Clinical trial NCT04049552
Conditions: Keloid
Sponsor: The University of Texas Health Science Center at San Antonio
Start date: 2020-01-24; Completion date: 2021-05-02
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
1. To test whether topical rapamycin regresses established keloids in humans by measuring surface area and height changes in the scar over time (6 months)
2. To test safety of product and feasibility of conduct for future clinical trial

Detailed description:
This pilot trial will use daily 0.5-1.0 ml applications of 8% RAPA (Rapamycin) in a petrolatum vehicle to treat established keloid lesions in 5 persons with at least 2 chronic keloids in similar body regions (greater than 1-year duration). Treatment will be applied once daily for 6 months. One keloid will receive 8% RAPA ointment and the other keloid will receive petrolatum-only ointment as a control. Surface areas and height of keloids will be monitored pre- and post-treatment to evaluate responses.

Keloid surface area and height changes will be measured pre-treatment and thereafter on a monthly basis using standardized digital photography with a tripod-mounted 8MP Canon S5is camera and calipers to measure keloid height (37).

Surface areas of all photographed lesions will be measured with Image J (http://rsbweb.nih.gov/ij/index.html), a public image-processing program that was used to analyze preliminary data and this study will use the same approach.

Arms: arm 1: Rapamycin ointment will be applied to one keloid on the subject arm 2: Placebo will be applied as a control on one keloid on the subject
Interventions: intervention 1: Rapamycin 8% Ointment intervention 2: Placebo
Intervention descriptions: intervention 1: A compounded ointment containing 8% rapamycin intervention 2: Petrolatum ointment placebo

Protocol documents:
Prot_SAP_000.pdf: 
IRB# 19-0291H 
 
page 1 
Version 1.6  04-20-2020 
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COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title:  
Effect of topical rapamycin ointment on keloid regression: A pilot 
study in human subjects (RAPA-Keloid) 
 
 
NCT number: NCT04049552 
 
 
IRB Approval Date: 04/30/20 
 
 
Unique Protocol ID: HSC20199291H 
 


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CLINICAL RESEARCH PROTOCOL 
 
 
 
 
Effect of topical rapamycin ointment on keloid regression:  
A pilot study in human subjects (RAPA-Keloid) 
 
 
Sponsor-Investigator: 
Dean L. Kellogg, Jr., MD 
Professor 
UT Health Science Center 
Department of Medicine – Division of Geriatrics, Gerontology and 
Palliative Medicine 
7703 Floyd Curl, MC 7885 
San Antonio, TX 78229-3900 
210-617-5197 
 
 
Study Product: 
Rapamycin, 8% topical ointment 
Protocol Number: 
HSC20190291H 
IND Number: 
144448 
NCT#: 
NCT04049552 
 
 
Funding Sponsor: 
Grant Award through NIH-NIA to The University of Texas 
Health Science Center – Department of Medicine 
 
 
 
 
 
Initial version: v1.0_04-17-2019 last revised v1.6 04-20-2020 


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                                                           TABLE OF CONTENTS 
 
STUDY SUMMARY ................................................................................................................................................................ 6 
1. INTRODUCTION ................................................................................................................................................................. 7 
1.1. 
BACKGROUND .................................................................................................................................................... 7 
1.2. 
INNOVATION ....................................................................................................................................................... 7 
1.3. 
PRELIMINARY DATA ............................................................................................................................................. 8 
1.4. 
INVESTIGATIONAL AGENT .................................................................................................................................... 9 
1.5. 
DOSE RATIONALE AND RISK/BENEFITS ................................................................................................................ 9 
2. STUDY OBJECTIVE ......................................................................................................................................................... 10 
3. STUDY DESIGN ............................................................................................................................................................... 10 
3.1. 
SUBJECTS ........................................................................................................................................................ 10 
3.2. 
GENERAL DESIGN ............................................................................................................................................. 10 
3.3. 
STUDY ENDPOINTS ........................................................................................................................................... 11 
3.4. 
POTENTIAL RISKS TO SUBJECT SAFETY ............................................................................................................. 11 
3.4.1. 
DRUG ADMINISTRATION. ................................................................................................................................... 11 
3.4.2. 
BLOOD WITHDRAWAL ........................................................................................................................................ 11  
3.4.3. 
PSYCHOSOCIAL... ............................................................................................................................................. 11 
4. SUBJECT SELECTION AND WITHDRAWAL ................................................................................................................. 11 
4.1. 
INCLUSION CRITERIA ......................................................................................................................................... 11 
4.2. 
EXCLUSION CRITERIA ........................................................................................................................................ 11 
4.3. 
SUBJECT RECRUITMENT AND SCREENING .......................................................................................................... 12 
4.4. 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................................... 12 
4.4.1. 
WHEN AND HOW TO WITHDRAW SUBJECTS ........................................................................................................ 12 
4.4.2. 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS ....................................................................... 12 
5. STUDY DRUG .................................................................................................................................................................. 13 
5.1. 
DESCRIPTION ................................................................................................................................................... 13 
5.1.1. 
RAPAMYCIN [FROM STREPTOMYCES HYGROSCOPICUS ≥95% (HPLC), POWDER (SIGMA ALDRICH)] ...................... 13 
5.1.2. 
PETROLATUM (VASELINE, VEHICLE ONLY) ........................................................................................................... 14 
5.1.3. 
COMPOUNDED INVESTIGATIONAL PRODUCT ........................................................................................................ 14 
5.2. 
TREATMENT REGIMEN ....................................................................................................................................... 14 
5.3. 
ADMINISTRATION OF STUDY DRUG ..................................................................................................................... 15 
5.4. 
SUBJECT COMPLIANCE MONITORING ................................................................................................................. 15 
5.5. 
PRIOR AND CONCOMITANT THERAPY ................................................................................................................. 15 
5.5.1. 
EXCLUSIONARY MEDICATIONS:........................................................................................................................... 15 
5.5.2. 
POSSIBLE DRUG INTERACTIONS: ........................................................................................................................ 15 
5.6. 
PACKAGING ...................................................................................................................................................... 15 
5.7. 
MANAGEMENT OF STUDY DRUG ........................................................................................................................ 15 
5.7.1. 
STORAGE ......................................................................................................................................................... 15 
5.7.2. 
DISPENSING OF STUDY DRUG ........................................................................................................................... 16 
5.7.3. 
RETURN OR DESTRUCTION OF STUDY DRUG ...................................................................................................... 16 
6. STUDY PROCEDURES .................................................................................................................................................... 16 
6.1. 
VISIT 1 – CONSENT, SCREENING AND BASELINE ................................................................................................. 16 
6.1.1. 
INFORMED CONSENT ........................................................................................................................................ 16 
6.1.2. 
SCREENING AND BASELINE ................................................................................................................................ 16 
6.1.3. 
STANDARDIZED DIGITAL PHOTOGRAPHY AND CALIPER MEASURESMENTS - ANALYSIS ............................................ 17 
6.2. 
VISIT 2 (APPROXIMATELY 4 WEEKS AFTER VISIT 1) – MONTH 1 OF TREATMENT ..................................................... 17 
6.3. 
VISIT 3 (APPROXIMATELY 4 WEEKS AFTER VISIT 2) – MONTH 2 ............................................................................ 17 
6.4. 
VISIT 4 (APPROXIMATELY 4 WEEKS AFTER VISIT 3) – MONTH 3 ............................................................................ 17 


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6.5. 
VISIT 5 (APPROXIMATELY 4 WEEKS AFTER VISIT 4) – MONTH 4 ............................................................................ 17 
6.6. 
VISIT 6 (APPROXIMATELY 4 WEEKS AFTER VISIT 5) – MONTH 5 ............................................................................ 18 
6.7. 
VISIT 7 (APPROXIMATELY 4 WEEKS AFTER VISIT 6) – MONTH 6 – FINAL STUDY VISIT ............................................ 18 
7. STATISTICALPLAN ......................................................................................................................................................... 18 
7.1. 
STATISTICAL METHODS ..................................................................................................................................... 18 
8. SAFETY AND ADVERSE EVENTS ................................................................................................................................. 19 
8.1. 
DEFINITIONS ..................................................................................................................................................... 19 
8.1.1. 
ADVERSE EVENT (AE) ...................................................................................................................................... 19 
8.1.2. 
SERIOUS ADVERSE EVENT (SAE) ...................................................................................................................... 19 
8.1.3. 
UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR OTHERS (UPIRSO)............................................. 19 
8.1.4. 
ADVERSE EVENT REPORTING PERIOD ............................................................................................................... 19 
8.1.5. 
PRE-EXISTING CONDITION ................................................................................................................................. 20 
8.1.6. 
ABNORMAL LABORATORY VALUES ..................................................................................................................... 20 
8.1.7. 
HOSPITALIZATION, PROLONGED HOSPITALIZATION OR SURGERY ......................................................................... 20 
8.2. 
RECORDING OF ADVERSE EVENTS ..................................................................................................................... 20 
8.3. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ...................................................... 21 
8.3.1. 
INVESTIGATOR REPORTING: NOTIFYING THE PEPPER CENTER DSMB .................................................................. 21 
8.3.2. 
INVESTIGATOR REPORTING: NOTIFYING THE UTHSCSA IRB ............................................................................... 21 
Notifying the IRB and or FDA if SAE or UPIRSO ........................................................................................... 21 
8.4. 
MEDICAL MONITORING ...................................................................................................................................... 22 
8.5. 
STOPPING RULES ............................................................................................................................................. 23 
9. DATA HANDLING AND RECORDKEEPING .................................................................................................................. 23 
9.1. 
CONFIDENTIALITY ............................................................................................................................................. 23 
9.2. 
SOURCE DOCUMENTS ....................................................................................................................................... 23 
9.3. 
CASE REPORT FORMS ...................................................................................................................................... 23 
9.4. 
DATA MANAGEMENT ......................................................................................................................................... 23 
9.5. 
RECORDS RETENTION ....................................................................................................................................... 24 
10. STUDY MONITORING, AUDITING ,AND INSPECTING ............................................................................................... 24 
10.1. 
STUDY MONITORING PLAN ................................................................................................................................ 24 
10.2. 
AUDITING AND INSPECTING ................................................................................................................................ 24 
11. ETHICAL CONSIDERATIONS ....................................................................................................................................... 24 
12. STUDY FINANCES ......................................................................................................................................................... 25 
12.1. 
FUNDING SOURCE ............................................................................................................................................ 25 
12.2. 
CONFLICT OF INTEREST .................................................................................................................................... 25 
12.3. 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................................... 25 
13. PUBLICATION PLAN ..................................................................................................................................................... 25 
14. REFERENCES ................................................................................................................................................................ 26 
15. ATTACHMENTS ............................................................................................................................................................. 28 
16. SUMMARY OF PROTOCOLCHANGES ........................................................................................................................ 29 
 


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List of Abbreviations 
 
 
 
mTOR – formerly mammalian Target of Rapamycin 
RAPA – rapamycin 
P-gp – permeability glycoprotein 
CLOX – clock drawing task 
IL-6 – interleukin 6, a pro-inflammatory cytokine and an anti-inflammatory myokine 
VEGF – vascular endothelial growth factor 
NGF – nerve growth factor 
TGF-B1 – transforming growth factor beta-1


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       Study Summary 
Title 
Effect of Topical Rapamycin Ointment on Keloid Regression: A pilot study in 
human subjects 
Protocol Number 
HSC20190291H 
Phase 
Pilot 
Methodology 
For each participant, one keloid will be treated with topical RAPA ointment 
while the second keloid will serve as an untreated control. 8% RAPA ointment 
will be applied to the ‘treatment’ keloid and the second receives petrolatum-
only vehicle, to allow each subject to be his/her own control. 
Study Duration 
7 months including screening and post treatment follow up 
Study Center(s) 
Audie L. Murphy VA Hospital 
Objective 
1. To test whether topical rapamycin regresses established keloids in humans 
by measuring surface area and height changes in the scar over time (6 
months) 
2. To test safety of product and feasibility of conduct for future clinical trial 
Number of Subjects 
Screen up to 20 participants to achieve 5 completers 
Inclusion Criteria 
1. Age 18-75 years old with at least 2 keloid scars (extant at least 1 year) in 
similar body locations  that are easy to reach to apply ointment 
2. Subjects will be in good health with all chronic diseases (hypertension, 
coronary artery disease, etc.) clinically stable  
3. Cognitive functioning (CLOX1 ≥10 and CLOX2 ≥12 ) sufficient to provide 
informed consent and be able physically to apply QD ointment to affected 
area 
4. Able to attend monthly clinic visits for 6 months 
Exclusion Criteria 
1. Diagnosis of diabetes 
2. Exclusionary medications: systemic steroid or immunosuppressant therapy 
within past 6 months or local area steroidal treatment within 3 months  
3. History of allergy to rapamycin or petrolatum-based products 
Study Product, Dose, 
Route, Regimen 
8% rapamycin in petrolatum ointment vs. vehicle only 
Duration of 
administration 
6 months, once daily 
Statistical Methodology 
Keloid surface area and height data will be analyzed using ANOVA 
 


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 1. Introduction 
 
This document is a protocol for a human research study. This study shall be conducted according to Good 
Clinical Practice guidelines as adopted by FDA, applicable government regulations, and Institutional 
research policies and procedures.  
1.1. Background 
Keloids are dermal fibroproliferative lesions induced by skin wounding and are most common in darker 
pigmented persons, particularly Africans, Hispanics, and Asians with up to 16% of these minority 
populations being at risk (17). Keloids can cause significant physical discomfort including pruritis, pain, 
and limitation of joint mobility; however, the worst sequelae are significant cosmetic defects and 
deformities. No truly effective keloid therapy exists, yet one is clearly needed. No laboratory animal 
models of keloids exist; instead, most work has been done on post-surgical samples with subsequent cell 
culture. Because keloid recurrence rate is high (up to 54% after excision) obtaining a biopsy solely for 
research can be considered unethical (17, 19). Based on cell culture studies, increased production of 
cytokines and growth factors including IL-6, VEGF, NGF, and TGF-B1 that activate of the mechanistic 
(formerly mammalian) Target of Rapamycin (mTOR) are mechanistically involved in keloid formation (18).  
As activation of mTOR is likely involved in the keloid formation, extant knowledge suggests that inhibition 
of mTOR activity with agents such as rapamycin would inhibit keloid development and maintenance.  
1.2. Innovation 
Because keloid recurrence rate is high (up to 54% after excision) obtaining a biopsy solely for research, 
though not often done, has revealed some pathophysiological mechanisms in keloid formation and 
maintenance (17, 19). Based on such cell culture studies with cells derived from human keloid biopsies, 
increased production of cytokines and growth factors including IL-6, VEGF, NGF, and TGF-B1 that 
activate of the mechanistic (formerly mammalian) Target of Rapamycin (mTOR) are mechanistically 
involved in keloid formation (18).  Furthermore, and particularly relevant to our proposal, tissue extracts 
obtained from established keloid scar tissue demonstrated elevated expression of mTOR, p70KDa S6 
kinase (p70S6K), and increased levels of their activated forms, suggesting roles in already extant keloid 
scars (14).  Given that many mechanisms implicated in keloid development involve activation of mTOR, 
mTOR inhibition has been suggested as a potential therapeutic approach to preventing keloids (14, 20, 
21). In addition, findings that established keloid scars contain elevated expression of mTOR, p70KDa S6 
kinase (p70S6K), and their activated forms, mTOR inhibition may facilitate treatment of already extant 
keloids (14).  Rapamycin (RAPA) is an FDA approved mTOR antagonist. Work in our laboratory 
established that this agent could be delivered transdermally as an ointment without producing measurable 
levels in the circulation and with no systemic effects. Subsequent serendipitous work in our laboratory 
suggested that application of topical RAPA ointment regressed established keloids, again without 
systemic effects. We will test this innovative topical treatment in persons susceptible to keloids who have 
established keloid scars that have not received any prior treatment. 
 
The number of diagnosed keloids is increasing as decorative piercing is increasingly practiced, especially 
in visible anatomical sites and in younger age groups. Patients suffering from visible keloids may be 
affected by their disfigurement and suffer psychological consequences. Indeed, the quality of life can be 
severely impaired (40). There is no single effective therapeutic treatment for keloids. Numerous 
treatments have been described including occlusive dressings, compression therapy, steroid injections, 
imiquimod cream, laser therapy, surgical excision, cryosurgery, 5-fluorouracil, bleomycin, interferon 
therapy, and even radiation treatments (31). Unfortunately, these treatments are ineffective long-term and 
post-treatment recurrence is common (8, 40). A simple, effective, and safe treatment is needed. 
 
 


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1.3. Preliminary data 
Our preliminary data showed that topically applied 8% RAPA ointment produces measurable drug levels 
in skin, but no systemic levels and was devoid of systemic effects. We also observed that a skin punch 
biopsy site pretreated with 8% RAPA ointment in a keloid-prone volunteer never underwent keloid 
formation while the site treated with vehicle alone did, suggesting that topical RAPA can prevent keloid 
formation. We subsequently examined whether applying 8% RAPA ointment to an established keloid 
could regress the lesion. Indeed, the lesion did regress with application of 8% RAPA ointment.  
 
Our laboratory completed an NIA funded investigation into the effects of mTOR blockade by topical RAPA 
on blood flow in vivo in middle-aged human volunteers. In preparation for blood flow experiments, we 
compared the ability of topical 1% versus 8% RAPA ointments to deliver RAPA into skin. The 1% and 8% 
RAPA ointments were applied over different intradermal microdialysis probes to examine which, if either, 
RAPA concentration would deliver the agent into skin. Microdialysis perfusates from the cutaneous 
interstitial space were collected and measured by HPLC-mass spec. These experiments showed that 
topical application of 1% RAPA ointment produced inconsistent interstitial RAPA levels, but 8% RAPA 
ointment universally produced measurable skin interstitial levels. Simultaneous blood sampling showed 
that topical 8% RAPA ointment produced no measurable systemic level. Based on these results with 
application time of a few hours, 8% RAPA ointment was chosen for subsequent experiments of a week’s 
duration. In our week-long studies, 8% RAPA ointment produced an average level of 11.47±4.03ng/ml in 
skin after 7 days of application, again with no detectable RAPA level in blood.  
 
As part of the original RAPA study, 3mm skin punch biopsies are performed, one at a site that received 
8% RAPA for a week and a second biopsy done at a nearby site that was treated with the ointment 
vehicle only. During a post-biopsy visit with one keloid-prone subject, we noted that the biopsy site that 
received vehicle only healed with a small keloid while the site that received 8% RAPA ointment healed 
without any lesion whatsoever. This serendipitous observation suggested that 8% RAPA ointment could 
prevent keloid formation. 
 
To explore this possibility a keloid-prone volunteer applied 8% RAPA ointment to an established keloid 
once per day. Digital photographs with metric rulers adjacent to the keloid were taken to objectively 
monitor changes in lesion size. Surface area calculations from the digital photos were calculated by image 
analysis with     Image J. This program can 
measure surface areas based on pixel analyses 
when calibrated against a standard; in our case 
the standard was a millimeter ruler in the 
photograph, adjacent to the keloid.  
 
After 2 months of treatment the volunteer stated 
that he believed the lesion was getting smaller, 
although this was not apparent from lesion 
surface area calculations. (In retrospect, we 
speculate in the first months of treatment the 
surface area did not decrease but the height of 
the 
lesion 
above 
the 
surrounding 
skin 
decreased). After 4 months, the keloid surface 
area calculated from the photographs showed a 
tendency toward reduction. After 7 months, 
surface area calculations made by 3 different 
blinded observers with NIH Image J from digital 
photographs taken under identical lighting and 
distance conditions showed a clear reduction in 
surface area (see figure, prior page-calculated 


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surface area in cm2 with linear regression lines for months 4-7). The plot shows the lesion area measured 
by three readers from multiple photographs vs. follow-up time. The data were analyzed using analysis of 
variance (ANOVA) for repeated measurements (22). The statistical model included the effect of follow-up 
time, a random effect of photograph within follow-up time, a random effect of reader, an interaction of time 
and reader, an interaction of reader and photograph, and a residual error. The largest variance 
component was due to reader (variance component estimate 0.0036) with the residual error being the 
second largest (0.0011); estimates of the other variance components were substantially smaller 
(photograph within time 0.0002, reader by time 0.0002, and reader by photograph 0.0001). There was a 
significant linear trend (slope = -0.0013, P=0.0163); the quadratic trend was not statistically significant 
(P=0.2728). The negative linear trend was observed for each reader (Reader 1 -0.0016, P=0.0066; 
Reader 2 -0.0008, P=0.1118; Reader 3 -0.0013, P=0.0459). This exciting observation led us to propose 
this pilot study to test topical application of 8% RAPA ointment to regress keloids. 
1.4. Investigational Agent 
Rapamycin (RAPA) concentration of 8% RAPA in a petrolatum vehicle will be compounded and supplied 
by Doyle’s Pharmacy (Houston, TX). We will have subjects self-administer study product or placebo to be 
applied directly to each treatment keloid. This schedule replicates that which generated our preliminary 
keloid-regressing results. Our placebo control ointment will be the petrolatum vehicle only. Both ointments 
will have the same consistency and smell.  
1.5. Dose Rationale and Risk/Benefits 
Our pilot trial will use 0.5-1.0ml applications of 8% RAPA in a petrolatum vehicle to established keloid 
lesions in 5 persons with at least 2 chronic keloids greater than 1-year duration in similar body regions. In 
preliminary studies, we found that applying this 8% RAPA ointment reliably produced local transdermal 
delivery of RAPA without producing any measurable RAPA levels in systemic blood (6). Treatment will be 
applied once daily for 6 months.  Surface areas of keloids will be monitored monthly and compared over 
time to evaluate responses.  
 
Topical RAPA Ointment: RAPA from LC Labs was used in our preliminary studies (7, 11). Initially, we 
used a formulation of 1% RAPA in a petrolatum vehicle (6). This topical preparation had been 
demonstrated to regress skin angiofibromas in tuberous sclerosis patients (6). No systemic RAPA blood 
levels, alterations in complete blood counts, changes in complete metabolic profiles, or skin irritation 
occurred in the tuberous sclerosis patients in that study (6). An alternative topical formulation of RAPA in 
a vehicle of either 50:40:10 capric acid/isopropyl myristate/benzoyl alcohol or 50:50 capric acid/benzoyl 
alcohol has also been tested in humans (15). The latter formulations, in up to 8% RAPA concentrations, 
improved psoriasis, was undetectable in blood, and produced no clinical blood test changes; however, a 
few participants had adverse reactions to the vehicle.  Because topical 1% RAPA in petrolatum was 
documented to exert local effects without any systemic effects or adverse reactions to the vehicle, we 
chose this formulation and strength for our initial studies. We assessed transdermal delivery by applying 
the 1% RAPA ointment over an intradermal µD probe and sampled RAPA delivery into the cutaneous 
interstitial space. We found 1% RAPA produced measurable interstitial RAPA concentrations in some, but 
not all cases. We therefore increased the RAPA concentration in petrolatum to 8% and repeated our µD 
measurements.  We found that we could reliably achieve an interstitial level of 11.47±4.03ng/ml RAPA 
with this 8% RAPA ointment that was chosen for further studies. This 8% RAPA formulation subsequently 
prevented keloid formation at a skin biopsy site and regressed an established keloid in a keloid-prone 
subject leading to the present pilot proposal. 
 
One keloid will be treated with topical RAPA while the second keloid will serve as an untreated control by 
receiving petrolatum vehicle only. 8% RAPA ointment will be applied to the ‘treatment’ keloid but not the 
second, to allow each subject to be his/her own control. 
 
 
 


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Potential Risks: In a randomized, double blind, vehicle-controlled multicenter study of 179 patients with 
facial angiofibromas secondary to tuberous sclerosis complex, 59 enrolled and randomized to 1% RAPA, 
63 to 0.1% RAPA, and 57 to the vehicle-only group (23). Topical rapamycin was generally well-tolerated, 
with no measurable systemic absorption. Nearly all AEs were mild, with no drug-related moderate, 
severe, or serious events.  
 
Apparent drug-related adverse effects at the application site were limited to 10% or less incidence for: 
• 
Discomfort or pain 
• 
Pruritis 
• 
Acne 
• 
Erythema 
• 
Irritation 
 
In this same trial, generalized symptoms occurred in a few subjects, including nasopharyngitis, nasal 
congestion, sinusitis, application site papules and applications site paresthesia. There were no reports of 
generalized symptoms such as pruritis, nausea, mouth ulceration or cough. 
 
2. Study Objective 
We will test the primary hypothesis that treatment of extant keloids with 8% topical RAPA ointment will 
regress keloid surface area and height. 
 
Finally, to assess safety, we will gather data on anticipated common side effects of the medication, 
including any adverse drug reactions other than those listed as potential risks in Section 1.5 above. 
 
Objectives:  
1. To compare the effect of topical RAPA 8% ointment to treat established keloid versus untreated keloid 
2. To test whether regression of surface area occurs after 6 months of treatment 
3. To test whether regression of height of treated keloid occurs after 6 months 
 
3. Study Design 
3.1. Subjects 
We will screen up to 20 persons ages 18-75 without diabetes or unstable, chronic diagnoses. We intend 
to complete 5 subjects achieving 6 months of treatment with topical RAPA. Refer to Section 4, 
Inclusion/Exclusion Criteria. 
3.2. General Design 
Our pilot trial will use daily 0.5-1.0ml applications of 8% RAPA in a petrolatum vehicle to treat established 
keloid lesions in 5 persons with at least 2 chronic keloids in similar body regions (greater than 1-year 
duration). Treatment will be applied once daily for 6 months. One keloid will receive 8% RAPA ointment 
and the other keloid will receive petrolatum-only ointment as a control. Surface areas and height of 
keloids will be monitored pre- and post-treatment to evaluate responses.  
 
We will measure keloid surface area and height changes pre-treatment and thereafter on a monthly basis 
using standardized digital photography with a tripod-mounted 8MP Canon S5is camera and calipers to 
measure keloid height (37). 
 
Surface areas of all photographed lesions will be measured with Image J (http://rsbweb.nih.gov/ij/index.html), 
a public image-processing program that we used to analyze our preliminary data and will use the same 
approach in this study. 


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3.3. Study Endpoints 
 
Primary outcome:  
 
• 
Change in keloid surface area and keloid height 
3.4. Potential Risks to Subject Safety 
3.4.1. Drug Administration. 
The most common side effects of rapamycin include: 
 
          TOPICAL: 
SYSTEMIC: (≥ 20%) 
• Discomfort or pain 
• Stomatitis 
• Acne 
• Dizziness 
• Pruritis 
• Diarrhea 
• Chest pain 
• Myalgia 
• Erythema 
• Abdominal pain 
• Peripheral 
• Hypercholesterolemia 
• Irritation 
• Nausea 
• URI 
 
• Rash 
• Nasopharyngitis 
• Headache 
 
 
3.4.2. Blood withdrawal.  Subjects will undergo venipuncture to obtain blood specimen for complete 
blood count (CBC) and comprehensive chemistry (CMP) for general safety purposes. Although our 
research staff are experienced in venipuncture and aseptic technique, the most common risks to 
phlebotomy include mild pain from the needlestick or venous catheter, bleeding, bruising, and rarely 
infection. 
3.4.3. Psychosocial. Subjects may experience psychological distress from assessments of cognitive 
function (CLOX), which will be minimized with use of privacy barriers. 
 
4.  Subject Selection and Withdrawal 
4.1. Inclusion Criteria 
• 
Both sexes of ages 18-75 years in good general health 
• 
All ethnic groups regardless of Veteran status 
• 
Must have at least two (2) keloids present for at least 1 year, located in a similar body area that 
can be easily reached, and be willing to self-administer investigational ointment and placebo 
control 
• 
Cognitive functioning (CLOX1 ≥10 and CLOX2 ≥12 ) sufficient to provide informed consent and be able 
physically to apply QD ointment to affected area 
• 
Negative pregnancy test 
 
4.2.  Exclusion Criteria 
• 
Diagnosis of active or chronic skin disorders  
• 
History of, or active treatment for local or systemic infections, especially of skin 


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• 
Current treatment with systemic steroid or immunosuppressant therapy within the past 6 months or 
local steroidal treatment within 3 months. Potential subjects may be re-screened if local treatment is 
discontinued for the 3-month period. 
• 
Active/unstable conditions: inflammatory, thyroid, autoimmune, gastrointestinal (GI), hematologic, or 
neoplastic disorders. Subjects with clinical lab values outside the normal range and determined to be 
clinically significant by investigator will be excluded.  
• 
Subject is considered unsuitable for the study in the opinion of the investigator for any other reason 
4.3. Subject Recruitment and Screening 
Subjects will be recruited and by referral from any Audie L. Murphy VA Hospital outpatient clinic or 
research unit, through medical record review, and by referral from dermatology and other outpatient 
clinics at UT Health San Antonio. Fliers and other means of advertisement may be distributed per 
applicable institutional policy. 
 
Screening will be performed following consent at Visit 1, prior to baseline data collection and 
assessment of eligibility criteria listed above. 
 
4.4. Early Withdrawal of Subjects 
4.4.1. When and How to Withdraw Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
 
Withdrawal of full consent for a study means that the subject does not wish to receive further 
investigational treatment and does not wish to or is unable to continue further study participation. This 
may include any follow-up in person, by phone, through third parties including relatives or friends, via 
discussion with other treating physicians, and by use of medical records. Subject data up to withdrawal of 
full consent will be included in the analysis of the study. Any subject may withdraw full consent to 
participate in the study at any time during the study. The Investigator will discuss with the subject 
appropriate procedures for withdrawal from the study. 
4.4.2. Data Collection and Follow-up for Withdrawn Subjects 
 
If a subject withdraws consent to participate in the study, attempts will be made to obtain permission and 
capture final photographic images of the keloids and measurement before being disenrolled. 
 
If subjects are withdrawn prematurely from the study, Principal Investigator will consult with Study 
Statistician about handling any incomplete data set as compared to the full data set that fully supports the 
analysis. The Principal Investigator will determine whether to replace the withdrawn subject to achieve 
the goal of 5 completers. 
 
Lost to follow up (LTFU) will be defined as a subject not answering or responding to 2 or more 
consecutive phone follow up calls after starting study medication, or after returned-receipt of 1 certified 
letter concerning discontinuation of participation in the study.  
 
 
 
 
 


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5. Study Drug  
5.1. Description 
5.1.1. Rapamycin powder (from a supplier to Doyle’s pharmacy) 
Synonym: 23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine, AY 22989, Sirolimus;  
PubChem Substance ID 57654583 
CAS No. 53123-88-9 
 
An FDA-approved macrocyclic triene antibiotic forms a complex with FKBP12 that binds to and inhibits 
the molecular target of rapamycin (mTOR). Rapamycin (RAPA) is a potent immunosuppressant and has 
anticancer activity. 
 
Mechanism of Action 
The RAPA oral formulation developed by Pfizer (RAPAMUNE, sirolimus) inhibits T lymphocyte 
activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and 
IL-15) stimulation by a mechanism that is distinct from that of other immuno-suppressants. Sirolimus 
also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 
(FKBP-12), to generate an immunosuppressive complex. The sirolimus: FKBP-12 complex has no effect 
on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of 
Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell 
proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. Dosage forms and 
strengths include: oral solution (60mg/60mL in amber glass bottle) and oral tablets (0.5, 1, and 2mg). 
 
Drug interactions with systemic use include: Inducers of CYP3A4 and P-gp may decrease sirolimus 
concentrations whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations. Avoid 
concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., 
ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and  
P-gp. Avoiding consumption of grapefruit juice is also cited. 
 
Safety 
From oral administration, serious allergic reactions identified by the manufacturer include: 
• 
swelling of face, eyes, or mouth 
• 
trouble breathing or wheezing 
• 
throat tightness 
• 
chest pain or tightness 
• 
feeling dizzy or faint 
• 
rash or peeling of skin 
 
In previous human studies cited earlier in this protocol, topical administration did not produce systemic 
or serious reactions. See Section 3.4 for Potential Risks due to topical RAPA. Participants will be 
instructed to notify the research team and get help right away if any of the above symptoms of an 
allergic reaction occur. 
 
Storage 
The powder is packaged 1 mg in a glass bottle with instructions to keep container tightly closed in a dry 
and well-ventilated place. 
 
 
 
 


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5.1.2. Petrolatum (Vaseline, vehicle only) 
Mechanism of Action 
Petrolatum is a pale yellow to yellow-colored, translucent, soft unctuous mass. It is odorless, tasteless, 
and not more than slightly fluorescent by daylight, even when melted. Petrolatum is an inert material 
with few incompatibilities. 
 
Safety 
Petrolatum is mainly used in topical pharmaceutical formulations and is generally considered to be a 
nonirritant and nontoxic material. Animal studies, in mice, have shown petrolatum to be nontoxic and 
noncarcinogenic. Although petrolatum is generally nonirritant in humans following topical application, 
rare instances of allergic hypersensitivity reactions have been reported, as have cases of acne, in 
susceptible individuals following repeated use on facial skin. However, given the widespread use of 
petrolatum in topical products, there are few reports of irritant reactions. The allergic components of 
petrolatum appear to be polycyclic aromatic hydrocarbons present as impurities. The quantities of these 
materials found in petrolatum vary depending upon the source and degree of refining. Hypersensitivity 
appears to occur less with white petrolatum and it is often the preferred material for use in cosmetics 
and pharmaceuticals. 
 
Storage 
Petrolatum is an inherently stable material owing to the unreactive nature of its hydrocarbon 
components; most stability problems occur because of the presence of small quantities of impurities. On 
exposure to light, these impurities may be oxidized to discolor the petrolatum and produce an 
undesirable odor. Petrolatum should not be heated for extended periods above the temperature 
necessary to achieve complete fluidity (approximately 70°C/158°F). When heated to decomposition it 
emits acrid smoke and irritating fumes. 
 
Petrolatum may be sterilized by dry heat. Petrolatum should be stored in a well-closed container, 
protected from light, in a cool, dry place. 
 
Regulatory Status 
GRAS listed. Accepted for use in certain food applications in many countries worldwide. Included in the 
FDA Inactive Ingredients Database (ophthalmic preparations; oral capsules and tablets; otic, topical, 
and transdermal preparations).  
 
5.1.3. Compounded investigational product 
 
The investigational product and the placebo will be compounded and supplied by Doyle’s Pharmacy in 
Houston, TX. A certificate of analysis from the source for the powder form of RAPA used in 
compounding can be provided. The literature states the compounded product will remain stable for 3 
months (6) and extended stability testing will not be performed since new product can be ordered every 
2 months through duration of the trial. 
 
5.2. Treatment Regimen 
Each ointment (8% RAPA and placebo) will be applied to the appropriately designated keloid (RAPA 
experimental or placebo control) once daily for 6 months.  
To avoid treatment confusion, the chosen keloids will be marked with a color-code by permanent marker; 
one color  will be red, and a second will be green. Metered dispensers will be similarly color coded. The 
dispenser coded in red will be applied to the keloid labeled "right" and the lime green coded dispenser 
will be applied to the keloid labeled "left." Participants will be given color-coded photographs of the 2 


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keloids with identified landmarks to show which keloid receives which color-coded ointment.  
5.3. Administration of Study Drug 
The initial application will be done in the laboratory for subject education. Color-coded permanent markers 
will be given to participants to re-mark sites as needed. 
Participants will be responsible thereafter for applying the different ointments to the color designated keloids 
once daily for the study’s duration. Two medication dispensers (8% RAPA and vehicle control) will be given 
to each subject on a monthly basis.  
Subjects will be instructed to turn the Topi-CLICK of each container once per application and apply all the 
expressed ointment to the matching, color-coded keloid. Subjects will be instructed to apply ointments after 
bathing or showering, avoid washing the treated areas for at least 4 hours after application, avoid cross-
contamination between sites by washing hands between applications, and use new disposable gloves 
(provided by study) for each ointment application.  
 
By managing with color-coded dispensers to match lesions, the participants will be “blind” to which lesion is 
receiving placebo and which keloid gets active treatment. 
 
5.4. Subject Compliance Monitoring 
Subjects will be called weekly between Visits 1 and 2 to verify compliance and at midpoints between Visits 2 
and 7. Subjects also receive a drug diary to help record administrations and any notable effects, which 
supports reporting the participant’s experiences at phone follow-ups and clinic visits. 
Each dispenser will be weighed before being given out and at monthly intervals to quantify compliance.  
 
5.5. Prior and Concomitant Therapy 
5.5.1. Exclusionary medications:  
• 
Systemic steroid or immunosuppressant therapy 
• 
Body lotions, astringents, or other skin applications including cosmetics and especially 
sunscreen to the keloid area(s) 
• 
Other antifungal, antibiotic, or topical preparations 
5.5.2. Possible drug interactions: 
• 
See Section 5.1 above 
 
5.6. Packaging    
Drug and placebo will be supplied by the compounding pharmacy in a metered dispenser called the Topi-
CLICK® container. The opaque Topi-CLICK® dispenses 0.5-1mL of ointment, protects the product 
from light exposure, and serves to conceal any subtle differences between placebo and investigational 
product. 
 
5.7. Management of Study Drug 
5.7.1. Storage 
The compounded preparation of 8% RAPA in petrolatum will be stored in a locked cabinet at room 


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temperature in a cool, dry place.  
5.7.2. Dispensing of Study Drug 
Designated study staff maintain the drug purchase documentation and administration logs to track how, 
when and to whom the investigational drug was assigned. Inventory is managed by the research 
pharmacy. Study clinical staff keep administration records regarding dosing compliance, returned/unused 
drug, and any damaged or wasted study drug product.  Routine Study Drug reconciliation will be 
performed based on clinical site policy and standard operating procedures. 
5.7.3. Return or Destruction of Study Drug 
The procedures for final reconciliation of the site’s drug supply at the end of the study will be in 
accordance with research pharmacy standard operating procedures. 
 
Unused study product will be disposed in accordance within the standard medication destruction policies 
of the hospital. 
 
6. Study Procedures 
Study visits. All study visits will be performed at the Audie L. Murphy VA Hospital or by telephone. 
6.1. Visit 1 – Consent, Screening and Baseline 
6.1.1. Informed Consent 
Eligible subjects will be asked to come to the research area to review and sign the consent form. Staff 
conducting the consent process adhere to local standard operating procedure (SOP) for consent 
administration. When scheduling consent appointments, staff will ask participants to arrive fasting. 
6.1.2. Screening and Baseline 
Following consent and signature, participants will undergo minimal cognitive screen (CLOX1 ≥10 and 
CLOX2 ≥12) to ensure consent is valid. Study staff will: 
•  Obtain vital signs, height and weight, lab work (fasting) to ensure safety and rule out systemic 
infection (complete blood count [CBC], comprehensive metabolic panel [CMP], lipid panel, and 
urine pregnancy test) 
•  Document medical history, concomitant medication review, physical examination, and  
•  Perform evaluation of eligibility criteria listed in Sections 4.1 – 4.2 above. 
 
Additional baseline activities and data collection to include: 
• 
Current and recent medications within past 3 months 
• 
Marking of keloid lesions selected for study  
• 
Photography and caliper measurements 
o Standard calipers will be used for measuring height of keloid above normal skin surface 
o Photography and use of Image J software – Study staff will upload digitized photographs 
and transfer directly from camera to computer software; images of the keloid are 
visualized, and outlined with an electronic drawing tool contained in the software. The 
software calculates the surface area within the outlined region and stores the data in 
Image J for analysis (see Analysis section next page). 
• 
1st medication administration for education 
• 
Investigational medication prescribed/dispensed for 1 month, and participant is given written 
instructions for self-administering medication and care of the study lesion 


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• 
Schedule Visit 2 
 
Study staff will contact participants weekly by phone for follow up (3 calls) during the first month of 
treatment. If the participant has a SmartPhone, a scheduled video visit (such as FaceTime, Imo or 
Skype) is optional to conduct weekly interim assessments but not required. Visits 2-7 must be 
performed in the research area and cannot be conducted virtually due to photography standardization. 
 
Standardized digital photography and caliper measurements - Analysis 
We will measure keloid surface area and height changes pre-treatment and thereafter on a monthly 
basis using standardized digital photography with a tripod-mounted 8MP Canon S5is camera and 
calipers to measure keloid height (37). The key to successful use of photography is to maintain 
consistent image quality and thus ensure that images can be compared fairly. Factors that influence 
image quality will be standardized including lighting, 10cm distance from keloid surface, super macro 
camera setting, a proper center of focus perpendicular to the keloid surface, and inclusion of a standard 
millimeter ruler as a reference for calculation of surface areas by Image J. Photos thus taken will be 
suitable for sequential measurements over the 6 months of the study because they will be taken by the 
same camera at the same angle under identical conditions and using the same standardized ruler by 
the same person. Image J (http://rsbweb.nih.gov/ij/index.html), is a public domain image-processing 
program that can calculate area and pixel value statistics of user-defined selections, measure distances 
and angles, create density histograms, and line profile plots from digital images. Spatial calibration is 
available to provide real dimensional measurements in standard units such as mm2. We used Image J 
to analyze our preliminary data and will use the same approach in this study. Surface areas of all 
photographed lesions will be measured with Image J by three trained reviewers blinded to all aspects of 
the photograph (date taken, treatment, subject, etc.). In addition, keloid height measurements (the 
maximum vertical elevation above normal skin) in millimeters will be made with calipers (37). Prior to 
measurements, we conduct training sessions for the readers to improve agreement among readers. 
Reviewers will be trained to standardized definitions (color, texture, etc.) of lesions thus minimizing 
inter-reviewer variability. We also will assess agreement within readers by repeating the measurements 
at a later time. The percentage of keloid flattening will be calculated as the percentage reduction 
normalized to pre-treatment height. Finally, we will record clinical observations of keloid changes to 
extend and subjectively verify our objective measurements. 
6.2. Visit 2 (approximately 4 weeks after Visit 1) – Month 1 of treatment 
• 
Adverse event review and urine pregnancy test 
• 
Keloid observation and clinical assessment 
• 
Photography and caliper measurements – (same as baseline) 
• 
Dispense medication 
6.3. Visit 3 (approximately 4 weeks after Visit 2) – Month 2 
• 
Adverse event review and urine pregnancy test 
• 
Keloid observation and clinical assessment 
• 
Photography and caliper measurements – (same as baseline) 
• 
Dispense medication 
6.4. Visit 4 (approximately 4 weeks after Visit 3) – Month 3 
• 
Same as above, plus repeat CBC, CMP, lipid panel 
6.5. Visit 5 (approximately 4 weeks after Visit 4) – Month 4 
• 
Same as above and urine pregnancy test   


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6.6. Visit 6 (approximately 4 weeks after Visit 5) – Month 5 
• 
Same as above and urine pregnancy test  
6.7. Visit 7 (approximately 4 weeks after Visit 6) – Month 6 – Final Study Visit 
We will ask participants to return to the hospital to undergo post-treatment procedures, conclude the 
study data collection and disenrollment processing. 
 
•  Vital signs, weight, and lab work to ensure safety or rule out systemic infection or effects (CBC, 
CMP, lipid panel) 
•  Update medical history, concomitant medications, focused physical examination, and  
•  Evaluation of medication compliance 
• 
Final adverse event review 
• 
Keloid observation and clinical assessment 
• 
Photography and caliper measurements – (same as baseline) 
 
6.8. Summary Visit Schedule 
 
Event 
Screening & 
Baseline 
Visit 1  
Visit 2 
(V1 +1m) 
Visit 3 
 (V2 
+1m) 
Visit 4 
 (V3 
+1m) 
Visit 5 
(V4 +1m) 
Visit 6 
(V5 +1m) 
Visit 7 
 (V6 
+1m) 
Consent 
X 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
Height 
(V1 
only) 
and weight 
X 
 
 
 
 
 
 
X 
CLOX exam 
X 
 
 
 
 
 
 
 
Urine HCG, monthly 
X 
 
X 
X 
X 
X 
X 
 
Labs: CBC, CMP, and 
lipid panel 
X 
 
 
 
X 
 
 
X 
History 
X 
 
 
 
 
 
 
X 
Physical Exam 
X 
 
 
 
 
 
 
X 
ConMed Review 
X 
 
X 
X 
X 
X 
X 
X 
Keloid Observed 
 
X 
X 
X 
X 
X 
X 
X 
Photo and Caliper 
 
X 
X 
X 
X 
X 
X 
X 
Dispensing Rx 
 
X 
X 
X 
X 
X 
X 
 
Medication Instructions 
and phone calls weekly 
between V1-V2 and at 
midpoint between V2-7 
for compliance 
monitoring 
 
X 
X 
X 
X 
X 
X 
 
AE Review 
 
 
X 
X 
X 
X 
X 
X 
Questionnaires 
 
X 
 
 
 
 
 
X 
Disenrollment 
 
 
 
 
 
 
 
X 
 
7. Statistical Plan 
7.1. Statistical Methods 
For all analyses, the statistical threshold for significance will be set at p<0.05. 
 
Keloid surface area and height data will be analyzed using ANOVA for repeated measurements using a 


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model similar to that described for the analysis of the preliminary data (see INNOVATION, above) with 
the addition of a random effect for subject (47). This analysis can be modified to include between-
subject factors if such factors (sex, race, etc.) are identified for investigation. 
 
8. Safety and Adverse Events 
8.1. Definitions 
8.1.1. Adverse Event (AE) 
In general, AE is used very broadly and encompasses physical and psychological harms and includes:   
 
 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated 
with the subject’s participation in the research, whether or not it is considered related to the subject’s 
participation in the research. 
 
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 
8.1.2. Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that:  
• 
results in death; 
• 
is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• 
results in inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
8.1.3. Unanticipated Problems Involving Risk to Subjects or Others (UPIRSO) 
Any incident, experience, or outcome that meets all of the following criteria:  
• 
Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• 
Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• 
Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
8.1.4. Adverse Event Reporting Period 


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The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up. For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
8.1.5. Pre-existing Condition 
A preexisting condition is one that is present at the start of the study. A pre-existing condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
At screening, any clinically significant abnormality should be recorded as a preexisting condition. At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event.  
 
8.1.6. Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a clinically significant degree requiring active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
8.1.7. Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise in this protocol. Any condition responsible for 
surgery should be documented as an AE if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an AE in the 
following circumstances: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition (e.g., colonoscopy, SCI annual evaluation, respite care).  
• 
Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
8.2. Recording of Adverse Events 
At each contact with the subject, the investigator or study staff will seek information about adverse events 
by specific questioning and, if appropriate, by examination.  Information on all AEs will be recorded 
immediately in the source documentation. Site staff will record AEs using the appropriate data collection 
form in REDCap, which will be exported as an AE Log (See Section 9.3) for periodic review, at least 
monthly and ad hoc, depending on severity and expected/unexpected nature of the event. 
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. SAEs that are still ongoing at the 
end of the study period will be followed up to determine the final outcome. Any SAE that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported per Institutional policy and according to FDA requirements. 


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8.3. Reporting of Serious Adverse Events and Unanticipated Problems 
 
SAEs and UPIRSOs will be reported per local IRB policy and procedure. 
 
Each subject is evaluated for any adverse events (AE). Any event that is reported to either the principal 
investigator or designated research staff by either the subject or medical staff caring for the subject and 
which meets the criteria will be documented. Any AE reported as serious will necessitate an adverse 
event report, which will be submitted to the IRB, R&D Committee, and to the Pepper Center DSMB.   
 
Unanticipated risks to subjects or others (UPIRSO) that are a result of study participation are promptly 
reported to the IRB, the VA R&D Committee, and, if deemed appropriate, to the Pepper Center DSMB. 
The report will include a description of the event, when and how it was reported, as well as any official 
chart records or documentation to corroborate the event or the reporting of the event. All adverse events 
will be graded as mild, moderate, or severe. All adverse events will be summarized annually and 
submitted to the IRB and R&D Committees. Any action resulting in a temporary or permanent suspension 
of this study (e.g. local site IRB actions) will be reported to FDA or drug manufacturer per IRB stipulations. 
8.3.1. Investigator reporting: notifying the Pepper Center DSMB 
 
Any study-related SAE-UPIRSO, must be reported to the Principal Investigator by telephone within 24 
hours of the event. To report such events, a Serious Adverse Event (SAE) form must be completed and 
submitted within 24 hours.  The investigator will keep a copy of this SAE form on file at the study site.   
 
Report SAEs by email and facsimile to: 
 
Dean L. Kellogg, Jr, MD, PhD 
or 
Sara E. Espinoza, MD 
Professor, Medicine-Geriatrics 
Associate Professor, Medicine-Geriatrics 
Email: kelloggd@uthscsa.edu 
Email: espinozas2@uthscsa.edu 
210-617-5132 fax      210-235-3681 pager 
210-310-5859 
 
Within the following 48 hours, the Principal Investigator provides further information on the SAE or the 
UPIRSO in the form of a written narrative. This should include a copy of the completed SAE form, and 
any other diagnostic information that will assist the understanding of the event.   
8.3.2. Investigator reporting: notifying the UTHSCSA IRB 
 
Notifying the IRB and or FDA if SAE or UPIRSO 
 
• Within 7 calendar days 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening, and  
 
• Within 15 calendar days 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 


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-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the criteria 
for reporting (reporting within 15 calendar days from when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
– suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
 
Additional reporting requirements 
 
Post marketing surveillance and adverse events may be submitted on FDA Form 3500A or in a narrative 
format. The contact information for submitting safety reports is noted below: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Dermatology and Dental Products (DDDP) 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
Phone: (301) 796-2290 
Fax: (301) 796-9712  
 
8.4. Medical Monitoring 
The Investigator and or Co-PI will review the safety and progress of this study on a monthly basis or when 
needed if SAE or SAE-UPIRSO occurs.   
 
8.5. Investigator Reporting of Protocol Deviations/Violations 
Departures during the conduct of a research study constitute a protocol deviation, violation or exception and as 
such must be reported to the UTHSCSA IRB. 
 
Tracking and reporting of protocol deviations and violations to the IRB is the responsibility of the PI. To 
determine whether deviations or violations require prompt reporting or other action, refer to the IRB document 
entitled “Decision Tree – Evaluating Departures” on the IRB website. Failure to report departures from the 
protocol according to IRB policy may constitute possible non-compliance, which will require a Prompt Report 
Form and possible FDA reporting by IRB. 
 
8.5.1. Deviations and violations may be identified in a number of ways including:  
• 
A report by an individual can be made directly to the IRB Office.  
• 
The IRB may learn of event through its continuing review of ongoing research.  
• 
Compliance reviews (audits) conducted by the Office of Regulatory Affairs and Compliance or one 
of the HSC affiliated institutional compliance offices.  
• 
A report by an individual can be made directly to the Office of Regulatory Affairs and Compliance 
(Hotline) or one of the HSC affiliated institutional compliance offices.  
• 
A report by another committee, department, institution, or official.  
• 
An audit or report from the study sponsor or sponsor’s monitoring entity. 
 
8.5.2. Definitions of Protocol Deviations/Violations  
• 
Protocol deviations – such as out of window visit, missed lab, usually recognized after the fact, 
etc. 
• 
Protocol violations – enrolling an ineligible participant, using wrong consent version, willful act of 


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not following protocol 
• 
Emergency 
violations 
Refer 
to 
UTHSCSA 
IRB 
Policy 
website: 
https://research.uthscsa.edu/irb/policy/deviations for more information 
 
 
8.6. Stopping Rules  
 
Should a subject develop a rash during study intervention, RAPA medication will be stopped and their 
participation will cease. 
 
Should a female participant of childbearing age become pregnant during study intervention, RAPA medication 
will be stopped and participation will be withdrawn. 
 
In the unlikely event that a study-related death or SAE occurs, the decision to stop the trial, either temporarily 
or permanently, will be the collaborative responsibility of the Pepper Center DSMB and the Principal 
Investigator. 
9. Data Handling and Record Keeping 
9.1. Confidentiality 
Information learned about all subjects will be kept confidential.  All data and protected health information in 
paper form will be kept confidential by assigned anonymous identifier and kept secured (password protected 
and/or double locked). Subjects will not be identified in any way in any publication.   
9.2. Source Documents 
Source data are contained in source documents found in paper subject files at the research site and in VA 
CPRS medical records.  Print all entries legibly in blue or black ink. Erasures and white-out material are 
prohibited. If any entry error has been made on paper, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it. All such changes must be initialed and dated. 
For clarification of illegible or uncertain entries, print the clarification above the item, then initial and date it. 
9.3. Case Report Forms 
The study case report forms (CRF) are the primary data collection instruments for the study. Data requested 
on the CRF will be collected from the subject encounter and from the subject diaries, pharmacy logs, and 
medical records (VA CPRS), then entered into the REDCap database. All missing data will be routinely 
queried, corrected, and or explained. If a space on the CRF is left blank because the procedure was not 
done or the question was not asked, write “N/D”. If the item is not applicable to the individual case, write 
“N/A”.   
9.4. Data Management 
Database Management Software: All data management for this project will be maintained using the UT 
Health San Antonio REDCap platform which is managed by the Department of Epidemiology and Biostatistics.  
Data System: REDCap is a computing environment developed by Vanderbilt University consisting of a 
collection of instruments, under the management of UT Health San Antonio’s systems, policies, and 
procedures that govern its informatics operations. Data projects are designed to be end-user oriented and 
constructed to optimize workflow and minimize errors.  
All data will be input using a web front-end interface. All users are individually assigned authorization for 
access to specific components of the database application. Information that is input is checked for logical and 
range consistency and mandatory data fields must be entered in order to input a record.  


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9.5. Records Retention 
The regulatory binder is maintained by the assigned OAIC Pepper Center Regulatory Coordinator and stored in 
the PI Research Folder at Barshop Institute if conducted at UTHSA site and on designated VHASTX server if 
conducted at VA. 
 
The Principal Investigator is responsible for maintaining study essential documents for at least 3 years after the 
funding grant period ends or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product, whichever is longer.  
 
These documents should be retained for a longer period if required by a funding agency, the FDA or other 
institutional retention policy. In such an instance, it is the responsibility of the VA Audie Murphy Hospital or 
Principal Investigator to inform the institution as to when these documents no longer need to be retained.  
 
10. 
Study Monitoring, Auditing, and Inspecting 
10.1. Study Monitoring Plan 
The Principal Investigator will ensure that the designated regulatory coordinator or other quality assurance 
reviewer is given access to all the above noted study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct study monitoring visits as assigned. 
10.2. Auditing and Inspecting 
The Principal Investigator will permit study-related monitoring, audits, and inspections by the IRB, the funding 
sponsor, the OAIC Pepper Center Data Safety and Monitoring Board (DSMB), government regulatory bodies, 
and University compliance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11. 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 
21 part 312) applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Institutional Review Board (IRB), in agreement with 
local legal prescriptions, for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to 
the funding sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  
 


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12. 
Study Finances 
12.1. Funding Source 
 
This pilot study is financed through a grant from the Department of Medicine 
12.2. Conflict of Interest 
 
None reported. All VA investigators submit Conflict of Interest Disclosure forms as part of the review and 
approval process. 
12.3. Subject Stipends or Payments 
 
There are no funds available to reimburse participants for time and transportation. The participants who 
screen pass and move on to study intervention will receive a box of surgical gloves, a surgical pen in two 
colors, and study medication and placebo at no cost. 
 
13. 
Publication Plan 
The study will be registered and published on www.clinicaltrials.gov in accordance with FDAAA and 
institutional policy. 
 
The Institution and its respective designees may present or publish the results of a scientific investigation 
involving this study in accordance with ICJME standards and guidelines. 


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14. 
References 
 
1. 
Blit PH, and Jeschke MG. Keloids: what do we know and what do we do next? Translational Research 
159: 173-174, 2012. 
2. 
Brusselaers N, Pirayesh A, Hoeksema H, Verbelen J, Blot S, and Monstrey S. Burn scar 
assessment: A systematic review of objective scar assessment tools. Burns 1157-1164, 2010. 
3. 
Durani P, and Bayat A. Levels of evidence for the treatment of keloid disease. J Plastic, Recons 
Aesthetic Surgery 61: 4-17, 2008. 
4. 
Funayama E, Chodon T, Oyama A, and Sugihara T. Keratinocytes Promote Proliferation and Inhibit 
Apoptosis of the Underlying Fibroblasts: An Important Role in the Pathogenesis of Keloid. J Invest Dermatol 
121: 1326-1331, 2003. 
5. 
Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, and Jeschke. MG. Hypertrophic Scarring and 
Keloids: Pathomechanisms and Current and Emerging Treatment Strategies. Mol Med 17:113-125, 2011. 
6. 
Haemel AK, O'Brien AL, and Teng JM. Topical Rapamycin. Arch Dermatol 146: 715-718, 2010. 
7. 
Harrison DE, Strong R, Sharp ZD, Nelson JD, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, 
Frenkel K, Carter CS, Pahor M, Javors MJ, Fernandez E, and Miller RA. Rapamycin fed late in life 
extends lifespan in genetically heterogeneous mice. Nature 460: 392-395, 2009. 
8. 
Khoo YT, Ong CT, Mukhopadhyay A, Han HC, Do DV, Lim IJ, and Phan TT. Upregulation of 
Secretory Connective Tissue Growth Factor (CTGF) in Keratinocyte-Fibroblast Coculture Contributes to 
Keloid Pathogenesis. J Cellular Physiol 208: 336–343, 2006. 
 9. 
Koenig MK, Bell CS, Hebert AA, Roberson J, Samuels JA, Slopis JM, Tate P, and Northrup H. 
Efficacy and Safety of Topical Rapamycin in Patients With Facial Angiofibromas Secondary o Tuberous 
Sclerosis Complex: The TREATMENT Randomized Clinical Trial.  JAMA Dermatology 154(7): 773-780, 2018. 
10. Liao W-T, Yu H-S, Arbiser JL, Hong C-H, Govindarajan B, Chai C-Y, Shan W-J, Lin Y-F, Chen G-
S, and Lee C-H. Enhanced MCP-1 release by keloid CD14+ cells augments fibroblast proliferation: role of 
MCP-1 and Akt pathway in keloids. Exp Dermatol 19: e142–e150., 2010. 
11. Lim IJ, Phan T-T, Tan E-K, Nguyen T-TT, Evelyne Tran, Longaker MT, Song C, Lee S-T, and 
Huynh H-T. Synchronous Activation of ERK and Phosphatidylinositol 3-Kinase Pathways Is Required for 
Collagen and Extracellular Matrix Production in Keloids. J Biol Chem 278: 40851-40858, 2003. 
12. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors 
MJ, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, 
and Strong R. Rapamycin but not resveratrol or simvastatin, extends life span of genetically heterogenous 
mice. J Gerontol A Biol Sci Med Sci 66: 191-201, 2011. 
13. Mogili NS, Krishnaswamy VR, Jayaraman M, Rajaram R, Venkatraman A, and Korrapati PS. 
Altered angiogenic balance in keloids: a key to therapeutic intervention. Translational Research 182–189, 
2012. 
14. Ogawa R. The Most Current Algorithms for the Treatment and Prevention of Hypertrophic Scars and 
Keloids. Plast Reconstr Surg 125: 557-568, 2010. 
15. Ong CT, Khoo YT, Mukhopadhyay A, Do DV, Lim IJ, Aalami O, and Phan TT. mTOR as a potential 
therapeutic target for treatment of keloids and excessive scars. Exp Dermatology 16: 394–404, 2007. 
16. Ormerod AD, Shah SAA, Copeland P, Omar G, and Winfield A. Treatment of psoriasis with topical 
sirolimus: preclinical development and a randomized, double-blind trial. Br J Derm 152: 758-764, 2005. 
17. Poulalhon N, Farge D, Roos N, Tacheau C, Neuzillet C, Michel L, Mauviel A, and Verrecchia F. 
Modulation of Collagen and MMP-1 Gene Expression in Fibroblasts by the Immunosuppressive Drug 
Rapamycin. J Biol Chem 281: 33045–33052, 2006. 
18. Robles DT, and Berg D. Abnormal wound healing: keloids. Clinics in Dermatology 25: 26–32, 2007. 
19. Seifert O, and Mrowietz U. Keloid scarring: bench and bedside. Arch Derm Res 301: 259–272, 2009. 
20. Shaffer JJ, Taylor SC, and Cook-Bolden F. Keloidal scars: A review with a critical look at therapeutic 
options. J Am Acad Dermatol 46: S63-97, 2002. 
21. Syed F, Sanganee HJ, Bahl A, and Bayat A. Potent Dual Inhibitors of TORC1 and TORC2 
Complexes (KU-0063794 and KU-0068650) Demonstrate In Vitro and Ex Vivo Anti-Keloid Scar Activity. J 


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Invest Dermatol 133: 1340-1350, 2013. 
22. Syed F, Sherris D, Paus R, Varmeh S, Pandolfi PP, and Bayat A. Keloid Disease Can Be Inhibited 
by Antagonizing Excessive mTOR Signaling With a Novel Dual TORC1/2 Inhibitor. Am J Path 181: 1642–
1658, 2012. 
23. Winer BJ. Statistical Principles in Experimental Design. New York: McGraw Hill, 1971. 
 
 
 


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15. 
Attachments 
A. Sample Consent Form 
B. Grant award 
C. SOP for drug management (pending) 
D. Imaging instructions for photography (pending) 
 
 
 


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16. SUMMARY OF PROTOCOL CHANGES 
 
Date of Change 
Version 
Section Modified 
Before Change 
After Change 
04-16-19 
1.0 initial to IRB 
all 
NA 
NA 
04-30-19 
1.1  
IRB number, version date 
04-30-19 
Pending 
Updated to 20190291H 
05-14-19 
1.2 
Section 4.1 Inclusion 
 
 
 
 
Section 5.7 
 
 
 
Stopping Rules 
 
 
 
 
 
General formatting update 
Change criterion 
 
 
 
 
Drug inventory managed 
by clinical study staff 
 
 
¶ 1, regarding AE due to 
drug 
Added “negative 
pregnancy test” and 
made Urine HCG “prn” in 
Summary Visit Table 
 
Drug storage and 
management by 
Research Pharmacy 
 
Replaced ¶ 1 to state 
stopping drug and 
withdrawal from study if 
participant develops a 
rash 
 
Corrected formatting of 
margins Sect 8.3 to end 
06-05-19 
1.3 
Section 5 
Sigma Aldrich 
Changed to “supplier to 
Doyle’s 
pharmacy”; 
removed Sigma Aldrich 
as needed 
07-15-19 
1.4 
Visit Schedule Table and 
Visit narratives 
CBC, BMP 
Modified Safety Labs: 
Replaced 
BMP 
with 
CMP and added lipids; 
plus repeat labs at Visit 
4 and urine pregnancy 
testing monthly (per FDA 
recommendation) 
02-13-20 
1.5 
Study Drug and Visits 
Topi-pump 
Changed dispenser to 
Topi-click 
04-20-20 
1.6 
Cover page 
NCT# pending 
NCT# updated