Clinical trial NCT03760250
Conditions: Keloid
Sponsor: University of Pennsylvania
Start date: 2019-02-05; Completion date: 2020-09-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-arm, pilot study on the effects of topical imiquimod treatment in preventing keloid recurrence after surgical excision. Keloids are abnormal scars that form in certain genetically predisposed individuals following trauma to the skin. They can be physically disabling and cause social impairment. Many therapies have been proposed and trialed for the permanent removal of keloids, but they all have limited efficacy. Topical imiquimod therapy has been reported to decrease keloid recurrence following keloidectomy in human patients. Given all previous reports of adjuvant imiquimod therapy to keloidectomy initiated imiquimod therapy after keloidectomy, the investigators would like to test the efficacy of topical imiquimod pre-treatment in preventing keloid recurrence after surgical excision. Therefore, the investigators are initiating an open-label pilot study of 10 patients age 18 or greater with keloids on the trunk and extremities excluding the groin and hands and feet who present to the dermatology clinic for standard of care keloid excision. Key exclusion criteria include vulnerable populations, immunocompromised state, hypersensitivity to study drug components, and keloids outside of specified areas. The main study intervention will be 6 weeks of treatment with topical 5% imiquimod cream, starting 1 week prior to surgical excision.

Detailed description:

Arms: arm 1: 5% Imiquimod cream once daily to keloid area 5-times a week for 6 weeks, starting 1-week prior to keloid excision
Interventions: intervention 1: Imiquimod 5% cream
Intervention descriptions: intervention 1: Imiquimod 5% Cream application to keloid skin area 5-times per week for 6 weeks, starting 1-week before keloid excision

Protocol documents:
Prot_SAP_001.pdf: 
  
CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study sponsor 
 
 
 
 
 
 
 
 
OPEN-LABEL, SINGLE-ARM PILOT STUDY OF THE EFFECTS 
OF TOPICAL 5% IMIQUIMOD CREAM ON PREVENTING 
KELOID RECURRENCE AFTER SURGICAL KELOIDECTOMY  
 
 
 
Regulatory Sponsor: 
Thomas Leung, M.D., Ph.D. 
Department of Dermatology 
421 Curie Boulevard 
Philadelphia, PA 19104 
(215) 746-7043 
 
Funding Sponsor: 
Unfunded 
Study Product: 
5% Imiquimod Cream 
IRB Protocol Number: 
831625 
IND Number: 
IND Exempt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: [09/04/2018] 
Amended: 
[10/09/2018] 
Amended: 
[03/15/2019] 
 
CLINICAL RESEARCH PROTOCOL 


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Table of Contents 
 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................... 2 
1.1 
BACKGROUND................................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 3 
1.3 
PRECLINICAL DATA ......................................................................................................................... 3 
1.4 
CLINICAL DATA TO DATE ................................................................................................................. 4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS............................................................................................. 4 
2 
STUDY OBJECTIVES .......................................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN ........................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................... 6 
3.3 
SECONDARY STUDY ENDPOINTS...................................................................................................... 6 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 6 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 6 
4.1 
INCLUSION CRITERIA ....................................................................................................................... 6 
4.2 
EXCLUSION CRITERIA ...................................................................................................................... 6 
4.3 
SUBJECT RECRUITMENT AND SCREENING ........................................................................................ 6 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................. 7 
4.4.1 
When and How to Withdraw Subjects...................................................................................... 7 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................... 7 
5 
STUDY DRUG ....................................................................................................................................... 7 
5.1 
DESCRIPTION.................................................................................................................................. 7 
5.2 
TREATMENT REGIMEN ..................................................................................................................... 8 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .......................................................... 8 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG...................................................................... 8 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 8 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 9 
5.7 
PACKAGING .................................................................................................................................... 9 
5.8 
BLINDING OF STUDY DRUG .............................................................................................................. 9 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 9 
5.9.1 
Receipt of Drug Supplies ......................................................................................................... 9 
5.9.2 
Storage ..................................................................................................................................... 9 
5.9.3 
Dispensing of Study Drug ........................................................................................................ 9 
5.9.4 
Return or Destruction of Study Drug ........................................................................................ 9 
6 
STUDY PROCEDURES ...................................................................................................................... 10 
6.1 
VISIT 1 ......................................................................................................................................... 10 
6.2 
VISIT 2 – PROCEDURE VISIT........................................................................................................... 11 
6.3 
VISITS 3 AND 4 .............................................................................................................................. 11 
6.4 
VISIT 5 ......................................................................................................................................... 11 
6.5 
PHONE FOLLOW-UP (ENCOUNTER 6) .............................................................................................. 11 
7 
STATISTICAL PLAN .......................................................................................................................... 12 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 12 
7.2 
STATISTICAL METHODS ................................................................................................................. 12 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 12 
8.1 
DEFINITIONS ................................................................................................................................. 12 


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8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................. 14 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS.................................. 14 
8.3.1 
Investigator reporting: notifying the Penn IRB ....................................................................... 14 
8.4 
MEDICAL MONITORING .................................................................................................................. 15 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 16 
9.1 
CONFIDENTIALITY.......................................................................................................................... 16 
9.2 
RECORDS RETENTION ................................................................................................................... 16 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................... 16 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 16 
10.2 
AUDITING AND INSPECTING ............................................................................................................ 16 
11 
ETHICAL CONSIDERATIONS ........................................................................................................... 16 
12 
STUDY FINANCES ............................................................................................................................. 17 
12.1 
FUNDING SOURCE ........................................................................................................................ 17 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 17 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ 17 
13 
PUBLICATION PLAN ......................................................................................................................... 17 
14 
REFERENCES .................................................................................................................................... 17 
15 
ATTACHMENTS ................................................................................................................................. 18 
 
 
 


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List of Abbreviations 
 
actinic keratosis (AK) 
human papilloma virus (HPV) 
Toll-like-receptor-7 (TLR7) 
 
 
 
 
 
 
 


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Study Summary 
Title 
Open-label, single-arm pilot study of the effects of topical 5% Imiquimod cream 
on preventing keloid recurrence after surgical keloidectomy 
Short Title 
Imiquimod for preventing keloid recurrence 
IRB Protocol Number 
 
Phase 
Pilot study 
Methodology 
Open-label, single-arm 
Study Duration 
Enrollment of patient will take place over the next year. The project will begin 
as soon as the IRB is approved. 
Study Center(s) 
Single-center 
Objectives 
Primary objective: 
- 
To assess the efficacy of topical 5% Imiquimod cream on decreasing 
keloid recurrence after excision. 
Secondary objectives: 
- 
To assess the tolerability of topical 5% Imiquimod cream 
Number of Subjects 
10 
Diagnosis and Main 
Inclusion Criteria 
Key inclusion criteria 
Patients age ≥ 18 with keloids < 5cm on trunk (below neck and excluding groin) 
and extremities (excluding hands and feet) requesting excision 
Able and willing to provide informed consent 
Key exclusion criteria 
Pregnant or breastfeeding  
Taking systemic immunosuppressive medication, life threatening disease, or 
inherent sun-sensitivity 
Hypersensitivity to study drug 
Age < 18 
Keloids located in sections as noted above 
Unable to follow-up for 10 weeks 
Involvement in a trial of another experimental intervention within 30 days 
Unable or unwilling to provide informed consent 
Study Product, Dose, 
Route, Regimen 
5% Imiquimod cream, topical application to cover skin lesion once daily x 5 
days per week for 6 weeks 
Duration of 
administration 
6 weeks 
Reference therapy 
None 
Statistical 
Methodology 
Response rate will be presented as a percentage, with 95% confidence 
intervals. Other endpoints will be presented descriptively, with an appropriate 
measure of variation (e.g. standard deviation) if necessary. 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
 
This is an open-label, single-arm, pilot study on the effects of topical imiquimod treatment in preventing 
keloid recurrence after surgical excision. Keloids are abnormal scars that form in certain genetically 
predisposed individuals following trauma to the skin. They can be physically disabling and cause social 
impairment. Many therapies have been proposed and trialed for the permanent removal of keloids, but they 
all have limited efficacy. (1)  
 
Topical imiquimod therapy has been reported to decrease keloid recurrence following keloidectomy in 
human patients (8-13). In our lab, we observed that topical imiquimod pre-treatment (imiquimod initiated 
prior to onset of trauma) improves wound closure and decreases scar formation in mouse ear-punch models 
of wound healing. Given all previous reports of adjuvant imiquimod therapy to keloidectomy initiated 
imiquimod therapy after keloidectomy, we would like to test the efficacy of topical imiquimod pre-treatment 
in preventing keloid recurrence after surgical excision. 
 
1.1 Background 
 
Keloids are benign dermal fibroproliferative tumors that represent a form of abnormal wound healing 
following any insult to the deep dermis, including lacerations, abrasions, surgery, piercings, vaccinations, 
and burns in predisposed individuals (1). They are distinguished from hypertrophic scars, another type of 
abnormal scar formation, by their extension beyond the borders of the original wound, failure to regress 
spontaneously, and tendency to recur following excision (1).  
 
Keloids tend to occur more frequently in dark-skinned individuals, with an incidence of up to 16% in those 
of black and Hispanic backgrounds (2). These lesions appear to affect male and female subjects equally 
and most commonly occur in persons aged 10-30 years (2). They typically form on the ears, face, chest, 
and shoulders and can cause pain, burning, itching, and restriction of motion. Furthermore, the scars can 
be extremely disfiguring and potentially cause significant social and psychological distress in affected 
individuals.  
  
The process by which keloids develop is poorly understood, though most theories of keloid etiology relate 
to fibroblast dysfunction (2). These lesions are difficult to treat, as they frequently recur following excisional 
removal. Current treatment options include surgical excision, laser, intralesional injections, pressure and 
silicone dressings, topical preparations, oral agents, radiation, and cryotherapy (1). Oftentimes, surgical 
excision is combined with adjuvant therapies such as corticosteroids and immunomodulators at the time of 
skin closure because surgical excision alone has recurrence rates ranging between 45% and 100% (3). 
Additionally, because surgical excision requires complete removal of all abnormal tissue, post-excision 
keloid recurrence may lead to a larger keloid than prior to excision. Although many adjuvant therapies to 
surgical excision and modalities for keloid removal have been proposed, there has been no consensus 
regarding how to best treat these lesions, and there is currently no medication approved for the indication 
of reducing keloid recurrence after excision.  
 
Imiquimod is an immunomodulating agent that binds to Toll-like-receptor-7 (TLR7) and acts as a potent 
inducer of interferon and cytokine release at the site of skin application. It has been shown to decrease 
excessive collagen production and upregulate certain apoptosis-related genes in keloid fibroblasts (4). 
When formulated as a 5% cream, Imiquimod is a safe and well-tolerated drug. Side effects include skin 
erosion, excoriation, flaking, and edema at site of application (5). 


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1.2 Investigational Agent 
 
Imiquimod is an immune response modifier that binds to TLR7 and, when applied topically to the skin, 
induces the production of a variety of cytokines (6). It is manufactured as a cream at concentrations of 
2.5%, 3.75%, and 5%. 5% Imiquimod is currently approved for the treatment of actinic keratosis (AK), 
superficial basal cell carcinoma, and external genital and perianal warts (condylomata acuminata) from 
human papilloma virus (HPV) infection (7).  
 
Imiquimod is applied topically, and percutaneous absorption of Imiquimod is minimal. 5% Imiquimod cream 
will be used in this study. Each gram of 5% Imiquimod cream contains 50 mg of Imiquimod in an off-white 
oil-in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white 
petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, 
methylparaben, and propylparaben (7). 
 
A mean peak serum drug concentration of 0.4 ng/ml was observed in a small study of 12 patients with 
genital/perianal warts following an average applied dose of 4.6 mg. In patients with actinic keratosis who 
applied 5% Imiquimod cream topically 3-times weekly for 16 weeks, the mean peak drug concentrations at 
the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for applications to face (12.5 mg Imiquimod), 
scalp (25 mg Imiquimod), and hands/arms (75 mg Imiquimod), respectively. After up to 3 weeks of dosing 
with the 3.75% cream (18.75 mg/day applied to the face and scalp) in 17 patients with actinic keratosis, the 
mean peak serum Imiquimod concentration was 0.323 ng/mL with a median tmax of 9 hours after dosing. It 
appears that systemic exposure may be more dependent upon surface area of application than amount of 
applied dose. The half-life of the 3.75% cream was 29.3 +/- 17 hours at the end of the study; therefore, 
steady-state concentrations are anticipated to occur by day 7 with once daily dosing. The apparent half-life 
of the 5% cream was about 10-times greater with topical dosing than the 2-hour apparent half-life seen 
following subcutaneous dosing, suggesting prolonged retention in the skin. (7) (16) 
1.3 Preclinical Data 
 
Multiple case reports have suggested that Imiquimod application to 
the sites of surgical wounds and to hypertrophic scars may reduce 
scar occurrence/recurrence. In our lab, we have shown that topical 
application of 5% Imiquimod increases the rate of wound closure 
and leads to increased tissue regeneration with decreases in 
scarring in mouse ear hole punch models of tissue regeneration. In 
our preclinical study, we applied 5% Imiquimod cream for 5 days 
one week prior to ear hole punch (Figure 1A). In the presence of 
Imiquimod, there is a marked increase in the rate of closure when 
compared to control (Figure 1C) often leading to complete closure 
of the wound (Figure 1B, D). The drug treated group also 
demonstrates more complete regeneration of skin appendages 
such as sebaceous glands (arrowhead) and ear cartilage (arrow) 
in the new tissue (Figure 1D), a feature consistent with tissue 
regeneration and not scar formation.  
 
To eliminate the possibility that this Imiquimod phenotype is simply 
due to nonspecific skin irritation, other skin irritants such as 
calcipitriol and 12-O-tetradecanoylphorbol-13-acetate (TPA) were 
also tested. Wound closure rates were not significantly reduced 
compared to vehicle control in each case (data not shown). 
 
These preliminary results suggest that Imiquimod application 
enhances wound closure and biases the healing process towards 
tissue regeneration and away from scarring. 
 
Figure 1 Topical Imiquimod treatment improves 
mouse ear wound healing 


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1.4 Clinical Data to Date 
 
Case series and prospective trials of 5% Imiquimod after surgical keloidectomy have been reported. 
However, the results have been variable. As summarized in Table 1, post-excision treatment with 
Imiquimod appears to be most effective in preventing recurrence of keloids on the ears but has limited 
efficacy in other locations. Additionally, some studies were limited by poor patient follow-up compliance. 
 
All of the reported studies were designed such that Imiquimod was started after surgical excision of keloids. 
There are no reports of initiating Imiquimod prior to surgical excision, and our preclinical data suggests that 
there may be a benefit to pre-excision Imiquimod therapy. 
 
Table 1 Summary of published clinical data for Imiquimod therapy post-keloidectomy 
Reference study 
Number of 
keloids 
Sites treated 
Recurrence (%) 
Follow-up 
duration 
Berman (2002) (8) 
11 (10 patients) 
Earlobe (10) and 
back (1) 
0 (0%) 
24 weeks 
Martin-Garcia (2005) (9) 8 (6 patients) 
Earlobe 
2 (25%) 
24 weeks 
Stashower (2006) (10) 
8 (4 patients) 
Earlobe 
0 (0%) 
12 months 
Maholtra (2007) (11) 
3 (2 patients) 
Presternal 
3 (100%) 
12 weeks 
Cacao (2009) (12) 
9 (9 patients) 
Trunk 
8 (89%) 
12 weeks 
Frias (2018) (13) 
41 (25 patients) 
Trunk (9), 
suprapubic (2), 
extremity (4), 
auricular (20) 
9 trunk (100%),       
0 suprapubic (0%),  
4 extremity (100%), 
3 auricular (15%) 
6 months 
 
1.5 Dose Rationale and Risk/Benefits 
 
Once daily application of 5% Imiquimod cream is currently approved by the FDA for the treatment of many 
skin disorders. Although the exact mechanism of action has not been elucidated, when used to treat pre-
cancerous lesions and skin cancers, Imiquimod results in inflammation, which destroys the lesion and can 
result in complete regression. Additionally, as mentioned above, Imiquimod has been shown to be effective 
in preventing recurrence after surgical keloidectomy, though to a varying degree depending on the site of 
the lesion.  
 
The proposed dosage regimen for this study is in accordance with the current recommended dosing for 
superficial basal cell carcinoma – apply once daily before bedtime 5-times per week for a total of 6 weeks. 
This regimen has been shown to be safe, tolerable as well as effective in inducing molecular and clinical 
responses in patients.  
 
Areas treated with imiquimod may become inflamed. The symptoms may include itching, burning, redness, 
ulceration (sores), scabbing, flaking, and pain. There could be increased sensitivity to the sun in areas of 
drug application. This could be avoided by proper sun protection such as wearing protective clothing and/or 
applying sunscreen of SPF 30 or greater 15 minutes prior to sun exposure with reapplication every 2 hours. 
Systemic side effects may include “flu-like” symptoms such as fever, fatigue, headache, nausea, diarrhea, 
and muscle pain. These symptoms are less common and are generally mild. 
 
Unlike previously reported studies, this study aims to initiate treatment with Imiquimod one week prior to 
keloidectomy.  Our preclinical data suggests that pre-treatment with Imiquimod prior to injury increases 
wound healing and decreases scar formation. Additionally, it has been shown that when using 


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corticosteroids as an adjunct to surgical excision, it is best to initiate treatment in the preoperative period 
and continue treatment for up to 3 months post-excision (14). 
 
Because the effects of the drug are not well studied in pregnancy and during breastfeeding, it is possible 
that there are harmful side effects that are not yet known to both the mother and unborn or breast-feeding 
child. Therefore, pregnant and breastfeeding subjects are excluded from the study. Additionally, the risks 
of this study includes risks of breach of confidentiality. While every effort will be made to protect the 
confidentiality of study subjects, there is a potential risk of an inadvertent or unintended breach of 
confidentiality. 
 
As demonstrated in patients who have used 5% Imiquimod for other FDA approved indications, risks of 
topical application of 5% imiquimod are minimal. Additionally, previous studies as well as our preclinical 
data indicates that 5% imiquimod could modulate wound healing and prevent keloid recurrence in patients 
when applied prior to keloid-excision and continued after the procedure. Therefore, we believe that the 
benefit of possible decrease in keloid recurrence outweighs the minimal risks posed by topical 5% 
imiquimod therapy. 
2 Study Objectives 
 
Primary Objective 
To assess the efficacy of 5% Imiquimod cream on preventing keloid recurrence after excision. Subjects will 
be evaluated by a consultant dermatologist at 2, 4, and 8 weeks following excision and by phone 12 weeks 
after excision to assess for clinical evidence of lesion recurrence. 
 
Secondary Objectives 
To assess the safety and tolerability of 5% Imiquimod in subjects undergoing keloid excision. Subjects will 
be evaluated by a consultant dermatologist at 2, 4, and 8 weeks following excision to assess for local site 
reaction such as redness, discomfort, swelling, and ulceration. 
3 Study Design 
3.1 General Design 
 
• 
Prospective, open-label, non-randomized, single-arm pilot study 
• 
Subjects are expected to participate for a total of approximately 14 weeks from initial dermatology 
consultation visit 
 
 
 
 
 
 
 
 
Patient evaluated in clinic 
and enrolled in study if 
appropriate.  
Keloid excision procedure 
appointment scheduled.  
5% Imiquimod prescribed. 
Surgical keloidectomy 
1 week prior to excision: 
Apply Imiquimod once daily 
before bedtime for 5 days. 
Follow-up in dermatology 
clinic at 2, 4, and 8 weeks 
post-keloidectomy.  
Phone follow-up 12 weeks 
post-keloidectomy. 
Patient continues to apply Imiquimod 
once daily before bedtime 5-times per 
week for 5 additional weeks. 
Excision sample sent to pathology 
(standard of care)  


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3.2 Primary Study Endpoints 
 
To assess the efficacy of 5% Imiquimod cream on decreasing keloid recurrence after excision when initiated 
prior to excision 
3.3 Secondary Study Endpoints 
 
To investigate the tolerability of 5% Imiquimod cream 
3.4 Primary Safety Endpoints 
 
To assess the safety and tolerability of 5% Imiquimod in subjects undergoing keloid excision. 
 
At each clinic follow-up visit (2, 4, 8 weeks after excision), the investigator will rate the local site reaction on 
the following scale: 
• 
None 
• 
Mild reaction (slight redness, discomfort, no swelling, no ulceration) 
• 
Moderate reaction (redness, pain and swelling, no ulceration) 
• 
Severe reaction (redness, pain, swelling, and ulceration) 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
 
1. Age ≥ 18 
2. Men and women who present clinically with keloids requesting excision 
3. Any number of keloids 
4. Keloid no larger than 5cm in diameter at the base 
5. Clinical findings consistent with keloid formation, including: a scar that does not spontaneously 
regress, extends beyond borders of normal tissue, may be pruritic, may be painful.  
6. Location of keloid in low-risk areas – areas other than above the neck, hands, feet, or groin 
7. Able and willing to give informed consent 
4.2 Exclusion Criteria 
 
1. Age < 18 
2. Hypersensitivity to 
Imiquimod or to any of the excipients (methylhydroxybenzoate, 
propylhydroxybenzoate, cetyl alcohol, and stearyl alcohol) 
3. Involvement in a trial of another experimental intervention within 30 days 
4. Life threatening disease 
5. Use of immunosuppressive medications such as oral corticosteroids 
6. Bleeding disorders 
7. Not available for follow-up for 10 weeks 
8. Pregnant, intention to become pregnant during treatment phase of trial, or breastfeeding 
4.3 Subject Recruitment and Screening 
 
Patients will be recruited through the routine work of the Dermatology departments at the Hospital of 
the University of Pennsylvania. Recruitment and consent will be obtained by the principle investigator or 
another Dermatology physician as delegated by the investigator seeing the patient in the outpatient clinic. 
Patients seen in the outpatient clinic with clinical representation of keloids will be approached by the 


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Dermatology attending as part of clinical evaluation, and written, informed consent will be obtained from 
the patient prior to any research related procedures are conducted. 
 
It will be explained to the potential participant that entry into the trial is entirely voluntary and that their 
treatment and care will not be affected by their decision. Should any Penn affiliates be approached, that 
their decision of whether to participate will not impact their standing with the institution. It will also be 
explained that they can withdraw at any time. In the event of their withdrawal it will be explained that their 
data collected so far will be retained and used as part of the study analysis.  
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
 
The participant will stop Imiquimod treatment early for the following reasons: 
• 
New clinical/diagnostic information (e.g. pathology report) suggests a diagnosis other than keloid 
• 
Intolerable local or systemic toxicity from Imiquimod 
• 
Clinical evidence of keloid recurrence. These participants will progress to intralesional steroid 
injections or excision as per standard of care. 
• 
Any participant who becomes pregnant during the study 
• 
Withdrawal of consent 
 
Subjects who withdraw consent will be withdrawn from the trial. The subjects will be made aware that this 
will not affect their standard of care. Subjects will be made aware (via the information sheet and consent 
form) that should they withdraw the data collected will be retained and used as part of the study analysis. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Protected Health Information to be collected include names and medical record numbers. Additional 
information that is to be collected from patient’s electronic medical record are: 
- 
Race/ethnicity/gender 
- 
And all elements of dates for dates that are directly related to the patient 
- 
Current medications 
- 
Symptoms related to treatment 
- 
Physical examination 
- 
Treatment and response 
- 
Unidentifiable photodocumentation of lesions 
 
Patients who choose to withdraw from the trial will be asked for permission for phone follow-up 12 weeks 
after excision date. 
 
Patients who are withdrawn from the study for any reason but have initiated at least 1 imiquimod treatment 
will be seen in the outpatient clinic for one additional follow-up visit after their withdrawal date to observe 
the application site. 
 
This information will be associated with a study ID. A master list with PHI and study IDs will be maintained 
by personal investigators in a secure location. Access will be given to only study personnel as needed. 
Data sets will only include assigned study IDs. Data will be backed up as a password protected file on a 
Penn Medicine secure server. Links to identifiers will be destroyed after the study is completed. 
5 Study Drug  
5.1 Description 
 


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Imiquimod is a topical immunomodulator approved for the treatment of actinic keratosis, superficial basal 
cell carcinoma, and external genital and perianal warts (condylomata acuminata) from human papilloma 
virus (HPV) infection. Each gram of 5% Imiquimod cream contains 50 mg of Imiquimod in an off-white oil-
in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, 
polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, 
methylparaben, and propylparaben (7). 
 
5% Imiquimod is supplied in single-use packets each of which contains 250mg of the cream, equivalent to 
12.5mg of Imiquimod. It is supplied in a box of 24 packets each (7). 
5.2 Treatment Regimen 
 
Topical dosage (5% cream) 
Apply a thin coat of Imiquimod cream to cover the entire lesion once daily 5-times per week prior to normal 
sleeping hours, for 6 weeks, starting 1 week prior to keloid excision. Cream should be left in place for 
approximately 8 hours. The target keloid should have a maximum diameter of no more than 5cm and be 
located on the trunk (excluding anogenital skin), below the neck, or extremities (excluding hands or feet). 
The treatment area should include a 1 cm margin of skin around the tumor. The diameter of cream droplet 
applied should range from 5 mm to 10 mm for keloid areas of 0.5 cm to 5 cm, respectively. Subjects should 
wash hands thoroughly prior to and after application of medication. Maximum to be prescribed: 36 packets 
during the 6-week treatment period.  
 
A rest period of several days during treatment may be required due to local skin reactions. Follow-up visits 
will be scheduled at 2, 4, and 8 weeks after excision and as needed for local skin reactions. 
 
The following dosing algorithm will be used at the 2 and 4 visits and unscheduled visits due to local toxicity 
to adjust the frequency of application accordingly. 
• 
If intolerable at 5 days per week; stop completely for 1 week then restart but at a reduced dose of 
3 days per week. Increase to 5 days per week as soon as tolerable. 
• 
If intolerable at 3 days per week, a further week off, start again at 3 days per week. Stop if 
intolerable. 
Subjects will be requested to contact the local investigator for advice before stopping or changing treatment. 
5.3 Method for Assigning Subjects to Treatment Groups 
 
This is a single-arm study. All patients will be receiving open-label active drug. 
5.4 Preparation and Administration of Study Drug 
 
The principle investigator or dermatology physician designated by the PI will prescribe the 5% Imiquimod 
cream for the patient. Study medication will consist of the number of packets as ordered by the PI necessary 
to treat the Keloid. The study drug will be purchased with start-up funds from the PI, and it will be provided 
to the patient free of charge. Study medication will be open label (see section for study drug details).  
5.5 Subject Compliance Monitoring 
 
Compliance with study procedures will be monitored throughout the trial. It is expected that the Investigator 
will comply with the protocol requirements and encourage subjects to follow all procedures carefully. 
Subject compliance with treatment administration will be calculated as the percentage of the reported 
number of doses administered compared to the number that should have been administered while the 
subject is on study. The total number of packets utilized will be compared to the total number prescribed. 
Additionally, application site will be evaluated for erythema and local site reaction. 


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5.6 Prior and Concomitant Therapy 
 
Concomitant medications/treatment for the keloid lesions should be kept to a minimum during the study. 
However, if considered necessary for the subject’s welfare they may be given at the discretion of the 
investigator according to the local standard of care. The drug, dose and duration should be recorded. 
 
Immunosuppressive medications including oral corticosteroids are specifically excluded for the duration of 
this study. A reconciliation of recorded medications in the electronic medical system will be performed at 
the screening visit. 
5.7 Packaging 
 
5% Imiquimod cream is supplied in single-use packets each of which contains 250mg of the cream, 
equivalent to 12.5mg of Imiquimod. 5% Imiquimod cream is supplied in a box of 24 packets each (7). 
 
As there is no blinding in this study, the imiquimod will be prescribed in its standard packaging, with 
additional labelling to comply with regulatory requirements. 
5.8 Blinding of Study Drug 
 
The study is not blinded. 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt log 
filled out and signed by the person accepting the shipment.  It is important that the designated study staff 
counts and verifies that the shipment contains all the items noted in the shipment inventory.  Any damaged 
or unusable study drug in a given shipment will be documented in the study files.  The investigator will make 
a notation of any damaged or unusable study treatments that were supplied to the investigator’s site. 
5.9.2 Storage 
 
The drug will be stored and handled per the specifications on the package insert. The drug will be stored 
at 4-25ºC (39-77ºF) with the temperature being monitored in a secure location contained in an appropriately 
designated secure area. Avoid freezing. Keep out of reach of children.  
5.9.3 Dispensing of Study Drug 
 
The study physician or designee in the dermatology clinic will dispense the medication and keep detailed 
dispensing records. The physician will write a prescription for the amount of medication to be dispensed. 
5.9.4 Return or Destruction of Study Drug 
 
At the completion of the study, subjects will be asked to return all unused medication at the final follow-up 
visit. There will be a final reconciliation of drug shipped, drug consumed, and drug remaining.  This 
reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies noted 
will be investigated, resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files.  


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6 Study Procedures 
 
Patients will be recruited through the routine work of the Dermatology departments at the Hospital of 
the University of Pennsylvania. Recruitment and consent will be obtained by the principle investigator or 
another Dermatology physician as delegated by the investigator seeing the patient in the outpatient clinic. 
Patients seen in the outpatient clinic with clinical representation of keloids will be approached by the 
Dermatology attending as part of clinical evaluation, and written, informed consent will be obtained from 
the patient prior to any research related procedures are conducted. 
 
It will be explained to the potential participant that entry into the trial is entirely voluntary and that their 
treatment and care will not be affected by their decision. It will also be explained that they can withdraw at 
any time. In the event of their withdrawal it will be explained that their data collected so far will be retained 
and used as part of the study analysis. 
 
 
Visit 1 
(Week 1) 
Visit 2 
(Week 2) 
Visit 3 
(Week 4) 
Visit 4 
(Week 6) 
Visit 5 
(Week 10) 
Phone 
encounter 
(Week 14) 
Informed 
consent 
X 
 
 
 
 
 
Urine 
pregnancy 
test 
X 
 
 
 
 
 
Imiquimod 
application 
X (start after 
visit) 
X 
X 
X 
 
 
Keloid 
excision 
 
X 
 
 
 
 
Excision 
specimen 
sent to 
pathology 
per SOC 
 
X 
 
 
 
 
Photograph 
of lesion 
X (optional) 
X (optional) 
X (optional) 
X (optional) 
X (optional) 
 
Evaluation 
of local site 
reaction 
 
X 
X 
X 
X 
 
Evaluation 
for 
recurrence 
 
 
X 
X 
X 
X 
 
6.1 Visit 1 
Diagnosis of keloid will be made clinically by a Dermatology attending in the University of Pennsylvania 
Dermatology outpatient clinic. If the patient meets all inclusion and exclusion criteria set by the study and 
wishes for the keloid to be surgically removed, the patient will be approached by the Dermatology team for 
recruitment into the study. The patient will be given the opportunity to have a further discussion about the 
study and receive answers to any questions they may have. If the patient is agreeable to participating in 
the study, written and informed consent will be obtained from the patient or the patient’s legally authorized 
representative. A medical history will be taken, demographic data will be collected, and photo-
documentation of the lesions will be recorded.  
 
A urine pregnancy test will be conducted prior to receiving study drug, for all female subjects of childbearing 
potential who are not postmenopausal > 1 year or surgically sterile. Subjects with a positive urine pregnancy 
test will be excluded from the study. Subjects will be asked to use contraception during treatment period. If 


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indicated, (missed period, unprotected sexual intercourse, or Investigator discretion), a urine pregnancy 
test may be administered subsequently at the discretion of the Investigator. 
 
A procedure appointment will be made for the surgical keloidectomy, and the subject will be instructed to 
apply Imiquimod 5% daily Monday to Friday the week prior to the scheduled excision date. The cream 
should be left in place for approximately 8 hours. The treatment area should include a 1 cm margin of skin 
around the tumor. The diameter of cream droplet applied should range from 5 mm to 10 mm for keloid areas 
of 0.5 cm to 5 cm, respectively. 
 
The subject will also continue applying 5% Imiquimod daily as instructed for 5 more weeks after surgery. 
Subjects will be followed-up in the outpatient clinic at 2, 4, and 8 weeks post-excision and by phone 12 
weeks post-excision. 
6.2 Visit 2 – Procedure visit 
Consent for and surgical removal of keloid will be performed in accordance with current standard of care. 
Keloid excision sample will be sent to pathology per standard of care.  
6.3 Visits 3 and 4 
 
Scheduled clinic visits will be at 2 and 4 weeks after the surgical excision (weeks 3 and 5 after initiation of 
Imiquimod). At these visits, the following will be recorded: 
• 
Subject compliance with therapy – if doses were missed 
• 
The investigator will evaluate for evidence of keloid recurrence 
• 
The investigator will rate the local site reaction on the following scale: 
o 
None 
o 
Mild reaction (slight redness, discomfort, no swelling, no ulceration) 
o 
Moderate reaction (redness, pain and swelling, no ulceration) 
o 
Severe reaction (redness, pain, swelling, and ulceration) 
• 
The dose of Imiquimod will be adjusted to according to the following algorithm: 
o 
If intolerable at 5 days per week; stop completely for 1 week then restart but at a 
o 
reduced dose of 3 days per week. Increase to 5 days per week as soon as tolerable. 
o 
If intolerable at 3 days per week, a further week off, start again at 3 days per week. Stop if 
intolerable. 
• 
Any new medication usage and health service usage data will be recorded.  
6.4 Visit 5 
Last scheduled clinic visit will be at 8 weeks after surgical excision (3 weeks after completing Imiquimod 
therapy). The investigator will evaluate for evidence of keloid recurrence at this visit and evaluate for any 
local site reactions per above. 
 
If treatment of the lesion with Imiquimod is stopped because of local toxicity, this will prompt an unscheduled 
clinic visit so that the dose adjustment algorithm can be implemented. 
 
If at any point during the treatment phase, the keloid is judged to have recurred, then the subject will 
progress immediately to intralesional injection or re-excision in accordance with current standard of care.  
 
6.5 Phone follow-up (Encounter 6) 
Patient will be contacted by phone 12 weeks after surgical excision of keloid (7 weeks after completing 
Imiquimod therapy). Patient will be asked about recurrence of keloid at excision site and any residual local 
site symptoms from Imiquimod therapy. 


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7 Statistical Plan 
7.1 Sample Size Determination 
 
In this open-label, single-arm pilot study, 10 patients will be enrolled.  
The sample size calculation was based on a historical recurrence rate of 70% at 8 week follow-up after 
excision alone and an expected 25% recurrence rate with Imiquimod treatment. Using 80 % power and 
alpha = 5 %, the estimated sample size required is 8. Allowing for a withdrawal rate of approximately 20 %, 
10 subjects will have to be enrolled.  
7.2 Statistical Methods 
 
Response rate will be presented as a percentage, with 95% confidence intervals. Other endpoints will be 
presented descriptively, with an appropriate measure of variation (e.g. standard deviation) if necessary. 
Patient demographics will be summarized.  
7.3 Subject Population(s) for Analysis 
 
All subjects who completed the study protocol will be included in the study analysis. 
8 Safety and Adverse Events 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
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). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  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 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 


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Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
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.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
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.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  The sponsor 
should also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 
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 degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  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. 


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• 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 must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
 
8.3.1 Investigator reporting: notifying the Penn IRB 
 
This section describes the requirements for safety reporting by investigators who are Penn faculty, affiliated 
with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The University of 
Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to study participation 
that are unforeseen and indicate that participants or others are at increased risk of harm.  The Penn IRB 
will not acknowledge safety reports or bulk adverse event submissions that do not meet the criteria outlined 
below.  The Penn IRB requires researchers to submit reports of the following problems within 10 working 
days from the time the investigator becomes aware of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other relevant 
sources of information, such as product labeling and package inserts.) 
AND 


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Related to the research procedures (An event is “related to the research procedures” if in the opinion 
of the principal investigator or sponsor, the event was more likely than not to be caused by the 
research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn IRB 
using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including Reportable Adverse 
Events” or as a written report of the event (including a description of the event with information regarding 
its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other 
study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious unexpected 
adverse event that is rare in the absence of drug exposure (such as agranulocytosis, hepatic 
necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) 
that in the opinion of the investigator placed one or more participants at increased risk, or affects 
the rights or welfare of subjects. 
8.4 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see section 
9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. 


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9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
9.2 Records Retention 
 
All data will be managed behind the Penn, password-protected server. All subject information will be kept 
in the university REDCAP database. Study documents will be archived after the study’s closure.  
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all the study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space 
to conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, government 
regulatory bodies, and University compliance and quality assurance 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 accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/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 sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 


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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.  See Attachment 
for a copy of the Subject Informed Consent Form.  This consent form will be submitted with the protocol for 
review and approval by the EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-
approved consent form, must be obtained before that subject undergoes any study procedure.  The consent 
form must be signed by the subject or legally acceptable surrogate, and the investigator-designated 
research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
Unfunded 
12.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
12.3 Subject Stipends or Payments 
There are no subject payments or stipends. Cost of keloid excision will be covered by the patient or patient 
insurance.  
13 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the principle investigator for the purposes of performing the study, will be published 
or passed on to any third party without the consent of the principle investigator or University of Pennsylvania 
Department of Dermatology. No subjects will be identified in any publications. 
14 References 
1. Leventhal D, Furr M, Reiter D. Treatment of Keloids and Hypertrophic Scars. Arch 
Facial Plast Surg. 2006;8:362-368. doi:10.1001/archfaci.8.6.362 
2. Chike-obi CJ, Cole PD, Brissett AE. Keloids : Pathogenesis , Clinical Features , and 
Management. Semin Plast Surg. 2009;1(212):178-184. doi:10.1055/s-0029-1224797. 
3. Mustoe TA, Cooter RD, Gold MH, et al. International clinical recommendations on scar 
management. Plast Reconstr Surg 2002;110:560–571 
4. Jacob SE, Berman B, Nassiri M, Vincek V. Topical application of Imiquimod 5% cream 
to keloids alters expression genes associated with apoptosis. Br J Dermatol 
2003;149(Suppl 66):62–65 
5. Bilu D, Sauder DN. Imiquimod: modes of action. Br J Dermatol 2003;(149 Suppl 66):5–
8 
6. Imbertson LM, Beaurline JM, Couture AM, et al. Cytokine induction in hairless mouse 
and rat skin after topical application of the immune response modifiers Imiquimod and S-
28463. J Invest Dermatol. 1998;110(5):734-739. doi:10.1046/j.1523-1747.1998.00174.x 
7. Aldara [package insert]. Bristol, TN: Graceway Pharmaceuticals; 2010. 
8. Berman B, Kaufman J. Pilot study of the effect of postoperative Imiquimod 5% cream on 
the recurrence rate of excised keloids. J Am Acad Dermatol. 2002;47(4):S209-S211. 
doi:10.1067/mjd.2002.126585 


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9. Martin-García RF, Busquets AC. Postsurgical use of Imiquimod 5% cream in the 
prevention of earlobe keloid recurrences: results of an open-label, pilot study. Dermatol 
Surg. 2005;31(11 Pt 1):1394-1398. http://www.ncbi.nlm.nih.gov/pubmed/16416606. 
10. Stashower ME. Successful Treatment of Earlobe Keloids with Imiquimod after 
Tangential Shave Excision. Dermatologic Surg. 2006;32:380-386. doi:10.1111/j.1524-
4725.2006.32077.x 
11. Malhotra AK, Gupta S, Khaitan BK, Sharma VK. Imiquimod 5% cream for the 
prevention of recurrence after excision of presternal keloids. Dermatology. 
2007;215(1):63-65. doi:10.1159/000102036 
12. Cação FM, Tanaka V, Messina MCDL. Failure of Imiquimod 5% cream to prevent 
recurrence of surgically excised trunk Keloids. Dermatologic Surg. 2009;35(4):629-633. 
doi:10.1111/j.1524-4725.2009.01101.x 
13. Frias J, Vargas R, Paez E, et al. Effects of Imiquimod 5% Cream in the Prevention of 
Excised Keloid Recurrence. Ski J Cutan Med. 2018;2(1):44-46. 
https://jofskin.org/index.php/skin/article/view/127/pdf. Accessed May 15, 2018. 
14. Brissett AE, Sherris DA. Scar contractures, hypertrophic scars, and keloids. Facial Plast 
Surg 2001;17(4): 263–272. 
15. Berman B, Flores F. The treatment of hypertrophic scars and keloids. Eur J Dermatol 
1998;8:591–595 
16. Imiquimod - Drug Summary. (2018). Retrieved from http://www.pdr.net/drug-
summary/Aldara-Imiquimod-1348 
15 Attachments 
• Sample Informed Consent Form 
• IND exemption letter 
 

ICF_000.pdf: 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT  
INFORMED CONSENT AND HIPAA 
AUTHORIZATION FORM 
 
Protocol Title:   
Open-label, single-arm pilot study of the effects 
of topical 5% Imiquimod cream on preventing 
keloid recurrence after surgical keloidectomy 
Principal 
Investigator: 
Thomas Leung, M.D., Ph.D. 
Department of Dermatology 
421 Curie Boulevard 
Philadelphia, PA 19104 
(215) 746-7043 
Emergency 
Contact: 
24 Hour Emergency # 215-662-6059 or 215-
662-2737 
Page Dermatology Resident on call 
  
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study. The purpose of this study 
is to evaluate whether or not the topical medication 5% Imiquimod cream (Aldara) 
is able to prevent recurrence of keloids after surgical removal when therapy is 
initiated one week before the date of surgery and continued for a total of 6 weeks. 
We hope that the results of this work will help us better understand this condition 
and identify a better treatment than what is currently available. Your participation 
is voluntary which means you can choose whether or not you want to participate. 
If you choose not to participate, there will be no loss of benefits to which you are 
otherwise entitled. Before you can make your decision, you will need to know what 
the study is about, the possible risks and benefits of being in this study, and what 
you will have to do in this study. The research team is going to talk to you about 
the research study, and they will give you this consent form to read. You may also 
decide to discuss it with your family, friends, or family doctor. You may find some 
of the medical language difficult to understand. Please ask the investigator and/or 
the research team about this form. If you decide to participate, you will be asked 
to sign this form. Your doctor may be an investigator in this research study. As an 
investigator, your doctor is interested both in your clinical welfare and in the 
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conduct of this study. Before entering this study or at any time during the research, 
you may want to ask for a second opinion about your care from another doctor 
who is not an investigator in this study. You do not have to participate in any 
research study offered by your doctor. 
 
What is the purpose of this research study? 
Keloids, or abnormally enlarged scars, are common skin concerns for which we 
currently do not have effective treatments. The purpose of this study is to evaluate 
whether or not the topical medication 5% Imiquimod cream (Aldara) is able to 
prevent recurrence of keloids after surgical removal when therapy is initiated one 
week before the date of surgery and continued for a total of 6 weeks. We will be 
evaluating both the effectiveness and tolerability of this drug, and we hope that the 
results of this work will help us better understand this condition and identify a better 
treatment than what is currently available.  
 
The use of 5% Imiquimod cream for this indication (prevention of keloid 
recurrence) is still investigational. However, topical application of 5% Imiquimod 
cream has been approved by the FDA for a number of other skin conditions such 
as actinic keratosis (a precancerous lesion), superficial basal cell carcinoma, and 
anogenital warts.  
 
How long will I be in the study? How many other people will be 
in the study? 
Your participation in the study is up to 14 weeks. There are expected to be 10 
patients in the study. The study is being conducted at the University of 
Pennsylvania only. 
 
What am I being asked to do? 
If you choose to participate in the study, after reviewing and signing this informed 
consent, you will be asked to use the study medication, 5% Imiquimod cream 
(Aldara), 5 times a week at bed time for a total of 6 weeks, starting one week 
prior to your scheduled keloid excision date. Your keloid removal surgery will be 
scheduled and performed in accordance with the standard of care. You will also 
be asked whether or not we would be permitted to collect photographs of the 
lesion that is to be removed as well as the surgical site at follow-up visits. You 
will also be asked if a portion of the keloid specimen that was excised can be 
used for research to study the effects of the medication on the lesions. You will 
also be asked to return for follow-up visits 2, 4, and 8 weeks after your keloid 
removal surgery to evaluate for side effects of therapy and evidence of keloid 
recurrence. Lastly, you will be asked whether you are willing to be contacted by 
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phone 12 weeks after your keloid removal surgery to further inquire about any 
lasting symptoms and/or keloid recurrence.  
 
 
 
 
Visit 1 
(Week 1) 
Visit 2 
(Week 2) 
Visit 3 
(Week 4) 
Visit 4 
(Week 6) 
Visit 5 
(Week 10) 
Phone 
encounter 
(Week 14) 
Informed 
consent 
X 
 
 
 
 
 
Urine 
pregnancy 
test 
X 
 
 
 
 
 
Imiquimod 
application 
X (start 
after visit) 
X 
X 
X 
 
 
Keloid 
excision 
 
X 
 
 
 
 
Excision 
specimen 
sent to 
pathology 
as 
indicated 
by 
treatment 
guidelines 
 
X 
 
 
 
 
Photograph 
of lesion 
X 
(optional) 
X 
(optional) 
X 
(optional) 
X 
(optional) 
X 
(optional) 
 
Evaluation 
of local site 
reaction 
 
X 
X 
X 
X 
 
Evaluation 
for 
recurrence 
 
 
X 
X 
X 
X 
 
Photography 
If you decide to volunteer, you will have photographs taken of the lesion that is 
being removed. Efforts will be taken to ensure that the photograph is not 
identifiable – jewelry, tattoos, name tags, or unique clothing will not be 
photographed, if possible. However, if the lesion is near a recognizable feature, 
such as a tattoo, there is still the possibility that you may be identified by the 
photograph. 
 
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 I wish to have photographs taken 
 
Subject initials: _______ 
 
 I do not wish to have photographs taken 
Subject initials: _______ 
 
What are the possible risks or discomforts?  
5% Imiquimod (Aldara) is an FDA approved medication for multiple skin 
conditions. The side effects of this medication is well studied and documented. 
Areas treated with imiquimod will become inflamed. The symptoms may include 
itching, burning, redness, ulceration (sores), scabbing, flaking, and pain.  
There could be increased sensitivity to the sun in areas of drug application. This 
could be avoided by proper sun protection such as wearing protective clothing 
and/or applying sunscreen of SPF 30 or greater 15 minutes prior to sun exposure 
with reapplication every 2 hours. 
 
Systemic side effects may include “flu-like” symptoms such as fever, fatigue, 
headache, nausea, diarrhea, and muscle pain. These symptoms are less 
common and are generally mild. 
 
While every effort will be made to protect your confidentiality there is a potential 
risk of an inadvertent or unintended breach of confidentiality. While every effort 
will be made to protect your private information there is a potential risk of loss of 
that privacy.  
 
Reproductive risks:  Because the effects of the drug are not well studied in 
pregnancy and during breastfeeding, it is possible that there are harmful side 
effects that are not yet known to both the mother and unborn or breast-feeding 
child.  If you are currently pregnant or breastfeeding, it is important that you inform 
the investigator because you will not be able participate in the study.  If you are 
able to become pregnant, you will be given a urine pregnancy test before entry into 
the study.  You are asked to use a medically accepted method of birth control (such 
as oral contraceptives, long-acting reversible contraception, or barrier 
contraception.) while you participate in the study.  You should not become 
pregnant while you are taking this drug.  If you do become pregnant, you must tell 
the investigator and consult an obstetrician or maternal-fetal specialist. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be 
important to you.  This includes information that, once learned, might cause you to 
change your mind about being in the study.  We will notify you as soon as possible 
if such information becomes available. 
 
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What are the possible benefits of the study?  
You may not get any benefit from being in this research study. However, there 
have been studies and reports indicating that topical imiquimod therapy could be 
effective in preventing keloid recurrence after surgical removal of the keloid, 
although it is not guaranteed. Additionally, the information gained from the 
research may have benefit to society by improving how dermatologists are able 
to take care of patients with similar skin conditions. 
 
What other choices do I have if I do not participate?  
 
If you choose not to participate in this study, you could discuss with your 
dermatologic physician about the alternative therapies available, such as 
pressure dressing, intralesional steroid (Kenolog) injection, and irradiation. 
 
Will I be paid for being in this study? 
There is no compensation for participation in this study.  
 
Will I have to pay for anything? 
You are still responsible for any deductibles or applicable co-pays for routine 
office visits, scans and blood work. The keloid excision will be performed per 
standard of care, and the cost of the procedure will be charged to you or your 
insurance per standard billing procedures.  
The study drug, Aldara (5% Imiquimod Cream) will be provided by the study at 
no cost to you. Follow-up visits in the clinic 2, 4, and 8 weeks after surgery will be 
covered by the study, and you will not be charged. 
 
What happens if I am injured from being in the study?  
We will offer you the care needed to treat injuries directly resulting from taking 
part in this research.  We may bill your insurance company or other third parties, 
if appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you 
other compensation for the injury.  You do not give up your legal rights by signing 
this form.   
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of the research study as soon as possible.  The 
researcher’s name and phone number are listed in the consent form. 
 
When is the study over?  Can I leave the Study before it ends? 
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This study is expected to end after all participants have completed all visits, and 
all information has been collected.  This study may also be stopped at any time by 
your physician or the principle investigator without your consent because: 
• 
The Primary Investigator feels it is necessary for your health or safety.  
Such an action would not require your consent, but you will be informed if 
such a decision is made and the reason for this decision. 
• 
If additional clinical information such as pathology findings change the 
diagnosis of your lesion. You will be informed by the investigator if such 
information becomes available and could be relevant to your clinical care. 
• 
You have not followed study instructions.  
• 
The Principal Investigator has decided to stop the study. 
If you decide to participate, you are free to leave the study at anytime.  Withdrawal 
will not interfere with your future care.   
 
Who can see or use my information?  How will my personal 
information be protected?   
The study team will do our best to make sure that the personal information obtained 
during the course of this research study will be kept private.  all information will be 
kept on a secure, password-protected Penn Medicine database that can only be 
accessed by study personnel. However, we cannot guarantee total privacy.  Your 
personal information may be given out if required by law.  If information from this 
study is published or presented at scientific meetings, your name and other 
personal information will not be used.  
 
Electronic Medical Records and Research Results  
  
What is an Electronic Medical Record and/or a Clinical Trial Management  
System?  
 
An Electronic Medical Record (EMR) is an electronic version of the record of your 
care within a health system. An EMR is simply a computerized version of a paper 
medical record.  
 
A clinical trial management system (CTMS) is used to register your information 
as a participant in a study and to allow for your research data to be 
entered/stored for the purposes of data analysis and any other required activity 
for the purpose of the conduct of the research.  
 
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study, information related 
to your participation in the research (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UPHS. 
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Information related to your participation in clinical research will also be contained 
in the CTMS. 
 
If you have never received care within UPHS and are participating in a University 
of Pennsylvania research study that uses UPHS services, an EMR will be 
created for you for the purpose of maintaining any information produced from 
your participation in this research study.  The creation of this EMR is required for 
your participation in this study. In order to create your EMR, the study team will 
need to obtain basic information about you that would be similar to the 
information you would provide the first time you visit a hospital or medical facility 
(i.e. your name, the name of your primary doctor, the type of insurance you 
have). Information related to your participation in the study (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in this EMR.  
Once placed in your EMR or in the CTMS, your information may be accessible to 
appropriate UPHS workforce members that are not part of the research team.  
Information within your EMR may also be shared with others who are determined 
by UPHS to be appropriate to have access to your EMR (e.g. health insurance 
company, disability provider, etc.). 
 
What information about me may be collected, used or shared 
with others?   
The information that will be collected as a part of the study includes: 
• Demographic information: race/ethnicity/gender 
• Date of birth 
• Telephone number 
• Current medication list 
• Description/documentation of the dermatologic physician’s physical exam  
• Treatment received and response to treatment 
• Symptoms and side effects related to treatment 
• Photo documentation of lesions treated 
De-identified information collected in this study, including de-identified 
photographs of the lesion, may be presented in research settings such as 
published in scientific peer-reviewed journals or presented at scientific 
conferences. 
 
Why is my information being used? 
Your information is used by the research team to contact you during the study. 
Your information and results of tests and procedures are used to: 
• do the research 
• oversee the research 
• to see if the research was done right 
• to evaluate and manage research functions.   
 
Who may use and share information about me?   
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The following individuals may use or share your information for this research 
study: 
• The investigator for the study and the study team  
• Other authorized personnel at Penn, including offices that support research 
operations 
• Other research personnel with access to the databases for research and/or 
study coordination and as otherwise approved by the IRB 
 
Who, outside of the School of Medicine, might receive my 
information?  
Oversight organizations 
• The Office of Human Research Protections 
• The study data and safety monitoring board 
 
Once your personal health information is disclosed to others outside the School 
of Medicine, it may no longer be covered by federal privacy protection 
regulations.   
The Principal Investigator or study staff will inform you if there are any additions 
to the list above during your active participation in the trial. Any additions will be 
subject to University of Pennsylvania procedures developed to protect your 
privacy. 
 
How long may the School of Medicine use or disclose my 
personal health information?   
Your authorization for use of your personal health information for this specific 
study does not expire.  
 
Your information may be held in a research database.  However, the School of 
Medicine may not re-use or re-disclose information collected in this study for a 
purpose other than this study unless: 
• You have given written authorization  
• The University of Pennsylvania’s Institutional Review Board grants 
permission 
• As permitted by law  
 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose your 
health information at any time.  You do this by sending written notice to the 
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investigator for the study.  If you withdraw your permission, you will not be able to 
stay in this study. 
 
What if I decide not to give permission to use and give out my 
health information? 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject HIPAA Authorization 
describing your confidentiality and privacy rights for this study.  
 
By signing this document, you are permitting the School of Medicine to use and 
disclose personal health information collected about you for research purposes 
as described above. 
 
Who can I call with questions, complaints or if I’m concerned 
about my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research 
subject, you should speak with the Principal Investigator listed on page one of this 
form.  If a member of the research team cannot be reached or you want to talk to 
someone other than those working on the study, you may contact the Office of 
Regulatory Affairs with any question, concerns or complaints at the University of 
Pennsylvania by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer.  Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. 
You are also allowing the University of Pennsylvania to disclose that personal 
health information to outside organizations or people involved with the 
operations of this study. 
 
A copy of this consent form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
 
 
 
 
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________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 
 
 
 
 
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