Predicting Inflammatory Skin Disease Response to IL-23 Blockade
Phase: PHASE4
Conditions: Psoriasis Vulgaris
Sponsor: University of California, San Francisco

 
 PREDICTING INFLAMMATORY SKIN DISEASE RESPONSE TO IL-23 BLOCKADE 
(NCT04541329)  
DOCUMENT DATE 8/24/23 

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JEFFREY CHENG
Clinical Research Protocol
PREDICTING INFLAMMATORY SKIN DISEASE RESPONSE TO IL23 
BLOCKADE
Protocol Number:
19-29813
Version Date:
Investigational Product:
IND Number:
Development Phase:
Sponsor:
Raymond Cho and Jeffrey Cheng
Department of Dermatology
1701 Divisadero St. 4th Floor
San Francisco, CA 94143
Funding Organization:
Principal Investigator:
Name: Raymond Cho
Telephone: 650 520 0208
Fax:
E-mail: Raymond.cho@ucsf.edu
Medical Monitor:
Name:
Telephone:
Fax:
E-mail:
Coordinating Center:
If applicable
Approval:
PI or Sponsor Signature (Name and Title) 
Date
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  

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PROTOCOL AGREEMENT
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Raymond Cho (myself) with complete and timely information, as outlined in 
the protocol.  It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol.
Protocol Number:  19-29813
Protocol Title:  Predicting inflammatory skin disease response to IL23 blockade
Protocol Date:  TBD
Investigator Signature 
Date
Print Name and Title
Site #
Site Name
Address
Phone Number

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TABLE OF CONTENTS
1
BACKGROUND ..................................................................................................................8
1.1
Overview of Non-Clinical Studies...............................................................................8
1.2
Overview of Clinical Studies .......................................................................................8
2
STUDY RATIONALE.........................................................................................................8
2.1
Risk / Benefit Assessment............................................................................................8
3
STUDY OBJECTIVES........................................................................................................8
3.1
Primary Objective ........................................................................................................8
3.2
Secondary Objectives...................................................................................................8
4
STUDY DESIGN..................................................................................................................8
4.1
Study Overview............................................................................................................8
5
CRITERIA FOR EVALUATION......................................................................................9
5.1
Primary Efficacy Endpoint...........................................................................................9
5.2
Secondary Efficacy Endpoints.....................................................................................9
5.3
Safety Evaluations........................................................................................................9
6
SUBJECT SELECTION .....................................................................................................9
6.1
Study Population..........................................................................................................9
6.2
Inclusion Criteria..........................................................................................................9
6.3
Exclusion Criteria ........................................................................................................9
7
CONCURRENT MEDICATIONS.....................................................................................9
7.1
Allowed........................................................................................................................10
7.2
Prohibited.....................................................................................................................10
8
STUDY TREATMENTS.....................................................................................................10
8.1
Method of Assigning Subjects to Treatment Groups...................................................10
8.2
Blinding........................................................................................................................10
8.3
Test and Control Formulation......................................................................................10
8.4
Supply of Study Medication at the Site .......................................................................10
8.5
Study Medication Accountability ................................................................................11
8.6
Measures of Treatment Compliance ............................................................................11
9
STUDY PROCEDURES AND GUIDELINES..................................................................11
9.1
Clinical Assessments....................................................................................................11
9.2
Pharmacokinetic Measurements ..................................................................................12
10 EVALUATIONS BY VISIT................................................................................................12
10.1 Visit 1...........................................................................................................................12
10.2 Visit 2 (2 weeks after Visit #1) ....................................................................................12
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................13
11.1 Adverse Events ............................................................................................................13
11.2 Serious Adverse Experiences (SAE)............................................................................14
11.3 Medical Monitoring .....................................................................................................15

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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ...................................15
12.1 Withdrawal of Subjects................................................................................................15
12.3 Replacement of Subjects..............................................................................................15
13 PROTOCOL VIOLATIONS..............................................................................................15
14 STATISTICAL METHODS AND CONSIDERATIONS................................................16
14.1 Data Sets Analyzed ......................................................................................................16
14.2 Demographic and Baseline Characteristics..................................................................16
14.3 Analysis of Primary Endpoint......................................................................................16
14.4 Analysis of Secondary Endpoints ................................................................................16
14.5 Interim Analysis...........................................................................................................16
14.6 Sample Size and Randomization..................................................................................16
15 DATA COLLECTION, RETENTION AND MONITORING........................................16
15.1 Data Collection Instruments.........................................................................................16
15.2 Data Management Procedures .....................................................................................17
15.3 Data Quality Control and Reporting ............................................................................17
15.4 Archival of Data...........................................................................................................17
15.5 Availability and Retention of Investigational Records................................................17
15.6 Monitoring ...................................................................................................................18
15.7 Subject Confidentiality ................................................................................................18
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS...................18
16.1 Protocol Amendments..................................................................................................18
16.2 Institutional Review Boards and Independent Ethics Committees..............................18
16.3 Informed Consent Form...............................................................................................19
16.4 Publications..................................................................................................................19
16.5 Investigator Responsibilities........................................................................................20

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LIST OF ABBREVIATIONS
none

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PROTOCOL SYNOPSIS
TITLE
PREDICTING TREATMENT RESPONSE FOR 
INFLAMMATORY SKIN DISEASE
SPONSOR
self
FUNDING 
ORGANIZATION
none
NUMBER OF SITES
1
RATIONALE
To develop a predictive algorithm to determine whether a given 
patient with psoriasis will respond to one of the multiple specific 
pathway blocking FDA-approved psoriasis biologic medications.  
STUDY DESIGN
interventional trial with molecular profiling of skin samples
PRIMARY 
OBJECTIVE
To obtain pre-treatment psoriatic skin samples for molecular profiling  
prior to treatment with  tildrakizumab to correlate with and to predict 
treatment response
SECONDARY 
OBJECTIVES
NUMBER OF 
SUBJECTS
10
SUBJECT 
SELECTION
CRITERIA
Inclusion Criteria: > 18 years of age, Patients with moderate-severe 
psoriasis or atypical psoriasis with either non-biologic treatment 
failure or > 5% body surface area affected. 
Exclusion Criteria: 
tuberculosis, active serious infection, active systemic malignancy, or 
received a systemic medication for psoriasis within 3 months of study 
screening. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION
Tildrakizumab 100 mg subcutaneous injection
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION
n/a

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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY
The time commitment for the first visit will be approximately 1.5 
hours to discuss the study, consent the patient, and perform the 
biopsy.
The second visit will last approximately 15 minutes
The third and fourth visits will last approximately 30 minutes.
With a total time committment of ~ 2 hrs 45 minutes
CONCOMMITANT 
MEDICATIONS
Allowed: 
Prohibited: other systemic medications for psoriasis
EFFICACY 
EVALUATIONS
PRIMARY ENDPOINT

molecular gene expression profiling of skin cell populations.
SECONDARY 
ENDPOINTS

Psoriasis Area and Severity Index (PASI) score
OTHER 
EVALUATIONS
SAFETY 
EVALUATIONS
Re-evaluation of biopsy site at follow-up visit in 14 days for wound 
infection
In person medical visit for physical exam and history 4 weeks and 16 
weeks after start of medication
PLANNED INTERIM 
ANALYSES 
When approximately 50% of patients have completed the study 
through Visit 4, an interim analysis for safety will be conducted by the 
investigator. Serious adverse events will be monitored by the 
committee on an ongoing basis throughout the study.
STATISTICS
Primary Analysis Plan
We will rely heavily on RNA-seq analysis, in some cases 
complemented with DNA sequencing and protein assessments. The 
RNAseq data will be normalized and compared in diseased vs normal 
skin and differential expression discerned at a significance level of 5% 
in a single test, in a two-group comparison, using a Negative Binomial 
mode. Numerous qualitative analyses will be performed as well.
Rationale for Number 
of Subjects
Bulk RNA-seq studies have required ~100 patients to distinguish 
markers for different inflammatory skin diseases.  We anticipate with 
single cell RNA-seq, fewer patients may be necessary. This is also a 
pilot trial and due to the cost of the molecular profiling will start with 
an initially smaller # of patients.

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1
BACKGROUND
Cutaneous inflammation represents the most common skin pathology, placing pervasive 
burdens on health care cost and quality of life. Biologic immunomodulatory therapies now 
enable improvement of major rashes such as psoriasis and atopic dermatitis; however, a 
significant minority of patients do not adequately respond to these medications. Given the 
multiple medication options that target different inflammatory pathways, significant 
expense and serious side effects of these immunomodulatory medications, it is imperative 
that we develop mechanisms to better predict whether a patient will respond to a given 
drug.  
1.1
. Overview of Non-Clinical Studies
1.1
We will be collecting skin tissue from psoriatic patients for the purposes of 
analyzing gene activity in these samples.
1.2
Overview of Clinical Studies
Patient will be assessed for improvement in their psoriasis using the Psoriasis Area and 
Severity Index (PASI) score.  Patients will be administered tildrakizumab (a FDA-
approved medication for psoriasis) following manufacturer’s and FDA indications and 
dosing schedule.
2
STUDY RATIONALE
The researchers want to find a way to predict whether a person with psoriasis will respond 
to a given medication. In this study, patient will start tildrakizumab (a FDA-approved 
medication for psoriasis). Prior to treatment, a small piece of psoriasis-affected skin will 
be sampled and molecularly profiled. We will then analyze the molecular profiles and 
compare to patient tildrakizumab treatment response to predict which future patients will 
best respond to this medication.
2.1
Risk / Benefit Assessment
Regarding the tildrakizumab treatment, this is a FDA approved medication for psoriasis.  
The same risks/benefits assessment for a psoriatic patient in our clinics as to whether to 
start this medication apply.
Regarding the skin biopsy, there is minimal risk to patients as punch biopsies are standard 
dermatologic procedures that are performed frequently with minimal side effects, which 
include bleeding, pain, infection, scar, changes in skin coloration, and allergic reaction to 
anesthesia. Knowledge may be gained about health conditions and patient may derive a 
feeling of contribution to knowledge in the health field
3
STUDY OBJECTIVES
3.1
Primary Objective
Our primary objective is to identify the genes that are differentially expressed in psoriatic 
skin between patients that do and do not respond to tildrakizumab

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3.2
Secondary Objectives
There is no secondary objective.
4
STUDY DESIGN
4.1
Study Overview
This is a single center study in which patients with psoriasis or atypical psoriasis will 
donate small samples of that skin and/or normal tissue prior to treatment with the FDA-
approved psoriasis medication, tildrakizumab.
5
CRITERIA FOR EVALUATION
5.1
Primary Efficacy Endpoint
We will evaluate if there are genes which are statistically significantly upregulated or 
downregulated in specific cell populations, based on RNA sequencing.
For assessment of psoriasis improvement, we will use the Psoriasis Area and Severity 
Index (PASI) scoring system.
5.2
Secondary Efficacy Endpoints

There are no secondary endpoints.
5.3
Safety Evaluations

The biopsy site will be evaluated at time of suture removal for any signs of superficial 
infection.

Patients will have standard follow-up visits to assess efficacy and side effects of 
tildrakizumab, as would any of our non-trial patients started on this medication.
6
SUBJECT SELECTION
6.1
Study Population
Subjects with a diagnosis of psoriasis or atypical psoriasis who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.  
6.2
Inclusion Criteria
1.
Male or female ≥18 years of age at clinic visit.
2.
Documentation of moderate-severe psoriasis or atypical psoriasis.
3.
Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study.

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6.3
Exclusion Criteria
4.
Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data (e.g. tuberculosis, 
active serious infection, active systemic malignancy)
5.
tuberculosis, active serious infection, active systemic malignancy,
6.
or received a systemic medication for psoriasis within 3 months of study screening
CONCURRENT MEDICATIONS
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.
6.4
Allowed Medications and Treatments
Prohibited Medications and Treatments
The following medications are prohibited during the study and administration will be 
considered a protocol violation.
phototherapy, systemic medications for psoriasis (e.g. corticosteroids, other biologic 
medications, methotrexate, cyclosporine)
7
STUDY TREATMENTS
7.1
Method of Assigning Subjects to Treatment 
Groups
All patients in the trial are treated.
7.2
Blinding
None
7.3
Formulation of Test and Control Products
Standard manufacturer formulation
7.3.1
Formulation of Test Product
Standard manufacturer formulation
7.3.2
Formulation of Control Product
none
7.3.3
Packaging and Labeling
Standard manufacturer formulation

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7.4
Supply of Study Drug at the Site
7.4.1
Dosage/Dosage Regimen
100 mg subcutaneous injection at 0, 4, and 16 weeks.
7.4.2
Dispensing
physician administered in clinic, From the investigational pharmacy at UCSF.
7.4.3
Administration Instructions 
physician administered in clinic
7.5
Supply of Study Drug at the Site
physician administered in clinic
7.5.1
Storage
From the investigational pharmacy at UCSF.
7.6
Study Drug Accountability
By the investigational pharmacy at UCSF.
7.7
Measures of Treatment Compliance
physician administered in clinic
8
STUDY PROCEDURES AND GUIDELINES
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities.
8.1
Clinical Assessments
8.1.1
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening visit.  Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured.
8.1.2
Demographics 
Demographic information (date of birth, gender, race) will be recorded at Screening.

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8.1.3
Medical History 
Relevant medical history, including history of current disease, other pertinent 
dermatologic history, review of systems, and information regarding underlying diseases 
will be recorded at Screening. 
8.1.4
Physical Examination
A complete skin examination will be performed by either the investigator or a co-
investigator who is a physician at Visit #1.   Qualified staff (MD, NP, RN, and PA) may 
complete the abbreviated physical exam at all other visits.  New abnormal physical exam 
findings must be documented and will be followed by a physician or other qualified staff 
at the next scheduled visit. Photographic documentation of pre and post-treatment 
psoriatic lesions will be obtained.
8.1.5
Vital Signs
In standard clinical (non-research) dermatology visits, vital signs are not typically monitored prior 
to/after skin biopsies unless the patient complains of feeling unwell.
8.1.6
Oximetry
No oximetry will be taken for this skin study.
8.1.7
Spirometry
No spirometry will be taken for this skin study.
8.1.8
Other Clinical Procedures
No other clinical procedures will be taken for this skin study.
8.1.9
Adverse Events
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF).
8.2
Pharmacokinetic Measurements
No pharmacokinetic measurement will be taken for this skin study.
9
EVALUATIONS BY VISIT
9.1
Visit 1
1.
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate.
2.
Assign the subject a unique screening number.
3.
Record demographics data.
4.
Record medical history, including a history of rash, diagnosis date, and prior 
treatments.

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5.
Record concomitant medications.
6.
Perform a complete skin examination.
7.
Clean skin, anesthetize skin, take skin sample(s) (up to 2 6 mm punch biopsies), 
place suture.
8.
Photograph of biopsied lesional skin and other psoriatic lesions
9.
Part of the biopsied specimen will be sent for standard histopathology (if no 
previous histopathology from a similar  representative lesion has been done)
10.
Schedule subject for suture removal in 14 days.
11.
Baseline routine bloodwork (CBC,  quant gold, HIV, HB surface Ag, Anti-HB 
surface AB, anti-HB core AB, hepatitis C antibody, BUN/Creatinine, AST/ALT)
9.2
Visit 2 (2 weeks after Visit #1)
1.
Remove suture.
2.
Inspect biopsy site(s) to rule out infection.
3.
Administration of tildrakizumab if normal baseline laboratory results, no interim 
medical issues, and/or histopathology consistent with psoriasis or atypical psoriasis 
(if no previous histopathology)
9.3
Visit 3 (4 weeks after Visit #2)
4.
Interim medical history
5.
Physical examination
6.
Administration of tildrakizumab
9.4
Visit 4 (12 weeks after Visit #3)
7.
Interim medical history
8.
Physical examination
9.
Administration of tildrakizumab
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION
10.1 Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
a pharmaceutical product and that does not necessarily have a causal relationship with the 
treatment.  
AE Severity
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 

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found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious.
Table 1.  AE Severity Grading
Severity (Toxicity Grade)
Description
Mild (1)
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well.
Moderate (2)
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.
Severe (3)
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible.
Life-threatening (4)
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe.
AE Relationship to Study Drug
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2.
Table 2.  AE Relationship to Study Drug
Relationship
to Drug
Comment
Definitely
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis.
Probably
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions.
Possibly
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors.
Unrelated
An event that can be determined with certainty to have no relationship to the study 
drug.
10.2 Serious Adverse Experiences (SAE)
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes:

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
death

a life-threatening adverse experience

inpatient hospitalization or prolongation of existing hospitalization

a persistent or significant disability/incapacity

a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed. 
10.2.1 Serious Adverse Experience Reporting
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed.
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.  
10.3 Medical Monitoring
Dr. Raymond J. Cho or Jeffrey Cheng should be contacted directly at these numbers to 
report medical concerns or questions regarding safety.
Phone: (650) 520-0208
  
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS
11.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:

Subject withdrawal of consent (or assent)
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
12.3
Withdrawal of Subjects from the Study
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.  
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice.
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 

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the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early should still be offered Visit 2 for suture removal. 
12.4
Replacement of Subjects
Subjects who withdraw from the study will be replaced.  
12 PROTOCOL VIOLATIONS
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following:

Failure to meet inclusion/exclusion criteria

Use of a prohibited concomitant medication
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The investigator Jeffrey Cheng will determine if a protocol violation 
will result in withdrawal of a subject.
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files.
13 STATISTICAL METHODS AND CONSIDERATIONS
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.  
13.1 Data Sets Analyzed
All eligible patients who consent to the study and have a skin sample taken will have data 
analyzed.
13.2 Demographic and Baseline Characteristics
The following demographic variables at screening will be summarized: race, gender, age, 
rash type and biopsy site.  
13.3 Analysis of Primary Endpoint
After RNA sequencing performs, standard distribution-based statistical test for 
significantly overexpressed or under-expressed genes will be applied.
13.4 Analysis of Secondary Endpoints
There are no secondary endpoints.

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13.5 Interim Analysis
There are no interim analysis.
13.6
Sample Size and Randomization
10 samples will be collected for initial analysis. Distribution-based statistical analysis 
indicates that two-fold differences in gene transcription will be detected at this size.
14 DATA COLLECTION, RETENTION AND MONITORING
14.1 Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.  
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) OR paper 
CRF when the information corresponding to that visit is available.  Subjects will not be 
identified by name in the study database or on any study documents to be collected by the 
Sponsor (or designee), but will be identified by a site number, subject number and initials.
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the 
person entering or updating eCRF data and creates an electronic audit trail.  For paper 
CRFs:  If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change.
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study.
14.2 Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials.
14.3 Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. The 
study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented.

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14.4 Archival of Data
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.  
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures.
14.5 Availability and Retention of Investigational 
Records
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason.
14.6 Monitoring
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation.
14.7 Subject Confidentiality
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation submitted 
to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement.
15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312).
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 

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information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC).
15.1 Protocol Amendments
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days.
15.2 Institutional Review Boards and Independent 
Ethics Committees
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations.
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.  
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed.
15.3 Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 

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50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations.
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file.
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records.
15.4 Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996. 
15.5
Investigator Responsibilities
By signing the Agreement of Investigator form, the Investigator agrees to:
1.
Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects.
2.
Personally conduct or supervise the study (or investigation).
3.
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.
4.
Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64.
5.
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments.
6.
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee).
7.
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study.

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8.
Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports).
9.
Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.

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APPENDIX 1.  EXAMPLE OF SCHEDULE OF STUDY VISITS
VISIT 1
(Day 1)a
VISIT 2
(Day 15)a
VISIT 3 
(DAY 43)*
VISIT 4
(DAY 127)*
Informed Consent
X
Medical History
X
X
X
X
Skin Exam
X
X
X
Abbreviated Physical Exam
X
Biopsy
X
Suture removal and biopsy site 
check
X
Treatment Administration
X
X
X
Baseline routine bloodwork
X
a 
 5 days

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Protocol Template © CFFT TDN   Effective: 12 SEP 2007