Clinical trial NCT03494881
Conditions: Chronic Spontaneous Urticaria
Sponsor: Mayo Clinic
Start date: 2019-07-30; Completion date: 2025-02-25
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an exploratory study designed to generate preliminary data in evaluating the efficacy of Nucala in the treatment of chronic spontaneous urticaria.

Detailed description:
This is an open-label, single arm exploratory study of mepolizumab in the treatment of CSU. The primary endpoint will be the mean reduction in the seven day urticaria activity score (UAS7) before and after 10 weeks of treatment with mepolizumab. Secondary endpoints will be the mean reduction of the urticaria control test (UCT) score and the weekly itch severity score (ISS) before and after treatment. Enrollment examination will include a standardized history and examination, baseline UCT score, CBC with differential, serum IgE level, chronic urticaria index, IgE Fc receptor antibody functional assay, and a 4 mm punch biopsy of lesional skin to confirm the urticarial tissue reaction includes eosinophils and is not neutrophilic predominant. Patients will discontinue all anti-histamines and start cetirizine 10 mg PO BID which may be continued throughout the study duration. Patients will be provided with a log book to track daily urticaria signs and symptoms in a standardized manner for UAS scoring. At week 0 (enrollment visit +7 days), baseline UAS7 and ISS score will be assessed and skin biopsy results reviewed. Patients with a confirmatory skin biopsy will receive 200 mg SC of mepolizumab at week 0,2,4,6,and 8. UAS-7 and weekly ISS score will be calculated at week 0, 4, 8, and 10. UCT scoring will be calculated at week 0 and at week 10. Repeat CBC with differential, serum IgE level, and measures of basophil serum activation (chronic urticaria index, IgE FC Receptor antibody functional assay) will be assessed at week 10. Attached to this document is a protocol summary.

Arms: arm 1: This is an open-label pilot investigation and all study participants are assigned to active treatment. There is no placebo arm in this study.
Interventions: intervention 1: Nucala
Intervention descriptions: intervention 1: All study participants will receive Nucala (2) 100mg SQ injections administered at two different anatomical sites at week zero, 2,4,6, and 8 for a total of 5 doses.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Mepolizumab for the Treatment of Chronic 
Spontaneous Urticaria: An Open-label, Single-
arm, Exploratory Study 
 
NCT03494881 
 
06June2023 


MEPOLIZUMAB FOR THE TREATMENT OF CHRONIC 
SPONTANEOUS URTICARIA: AN OPEN-LABEL, SINGLE-ARM, 
EXPLORATORY STUDY 
Regulatory Sponsor/ 
Principal Investigator- 
Co-Investigator: 
Jason C. Sluzevich, MD 
Arveen K. Bhasin, MD 
Study Site Location: 
Mayo Clinic Florida 
Departments of Allergy and Dermatology 
4500 San Pablo Road 
Jacksonville, FL   
Financial Supporter: 
GlaxoSmithKline 
Study Product: 
Mepolizumab (Nucala) 
Protocol Number: (IRBe) 
17-009322
IND Number: 
IND 138067(EXEMPT) 
Initial version: [25Aug2017] Version (1.0) 
Revised: [25Oct2018] Version (2.0)  
Revised: [20 AUG 2019] Version (2.1) 
Revised: [06 JUN 2023] Version (2.11) 
Table of Contents 


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STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 7 
1.1 
BACKGROUND .................................................................................................................................... 7 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 7 
1.3 
PRECLINICAL DATA ............................................................................................................................. 7 
1.4 
CLINICAL DATA TO DATE..................................................................................................................... 7 
1.5 
DOSE RATIONALE................................................................................................................................ 8 
1.6 
RISKS AND BENEFITS ........................................................................................................................... 8 
2 
STUDY OBJECTIVES .......................................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................................... 9 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 9 
3.2 
NUMBER OF SUBJECTS ......................................................................................................................... 9 
3.3 
DURATION OF PARTICIPATION ............................................................................................................ 10 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 10 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 10 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 10 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 11 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 12 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 12 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 12 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 13 
5 
STUDY DRUG .................................................................................................................................... 13 
5.1 
DESCRIPTION .................................................................................................................................... 13 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 13 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 13 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 13 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 13 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 13 
5.7 
PACKAGING ...................................................................................................................................... 14 
5.8 
MASKING/BLINDING OF STUDY........................................................................................................... 14 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 14 
5.9.1 
Receipt of Drug Supplies .......................................................................................................... 14 
5.9.2 
Storage ................................................................................................................................... 14 
5.9.3 
Dispensing of Study Drug ......................................................................................................... 14 
5.9.4 
Return or Destruction of Study Drug ......................................................................................... 15 
6 
STUDY PROCEDURES ...................................................................................................................... 16 
6.1 
VISIT 1 (WEEK -2/BASELINE & ENROLLMENT) ..................................................................................... 16 
6.2 
VISIT 2 (WEEK 0± 5 DAYS) ................................................................................................................. 16 
6.3 
VISIT 3 (WEEK 2± 1 DAYS) ................................................................................................................. 16 
6.4 
VISIT 4 (WEEK4 ± 5 DAYS) ................................................................................................................. 16 
6.5 
VISIT 5 (WEEK 8 ± 5 DAYS) ................................................................................................................ 17 
6.6 
VISIT 6 (WEEK 12± 5 DAYS) ................................................................................................................ 17 
6.7 
VISIT 7 (WEEK 16± 5 DAYS) ................................................................................................................ 17 
6.8 
VISIT 8 (WEEK 20± 5 DAYS) ................................................................ ERROR! BOOKMARK NOT DEFINED. 


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6.9 
VISIT 9 (WEEK 24 ± 5 DAYS) ............................................................... ERROR! BOOKMARK NOT DEFINED. 
6.10 
VISIT 10 (WEEK 28 ± 5 DAYS) ......................................................... ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ......................................................................................................................... 19 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 19 
7.2 
STATISTICAL METHODS ..................................................................................................................... 19 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 19 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 20 
8.1 
DEFINITIONS ..................................................................................................................................... 20 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 21 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 22 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ............................................................. 22 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA ..................................................................... 23 
8.4 
UNMASKING/UNBLINDING PROCEDURES ............................................................................................. 23 
8.5 
STOPPING RULES ............................................................................................................................... 23 
8.6 
MEDICAL MONITORING ..................................................................................................................... 23 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 23 
9.1 
CONFIDENTIALITY ............................................................................................................................. 23 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 24 
9.3 
CASE REPORT FORMS ........................................................................................................................ 24 
9.4 
RECORDS RETENTION ........................................................................................................................ 25 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 25 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 25 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 26 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 26 
12 
STUDY FINANCES ............................................................................................................................ 26 
12.1 
FUNDING SOURCE ......................................................................................................................... 26 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 26 
12.3 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 27 
13 
PUBLICATION PLAN ....................................................................................................................... 27 
14 
REFERENCES ................................................................................................................................... 27 
15 
ATTACHMENTS ............................................................................................................................... 28 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSU 
Chronic Spontaneous Urticaria 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UAS 
Urticaria Activity Score 
UCT 
Urticaria Control Test 
  
 
 
 
        
  
 
 
 
      
 
 
 


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Study Summary 
Title 
Mepolizumab for the Treatment of Chronic Spontaneous Urticaria: 
An Open-Label, Single-Arm, Exploratory Study 
Running Title 
Mepolizumab (Nucala) for the Treatment of Chronic Spontaneous 
Urticaria 
Protocol Number 
17-009322 
Phase 
Investigational Exploratory Trial 
Methodology 
Single arm, Open‐label, Exploratory Trial 
Overall Study 
Duration 
13 months (10 month accrual period) 
Subject Participation 
Duration 
12 weeks 
Single or Multi-Site  
Mayo Clinic Florida 
Objectives 
To investigate the potential efficacy of mepolizumab (Nucala) in 
the treatment of biopsy proven chronic spontaneous urticaria 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
 
Main inclusion criteria: 
18 years old or older at time of consent with history and physical exam 
consistent with CSU, lasting greater than 6 weeks and unresponsive to 
oral antihistamines 
 
Study Product, Dose, 
Route, Regimen 
Mepolizumab (Nucala) 200 mg SQ every 2 weeks x 10 weeks 
Duration of 
Administration 
10 weeks 
Reference therapy 
None 


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Statistical 
Methodology 
This is an exploratory study designed to generate preliminary data in 
evaluating the efficacy of mepolizumab (Nucala) in the treatment of 
CSU. The primary outcome measure is derived from the UAS7 used to 
quantify number of hives and daily pruritus.  
 
A paired t-test will be used to evaluate mean differences before and after 
treatment at a p=0.05 significance level.  The primary endpoint of the 
study is the UAS7.  A 10 point change in the UAS7 has been reported to 
be the minimal clinically significant difference in therapeutic trials for 
urticaria. The study is powered at 99% to detect a 10 point change in the 
UAS7 at a 5% significant level with the proposed accrual target of 20 
patients. 
 
 


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1. Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the protocol, Good Clinical Practice standards, and applicable United States 
government regulations and Mayo Clinic research policies and procedures.  
1.1 
Background 
Chronic spontaneous urticaria (CSU) is a common skin disorder affecting 0.1 to 1% of the 
general population and is characterized by recurrent, transitory, pruritic erythematous plaques 
present for a minimum of 6 weeks. In 30 to 50% of CU cases, there is an autoimmune etiology 
with autoantibodies against IgE, FcεRI or FcεRII (CD23). These autoantibodies are postulated to 
bind to the surface of mast cells and basophils initiating a signal transduction cascade resulting in 
the secretion of histamine and other inflammatory mediators which produce the observed clinical 
features of edema, erythema, and localized pruritus. The impact of CSU on quality of life is quite 
significant with most cases lasting an average of 3 to 5 years. 
1.2 
Investigational Agent 
Mepolizumab (Nucala) is a human interleukin‐5 antagonist indicated for add-on maintenance 
treatment of patients with severe asthma with an eosinophilic phenotype.  For this study, it will 
be supplied as a 100 mg lyophilized powder for reconstitution to be administered subcutaneously 
by trained study personnel.  
1.3 
Preclinical Data 
Interleukin‐5 has been previously established to stimulate proliferation and maturation of 
eosinophils. Eosinophils release major basic protein (MBP) which induces mast cell and basophil 
degranulation [1,3] 
1.4 
Clinical Data to Date 
Since more than half of the patients with CSU do not show evidence of auto-Abs either against the 
high-affinity IgE receptor or against IgE Ab, additional therapeutic approaches are needed. An 
alternative pathway for allergen-independent histamine release by basophils and mast cells is 
through major basic protein (MBP) released by eosinophils.  Incubation of human basophils and 
mast cells with MBP results in a non-cytotoxic, dose-dependent histamine release from target cells 
within 30 min. Additionally, IgE binding to the low-affinity IgE receptor (FceRII/CD23) on 
eosinophils also results in eosinophilic activation and MBP release.   
Therefore, we hypothesize the IL-5 neutralizing properties of mepolizumab (Nucala) on eosinophil 
maturation and function may have therapeutic utility in the management of CSU.  Support for the 


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relevance of these mechanisms in the pathogenesis in CSU is reflected by the accumulation of 
interstitial and perivascular dermal eosinophils in lesional skin biopsies. Elevated levels of IL-5 
mRNA expression have also been demonstrated from both eosinophilic and lymphocytic 
components of the inflammatory infiltrate. 
1.5 
Dose Rationale  
The dosing of mepolizumab (Nucala) in this study will be 200 mg SQ administered at weeks 
0,2,4,6 and 8. We are aware of prior investigations establishing that monthly doses of Nucala are 
effective in reducing peripheral eosinophilia and that higher and more frequent dosing are not 
associated with a longer or more sustained clinical response in reducing asthma exacerbations. We 
are also aware of prior studies where a 300 mg monthly SQ dose has been safe and effective in 
treating Eosinophilic Granulomatous Polyangiitis and Hypereosinophilic Syndrome. The concern 
in this study is with respect to what is the minimum effective dose that reduces peripheral 
eosinophilia and is also sufficiently inhibitory to prevent pathologic eosinophilic accumulation in 
lesional skin in response to an acute inflammatory signal. We reviewed early published reports of 
IV Nucala at 750 mg in atopic dermatitis that failed to demonstrate efficacy and the authors raised 
the possibility that more frequent administration may have been helpful. Although the mechanism 
of eosinophilic recruitment into the skin in atopic dermatitis and chronic urticaria differs, existing 
data does suggest more frequent dosing can be beneficial for skin disorders especially given the 
nature of the inflammatory cascade in chronic urticaria. As this is a proof of concept study and the 
safety profile of Nucala has been established to be extremely robust, we felt to error on the side of 
more frequent administration to avoid missing a potential therapeutic effect. We are open to 
considering a monthly 300 mg SQ dose, if there are significant safety concerns with the proposed 
dosing interval of 200 mg SQ q2 weeks. 
1.6 
Risks and Benefits 
The postulated benefits of Nucala include sustained immunomodulatory effects resulting in 
improvement of pruritus and clearance of lesional skin without the direct end organ toxicities seen  
The following risks of Nucala are felt to be low and manageable with the study protocol and do 
not outweigh the aforementioned benefits: 
1. Hypersensitivity Reactions 
Anaphylaxis has occurred following administration of Nucala. This risk is idiosyncratic and will 
be minimized by administrating Nucala in a supervised medical setting and requiring study 
participants to carry epinephrine autoinjectors at all times. 
 


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2. Acute Asthma Symptoms or Deteriorating Disease 
Nucala is not indicated for the treatment of acute asthma symptoms or acute exacerbations. This 
risk will be minimized by screening all study participants with asthma via the asthma control test 
(ACT) questionnaire and peak flow measures at each visit. Those with ACT scores less than 20 
and/or peak flow measures greater than 10% below their personal best will not receive the study 
drug on the day of their visit. Subjects with severe asthma (requiring high-dose inhaled or systemic 
corticosteroids) will be excluded from the study. 
3. Opportunistic Infections: Herpes Zoster 
In controlled clinical trials, two serious adverse reactions of herpes zoster occurred in subjects 
treated with Nucala compared with none in placebo. The mechanism by which this adverse 
reaction occurs is unclear. Subjects will be monitored for signs and symptoms of shingles and 
treated should shingles develop. 
4. Reduction of Corticosteroid Dosage 
Reductions in corticosteroid dose, if appropriate, will be gradual and performed under the direct 
supervision of a physician.  
5. Parasitic (Helminth) Infection 
Eosinophils may be involved in the immunological response to some helminth infections. Patients 
with known parasitic infections were excluded from participation in clinical trials. It is unknown 
if Nucala will influence a patient’s response against parasitic infections This risk will be minimized 
by excluding enrollment of study participants with known tapeworm or roundworm infections. 
2 Study Objectives 
The primary objective of this study is to investigate the potential efficacy of mepolizumab in the 
treatment of biopsy proven chronic spontaneous urticaria. The primary measurement of efficacy 
will be the mean reduction in the seven day urticaria activity score (UAS7) before and after 10 
weeks of treatment with mepolizumab. Secondary measure of efficacy will be the mean reduction 
of the urticaria control test (UCT) score and the weekly itch severity score (ISS) before and after 
treatment. 
3 Study Design 
3.1 
General Description 
This is an open-label, single arm exploratory study of mepolizumab in the treatment of CSU. The 
primary endpoint will be the mean reduction in the seven day urticaria activity score (UAS7) 
before and after 10 weeks of treatment with mepolizumab. Secondary endpoints will be the mean 


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reduction of the urticaria control test (UCT) score and the weekly itch severity score (ISS) before 
and after treatment. Enrollment examination will include a standardized history and examination, 
baseline UCT score, CBC with differential, serum IgE level, chronic urticaria index, IgE Fc 
receptor antibody functional assay, and a 4 mm punch biopsy of lesional skin. Patients will 
discontinue all anti-histamines and start cetirizine 10 mg PO BID which will be continued 
throughout the study duration. Patients will be provided with a log book to track daily urticaria 
signs and symptoms in a standardized manner for UAS scoring. At week 0 (enrollment visit +7 
days), baseline UAS7 and ISS score will be assessed and skin biopsy results reviewed. Patients 
with a confirmatory skin biopsy will receive 200 mg SC of mepolizumab at week 0,2,4,6,and 8. 
UAS-7 and weekly ISS score will be calculated at week 0, 4, 8, and 10. UCT scoring will be 
calculated at week 0 and at week 10. Repeat CBC with differential, serum IgE level, and measures 
of basophil serum activation (chronic urticaria index, IgE FC Receptor antibody functional assay) 
will be assessed at week 10. Attached to this document is a protocol summary. 
4 Number of Subjects 
Twenty 
4.1 
Duration of Participation 
Twelve weeks 
4.2 
Primary Study Endpoints 
The primary endpoint of the study will be the mean UAS7 reduction before and after 10 weeks of 
treatment with mepolizumab. The urticaria activity score (UAS) is a widely used CSU measure 
for daily pruritus and number of hives, which summed over a week, gives a UAS7 score. Study 
participants will document their CSU symptoms using a diary during the 10 week study period 
using the following daily scoring for a)  the number of wheals  [none (=0 points), <10 (=1 point), 
10–50 (=2 points), or >50 per day (=3 points)], and b) the intensity of pruritus [none (=0 points), 
mild (=1 point), moderate (=2 points), severe (=3 points)]. The daily UAS score is summed over 
a week to calculate the UAS7 score (range: 0–42). 
 
 
 
4.3 
Secondary Study Endpoints 
 
The secondary endpoints of the study are the mean reduction in the weekly itch severity score 
(ISS) and mean average change in the urticaria control test (UCT) score before and after 10 weeks 
of treatment with mepolizumab.  The weekly itch severity score is calculated using the pruritus 
score of the daily UAS score summed over a week (range: 0-21). The urticaria control test (UCT) 
is a more recently developed and validated outcome instrument to retrospectively assess urticaria 


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control. Each UCT item has 5 answer options scored 0-4 with low points indicating high disease 
activity and low disease control. The minimum and maximum UCT scores are 0-16 with 16 points 
indicating complete disease control.  
4.4 
Primary Safety Endpoints 
 
This is an exploratory efficacy study with no specific primary safety endpoint. Adverse events 
will be tracked and reported using Good Clinical Practice standards. 
4.5 
Identification of Source Data 
 
The following source data will be directly recorded on the Case Report Form (CRF): 
• UCT score 
• ISS score 
• UAS7 score 
• Screening and documentation of adverse events 
• Confirmation of patient counseling and education 
 
The following source data will not be directly recorded in the CRF, but will be captured in 
supportive documentation to include study source documents and the EMR: 
• Laboratory results and clinical interpretation of the values 
• Histopathologic interpretations of skin biopsy tissue. This will include the use of 
immunohistochemistry to identify IL-5 receptor expression in lesional skin taken 
prior to treatment.  
5 Subject Selection Enrollment and Withdrawal 
5.1 
Inclusion Criteria 
 
Informed subject consent will be obtained from those patients meeting the following inclusion 
criteria: 
• Male and female patients 18 years or older. 
• Clinical and/or histopathological diagnosis of conventional CSU 
• Unresponsive to oral antihistamine therapy 
• Good general health as confirmed by medical history 
• 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 


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5.2 
Exclusion Criteria 
 
Patients are to be excluded based on the following criteria: 
• Vulnerable study population  
• If you are female and pregnant 
• Biopsy proven neutrophilic rich urticarial which is unlikely to respond to mepolizumab 
given the postulated therapeutic mechanism 
• Known history of adverse reaction to mepolizumab (Nucala) 
5.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be enrolled from the Departments of Allergy and Dermatology at the Mayo Clinic in 
Florida. The study has an accrual target of 20 patients. In the year 2014, 188 unique patients with 
CSU were evaluated in the Dermatology and Allergy outpatient clinics at Mayo Clinic in Florida 
and thus no difficulties in accrual based on historical volumes are anticipated. Co-departmental 
participation aids in reaching accrual targets and minimizing referral bias. The accrual period will 
last 10 months. Patients will be provided with a Research Participant Consent and Privacy 
Authorization Form describing the study drug, protocol, inclusion and exclusion criteria, as well 
as risks and benefits of participation.  
5.4 
Early Withdrawal of Subjects 
5.4.1 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. Withdrawn subjects may be replaced within the 6-month accrual period. 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 and/or Investigators’ judgment, the 
patient’s condition required another form of treatment  
• Inclusion/Exclusion Discrepancy/Violation: Patient should not have been enrolled 
• 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 
 


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5.4.2 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. 
6 Study Drug  
6.1 
Description 
 
Nucala (mepolizumab) is a humanized IL-5 antagonist monoclonal antibody. It is expressed in a 
recombinant Chinese Hamster Ovary (CHO) cell line.  
Nucala is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for 
subcutaneous injection after reconstitution. Upon reconstitution with 1.2 mL of Sterile Water for 
Injection, the resulting concentration is 100 mg/mL and delivers 1 mL. 
6.2 
Treatment Regimen 
 
All study participants will receive Nucala 200 mg SQ at week 0, 2,4,6, and 8 for a total of 5 
injections. 
6.3 
Method for Assigning Subjects to Treatment Groups 
 
This is an open-label pilot investigation and all study participants are assigned to active treatment. 
There is no placebo arm in this study. 
6.4 
Preparation and Administration of Study Drug 
 
The study drug will be stored and dispensed at each study visit from the Mayo Clinic Research 
Pharmacy in Florida.  
6.5 
Subject Compliance Monitoring 
 
Study participants will receive Nucala subcutaneous injection at each follow-up visit. 
6.6 
Prior and Concomitant Therapy 
 
Study participants will stop other first-generation antihistamines and start cetirizine (Zyrtec) 10 
mg 1 tablet bid two weeks prior to the first dose of Nucala, and continue throughout the duration 
of the study. 


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Epinephrine auto-injectors will be dispensed to the participants on baseline visit and must be 
carried at all times. 
6.7 
 Packaging 
 
Each single-dose vial delivers mepolizumab 100 mg, polysorbate 80 (0.67 mg), sodium phosphate 
dibasic heptahydrate (7.14 mg), and sucrose (160 mg), with a pH of 7.0. 
 
A quantity of 200 Nucala (100 mg) vials will be shipped to the Mayo Clinic research pharmacy in 
Florida and then labeled upon receipt with statement “Caution: New Drug Limited by Federal law 
for investigational use.”  
6.8 
Masking/Blinding of Study  
 
This is an open-label pilot investigation. Masking and blinding procedures are not applicable.  
Qualitative and quantitative evaluations of response to treatment will be recorded.   
6.9 
Receiving, Storage, Dispensing and Return 
6.9.1 Receipt of Drug Supplies 
 
The drug will be shipped by GlaxoSmithKline to the Mayo Clinic research pharmacy in Florida. 
The pharmacy site will receive 200 100-mg vials of Nucala (mepolizumab). Upon receipt, an 
inventory will be performed and a drug receipt log filled out by the person accepting the shipment.  
Designated study staff will count and verify that the shipment contains all the items noted in the 
shipping invoice. Any discrepancies, damaged or unusable study drug in a given shipment will be 
documented in the study files. The sponsor-investigator must be notified immediately of any 
discrepancies, damaged or unusable products that are received. 
 
6.9.2 Storage 
 
Prior to dispensing, Nucala will be stored in a refrigerator, below 25°C (77°F) in the original 
carton and protected from light. Prior to SQ administration, Nucala will be reconstituted with 1.2 
mL Sterile Water for Injection, USP. 
6.9.3 Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation 


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form, and signed and dated by the study team. Drug dispensation will occur at scheduled follow-
up visits. 
6.9.4 Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug dispensed, 
drug returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, signed and dated.  Any discrepancies noted will be documented and investigated, prior to 
return or destruction of unused study drug.  Remaining drug will be destroyed on site will be 
documented in the study files. 
 


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7 Study Procedures 
7.1 
Visit 1 (Week -2/Screening & Enrollment) 
a) Informed Consent 
b) History & Physical 
c) 4 mm punch skin biopsy (4 mm punch skin biopsy within 6 months prior to visit 1 is 
acceptable) 
d) UCT score assessment 
e) Review and distribute UAS log book 
f) Blood work: CBC with differential, serum IgE level, chronic urticaria index, IgE Fc 
receptor antibody functional assay (Blood work within 6 months prior to visit 1 is 
acceptable) 
g) Urine Pregnancy Test (if applicable) 
h) Photograph Biopsy site (Photograph Biopsy site within 6 months prior to visit 1 is 
acceptable) 
i) Dispense cetirizine (Zyrtec) 10 mg PO BID (#140 tablets) 
7.2 
Visit 2 (Week 0± 5 days Baseline) 
 
a) UAS7 score assessment 
b) ISS score assessment 
c) Nucala 200mg injection 
d) Dispense epinephrine auto-injector 
7.3 
Visit 3 (Week 2± 5 days) 
 
a) UAS7 score assessment 
b) ISS score assessment 
c) Nucala 200mg injection 
d) Screen for adverse events 
7.4 
Visit 4 (Week 4 ± 5 days) 
 
a) UAS7 score assessment 
b) ISS score assessment 
c) Nucala 200mg injection 
d) Screen for adverse events  
 
 


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Visit 5 (Week 6 ± 5 days) 
a) UAS7 score assessment 
b) ISS score assessment 
c) Nucala 200mg injection 
d) Screen for adverse events  
 
7.5 
Visit 6 (week 8± 5 days) 
a) UAS7 score assessment 
b) ISS score assessment 
c) Nucala 200mg injection 
d) Screen for adverse events  
 
7.6 
Visit 7 (week 10± 5 days) 
a) UAS7 score assessment 
b) ISS score assessment 
c) UCT score assessment 
d) 4mm punch skin biopsy if residual disease 
e) Collect UAS log book 
f) Blood work: CBC with differential, serum IgE level, chronic urticaria index, IgE Fc 
receptor antibody functional assay 
g) Screen for adverse events  
h) Photograph biopsy site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Week 
Wk -2 
screen 
Wk 0 
baseline 
Wk 2 
Wk 4 
Wk 6 
Wk 8 
Wk 10 
Visit 
1 
2 
3 
4 
5 
6 
7 
Consent/Enroll 
X 
 
 
 
 
 
 
Distribute log book 
X 
 
 
 
 
 
 
Collect log book 
 
 
 
 
 
 
X 
Cbc with Diff 
X 
 
 
 
 
 
X 
Serum IgE 
X 
 
 
 
 
 
X 
CIU index 
X 
 
 
 
 
 
X 
IgE Fc Recpt Ab 
X 
 
 
 
 
 
X 
Urine HCG 
X 
 
 
 
 
 
 
UCT 
 
X 
 
 
 
 
X 
UAS 
 
X 
X 
X 
X 
X 
X 
ISS 
 
X 
X 
X 
X 
X 
X 
Skin Biopsy 
X 
 
 
 
 
 
X*** 
Nucala Inj* 
 
X 
X 
X 
X 
X 
 
Cetirizine 
(Zyrtec) 
Dispense 
X 
 
 
 
 
 
 
Epinephrine 
auto-injector 
Dispense 
 
X 
 
 
 
 
 
AE Screening** 
 
X 
X 
X 
X 
X 
X 
 
* Nucala Inj = denotes Nucala SQ injection during a visit 
** AE Screening = protocol directed screening for adverse events 
***At end of study if subjects have residual disease, will biopsy, as necessary, 
to check for lesional eosinophil tissue density  


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8 Statistical Plan 
8.1 
Sample Size Determination 
 
The statistical methods proposed in the study were reviewed with a Mayo staff statistician who 
also assisted in a formal power analysis. Demographic and laboratory characteristics will be 
analyzed using descriptive statistics. A paired t-test will be used to evaluate mean differences 
before and after treatment at a p=0.05 significance level.  The primary endpoint of the study is the 
UAS7.  A 10 point change in the UAS7 has been reported to be the minimal clinically significant 
difference in therapeutic trials for urticaria. The study is powered at 99% to detect a 10 point 
change in the UAS7 at a 5% significant level with the proposed accrual target of 20 patients. 
 
8.2 
Statistical Methods 
 
Descriptive Statistics 
 
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 
 
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 
 
Since this is an exploratory pilot study, no adjustment for multiple testing is needed. 
 
Interim Analysis 
 
There will not be any interim analysis given the low risk profile of the study formulation. 
 
8.3 
Subject Population(s) for Analysis 
 


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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. 
9 Safety and Adverse Events 
9.1 
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 results 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 local investigator 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 
Investigator’s Brochure, 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 
• 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 Nucala in a research subject. 
Initial screening for AE will include non-directed questioning of the patient at each follow-up visit 
during the study period.  
 
Serious Adverse Event 
Adverse events defined as serious will the following:  
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 


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• birth defect/anomaly 
 
and any problems/events that in the opinion of the sponsor-investigator may have adversely 
affected the rights, safety, or welfare of the subjects or others, or substantially compromised 
the research data. 
 
All adverse events that do not meet any of the criteria for serious, will be regarded as non-
serious adverse events as previously defined above.  
 
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 will 
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 will also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-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 sponsor-investigator should instruct each subject to report, to the sponsor-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
Any clinical laboratory abnormality that can reasonably be related to the administration of Nucala 
should be documented as an adverse event. 
 
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 use of Nucala. 
9.2 
Recording of Adverse Events 
At each contact with the subject, the study team will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be 


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recorded immediately in the source document, and also in the appropriate adverse event section of 
the case report form (CRF). All clearly related signs, symptoms, and abnormal diagnostic, 
laboratory or procedure results will be recorded in the source document. 
 
All adverse events occurring during the study period will 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 during the Adverse Event Reporting Period and is 
considered to be at least possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
9.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
9.3.1 Sponsor-Investigator reporting: notifying the Mayo 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:  
 


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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. 
9.3.2 Sponsor-Investigator reporting: Notifying the FDA 
 
This protocol is not being conducted under an FDA investigational new drug application.   
9.4 
Unmasking/Unblinding Procedures 
 
This is an open-label pilot investigation. Unmasking and unblinding procedures are not 
applicable.  
 
9.5 
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 study participants develop unexpected clinical flaring or 
significant worsening that appears temporally linked with Nucala administration. 
9.6 
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 10  “Study Monitoring, Auditing, and Inspecting”).  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. 
10 Data Handling and Record Keeping 
10.1 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  
 


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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. 
10.2 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, microfiches, 
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. 
10.3 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.  All entries will be printed legibly 
in black ink.  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-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 
 
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 Processing 
 


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All study date will be stored and analyzed at Mayo Clinic in Florida using the REDCap electronic 
data capture tool.  
 
Data Security and Confidentiality 
 
All source documents including clinical findings, observations or other activities will be stored in 
a REDCap database that will be designed by the Statistician.  Access to the REDCap database will 
be limited to the Principal Investigator, Investigators, and Statistician. 
 
Data Quality Assurance 
 
Once the study is completed the Principal Investigator will randomly select 3 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 
12 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.  
10.4 Records Retention 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” 
   
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 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 


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all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, 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 compliance offices. 
12 Ethical Considerations 
This study is to be conducted according to United States government regulations and 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 sponsor-
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 must be signed by 
the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. This study will not include vulnerable study populations. 
 
13 Study Finances 
13.1 Funding Source 
 
This investigator initiated study is funded by a research grant from GlaxoSmithKline to Mayo 
Clinic. 
13.2 Conflict of Interest 
 


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Any study team member who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor-
investigator prior to participation in this study. 
 
No financial conflicts of interested are anticipated or have been identified for this study. 
13.3 Subject Stipends or Payments 
 
No payment is given to study participants. 
14 Publication Plan 
 
The primary responsibility for publication of the study results is with the Primary Investigator. 
After the complication of study and prior to publication, the study results will be shared with 
GlaxoSmithKline. The study will be registered at ClinicalTrials.gov prior to subject recruitment 
along with the posting of the results within 12 months of final data collection for the primary 
outcome measure.  
15 References 
 
1. Greaves MW. Pathology and classification of urticaria. Immunol Allergy Clin North Am 
2014;34:1-9. 
2. Altrich ML, Halsey JF , Altman LC. Comparison of the in vivo autologous skin test with 
in vitro diagnostic tests for diagnosis of chronic autoimmune urticaria. Allergy Asthma 
Proc 2009;30:28-34. 
3. O'Donnell MC, Ackerman SJ, Gleich GJ , Thomas LL. Activation of basophil and mast 
cell histamine release by eosinophil granule major basic protein. J Exp Med 
1983;157:1981-91. 
4. Leifermen KM, Loegering DA, Gleich GJ. Production of wheal-and-flare skin reactions 
by eosinophil granule proteins. J Invest Dermatol 1984; 82:414. 
5. Ben-Zimra M, Bachelet I, Seaf M, Gleich GJ , Levi-Schaffer F. Eosinophil major basic 
protein activates human cord blood mast cells primed with fibroblast membranes by 
integrin-beta1. Allergy 2013;68:1259-68. 
6. Puccetti A, Bason C, Simeoni S, Millo E, Tinazzi E, Beri R et al. In chronic idiopathic 
urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via 
eosinophil activation. Clin Exp Allergy 2005;35:1599-607. 


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7. Smith DA, Minthorn EA , Beerahee M. Pharmacokinetics and pharmacodynamics of 
mepolizumab, an anti-interleukin-5 monoclonal antibody. Clin Pharmacokinet 
2011;50:215-27. 
8.  Mathias SD, Crosby RD, Zazzali JL, Maurer M , Saini SS. Evaluating the minimally 
important difference of the urticaria activity score and other measures of disease activity 
in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2012;108:20-
4. 
9. Weller K, Groffik A, Church MK, Hawro T, Krause K, Metz M et al. Development and 
validation of the Urticaria Control Test: a patient-reported outcome instrument for 
assessing urticaria control. J Allergy Clin Immunol 2014;133:1365-72, 72 e1-6. 
 
16 Attachments 
 
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