Topical Treatment for Superficial Disseminated Actinic Porokeratosis: A Single-Blinded Comparison Between Lovastatin/Cholesterol and Lovastatin
Phase: PHASE1
Conditions: Actinic Porokeratosis
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Topical treatment for superficial disseminated actinic porokeratosis: A Single-blinded 
Comparison Between Lovastatin/Cholesterol and Lovastatin 
 
PRINCIPAL INVESTIGATOR: Dr. Dirk Elston 
 
NCT04359823 
 
 
 
 

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1.0 
Objectives / Specific Aims 
• 
The purpose of this study is to evaluate the effectiveness of cholesterol/lovastatin 
versus lovastatin alone to treat porokeratosis. Our working hypothesis is that both 
topical cholesterol/lovastatin and lovastatin alone are helpful in treating patients with 
disseminated superficial actinic porokeratosis (DSAP).  
• 
Aims: 
• 1. To evaluate the response to treatment with topical cholesterol/lovastatin and 
lovastatin alone in a series of patients with the diagnosis of DSAP. 
• 2. To characterize lesion patterns following topical treatment and patterns of lesion 
regression.  
 
2.0 
Background 
Porokeratosis is a premalignant condition with a malignant transformation rate of 7.5%1. 
Variants include disseminated superficial actinic porokeratosis (DSAP), disseminated 
superficial porokeratosis, porokeratosis of Mibelli, porokeratosis palmaris et plantaris 
disseminate, porokeratosis ptychotropica, and linear porokeratosis.  
Porokeratosis is a rare condition involving clonal proliferation of abnormal keratinocytes 
that can be inherited or acquired. DSAP is the most common type of porokeratosis. It is 
described as a well circumscribed, erythematous macule with a peripheral rim of 
hyperkeratosis, also referred to as the coronoid lamella. While typically benign, lesions 
may develop into squamous cell carcinoma or Bowen’s disease1.  The lesions typically 
spare the palms and soles and are most prevalent on the extensor surfaces and back. DSAP 
typically presents in patients in their 30s and 40s who have a history of extensive 
ultraviolet radiation exposure. It is estimated to occur in a female to male ratio of 1.8:12. 
The exact pathogenesis for DSAP is currently unknown, however, the mevalonate genetic 
pathways are suspected to play a role in development. In one study, at least one mutation 
in the mevalonate pathway was found in 98% of familial cases and 70% of sporadic cases3. 
Treatment usually consists of destruction of the lesion utilizing cryotherapy, photodynamic 
therapy, carbon dioxide lasers, 5-fluorouracil. However, recent observations have 
suggested that various porokeratosis variants arise in areas affected by second-hit 
mutations in genes encoding components of the mevalonate pathway. Consequently, 
investigators from Yale University successfully treated a series of patients with topical 
cholesterol/lovastatin which resulted in complete clearance of DSAP lesions after 4 weeks 
of treatment4. 
It is hypothesized that statins will block the accumulation of toxic metabolites in the 
mevalonate pathway, while topical cholesterol will provide the essential nourishment to 
the cells4.  This study will provide a larger sample size and allow us to observe more 
definitive outcomes of the stain/cholesterol therapy. 
 
3.0 
Intervention to be studied  
Noninvasive in vivo imaging techniques have become an important diagnostic aid for skin cancer 
detection. Dermoscopy, also known as dermatoscopy, epiluminescence microscopy, incident light 
microscopy, or skin surface microscopy, is performed using a handheld instrument called a 

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dermatoscope or dermoscope, which has a transilluminating light source and standard magnifying 
optics (10×). The dermatoscope facilitates visualization of subsurface skin structures located 
within the epidermis, dermoepidermal junction, and papillary dermis, which are otherwise 
invisible to the unaided eye. Colors and structures visible with dermoscopy are required for 
generating a correct diagnosis. 
 
Dermlite dermatoscopes are approved by the FDA.  
 
We will utilize 2% cholesterol and 2% lovastatin ointment. It will be compounded by a 
pharmacist. Ointment will be applied on lesional skin with occlusion twice daily. 
Cholesterol and lovastatin are not approved by the FDA to be used in porokeratosis but are 
used off-label by physicians for the treatment of DSAP. 
 
Pharmacology  
Cholesterol is an animal sterol found in the body tissues (and blood plasma) of vertebrates. 
It can be found in large concentrations within the liver, spinal cord, and brain. Cholesterol 
is an important component of the membranes of cells, providing stability. Cholesterol is 
distributed universally in all animal tissues. It can be derived either from intestinal 
absorption of dietary cholesterol or from synthesis de novo within the body. Cholesterol 
itself in the animal system is the precursor of bile acids, steroid hormones, and provitamin 
D3. 
 
Lovastatin is a lactone metabolite isolated from the fungus Aspergillus terreus with 
cholesterol-lowering and potential antineoplastic activities. Lovastatin is hydrolyzed to the 
active 
beta-hydroxyacid 
form, 
which 
competitively 
inhibits 
3-hydroxyl-3-
methylgutarylcoenzyme A (HMG-CoA) reductase, an enzyme involved in cholesterol 
biosynthesis. In addition, this agent may induce tumor cell apoptosis and inhibit tumor cell 
invasiveness, possibly by inhibiting protein farnesylation and protein geranylgeranylation, 
and may arrest cells in the G1 phase of the cell cycle. Studies suggest that less than 5% of 
the oral dose reaches the general circulation as active inhibitors and the time to peak serum 
concentration is 2-4 hours. Lovastatin undergoes extensive first-pass metabolism so the 
availability of the drug in the system is low and variable. The peak concentrations of 
lovastatin when a dose of 10-40 mg is administered are reported to range from 1.04-4.03 
ng/ml and an AUC of 14-53 ng.h/ml. This indicates that lovastatin presents a dose-
dependent pharmacokinetic profile.  
Lovastatin is a HMG-CoA reductase inhibitors that has been used topically for the 
treatment of skin disorders such as acne, seborrhoea, rosacea, rhinophyma, atopic 
dermatitis, contact dermatitis and ichthyosis (US Patent 5,730,992 1998 and US Patent 
6,126,947 2000). Topical lovastatin at 49 mM (20 mg/ml) in 95% ethanol is well-tolerated 
with limited side effects. Muscle breakdown may occur resulting in signs and symptoms 
such as myalgias, fasciculations, cramping, myopathy, rhabdomyolysis and increased 
levels creatine kinases in the blood. The ethanol component may induce mild skin dryness. 
It was effective in the treatment of acne vulgaris, thus supporting the expectation of 
absorption through the skin. Lovastatin is known to cause reversible cell cycle arrest and 
effective concentrations depend on cell type and experimental conditions, but cell culture 

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concentrations of 2 to 20 µM (0.8–8.0 µg/ml) for up to 72 h result in reversible cell cycle 
arrest with cells beginning to cycle after 6 hrs5,6.    
 
4.0 
Study Endpoints  
• 
Percentage of clearance of disseminated superficial actinic porokeratosis lesions after 
12 weeks of therapy 
• 
Validated scale changes: Patient Quality of Life (RAND36, DLQI), Physician Global 
Assessment Scale (DSAP-PGA), Actinic Keratosis Field Assessment Scale 
• 
Clearance of coronoid lamella on dermoscopy (or photograph) after 12 weeks of 
therapy.  
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Inclusion Criteria  
• 
All patients 18 years and older with the diagnosis of disseminated superficial 
actinic porokeratosis.  
Exclusion Criteria 
• 
Patients with allergies or contraindications to lovastatin or cholesterol 
• 
Female patients currently pregnant or lactating.  
• 
Patients requiring their medications to be delivered to Alabama (Chemistry Rx 
does not dispense medications to this state) 
• 
Female patients with plans to become pregnant. 
o Patients actively taking approved forms of long-term 
contraception (oral contraceptives, implantable intrauterine 
devices, or other hormone eluting implants) will be allowed 
to participate as long as they have no plan to become 
pregnant during the course of the study. A urine pregnancy 
test will be administered to these patients to confirm that 
they can be included in the study. 
6.0 
Number of Subjects 
Approximately 50 subjects will be recruited. 
7.0 
Setting 
• 
Study Sites  
• 
Virtual video chat forums with patients living in the USA. 
• 
Medical University of South Carolina  
! Dermatology Clinics 
 
 
8.0 
Recruitment Methods 

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Recruitment will occur after standard of care visits to the Dermatology Clinics, virtual 
visits, and chart review of eligible patients.  
For standard of care visits, the first person to tell eligible patients about this study will be 
someone directly involved in their patient care. If they are interested, the aforementioned 
clinician and study team members will approach the patients without coercion and with the 
emphasis on the voluntary aspect of being on this study. Subjects will also be told in a 
caring manner that no matter what their decision is, it will not affect how their doctor cares 
for them as a patient or their care in general.   
Patients discovered via chart review will be contacted to be informed of the potential 
research opportunity under the same aforementioned conditions. Only patients who have 
indicated they are willing to be contacted for research opportunities on their MUSC profile 
will be eligible for this form of contact. In this instance the first person to contact them 
may not be someone directly involved in their patient care.  
Potential subjects who contact the study team members directly will also be considered for 
participation in the study. In this event, these potential subjects must have heard about the 
study through indirect information sources (clinicaltrials.gov, DSAP support groups, or 
other means by which the study team members did not directly advertise the study for 
purposes of recruitment). If they are interested, the aforementioned study team members 
will respond to them via email, and subsequently approach the patients virtually without 
coercion and with the emphasis on the voluntary aspect of being on this study. Subjects 
will also be told in a caring manner that no matter what their decision is, it will not affect 
how their doctor cares for them as a patient or their care in general.   
 
 
9.0 
Consent Process 
Written informed consent will be obtained from subjects. Informed consent will be 
obtained in a private room within the clinics or privately via virtual visits. All subjects will 
undergo a prescreening call by study team members during which they are informed of the 
details of the study, eligibility concerns, and given the opportunity to ask and questions or 
address concern about the study. They will be sent the consent form immediately 
afterward, allowing them ample time to review the document before meeting the study 
team in person or virtually during visit 1 (week 0). During visit 1, the trained study team 
member performing consent will then review the consent form with them once again and 
address any questions before the sign the document and return it to the team via email. 
Virtual consenting will be performed on REDcap. Only trained research team members 
will be obtaining informed consent. Training will be performed by Alan Snyder and only 
those who are trained will perform informed consent after they sign the study training log. 
No waiting period will be necessary between informing the subjects and obtaining the 
consent; however, subjects will be allowed to take home the unsigned consent form for 
review prior to signing it if needed.  
The virtual consent process for patients who contact study team members directly about 
potential interest in participating is summarized below: 
1. subjects contact our study team after hearing about our study from indirect sources 
2. Interested subjects are called by one of our study team members for a prescreening call 
in which we determine if they are eligible to participate in our study. This is also an 

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opportunity for Q&A for potential participants who may want eligibility information or 
details about the study prior to an official enrollment visit. 
3. Potential subjects are securely emailed a copy of the IRB-approved ICF and scheduled 
for an official enrollment video visit that is mutually agreeable for the investigators and 
potential participant. The time period between this email and the enrollment visit will 
provide participants ample time to review the ICF in detail so that they have the 
opportunity to prepare additional questions during the official enrollment visit. 
4. Investigators and potential participants engage in a video chat for consenting, in which 
REDCap will be used for execution of the consent process. Study participants will have the 
option to have the signed ICF sent to their personal email after it is signed by both parties. 
6. Subsequently, Visit 1 will proceed following the procedures in our protocol  
 
10.0 Study Design / Methods 
• Potential subjects will be approached for informed consent as directed in sections 
8.0 and 9.0. Pertinent project information, risks, and time commitment will be 
relayed to subjects. If subjects show interest in participating, they will be given 
consent forms to either sign or bring home for consideration. A urine pregnancy 
test will be administered to these patients to confirm that they can be included in 
the study. 
• If the patient is eligible for the study, he or she will be randomly assigned to one of 
two groups. They will have a 50/50 chance of being in either group. Neither the 
researchers nor you will make the choice to which group you are assigned.  The 
two groups are Group A (cholesterol/lovastatin) and Group B (lovastatin only). The 
patient will not be informed of which group they are in and will not be informed of 
what their study medication is, allowing single-blinding. Researchers will not be 
masked. 
• Enrolled subjects will be followed up at monthly intervals for three months via 
virtual check-in using an MUSC approved HIPAA compliant technology. At each 
visit, participants will undergo brief, limited physical examination (in order to 
determine disease severity and affected body surface area); additionally, clinical 
photographs of the lesion will be obtained in clinic or shared virtually with the 
investigators via secure email (sent to MUSC Outlook email). The physical exam 
will occur in-person or by using the virtual visit technology, which allows us to see 
the patient and visualize their skin findings.. Photographs will be stored in the 
coded study-specific medical record for further analysis of lesion features.  
• At each visit a Patient Quality of Life, Physician Global Assessment Scale, and 
Actinic keratosis Field Assessment Scale will be administered.  
• Patients will be contacted via virtual check-in visits at weeks 4, 8, and 12. Patients 
will be asked about compliance and any adverse effects experienced. Patients are 
also encouraged to contact Alan Snyder at any given point during the study if they 
think they are experiencing study-related side effects. Immediate consultation will 
follow to determine the severity of such event and necessary impacts on patient 
health and participation. Participants will also be contacted by phone by study team 
member to assess for any adverse effects at weeks 2 and 6 of treatment. 

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• Compounded topical medication prescribed to subjects will be self-applied twice 
daily. These medications will be prepared by Tidewater Pharmacy in Mount 
Pleasant, SC or Chemistry Rx in Philidelphia, PA. They will be prepared so the 
study will remain single-blinded (only investigators know which study drug they 
are receiving) and associated costs will not be covered by the research budget. The 
cost of the medication will be approximately $85 when dispensed by Tidewater 
Pharmacy, or $110 when dispensed by Chemistry Rx. The differences in costs are 
attributed to shipping and pharmacy fees. 
• Both pharmacies will be compounding the drugs to be used in this study, and the 
compounding formula (recipe) will be identical between these two compounding 
pharmacies. 
• Enrollment and prescription drug delivery to other states will not be performed 
until the respective state pharmacy boards confirm the legality of clinical telehealth 
interventions and out-of-state pharmacy prescriptions. All state and federal 
guidelines will be followed according to their regulations and recommendations. 
• Patient prescriptions will be called in to their respective pharmacies by credentialed 
study team members after enrollment is completed. Individual prescriptions will be 
called in to the aforementioned pharmacies so that the pharmacies can individually 
ship the medication to the respective participant. Both pharmacies are well aware of 
the study protocol and procedures for sending the prescription. This will occur by 
standard procedure of calling medications for patients:  
! 1. The study team member will call the pharmacist to 
inform them that a participant has been enrolled and ready 
to receive one of the two single-blinded drugs. The 
lovastatin/cholesterol combination has been assigned the 
arbitrary codename “RDC100”, and the lovastatin alone 
medication has been assigned the arbitrary codename 
“RDC15”. On the prescription label there will be the 
codename, application instructions, and storage instructions. 
! 2. Per standard procedure of calling in a prescription, the 
study 
team 
member 
will 
verbally 
inform 
the 
Tidewater/Chemistry Rx pharmacist of the patient name, 
birthday, and phone number so that the medication can be 
prescribed and so that the patient can be contacted by the 
pharmacist for shipping and payment purposes.  
! 3. The pharmacist will contact the patient over the phone in 
order to complete the medication payment over the phone 
and to identify the address to which the medication will be 
sent to. 
! 4. The subject will inform the study team member upon 
receival of the medication, confirm that they received the 
correct, randomized medication.  
! 5. All of the information related to drug disposal and 
reception 
will 
be 
recorded 
on 
the 
coded 
Drug 
Accountability Sheet, which is located separately in the 
secure box drive. 

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• Medications will be able to be shipped to all continental US states by Chemistry 
Rx, except Alabama. This is because Chemistry Rx does not have the license to 
dispense to Alabama. Therefore, any participant reliant upon an Alabama address 
to receive their medication will not be allowed to participate in this study. 
• Dermoscopic and clinical photographs will be subsequently analyzed for the 
presence of cornoid lamella. The team will record any additional dermoscopic or 
clinicals feature that may arise during the analyses.  
• Frequency of dermoscopic and clinical features will be analyzed against clinical 
involution to find possible predictors.  
• Procedures during the day of imaging: 
The doctor will identify the lesion(s) that will be analyzed. 
The lesion(s) will be measured and clinical and dermoscopy photographs will be 
taken. Facial images might be taken to assess lesions on the head area.  
Schedule of events: 
Event 
Screening 
Baseline 
Visit 1 
Week 4 
(virtual) 
Week 8 
(virtual) 
Week 12 
(virtual) 
Informed consent 
X 
 
 
 
Eligibility Assessment 
X 
 
 
 
Demographics 
X 
 
 
 
Physical Examination 
X 
 
 
 
Clinical photograph & 
Scale (3x) administration 
X 
X 
X 
X 
Dermoscopic 
photograph 
X 
 
 
 
Adverse events 
monitoring 
X 
X 
X 
X 
 
11.0 Data Management  
• Continuous data will be summarized using descriptive statistics (number of 
values, means, standard deviation, median, minimum and maximum). 
Categorical data will be summarized using frequency tables (frequencies and 
percent). 

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• We are comparing before and after photographs from the same patient, hence 
we employ analysis by paired t-test to compare baseline data with data after 
treatment. 
• Coded dermoscopic and clinical photographs may be obtained for further 
analyses. Files with patient images will be stored in a secure departmental drive 
that will only be accessible to study team members by their unique MUSC ID 
and password. 
! Photos shared directly via email to study team members will be 
also be uploaded to the participants respective coded folder on 
the Box drive.  
! These emailed photos (sent by the participant personal email) 
must be de-identified close up photos of the participants legs or 
arms, and sent only to study team members secure MUSC-
assigned Outlook email addresses. Photos that do not fit this 
criteria will be deleted upon receival and not used in the study. 
• All subject medical record information and data collection will be coded and 
stored on an MUSC Box drive only accessible to study team members, and will 
be protected by two-factor authentication. 
12.0 Withdrawal of Subjects  
1. 
Any adverse effect during patient’s treatment will require a thorough review of the adverse 
event by the study team members. Depending on the severity of the adverse event, the 
participant may be recommended to withdrawal from the study. The research team will 
continue to follow the patient until resolution of said adverse event has resolved. 
2. 
Upon subject’s verbal notification, the study team will evaluate the adverse event, they will 
proceed to document it and evaluate for subject safety. They will determine if subject is 
suitable to continue in the study. 
3. 
Information will be provided about safe discontinuation of the drug and if any clinical 
review needs to occur. For evaluation and reporting purposes, researchers may conduct an 
exit interview and ask subjects about the reason for early withdrawal. 
4. 
Subjects can participate in the study as long as they want. Subjects may verbally notify 
investigators if they wish to voluntarily withdrawal from the study and they will be 
removed immediately. 
 
13.0 Risks to Subjects 
• We anticipate minimal side effects and local irritation to be minimal. Muscle toxicity is 
a known adverse effect of statins. Patients will be notified during enrollment to watch 
out for common signs and symptoms such myalgias, fasciculations, cramping, 
myopathy and increased levels of CK. If an adverse event occurs, the subject must 
notify the study team members at their earliest convenience. Upon the subject’s verbal 
notification to the study team, the study team will evaluate the adverse event and will 
proceed to document it and evaluate for subject safety. They will determine if subject is 
suitable to continue in the study. 

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• If there is an increased frequency of any concerning adverse event in particular, all 
enrolled participants in the trial will be sent an individual notice. 
• There is a risk for possible breach of confidentiality as photographs of face may be 
taken to assess lesions on the head. However, all measures to keep information 
protected will be taken.  
• There is a risk of emotional discomfort while the subject takes the questionnaires. 
• A cumulative data assessment will be conducted every other month throughout the 
study’s duration by study team members. A report that includes any available efficacy 
data, as well as a record of anticipated adverse events, will be compiled and submitted 
to the IRB at that time. Any event meeting the criteria of an unanticipated problem 
involving risks to subjects or others will be immediately reported to the MUSC IRB, as 
required by HRPP 4.7- Unanticipated Problems and Adverse Events Policy and 
Procedures.  
• The plan for subject safety and minimizing risks of the research is as follows: 
Inspection of the treatment site at each visit. Adverse effects of topical 
lovastatin/cholesterol will be specifically assessed at each research visit by the 
investigator, per outlined procedures. Participants are encouraged to reach out to the 
study coordinator if they think they are experiencing any adverse events. Other 
expected adverse effects deemed intolerable by the patient will prompt reduction in the 
patient’s dose and treatment if indicated. Any condition necessitating cessation of the 
study drug will be followed to resolution.  
• However, the side effect profile associated with both topical cholesterol and lovastatin 
is extremely small. We do not anticipate there being any complications associated with 
treatment other than minor, local irritation. The rare chance of developing stain induced 
myopathy and its associated signs and symptoms will be addressed during enrollment 
and each individual visit.    
 
14.0 Potential Benefits to Subjects or Others 
Patients will may benefit from the intervention. Researchers hope that the treatment 
will help clear active DSAP lesions, but all benefits are hypothetical currently. 
 
15.0 Sharing of Results with Subjects 
Results may be shared with subjects at the end of the study per verbal request.  
 
16.0 Drugs or Devices   
5. 
Drugs will be compounded by Tidewater Pharmacy or Chemistry Rx prior to the patients 
week 0 visit. They will be stored at this pharmacy until the subject is able to pick it up or 
have it delivered to their home address. 
6. 
Investigators will be in charge to handle dermoscope and will be responsible to upload the 
images to the secured folder. The Dermatoscope is device used SOC for analysis of DSAP 
lesions. 
7. 
An investigational drug exemption support document has been submitted to the eIRB. 
References 
1.  
Sasson M, Krain AD. Porokeratosis and cutaneous malignancy. A review. Dermatol Surg. 

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2. 
Sertznig, P., von Felbert, V. and Megahed, M. (2012), Porokeratosis: present concepts. Journal of 
the European Academy of Dermatology and Venereology, 26: 404-412. doi:10.1111/j.1468-
3083.2011.04275.x 
3. Zhang Z, Li C, Wu F, et al. Genomic variations of the mevalonate pathway in porokeratosis. Elife. 
2015;4:e06322. Published 2015 Jul 23. doi:10.7554/eLife.06322 
4.  
Atzmony L, Lim YH, Hamilton C, et al. Topical cholesterol/lovastatin for the treatment of 
porokeratosis: A pathogenesis-directed therapy. J Am Acad Dermatol. 2020;82(1):123-131. 
doi:10.1016/j.jaad.2019.08.043 
5.  
Jakóbisiak M, Bruno S, Skierski JS, Darzynkiewicz Z. Cell cycle-specific effects of lovastatin. 
Proc Natl Acad Sci U S A. 1991;88(9):3628-3632. doi:10.1073/pnas.88.9.3628 
6.  
Keyomarsi K, Sandoval L, Band V, Pardee AB. Synchronization of tumor and normal cells from 
G1 to multiple cell cycles by lovastatin. Cancer Res. 1991;51(13):3602-3609. 
http://www.ncbi.nlm.nih.gov/pubmed/1711413.