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
topical vibration, topical ice, vapocoolants and topical anesthesia as methods to 
decrease the pain associated with the injection of BTX-A (9-12) without decreasing the 
efficacy of BTX-A. However, there is no consensus on standard of care for 
administration of anesthesia prior to BTX-A administration. While many surgeons use 
one or a combination of the anesthetizing methods above to decrease pain associated 
with the injection, others use none. 
 
 
OBJECTIVES 
The objective of this study is to determine whether there is a difference in clinical effect 
(weakness/paralysis of the frontalis muscle), duration of effect, level of discomfort and 
patient satisfaction in patients receiving topical anesthesia (2.5% lidocaine/2.5 % 
prilocaine cream, Impax Laboratories, LLC) on one side of the forehead and petrolatum 
ointment on the other prior to BTX-A administration for the treatment of forehead 
rhytides. 
 
Outcome Variables 
 Primary outcome variable is change of eyebrow excursion on each side of the 
forehead from baseline to each follow-up visit. 
 
 Secondary outcome variables 
o Duration of effect, defined as the elapsed time from injection to the end of 
botulinum, such that return of baseline frontalis function, i.e. within 2 mm 
of baseline value 
o Perception of pain immediately after injection at each side 
o Patient satisfaction for each side 
o Patient’s perception of difference in efficacy 
 
STUDY DESIGN 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
This is a prospective, randomized, double-masked, comparative study in patients who 
present at the Robert Cizik Eye Clinic with horizontal forehead rhytides requiring 
treatment with botulinum toxin Type A (Botox ®; Allergan, Irvine, CA, USA). 
 
PARTICIPANTS 
All patients who meet the following eligibility criteria may be enrolled. 
 
 
Inclusion criteria 
Patients who meet the following inclusion criteria may be enrolled: 
 Subjects 18 to 65 years of age 
 Presence of horizontal forehead rhytides 
 Good eyebrow excursion (≥5 mm) 
 Able to understand and sign an informed consent form that has been approved 
by the Committee for Protection of Human Subjects 
 
Exclusion criteria 
Patients who meet the following exclusion criteria may NOT be enrolled 
 Previous injection of botulinum toxin in the intended treatment area for the study 
within the last 4 months 
 Known allergy to botulinum toxin 
 Known history of sensitivity to local anesthetics of the amide type 
 Existing disorder of neuromuscular transmission (e.g. Myasthenia gravis or 
Lambert-Eaton syndrome) 
 Usage of medication with effect on neuromuscular function 
 Women of childbearing potential (who are not postmenopausal for at least 1 year 
or surgically sterile), who are pregnant or nursing or intend to become pregnant 
during the time of the study 
 Significant brow asymmetry (> 5mm) 
 Unable to follow-up for the duration of the study (16 weeks) 
 
STUDY DESIGN CONSIDERATIONS 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
 
Randomization 
A computer-generated randomization table will be used to assign which side of the 
forehead receives topical anesthetic and which side receives 41% petrolatum jelly 
(placebo) prior to the BTX-A for each participant. 
 
Masking 
The randomization information will only be known by the principal investigator 
performing the injections and will not be disclosed to the participants or the brow 
excursion examiner. 
 
Sample Size Calculations 
This study is design to compare change of eyebrow excursion from baseline at each 
side of forehead. Tzou (2005) reported that the standard deviation of eyebrow excursion 
was 2.31 mm in both European and Asian populations (16). To detect a 2 mm 
differences between 2 sides, a sample size of 14 is required to have 5% significance 
level and 90% power. 
 
Recruitment period 
Recruitment for this study is anticipated to take approximately 4-6 weeks. 
 
 
RECRUITMENT PROCEDURE 
All patients who meet eligibility criteria electing to undergo treatment with BTX-A will be 
offered this study. All patients interested will be provided with a written consent. Those 
who agree to participate, informed consent will be obtained and the participant will 
proceed into the Baseline Exam. 
 
Randomization Procedure 
Upon completion of the Baseline Visit and eligibility of the participant is confirmed, their 
randomization assignment will be obtained from the computer-generated randomization 
table. 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
 
TREATMENT 
For each patient, one half of the forehead, divided from the contralateral side by an 
imaginary vertical line through the dorsum of the nose, will be treated with a thick layer 
of topical 2.5% lidocaine/2.5 % prilocaine cream (Impax Laboratories, LLC), while the 
other will be treated with 41% petrolatum ointment. After, 30 minutes, the ointment will 
be wiped away and the forehead will be cleaned with an alcohol swab and allowed to. 
Botulinum toxin type A (Botox, Allergan Pharmaceutical, Irine, CA, USA) vials will be 
reconstituted with 0.9 % NaCl bacteriostatic solution by adding 2 ml to 100 units of 
lyophilized toxin. A 1cc syringe with a 30-gauge 1/2-inch needle will be used to 
administer at each site (1 syringe- needle for each side). Two units of BTX-A will be 
administered at each injection site. There will be 5 injection sites per side of forehead, 
for a total of 10 injection sites (20 units) for each participant. All injections will remain at 
least 2 cm from the superior orbital rim to reduce the potential of brow and eyelid ptosis. 
 
If there is toxin remaining in the vial, this will be stored/refrigerated until needed again. 
Before it is used, the cap will be cleaned off with an alcohol swab. If an open, 
reconstituted vial is not used after 48-72 hours, the toxin will be discarded (13). 
 
Participant perception of pain at the injection site will be evaluated by asking them to 
rate their pain, on a scale 0-10 for each side of the forehead (see Appendix 1). 
 
SCHEDULED STUDY VISITS AND ASSESSMENTS 
 
 
Baseline Visit 
After reviewing and signing the informed consent form, all potential participants will 
undergo a baseline evaluation in order to determine study eligibility, establish baseline 
ocular characteristics and determine randomization group based on the computer- 
generated assignment. Participant demographics including age, gender, and race will 
be recorded as well as medical and medication history which will include previous use 
of botulinum toxin and if so the location of the injection and the date. 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
 
Scheduled Follow-up Visits 
Participants will follow-up 2 weeks (+/- 3 days), 6 weeks (+/- 2 weeks) and 16 weeks 
(+/- 2 weeks) after the injection. 
 
Table 1. Time Windows for Scheduled Follow-up Visits (number of days after injections) 
 
Follow-Up Visit 
Ideal Follow-up Time 
Visit Window 
Week 2 
14 days 
11 days – 17 days 
Week 6 
42 days 
35 days – 49 days 
Week 16 
112 days 
98 days – 126 days 
 
 
Scheduled Assessments 
Table 2 outlines the schedule of assessments at each visit throughout the study period. 
Table 2: Schedule of Assessments 
Assessment 
Baseline 
Injection 
Week 2 
Week 6 
Week 16 
Informed Consent 
X 
Demographics 
X 
Medical/Ophthalmic History 
X 
Medication History 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
Exophthalmometry 
X 
X 
X 
X 
Bilateral Brow Excursion 
X 
X 
X 
X 
External Photography-relaxed neutral expression 
X 
X 
X 
X 
External Photography-maximal brow elevation 
X 
X 
X 
X 
Injection 
X 
Satisfaction Survey 
X 
X 
X 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
Universal Pain Scale 
X 
Randomization 
X 
Adverse Events 
X 
X 
X 
X 
 
Assessments 
The same examiner should perform the same assessments for each participant. 
 
 
Medications 
All current patient medications, including vitamins and supplements should be 
documented and reviewed, to assess for any medication that may affect neuromuscular 
function at all study visit. 
 
Exophthalmometry 
The distance between both lateral canthi will be measured using a Hertel 
exophthalmometer (mm) at Baseline, Week 2, Week 6 and Week 16 Visits. 
 
Brow Excursion 
Brow excursion will be assessed at Baseline, Week 2, Week 6 and Week 16. Visits. 
Examinations will be performed by a masked examiner. Eyebrow excursion will be 
measured by using a purple marking pen and placing a mark just above the brow, 
parallel to the center of the pupil while the participants is in a relaxed neutral 
expression. Then, the participant will then be asked to raise the brows and the 
excursion of the brow from resting position to maximum elevation will be measured in 
millimeters. 
 
External Photography 
Patients will be photographed at Baseline, Week 2, Week 6, and Week 16 Visits. 
Photos will be taken using the same digital camera. Patients will be photographed in 
both a relaxed, neutral expression, and while exhibiting maximal voluntary eyebrow 
elevation.  All photos will be transferred to Adobe Photoshop (Adobe Systems, INC). 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
The method described previously by Gordin EA et al. (8) will be used to assess eyebrow 
height. The lateral intercanthal distance will be measured to standardize the photos by 
drawing a horizontal line from one lateral canthus to the other. Baseline brow height will 
be obtained measuring the distance between the line and a point taken at the superior- 
most aspect of the eyebrow, positioned directly above the mid-pupillary axis. 
Measurements will be made at 150% magnification, viewing images on and Mac OS 
High Sierra Version 10.13.3 with a 15-in display and a screen resolution of 1920 x 1200 
pixels. The lateral intercanthal distance will be used to normalize the brow eight from 
each photograph to account for any differences in the camera-to-patient distance. For 
each patient, the ratio brow height to intercanthal distance will be calculated. Then the 
ratio obtained during the neutral brow position will be subtracted from that measure 
during active brow elevation for both sides (pretreatment with anesthetic and 
petrolatum) to yield brow elevation. This will be calculated for each picture taken at the 
baseline visit and at each follow up visit. 
 
Participant Appearance Satisfaction Survey 
Participant satisfaction survey will be conducted at Week 2, Week 6 and Week 16 
Visits. The survey will include questions about the overall appearance of their forehead 
for each side and will be recorded using a 5-point rating scale: 4 = very satisfied, 3 = 
satisfied, 2 = neutral, 1 = dissatisfied and 0 = very dissatisfied. Participants will also be 
asked if there is a noticeable difference between the 2 sides of their face. 
 
Universal Pain Scale Assessment 
Participant pain and/or discomfort will be assessed on the day of Injection (post 
injection) (Appendix 1) for each side. 
 
ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a participant who is 
administered a test article. The AE does not necessarily have a causal relationship with 
the treatment.  An AE can therefore be any unfavorable and unintended sign (including 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
an abnormal laboratory finding), symptom, or disease temporally associated with study 
treatments. 
A non-serious AE is defined as a change in a participant’s ophthalmic and/or medical 
health that is not life-threatening, does not require hospitalization, does not prolong a 
current hospitalization and is not disabling. All AEs must be reported whether they are 
considered study-related or not. 
 
 
Serious Adverse Events 
A serious adverse event is defined as any adverse experience occurring at any time 
during the study that results in: 
 Death 
 Life-threatening 
 Inpatient hospitalization 
 Prolongation of existing hospitalization 
 Disability or permanent damage (including vision threatening complications) 
 A congenital anomaly/birth defect 
 Required intervention to prevent permanent impairment or damage and/or 
other serious important medical events 
 
All SAEs will be submitted to the IRB pursuant to their IRB policy. 
 
 
Recording Instructions 
Mild, moderate, or severe should be used to describe the maximum intensity of the 
adverse event. 
 Mild – Does not interfere with the participant’s usual functions 
 Moderate – Interferes to some extent with the participant’s usual functions 
 Severe – Interferes significantly with the participant’s usual functions 
It should be noted that a severe intensity does not necessarily mean it is an SAE. 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
The investigator will also be asked to determine the likelihood of the relationship 
between the study intervention and the AE. 
 
Follow-up of Adverse Events 
For participants who have ongoing ocular adverse events at the time of their last follow- 
up visit, it is recommended that the Investigator schedule a follow-up visit to determine 
the outcome of the event. 
 
Safety Considerations 
At any point in the study, or after the study has concluded, a subject can return for 
examination if needed. An on-call ophthalmologist will be available at all times, and 
subjects will be given emergency contact information. 
 
Data Analysis 
Data will be summarized by mean (SD) and compared for continuous variables, e.g. 
age, eyebrow excursion, etc., and frequency (%) for discrete variables, e.g. sex, end of 
effect at each follow up, etc. Eyebrow excursion and patient satisfaction at each follow 
up as well as duration of effect and pain score will be compared between the topical 
anesthetic pretreated and non-pretreatment groups using paired t-test; while percent of 
end of effect at each follow-up visit, rate of complications and subjective pain will be 
compared using McNemar test. 
 
Data Storage and security 
To insure the privacy of our participants, only contributors to the study will be allowed to 
review and discuss study data. Each participant will be assigned a study number upon 
enrollment into the study. All subject identifiers will be removed. Study data will be 
systematized in a spreadsheet with subject identification numbers, age, sex, order in 
which the measurements were taken. 
 
Data collected will remain at the site of the study in a secured research office at Cizik 
Eye Clinic and will not be removed under any circumstance. All electronic data, 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
including photos, will be stored on password protected and encrypted devices and 
paper copies will be stored separate in a secured cabinet. 
 
Ethics 
IRB approval will be sought from the Committee for the Protection of Human Subjects 
(CPHS) for approval to recruit and enroll patients from the Robert Cizik Eye Clinic into 
this study. 
 
All information collected about study subjects during this study will be kept confidential. 
Protected health information will be used only to identify patients enrolled in the study 
and will not be disclosed to anyone not directly involved in the study. Study documents 
will be stored in a secure location. A master list of participants will be generated on 
paper and electronic format. This list will be stored in a separate location from the data 
collection forms in a secured locked cabinet and encrypted desktop password protected 
computer. At the completion of data analysis, all data with protected health information 
will be destroyed/shredded. 
 
All participants will be informed both verbally, and in the written informed consent, that 
there are no benefits or monetary compensation for participating in this research study. 
Participants will be given the opportunity to elect to have the botulinum injection without 
participation in the study, and participants will have the right to withdraw from the study 
at any time. 
 
Written, informed consent will be obtained from all participants by a member of the 
investigative team. 
 
References 
1.Scott AB. J PediatrOphthalmol Strabismus. 1980 Jan-Feb;17(1):21-5. 
2.Carruthers A, Carruthers J. Dermatol Surg. 1998 Nov;24(11):1189-94. Review. 
3. Carter SR, Seiff SR. IntOphthalmolClin.1997 Summer;37(3):69-79. 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
4. Charles PD. Am J Health Syst Pharm. 2004 Nov 15;61(22 Suppl 6):S11-23. Review. 
 
5. Carruthers A, Carruthers J. PlastReconstr Surg. 1995 Feb;95(2):427-8. No abstract 
available. 
 
6. Clark RP, Berris CE. PlastReconstr Surg. 1989 Aug;84(2):353-5. 
 
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12. Weiss RA, Lavin PT.Ophthalmic Plast Reconstr Surg. 2009 May-Jun;25(3):173-7 
 
13. Alam M, Bolotin D, Carruthers J, Hexsel D, Lawrence N, Minkis K, Ross 
EV.Dermatol Surg. 2015 Mar;41(3):321-6 
 
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16. Tzou et al, British Journal of Plastic Surgery (2005) 58, 183–195 


IRB NUMBER: HSC-MS-18-0908 
IRB APPROVAL DATE: 11/30/2018 
 
APPENDIX 1.