An Open-Label Pilot Study to Evaluate the Effectiveness and Tolerability of a Topical Composition Therapy for the Treatment of Cutaneous Mastocytosis
Phase: PHASE2
Conditions: Cutaneous Mastocytoses
Sponsor: Joseph Butterfield

 
An Open-label Pilot Study to 
Evaluate the Effectiveness and 
Tolerability of a Topical 
Composition Therapy for the 
Treatment of Cutaneous 
Mastocytosis 
 
NCT# 04846348 
 
August 18, 2022 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 1 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
An Open-Label Pilot Study to Evaluate the Effectiveness and Tolerability of a Topical 
Composition Therapy for the Treatment of Cutaneous Mastocytosis 
 
 
 
 
 
Regulatory Sponsor-Investigator    
 Joseph H. Butterfield, M.D. 
 
Study Site Location: 
 
 
 
Mayo Clinic Department of Allergy 
 
 
 
 
 
 
 
200 SW 1st Street 
 
 
 
 
 
 
 
Rochester, MN  
 
IRB Number: 
 
 
 
 
20-011876 
 
IND Number: 
 
 
 
 
146547 
 
Study Product: 
 
 
 
 
“Skin Guard” topical cream   
 
 
 
 
 
 
 
  
formulation containing:  
 
 
 
 
 
 
 
Diphenhydramine  
1% 
 
 
 
 
 
 
 
Trolamine Salicylate 10% 
 
 
 
 
 
 
 
Cromolyn sodium  
5%  
 
 
 
 
 
 
 
Vanicream 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: [07/23/21] Version (2.0) 
Revised: [11/11/2021] Version (3.0) 
Revised : [08/18/2022] Version (4.0) 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 2 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Table of Contents 
 
STUDY SUMMARY 
4 
1  INTRODUCTION 
5 
  1.1  BACKGROUND 
5 
  1.2  INVESTIGATIONAL AGENT 
6 
2  STUDY OBJECTIVES 
7 
3  STUDY DESIGN 
7 
  3.1  GENERAL DESIGN 
7 
  3.2 PRIMARY STUDY ENDPOINTS 
8 
  3.3 SECONDARY STUDY ENDPOINTS 
8 
  3.4  PRIMARY SAFETY ENDPOINTS 
8 
4  SUBJECT SELECTION ENROLLMENT AND WITHDRAWALS 
8 
  4.1  INCLUSION CRITERIA 
8 
  4.2  EXCLUSION CRITERIA 
9 
  4.3  SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING 
9 
  4.4  EARLY WITHDRAWAL OF SUBJECTS 
10 
      When and How to Withdraw Subjects 
10 
      Data Collection and Follow-up for Withdrawn Subjects 
10 
5  STUDY DRUG 
10 
  5.1 DESCRIPTION 
10 
  5.2  STUDY PROCEDURES 
10 
      Preparation and Administration of Study 
10 
      Subject Compliance Monitoring 
11 
  5.3  PRIOR AND CONCOMITANT THERAPY 
11 
  5.4   PACKAGING 
11 
  5.5  MASKING/BLINDING OF STUDY 
11 
  5.6  RECEIVING, STORAGE, DISPENSING AND RETURN 
11 
      Receipt of Drug Supplies 
11 
      Storage 
11 
      Dispensing of Study Drug 
11 
      Return or Destruction of Study Drug 
11 
6  STUDY PROCEDURES   
12 
  6.1  VISIT 1 
12 
  6.2  VISIT 2 
12 
 
12 
 
12 
 
12 
  6.6  PROTOCOL SCHEDULE OF EVENTS 
14 
7  STATISTICAL PLAN 
15 
  7.1  SAMPLE SIZE DETERMINATION 
15 
  7.2  STATISTICAL METHODS 
15 
  7.3  SUBJECT POPULATION FOR ANALYSIS 
16 
8  SAFETY AND ADVERSE EVENTS 
16 
  8.1  DEFINITIONS 
16 
  8.2  RECORDING OF ADVERSE EVENTS 
18 
  8.3  REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS 
18 
    Sponsor-Investigator reporting: Notifying the Mayo IRB 
18 
    Sponsor-Investigator reporting: Notifying the FDA 
19 
  8.4  UNBLINDING PROCEDURES 
19 
  8.5  STOPPING RULES 
19 
  8.6  MEDICAL MONITORING 
20 
9  DATA HANDLING AND RECORD KEEPING 
20 
  9.1  CONFIDENTIALITY 
20 
  9.2  SOURCE DOCUMENTS 
20 
  9.3  CASE REPORT FORMS 
20 
  9.4  RECORDS RETENTION 
21 
10  STUDY MONITORING, AUDITING, AND INSPECTING 
21 
  10.1  STUDY MONITORING PLAN 
21 
  10.2  AUDITING AND INSPECTING 
22 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 3 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
11  ETHICAL CONSIDERATIONS 
22 
12  STUDY FINANCES 
22 
  12.1  FUNDING SOURCE 
22 
13  PUBLICATION PLAN 
22 
14  REFERENCES 
23 
15 ATTACHMENTS 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 4 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Study Summary 
 
Title 
AN OPEN-LABEL PILOT STUDY TO EVALUATE THE 
EFFECTIVENESS AND TOLERABILITY OF A TOPICAL 
COMPOSITION  THERAPY FOR THE TREATMENT OF 
CUTANEOUS MASTOCYTOSIS 
Running Title  
Topical Composition for Cutaneous Mastocytosis 
Protocol Number 
Pending 
Phase 
Phase II Feasibility/Proof of Concept 
Methodology 
Open Label 
Subject participation 
Duration 
Two weeks 
Study Duration 
One year 
Single or Multi-Site 
Single Center 
Objectives 
To determine the effectiveness and tolerability of a novel topical 
preparation for the treatment of cutaneous lesions of mastocytosis. 
Number of Subjects 
10 
Diagnosis and Main 
Inclusion Criteria 
Cutaneous mastocytosis 
Study Product, 
Dose, Route, 
Regimen 
Topical composition ‘Skin Guard’ applied twice daily for four weeks. 
Duration of 
Administration 
2weeks 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 5 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
1  Introduction 
 
This human clinical research study will be carried out in accordance with the protocol, 
applicable United States government regulations and Mayo Clinic research policies and 
procedures. 
 
1.1 Background 
 
Condition to be studied 
Mastocytosis is a rare disorder of clonal mast cell proliferation. There are several 
subclasses of systemic mastocytosis (SM) ranging from indolent disease to aggressive 
disease, mast cell leukemia and mast cell sarcoma. The major criterion for defining 
systemic disease is the presence of mast cell (MC) infiltration of organs (commonly 
assessed by tissue or bone marrow biopsy). Patients with SM may or may not have 
cutaneous involvement. Whereas in cutaneous mastocytosis (CM), MC infiltration is 
limited to the skin. 
 
Why the investigational product may be beneficial 
 
Topical treatment of symptoms resulting from cutaneous involvement by mastocytosis 
(pruritus, flushing, urticaria, angioedema) is mainly limited to topical lubricants, topical 
corticosteroids, and topical antihistamines, medications that have individually been 
available for decades. In our own experience, topical cromolyn sodium 0.25% (children), 
and 1% or 5% (adults) can also be effective for relief of dermal symptoms.  
 
Excessive application of topical steroids can cause skin atrophy or delayed healing, while 
excessive absorption of topical antihistamines could lead to systemic side effects such as 
somnolence, dyskinetic symptoms, impairment of performance skills, anticholinergic 
symptoms and others.  
 
The product to be used will not contain corticosteroids and will use a lower concentration 
of diphenhydramine (1% vs 2%) than is currently available in over the counter 
preparations. By combining 3 ingredients, diphenhydramine, cromolyn sodium and 
trolamine we will leverage the different effects of various classes of medications to block 
mast cell mediator release (cromolyn sodium), to block mediator (histamine) receptors 
(diphenhydramine) and to inhibit production of prostaglandin D2 by topical 
cyclooxygenase blockade (trolamine salicylate). 
 
Pathophysiology relevant to potential study treatment action 
Symptoms from mastocytosis result from accumulation of these cells as well as local and 
remote effects of MC mediators. Mast cells are dynamos for the production of mediators 
that in the skin can stimulate symptoms by their effects on blood vessel constriction, 
vasopermeability, and excitation of nerve endings causing itching, hiving, swelling and 
flushing. The synergistic effect of targeting 3 of the most prevalent (and measurable) 
mediators should have a beneficial effect on dermatologic symptoms and will allow a lower 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 6 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
concentration (1% vs 2%) of diphenhydramine to be used than is commonly employed in 
OTC topical preparations of this medication. 
Description of the population to be studied 
 
Involvement of the skin in mastocytosis is equally common in men and women. Patients 
age 18 and above with CM or skin involvement in SM confirmed by skin biopsy who have 
bothersome, symptoms not controlled with topical and systemic medications will be 
eligible to participate in this study. Ten patients will be enrolled. Women who are pregnant 
or nursing will be excluded. 
 
1.2 Investigational Agents 
The proposed study refers to a topical composition of the following agents, each of which 
is currently approved for and is used in clinical practice: 
 
DIPHENHYDRAMINE 
 
Drug Class:H1 antihistamine 
 
Mechanism of Action Diphenhydramine acts as an antihistamine by competing with histamine for 
receptor sites on effector cells such as mast cells and basophils. 
 
Pharmacology Diphenhydramine is a first generation antihistamine of the ethanolamine class. It 
has antimuscarinic, antiemetic and sedative effects and competitively antagonizes the effect of 
histamine on histamine receptors in the GI tract, uterus, large blood vessels, and bronchial 
muscle. It has multiple other uses such as treating drug-induced extrapyramidal effects, vertigo 
and Meniere’s disease. Diphenhydramine is metabolized in the liver and the total body clearance 
of orally administered diphenhydramine is 11.7 to 49.2 mL/min/kg. 
 
TROLAMINE SALICYLATE 
 
Drug Class: Non-steroidal anti-inflammatory  
 
Mechanism of Action: The active moiety in trolamine salicylate is salicylic acid which, by 
inhibition of prostaglandin synthesis inhibits pain, inflammation and hyperemia. The 
downstream effect of inhibition COX-1 includes blocking synthesis of prostaglandin (PG) D2, a 
product of mast cells.      
 
Pharmacology: Available as an over-the-counter preparation, 10% topical trolamine salicylate is 
commonly used to treat musculoskeletal pain and osteoarthritis. 
 
CROMOLYN SODIUM (disodium cromoglycate) 
 
Drug Class: Anti inflammatory agent and mast cell stabilizer. 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 7 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Mechanism of Action: Cromolyn sodium blocks the release of histamine and SRS-A (slow-
reacting substance of anaphylaxis) from sensitized mast cells. 
 
Pharmacology: Cromolyn sodium is available in multiple dosage forms including an oral form 
used for treating gastrointestinal disorders in hypereosinophilic disorders and in mastocytosis; 
ophthalmic drops for treating allergic conjunctivitis; a nasal spray for treating allergic rhinitis; an 
inhalant solution for treating asthma, and is prepared in a compounded topical cream for 
treatment of cutaneous mastocytosis. Oral cromolyn sodium is poorly absorbed and the 
bioavailability of inhaled (8%), ophthalmic (0.03%), and oral (not more than 1%) is low. In one 
study of the absorption of oral [14C] disodium cromoglycate only 0.4% of an oral dose (20 mg) 
appeared in the 24 hr urine sample and 83% was recovered from the feces. While intravenous 
administration resulted in approximately equal amounts (30-50%) being excreted via the urine 
and feces (Walker SR, Evans ME, Richards AJ, Paterson JW. The fate of [14C] disodium 
cromoglycate in man. J. Pharm. Pharmac.1972; 24: 525-531) 
 
VANICREAM (OTC) 
 
Drug Class: Moisturizer; Vehicle for topical preparations 
 
Mechanism of Action: Vanicream is used as a topical lubricant that does not clog pores and is not 
absorbed. It is used by itself as a moisturizer and for compounding of topically applied skin care 
products.  
 
Pharmacology: Vanicream is formulated as an OTC preparation comprised of: purified water, 
white petrolatum, sorbitol solution, cetearyl alcohol, propylene glycol, ceteareth-20, simethicone, 
glyceryl monostearate, polyethylene glycol monostearate, sorbic acid, BHT. It is free of lanolin, 
fragrances, parabens and formaldehyde. Vanicream is compatible with numerous topical agents 
used for skin care. 
 
 
 
 
 
 
 
 
 
  
2  Study Objectives 
The primary objective of this study is to assess the effectiveness of twice daily application of 
trolamine salicylate 10%, sodium cromolyn 5%, and diphenhydramine 1% on symptoms 
resulting from cutaneous mastocytosis. 
 
3  Study Design 
 
3.1 General design  
This is a phase II nonrandomized, open-label pilot study of the effectiveness and 
tolerability of a novel composition comprised of daily application of trolamine salicylate 
10%, sodium cromolyn 5%, and diphenhydramine 1% in vanicream on skin producing 
cutaneous symptoms of mastocytosis. Subjects will be screened by the Department of 
Allergic Diseases at the Mayo Clinic in Rochester MN and interested qualified subjects 
will be consented and offered participation. The study is designed to establish 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 8 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
feasibility/proof of concept and will not include randomization or crossover components. 
Please see Section 6: Study procedures for a detailed description. 
 
3.2 Primary Study Endpoints  
 
Scorma Index[see below] 
The proportion of participants who achieved complete resolution or near-complete clearing 
of cutaneous symptoms of treated, involved skin after 2 weeks’ treatment will be evaluated 
using the SCORing MAstocytosis (SCORMA) index. SCORMA has been utilized to 
evaluate the severity of cutaneous mastocytosis and to correlate with serum tryptase levels. 
Repeated SCORMA determinations can “provide a rapid impression of changes in the 
clinical status” in mastocytosis (HeideR, van Doorn K, Mulder PG et al. Serum tryptase 
and SCORMA (SCORing MAstocytosis) index as disease severity parameters in childhood 
and adult cutaneous mastocytosis. Clinical and Experimental Dermatology 2008; 34: 462-
468.)  
 The SCORMA index is calculated by the formula A/5 +5B +2C/5 where 
A=Extent of skin involvement,  
B= Intensity (pigmentation/erythema + vesiculation  + elevation + positive Darier’s sign 
each rated 0[absent], 1[mild] 2[moderate] or 3[severe] ).  
C= subjective symptoms utilizing visual analog scale 1-10 of the following: provoking 
factor(s), flushing, diarrhea, pruritus, localized bone pain. 
 
Since it will be impractical for patients to apply Skin Guard to the entire body surface area, 
and not all areas of the skin will be involved to the same extent, we will limit application to 
between 9% and 18% of the skin (see SCORMA figure). In this regard we will attempt, 
when possible, to utilize equally involved sides of the torso or extremities to facilitate 
evaluation of effectiveness. We will generate not only a “Global” SCORMA value, but in 
addition a SCORMA value for the treated, involved skin. The latter should give a more 
accurate estimation of the effectiveness on treated areas. 
 
Quality of Life –SkinDex-16[see below]. Skindex-16, a validated measurement of the 
effects of skin diseases on patients’ quality of life will be utilized to follow this parameter. 
SkinDex has been used and adapted for dermatologic research internationally (Chren M-M, 
The SkinDex instruments to measure the effects of skin disease on quality of life. 
Dermatology Clinics 2012; 30: 231-236). 
 
3.3 Secondary Study Endpoints 
These will include mast cell mediator levels; serum tryptase, urinary leukotriene (LT) E4, 
n-methyl histamine (N-MH), and 2,3 dinor 11β prostaglandin(PG) F2α levels [Mayo 
Medical Labs]. 
 
3.4 Primary Safety Endpoints 
Minimal systemic absorption is expected with each of the active components. Safety 
endpoints to be measured at the initial and final visits and include Investigator and 
Participant observation of local skin tolerability including ratings of itching, swelling 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 9 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
stinging/ burning, and dryness on separate scales as none (0), mild (1), moderate (2), or 
severe (3). 
 
4   Subject Selection Enrollment and Withdrawal 
 
4.1 Inclusion criteria 
Informed subject consent will be obtained from those patients with the following inclusion 
criteria:  
● Biopsy proven cutaneous mastocytosis with or without evidence of systemic disease 
 
● Male and female patients 18 to 80 years of age 
 
● No UVB treatment of the skin for 6 months prior to study entry 
 
● No use of topical or systemic corticosteroids for 1 month prior to study entry 
 
● Good general health as confirmed by medical history 
● Female patients of child-bearing potential with negative urine pregnancy test who agree 
to use effective methods of birth control or remain abstinent during treatment. 
Participants must use birth control for the entire study and for at least 1 week after the 
last application of the study formulation. Acceptable methods of birth control include 
ongoing hormonal contraception methods, (such as birth control pills, patches, injections, 
vaginal ring, or implants), barrier methods (such as a condom (for men) or diaphragm 
used with a spermicide), intrauterine devices, tubal ligation, or abstinence. 
● Patients who are willing and capable of cooperating to the extent and degree required 
by the protocol; and 
● Patients who read and sign an approved informed consent for this study 
 
4.2 Exclusion criteria 
Patients are to be excluded based on the following criteria: 
 
●Vulnerable study population 
●Exposure to ultraviolet B (UVB) radiation to any region of the skin surface for 6 
months 
●Regular use of skin lightening agents within 1 month of study entry, including 
 
◦Topical corticosteroids 
 
◦ Topical bleaching products 
 
◦ Topical retinoids 
 
●Use of systemic preparations within 1 month of study entry, including: 
 
◦Systemic corticosteroids 
 
◦Systemic cyclosporine, interferon 
 
◦Systemic acitretin, etretinate, isoretinoin 
 
◦Systemic methotrexate, 
 
◦Systemic photoallergic, phototoxic and/or photosensitizing drugs 
 
●UV light therapy and sunbathing 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 10 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
●Inability to communicate or cooperate with the Principal Investigator and/or 
Investigators due to language problems, poor mental development or impaired cerebral 
function 
●Pregnant or nursing women 
●Women planning a pregnancy within the study period 
 
4.3 Subject Recruitment, Enrollment and Screening 
 
Subjects will be recruited from the Division of Allergic Diseases at the Mayo Clinic in 
Minnesota outpatient clinical practice. Patients will be provided with a Research Participant 
Consent and Privacy Authorization Form describing the study formulation, protocol, inclusion 
and exclusion criteria, as well as risks and benefits of participation. 
 
4.4 Early Withdrawal  of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
Patients are free to withdraw at any time and for whatever reason. No data will be collected for 
withdrawn subjects and withdrawn subjects will not be replaced. There will be no follow-up for 
withdrawn subjects. Pre-specified reasons for discontinuing include, but are not limited to, the 
following: 
 
● Patient request: Patient decided that he/she did not want to continue (for any reason). 
●Adverse Event: Patient experienced a related or unrelated event that would interfere with the 
study objectives/evaluation 
●Lost to Follow-up: Patient did not come in for a visit and could not be reached by phone 
●Treatment Failure: If in the Principal Investigator’s judgment, the patient’s condition required 
another form of treatment 
●Noncompliance: Patient is not complying with the protocol requirements (i.e. visit schedule, 
dosing, regimen, etc.); a patient is to be withdrawn if he/she misses two consecutive visits 
●Other: Any other reason 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a Participant withdraws from the study, no additional attempts will be made to contact the 
Participant. 
 
  
5  Study Drug 
 
5.1 Description 
The “skin guard” study formulation is a combination of components of FDA approved drugs 
trolamine salicylate 10%, sodium cromolyn 5%, and diphenhydramine 1% as well as the skin 
moisturizer Vanicream (OTC). The components will be compounded into a cream formulation 
and is intended for topical application to the skin. The drug product will be packaged in a 
polypropylene ointment jar with screw cap lid. 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 11 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
 
5.2 Study Procedures 
Preparation and Administration of Study Drug 
Each participant will receive both verbal and written instructions as to proper dosing and 
application and storage. The Mayo Clinic Research Pharmacy in Rochester, MN will prepare, 
store and distribute the study formulation. Participants will receive 2-one-half pound ointment 
jars of the study formulation. The jars will be returnedat the final visit.. The returned used jars 
will be weighed by the Principal Investigator or a study team member to determine the amount 
used/compliance. Should additional cream be required during the 2 weeks of the study, the 
patient can contact the principal investigator or the clinical study coordinator. Upon 
notification from the patient, an extra ½ pound jar will be sent to the patient by overnight 
express mail.   
Instructions will be provided as follows: Twice daily, apply a thin film of the study formulation 
to symptomatic areas of the skin including about one centimeter of normal appearing skin 
surrounding each area of involvement. Rub lightly and uniformly into the skin. An investigator 
will demonstrate correct application by using a bland emollient moisturizer. 
 
Subject Compliance Monitoring 
Adherence to the treatment regimen is of great importance. Poor compliance may result from 
lack of patient understanding, discomfort caused by the product and unrealistic expectations. 
Assessment of participant compliance will be determined by weighing ointment jars at the time 
of the final visit. Participants are not expected to use a specific amount of the study formulation  
. Rather, use will be individualized depending on the amount of symptomatically involved 
skin. Those who are non-compliant with the study protocol despite additional counseling and 
the opportunity to correct will be withdrawn. 
 
5.3 Prior and Concomitant Therapy 
With the exception of ordinary over-the-counter moisturizers, and sun protection, no 
concomitant topical medicines/therapies are permitted for 1 month prior to and during the 
study period. 
 
5.4 Packaging 
The study formulation will be packaged in a ½ pound ointment jar with screw lid. The jars of 
drug product will be labeled with each subject’s name, active contents, expiration, lot number 
and the following statement: “*EXTERNAL Use Only* *For investigational Use Only*”. 
 
5.5 Masking/Blinding of Study 
This is an open-label pilot investigation. Masking/blinding procedures are not applicable. 
Qualitative and quantitative evaluations of response to treatment will be recorded. Updated 
photographs will be included in participants’ records time 0, and week 4. 
 
5.6 Receiving, Storage, Dispensing and Return 
 
5.6.1Receipt of Drug Supplies: The study formulation will be compounded by the Mayo 
         Clinic Research Pharmacy in Minnesota for each subject. 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 12 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
 
5.6.2 Storage: The study formulation will be stored at room temperature 68o to 77o F 
        (20o-25oC), with excursions permitted between 59o to 86oF (15o-30oC), by the Mayo  
        Clinic Research Pharmacy in Minnesota. There are no special handling requirements. 
 
          5.6.3 Dispensing of Study Drug: Finalreconciliation by weight measurement and/or 
          number of returned empty jars will be performed by the Principal Investigator or study  
          team member to document study formulation dispensed and returned. This reconciliation  
          will be logged on the Case Report Form, and signed and dated by the Principal  
          Investigator and/or investigators. 
 
5.6.4 Return or Destruction of Study Drug: At the completion of the study, there will 
be a final reconciliation of the study formulation dispensed, returned and remaining. This 
reconciliation will be logged on the Case Report Form, signed and dated. Any 
discrepancies noted will be documented and investigated. Drug destroyed on site will be 
documented. Participants will be required to return any unused study drug at the end of 
the study period. 
 
 
 
6.1 Visit 1 (Week 0/Baseline) 
a) Assess degree of cutaneous involvement by SCORMA Index; Indicate area(s) of the skin to be 
treated; generate “Global” and “Local” SCORMA values; physical exam/vital signs 
b) Obtain β-HCG. Obtain baseline levels of tryptase, urinary N-MH, LTE4, and 2,3 dinor 11β 
PGF2α if (not obtained during prior 6 months). 
c) Review medical history and current medications 
d) Informed consent 
e) Patient to complete Quality of life questionnaire-SkinDex-16. 
f) Baseline photographs 
g) Review treatment protocol 
h) Dispense study formulation 
 
 
  
  
 
  
6.5 Visit 2-Final visit (Week 2 +/- 1 day) 
a) Reassess cutaneous mastocytosis severity by (Global & Local) SCORMA Indexes; monitor 
vital signs 
b) Investigator Assessment of Global Improvement   
c) Quality of life assessment:SkinDex-16 
d) Review changes to medical history and current medications 
e) Review contraception (female patients of childbearing potential) 
f) Review adverse events 
g) Review compliance 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 13 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
h) Repeat photographs 
i) Obtain levels of serum tryptase, urinary N-MH, LTE4, and 2,3 dinor 11β PGF2α 
j) Reconcile study formulation 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 14 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
6.6  Protocol Schedule of Events 
 
 
Study Activity 
Week 0 
Screening & 
Baseline 
Week 
2 
Visit Number 
1 
2 
Allowable visit window in days 
 
+/- 1 
Review Eligibility 
X 
 
Informed Consent 
X 
 
Medical History 
X 
X 
Dispense/Reconcile Medications 
X 
X 
Review Changes to Medical History and Medications 
 
X 
Quality of Life Scale:SkinDex-16 
X 
X 
SCORMA Index 
X 
X 
Physical Exam 
X 
 
Serum Tryptase, & urinary Mast cell mediators 
X 
 X 
Investigator Assessment of clinical response: initial and 
subsequent; vital signs 
X 
X 
Photography 
X 
X 
Adverse Event (Physician) 
 
X 
Adverse Event (Participant) 
 
X 
Review Dosing Compliance 
 
X 
Review Contraception 
X 
X 
β-HCGa 
X 
 
 
 
 
a: Urine pregnancy test (women of childbearing potential) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7  Statistical Plan 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 15 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
7.1 Sample Size determination 
 
Due to the pilot nature of the study, no formal statistical power/sample size calculations are 
necessary. The sample size of 10 patients will be sufficient for this pilot study to obtain a 
preliminary estimate of treatment efficacy and to generate data that will be useful in the design of 
a larger study. 
 
7.2 Statistical Methods 
Continuous variables will be summarized using the sample mean, median, standard deviation, 
interquartile range, and range. Categorical variables will be summarized using number and 
percentage of patients.  
 
7.2.1 Definition of response  
Complete response:  
Clinically significant SCORMA improvement in all 3 parameters of  treated, involved 
skin: % skin involvement; activity or symptoms &/or 
Improvement in all 3 SkinDex-16 domains (Emotions, symptoms, functioning) &/or 
Resolution of 75% of cutaneous lesions 
Near Complete response: 
Clinically significant SCORMA improvement in two of 3 parameters of treated, involved 
skin: % skin involvement; activity or symptoms and/or 
Improvement in 2 SkinDex-16 domains (Emotions, symptoms, functioning) &/or 
Resolution of >50% of cutaneous lesions 
Partial Response: 
Clinically significant SCORMA improvement in one 3 parameters of  treated, involved 
skin: % skin involvement; activity or symptoms and/or 
Improvement in 1 SkinDex-16 domain (Emotions, symptoms, or functioning) &/or 
Resolution of >25% of cutaneous lesions 
No response: 
No significant SCORMA improvement in any of 3 parameters of treated, involved skin: 
% skin involvement; activity or symptoms and/or 
Improvement in no SkinDex-16 domain (Emotions, symptoms, functioning) &/or 
Resolution of no cutaneous lesions. 
 
 *Additionally, for primary safety endpoints which will be scored as none, mild, moderate, or 
severe, the proportion of patients in each category at each follow-up time point will be estimated 
for each of the different safety endpoints. P-values of 0.05 or lower will be considered as 
statistically significant. 
 
Handling of missing data 
This is a prospective study and therefore we do not anticipate any missing data. In the event of 
any unexpected missing data, no attempt to impute this missing data will be made; missing data 
will simply be treated as missing in the statistical analysis. 
 
Multiplicity 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 16 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Since this is an exploratory pilot study, no adjustment for multiple testing is needed. P-value of 
0.05 or lower will be considered as statistically significant.  
 
Primary Hypothesis: 
 
The study seeks to demonstrate the effectiveness and tolerability of a novel topical composition 
consisting of 3 components (diphenhydramine, aspirin and cromolyn sodium) in a neutral skin 
moisturizing cream (Vanicream) for the treatment of cutaneous lesions of mastocytosis. This will 
be determined by the proportion of participants who achieve complete or near-complete response 
utilizing the SCORMA Index, and SkinDex-16 QOL.  
 
We will use the SCORMA index and SkinDex-16 as both continuous variables and categorical 
variables. Change in SCORMA  and of SkinDex-16 from baseline to the 2week follow-up visit 
will be estimated using sample mean, median, standard deviation, interquartile range, and range.  
SCORMA and SkinDex-16 will be compared from baseline to the follow-up time point using a 
paired Wilcoxon signed rank test. 
 
Interim Analysis 
There will not be any interim analysis given the low risk profile of the study formulation. 
 
7.3 Subject Populations(s) for Analysis 
Each participant who received the study drug will be included in the primary analysis regardless 
of study withdrawal for any reason. In the event of any study withdrawals, in secondary analysis 
we will examine the sensitivity of our results to the exclusion of patients who withdrew. 
 
8  Safety and Adverse Events 
 
8.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria: 
 ●Serious: Serious problems or events that result in significant harm, (which may be physical, 
psychological, financial, social, economic, or legal) or increased risk for the subject or others 
(including individuals who are not research subjects). These include: (1) death; (2) life 
threatening adverse experience; (3) hospitalization- inpatient, new, or prolonged; (4) 
disability/incapacity-persistent or significant; (5) birth defect/anomaly; (6) breach of 
confidentiality and (7) other problems, events, or new information (i.e. publications, DSMB 
reports, interim findings, product labeling change) that in the opinion of the Principal 
Investigator and/or Investigators may adversely affect the rights, safety, or welfare of the 
subjects or others, or substantially compromise the research data, AND  
●Unanticipated: (i.e. unexpected) problems or events are those that are not already described as 
potential risks in the protocol, consent document, not listed in the Research Participant Consent 
and Privacy Authorization Form, or not part of an underlying disease. A problem or event is 
“unanticipated” when it was unforeseeable at the time of its occurrence. A problem or event is 
“unanticipated” when it occurs at an increased frequency or at an increased severity than 
expected, AND 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 17 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
●Related: A problem or event is “related” if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of the study formulation in a 
research subject. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. Serious problems/events are defined as 
events that: 
 
● result in death 
 
● are immediately life threatening 
 
● result in a new or prolong and existing hospitalization 
 
● result in disability/incapacity; or 
 
● are persistent or significant birth defect/anomaly 
And/or per protocol may be problems/events that in the opinion of the Principal Investigator 
and/or Investigators may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromise the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious events. 
 
Adverse Event Reporting Period 
 For this study, the study treatment follow-up period is defined as the last scheduled visit. 
 
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 are to be followed by the Principal Investigator and/or 
Investigators 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 Principal Investigator and/or Investigators 
should instruct each subject to report and any subsequent event(s) that the Participant, or the 
Participant’s personal physician, believes might reasonably be related to participation in this 
study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality that can reasonably be related to the administration of the study 
formulation should be documented as an adverse event. 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 18 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Hospitalization, prolonged hospitalization, or surgery is to be reported as an adverse event if it 
can reasonably be related to the administration of the study formulation. 
 
8.2 Recording of Adverse Events 
At each contact with the subject, the Principal Investigator and/or Investigators 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 appropriate adverse 
event section of the Case Report Form. All clearly related signs and symptoms should be 
recorded. 
 
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 ultimately 
determined that the study treatment or participation is not the probable 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 at least possibly related to the study treatment or study participation will be recorded and 
reported immediately. 
 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
When and adverse event has been identified, the Principal Investigator and/or Investigators will 
take appropriate action necessary to protect the study participant and then document the event in 
the adverse event section of the Case Report Form. The Principal Investigator and/or 
Investigators will evaluate the event and determine the necessary follow-up and reporting 
required. 
 
8.3.1 Investigator reporting: notifying the Mayo Clinic IRB 
The Principal Investigator and/or Investigators will report, as soon as possible, but no later than 5 
working days after first learning of the problem/event, to the Mayo Clinic IRB any UPIRTSOs 
and Non-UPIRTSOs according to the Mayo Clinic IRB Policy and Procedures. 
Documentation of adverse events will include the following information collected in the adverse 
event section of the case report form (and entered into the research database): 
●Subject’s name 
●Medical record number 
●Disease 
●The date the adverse event occurred 
●Description of the adverse event 
●Relationship of the adverse event to the research 
●If the adverse event was expected 
●The severity of the adverse event (defined by a severity scale) 
●If any intervention was necessary 
●Resolution (was the incident resolved spontaneously, or after discontinuing treatment) 
●Date of resolution 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 19 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
The Principal Investigator and/or Investigators will review all adverse event reports to determine 
if specific reports need to be made to the IRB and FDA. The Principal Investigator and/or 
Investigators will sign and date the adverse event report when it is reviewed. For this protocol, 
only directly related SAEs/UPIRTSOs will be reported to the IRB. 
 
8.3.2 Investigator reporting: Notifying the FDA 
 
This protocol is being conducted under an FDA investigational new drug application. 
The sponsor-investigator will report to the FDA all unexpected, serious suspected adverse 
reactions according to the required IND Safety Reporting timelines, formats and requirements. 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse 
reaction.  This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days 
after the sponsor-investigator’s initial receipt of the information about the event.   
The sponsor-investigator must also notify the FDA (and sponsors  must notify all participating 
investigators) in an IND safety report of potential serious risks, from clinical trials or any other 
source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies for reporting under § 312.32(c)(1)(i)-(iv). 
Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no 
later than 15 calendar days after the sponsor-investigators initial receipt of the information about 
the event. 
 
8.4 Unmasking/Unblinding Procedures 
 
This is an open-label pilot investigation. Unmasking/unblinding procedures are not applicable. 
 
8.5 Stopping Rules 
 
This investigation is of low risk to study subjects. Stopping or interruption of the study may be 
necessary if a significant number of participants develop an unexpectedly severe dermatitis that 
does not resolve with decreased frequency of application. 
 
8.6 Medical Monitoring 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 20 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
It is the responsibility of the Principal Investigator and Investigators to oversee the safety of the 
study. This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above. Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
 
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 (HIPPA). 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 Principal 
Investigator and Investigators, by regulation, retain 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 will be made to obtain permission to collect at least vital status (long 
term survival status that the subject is alive) at the end of their scheduled study period. 
 
9.2 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
micorfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
All source documents including clinical findings, observations or other activities will be stored in 
a REDCap database that will be designated by the Statistician. Access to the REDCap database 
will be limited to the Principal Investigator, Investigators, and Statistician. 
 
9.3 Case Report Forms 
All data requested on the Case Report Form (CRF) will be recorded for each participant. A 
standardized CRF will be generated by REDCap. All missing data will be explained. If a space 
on the CRF is left blank because the question was not asked, “N/D” will be recorded. If the item 
is not applicable to the individual case, “N/A” will be recorded.  If any entry error has been 
made, a single straight line through the incorrect entry will be drawn and the correct data will be 
written above it. All such changes will be initialed and dated. Errors will not be erased or whited-

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 21 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
out. For clarification of illegible or uncertain entries, a clarification will be printed above the 
item, then initialed and dated. If the reason for the correction is not clear or needs additional 
explanation, details to justify the correction will be neatly included. 
 
Data Management, Processing, Security and Confidentiality 
 
Study data to be collected and managed using REDCap electronic data capture tools hosted at the 
Mayo Clinic. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; and 
4) procedures for importing data from external sources. 
 
 
Data Quality Assurance 
 
Once the study is completed the Principal Investigator will randomly select 5 participants and 
compare the data documented for each on the CRF with what is entered into the REDCap 
database. If there is any discrepancy, the Principal Investigator and/or Investigators will cross-
reference all 10 patients to ensure accuracy. 
 
Data Clarification Process 
 
For any data query the Principal Investigator and Investigators will meet to clarify the data 
queried and make corrections based on consensus. 
 
9.4 Records Retention 
 
The Principal Investigator and Investigators will maintain records and essential documents 
related to the conduct of the study. These will include subject case histories and regulatory 
documents. Participant names or other directly identifiable information will not appear on any 
reports, publications, or other disclosures of clinical study outcomes. 
 
The Principal Investigator will retain the specified records and reports for a minimum of five 
years after final study closeout, and original data will be retained, if possible. 
 
10  Study Monitoring, Auditing, and Inspecting 
 
10.1 Study Monitoring Plan 
 
The Principal Investigator will allocate adequate time for such monitoring activities. The 
Principal Investigator will also ensure that the monitor or other compliance of quality assurance 
reviewer is given access to all the study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). The Mayo Clinic Office of Research Regulatory Support 
will assist with study monitoring by review of informed consent documents, subject records and 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 22 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
study Regulatory Documents. Some monitoring may be done remotely, using the electronic 
medical records. Written monitoring reports will be issued to the PI. 
 
10.2 Auditing and Inspecting 
 
The Principal Investigator and Investigators will permit study-related monitoring, audits, and 
inspections by the IRB, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.). The 
Principal Investigator and Investigators 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 compliance offices. 
 
11 Ethical Considerations 
 
This study is to be conducted according to United States government regulations and Mayo 
Clinic institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study. The decision of the IRB concerning the conduct of the study will be made in writing to the 
Principal Investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure. The consent form is to be signed by 
the participant and the individual obtaining the informed consent. 
 
12  Study Finances 
 
12.1 Funding Source 
 
This study is to be financed by the Mayo Clinic. 
 
13 Publication Plan 
 
The Principal Investigator and Investigators hold primary responsibility for publication of the 
results of this study. 
 
 
14  References 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 23 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
 
The following references serve to define criteria for systemic and cutaneous mastocytosis 
Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol 
Allergy Clin North Am. 2014;34(2):207-18. 
 
Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and 
standardization in mastocytosis: consensus statements on diagnostics, treatment 
recommendations and response criteria. European journal of clinical investigation. 
2007;37(6):435-53. 
 
Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria 
and global classification of mast cell disorders with special reference to mast cell activation 
syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215-25. 
 
The following references serve to document the use of cromolyn sodium in the treatment of 
cutaneous mastocytosis 
 
Horan RF,Sheffer AL, Austen KF. Cromolyn sodium in the management of systemic 
mastocytosis. J. Allergy Clin Immunol 1990; 85: 852-858. 
 
Alexander RR. Disodium cromoglycate in the treatment of systemic mastocytosis involving only 
bone. Acta haemat 1985; 74: 108-110. 
 
The following references serve to document the use of topical and systemic antihistamines in 
the treatment of mastocytosis. 
 
Friedman BS, Santiago ML, Berkebile C, Metcalfe DD. Comparison of azelastine and 
chlorpheniramine in the treatment of mastocytosis. J. Allergy Clin Immunol 1993; 92; 520-526. 
 
Hadzijusufovic E, Peter B, Gleixner KV, Such K, Pickl WF, Thaiwong T et al. H1-receptor 
antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells. 
Experimental hematology 2010; 38: 896-907. 
 
 
The following reference serves to document the use of  the SCORMA index to evaluate disease 
severity of cutaneous mastocytosis 
 
HeideR, van Doorn K, Mulder PG et al. Serum tryptase and SCORMA (SCORing MAstocytosis) 
index as disease severity parameters in childhood and adult cutaneous mastocytosis. Clinical and 
Experimental Dermatology 2008; 34: 462-468. 
 
The following references serve to document the use of SKINDEX to measure QOL in patients 
with skin diseases 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 24 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Chren M-M, The Skindex instruments to measure the effects of skin disease on quality of life. 
Dermatology Clinics 2012; 30: 231-236. 
 
Chren M-M, Lasek RJ, Sahay AP, Sands LP. Measurement properties of skindex-16: a brief 
quality-of-life measure for patients with skin diseases. Journal of Cutaneous Medicine and 
Surgery 2001; 5: 205-110. 
 
The following references serve to document the use of aspirin and/or nonsteroidal medications 
in the treatment of symptoms of mast cell activation and mastocytosis 
 
Wong JT, Nagy CS, Krinzman SJ, MacLean JA, Bloch KJ. Rapid oral challenge-desensitization 
for patients with aspirin-related urticaria-angioedema . J Allergy Clin Immunology 2000; 105: 
997-1001. 
Butterfield JH. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other 
Lipid Mediat. 2009;88(3-4):122-4. 
Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical 
sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol. 
2008;147(4):338-43. 
Butterfield JH, Kao PC, Klee GC, Yocum MW. Aspirin idiosyncrasy in systemic mast cell 
disease: a new look at mediator release during aspirin desensitization. Mayo Clin Proc. 
1995;70(5):481-7. 
The following reference serves to document the combined use of antihistamines and 
cyclooxygenase inhibition in the treatment of systemic mastocytosis 
Crawhall JC, Wilkinson RD. Systemic mastocytosis: management of an unusual case with 
histamine (H1 and H2) antagonists and cyclooxygenase inhibition. Clinical and Investigative 
Medicine 1987; 10: 1-4. 
 
15. Attachments: 
a) Advertisement 
b) Patient Handout 
c) QOL questionnaire 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 25 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
ADVERTISEMENT 
 
An Open-label Pilot Study Evaluating the Effectiveness and Tolerability of a Topical Therapy for 
the treatment of Cutaneous Mastocytosis 
 
A Mayo Clinic Research Study 
 
Mayo Clinic is seeking ten individuals with skin involvement by mastocytosis to participate in a 
research study. 
 
The purpose of this study is to gather information on the effectiveness and tolerability of a novel 
composition of existing U.S. Food and Drug Administration (FDA) approved topical 
medications for the treatment of cutaneous mastocytosis with or without systemic involvement. 
 
You may be eligible to participate if you meet the following criteria: 
●18 years of age and older 
●Bothersome symptoms from skin involved by mastocytosis 
●No prior use of topical skin –lightening agents for 1 month prior to study entry 
●No current use of Interferon Alpha; Cladribine; Imatinib Mesylate; Midostaurin;   Avapritinib, 
Prednisone or other chemotherapy agents.  
●No current use of chemotherapeutic agents 
●Good general health as confirmed by medical history 
●Female patients of childbearing potential with a negative urine pregnancy test who agree to use 
effective methods of birth control or remain abstinent during treatment  
●Patients who are willing and capable of cooperating to the extent and degree required by the 
protocol 
●Patients who read and sign an approved informed consent for this study 
 
The study includes 2 visits over 2weeks. There will be no cost to participate. You will not be 
compensated for your time. 
 
Who can I contact for more information? 
Principal Investigator: 
 
Joseph H. Butterfield, M.D. 
Phone: 
507-2843783 
 
Email: 
Butterfield.joseph@mayo.edu 
 
Address: 
W15B Mayo Clinic 
200 SW 1st Street 
Rochester, MN 55901 
 
Primary Safety Endpoints Table 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 26 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Patient Name: 
 
Symptom (Patient/Physician) Week  
 
0 
2 
itching 
 
 
swelling 
 
 
stinging/burning 
 
 
dryness 
 
 
 
 
 
 
 
 
 
none (0), mild (1), moderate (2), or severe (3) 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 27 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
    
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 28 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
                
 
LOCAL SCORMA INDEX-FOR AREA(S) TREATED-Indicate Area(s) Treated 
 
A. Extent: Percent/area of skin treated-INDICATE AREA(S) TREATED 
B. Criteria: 
 
Intensity 
 
 
Intensity Items 
 1. Pigmentation 
[     ] 
 
 
 
0= Absent 
 2. Vesiculation 
[     ] 
 
 
 
1= Mild 
 3. Elevation 
 
[     ] 
 
 
 
2= Moderate 
 4. (+) Darier’s sign 
[     ] 
 
 
 
3= Severe 
C. Subjective Symptoms 
  
 
 
 
Visual Analog Scale 
 
1. Provoking Factor(s)  
0--------------------------------------------10 
2. Flushing 
 
 
0--------------------------------------------10 
3. Diarrhea 
 
 
0--------------------------------------------10 
4. Pruritus 
 
 
0--------------------------------------------10 
5. Localized Bone Pain  
0--------------------------------------------10 
 
SCORMA INDEX: A/5 + 5B + 2C/5  
[     ] 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 29 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
 
Clinical Response Assessment: Global SCORMA Assessment  
 
Week 
SCORMA 
% Resolution 
ASSESSMENT 
0 
 
 
 
2 
 
 
 
Complete response:  
Clinically significant SCORMA improvement in all 3 parameters of % skin involvement; 
activity or symptoms &/or  
Resolution of 75% of cutaneous lesions 
Near Complete response: 
Clinically significant SCORMA improvement in two of 3 parameters of % skin 
involvement; activity or symptoms and/or 
Resolution of >50% of cutaneous lesions 
Partial Response: 
Clinically significant SCORMA improvement in one 3 parameters of % skin 
involvement; activity or symptoms and/or 
Resolution of >25% of cutaneous lesions 
No response: 
No significant SCORMA improvement in any of 3 parameters of % skin involvement; 
activity or symptoms and/or 
Resolution of no cutaneous lesions. 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 30 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Clinical Response Assessment: Local SCORMA Assessment  
 
Week 
SCORMA 
% Resolution 
ASSESSMENT 
0 
 
 
 
2 
 
 
 
Complete response:  
Clinically significant SCORMA improvement in all 3 parameters of % skin involvement; 
activity or symptoms &/or  
Resolution of 75% of cutaneous lesions 
Near Complete response: 
Clinically significant SCORMA improvement in two of 3 parameters of % skin 
involvement; activity or symptoms and/or 
Resolution of >50% of cutaneous lesions 
Partial Response: 
Clinically significant SCORMA improvement in one 3 parameters of % skin 
involvement; activity or symptoms and/or 
Resolution of >25% of cutaneous lesions 
No response: 
No significant SCORMA improvement in any of 3 parameters of % skin involvement; 
activity or symptoms and/or 
Resolution of no cutaneous lesions. 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 31 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL 
 
Have you answered every item?   Yes   No  
 
THESE QUESTIONS CONCERN THE SKIN CONDITION WHICH HAS 
BOTHERED YOU THE MOST DURING THE PAST WEEK 
 
 
During the past week, how often have you been 
bothered by: 
 
 
 
 
 
Never 
Bothered 
 
Always 
Bothered 
 
 
 
 
______________________________ 
 
1. 
Your skin condition itching .
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
2. 
Your skin condition burning or stinging 
.
 
 
  0     1     2      3     4      5     6 
 
 
 
3. 
Your skin condition hurting .
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
4. 
Your skin condition being irritated .
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
5. 
The persistence / reoccurrence of your skin 
condition .
.
.
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
6. 
Worry about your skin condition 
(For example: that it will spread, get worse, scar, 
be unpredictable, etc) 
 
  0     1     2      3     4      5     6 
 
 
 
7. 
The appearance of your skin condition .
.
 
 
  0     1     2      3     4      5     6 
 
 
 
8. 
Frustration about your skin condition .
.
 
 
  0     1     2      3     4      5     6 
 
 
 
9. 
Embarrassment about your skin condition.
 
 
  0     1     2      3     4      5     6 
 
 
 
10. 
Being annoyed about your skin condition .
 
 
  0     1     2      3     4      5     6 
 
 
 
11. 
Feeling depressed about your skin condition 
 
  0     1     2      3     4      5     6 
 
 
 
12. 
The effects of your skin condition on your 
interactions with others 
(For example: interactions with family, friends, close 
relationships, etc) 
.
.
.
.
.
.
.
.
  
  0     1     2      3     4      5     6 
 
 
 
13. 
The effects of your skin condition on your desire 
to be with people 
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
14. 
Your skin condition making it hard to show 
affection .
.
.
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
15. 
The effects of your skin condition on your daily 
activities .
.
.
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 
16. 
Your skin condition making it hard to work or do 
what you enjoy .
.
.
.
.
.
.
.
 
 
  0     1     2      3     4      5     6 
 
 
 

Butterfield IND, Topical Composition for Cutaneous Mastocytosis 
 
 
Page 32 of 32 
Joseph H. Butterfield, MD 
 
CONFIDENTIAL