Analysis of Hydrocodone Compared to Acetaminophen and Ibuprofen for Post-nail Procedure Analgesia
Phase: PHASE4
Conditions: Nail Diseases, Nail Abnormality
Sponsor: Weill Medical College of Cornell University

Title: Analysis of hydrocodone compared to acetaminophen and ibuprofen for post-nail
procedure analgesia
NCT #: NCT05544734
Version Date: 08/15/2022

TITLE: Analysis of hydrocodone compared to acetaminophen and ibuprofen for post-nail
procedure analgesia
IRB Protocol #: 21-10024054
Version Date: 08/15/2022
Principal Investigator:
Co-Investigators:
Shari R. Lipner, MD, PhD
1305 York Avenue
New York, NY 10021
shl9032@med.cornell.edu
Jonathan Hwang, BS
420 E 70th St, LH 13D-1
New York, NY 10021
jkh4001@med.cornell.edu
Jose Ricardo, MD
653 E 14th St, Apt 4H
New York, NY 10009
jwr4001@med.cornell.edu
Participating Sites:
Weill Cornell Dermatology - 1305 York Avenue, New York, NY 10021
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Table of Contents
CONFIDENTIALITY STATEMENT .........................................................................................5
1. PROTOCOL SUMMARY ....................................................................................................6
1.1      Schema.....................................................................................................................8
1.2      Study Objectives and End Points.............................................................................4
1.2.1      Primary Objectives ....................................................................................................4
1.2.2      Secondary Objectives ...............................................................................................4
1.2.3
Exploratory Objectives ......................................................................................4
1.2.4      Primary Endpoints .....................................................................................................4
1.2.5      Secondary Endpoints................................................................................................4
2. BACKGROUND.......................................................................................................................... 4
2.1      Disease ...............................................................................................................................4
2.2      Investigational Agent/Device, or Surgical Treatment/Method..................................4
2.3      Rationale.............................................................................................................................5
2.4       Risk/Benefit Assessment.........................................................................................6
2.4.1      Known Potential Risks ..............................................................................................6
2.4.2      Known Potential Benefits ..................................................................................6
2.4.3      Assessment of Potential Risks and Benefits.....................................................6
3. STUDY DESIGN ......................................................................................................................... 6
3.1      Overall Design ...................................................................................................................6
3.2      Scientific Rationale for Study Design.......................................................................8
3.3      Justification for Dose .............................................................................................12
3.4      End of Study Definition.....................................................................................................9
4. SUBJECT SELECTION....................................................................................................13
4.1      Study Population ....................................................................................................13
4.2      Inclusion Criteria ....................................................................................................13
4.3      Exclusion Criteria ...................................................................................................13
4.4      Lifestyle Considerations.........................................................................................13
4.5      Screen Failures..................................................................................................................9
4.6      Strategies for Recruitment and Retention..............................................................14
5. REGISTRATION PROCEDURES............................................................................................ 10
5.1      Subject Registration (WCM only) ...........................................................................14
6. STUDY PROCEDURES ...................................................................................................14
6.1      Schedule of Assessments......................................................................................14
6.1.1      Screening Visit (-X days before start of treatment) .........................................14
6.1.2      Treatment Phase..............................................................................................15
7. STUDY INTERVENTION..................................................................................................15
7.1      Study Intervention/Device Description...................................................................15
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7.2      Availability..............................................................................................................15
7.3      Acquisition and Accountability ..............................................................................16
7.4      Formulation, Appearance, Packaging, and Labeling..............................................16
7.5      Product Storage and Stability.................................................................................16
7.6      Preparation.............................................................................................................16
7.7      Dosing and Administration.....................................................................................16
7.7.1      Dosing Delays/Dose Modifications..................................................................16
7.8      General Concomitant Medication and Supportive Care Guidelines.......................16
7.9      Duration of Therapy and Criteria for Removal from Study.....................................16
7.10 Duration of Follow Up ..............................................................................................17
7.11 Measures to Minimize Bias: Randomization and Blinding .......................................17
7.12 Study Intervention/Follow-up Compliance ...............................................................17
8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ...................................................................................17
8.1      Discontinuation of Study Intervention....................................................................17
8.2      Participant Discontinuation/Withdrawal from the Study ........................................18
8.3      Lost to Follow Up....................................................................................................18
9. CORRELATIVE/SPECIAL STUDIES ................................................................................19
9.1      Laboratory Correlative Studies ..............................................................................16
9.1.1      Title ± Laboratory Correlative Study #1 ...........................................................16
9.1.1.1 Collection of Specimen(s)................................................................................16
9.1.1.2 Handling of Specimen(s) .................................................................................16
9.1.1.3 Shipping of Specimen(s) (if multicenter).........................................................16
9.1.1.4 Site(s) Performing Correlative Study (if multicenter) ......................................16
9.2      Special Studies................................................................................................................16
9.2.1      Title ± Special Correlative Study #1.................................................................16
9.2.1.1 Assessment..............................................................................................................16
9.2.1.2 Method of Assessment....................................................................................16
9.2.1.3 Timing of Assessment.....................................................................................16
10. MEASUREMENT OF EFFECT ............................................................................................. 16
10.1 Response Criteria ..............................................................................................................16
10.2 Duration of Response .......................................................................................................16
10.3 Progression-Free Survival........................................................................................17
10.4 Other Response Parameters.....................................................................................17
11. DATA REPORTING / REGULATORY CONSIDERATIONS .............................................17
11.1 Data Collection...................................................................................................................17
11.1.1 REDCap........................................................................................................................17
11.2 Regulatory Considerations.......................................................................................17
11.2.1 Institutional Review Board/Ethics Committee Approval ....................................17
11.2.2 Ethical Conduct of the Study .............................................................................18
11.2.3 Informed Consent .......................................................................................................18
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11.2.4 Compliance with Trial Registration and Results Posting Requirements ...........19
11.2.5 Record Retention........................................................................................................19
12. STATISTICAL CONSIDERATIONS ................................................................................19
12.1 Study Design/Endpoints ...........................................................................................19
12.2 Sample Size/Accrual Rate.........................................................................................23
12.3 Stratification Factors ................................................................................................23
12.4 Analysis of Endpoints...............................................................................................23
12.4.1 Analysis of Primary Endpoints ........................................................................23
12.4.2 Analysis of Secondary Endpoints ...................................................................23
12.5 Interim Analysis........................................................................................................24
12.6 Reporting and Exclusions ........................................................................................24
12.6.1 Evaluation of Toxicity ......................................................................................24
12.6.2 Evaluation of Response...................................................................................24
13. ADVERSE EVENT REPORTING REQUIREMENTS........................................................24
13.1 Adverse Event Definition ..........................................................................................24
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events) ................24
13.1.2 Adverse Event Characteristics and Related Attributions ................................25
13.1.3 Recording of Adverse Events..........................................................................25
13.1.4 Reporting of AE to WCM IRB ...........................................................................25
13.1.5 Reporting Events to Participants.....................................................................25
13.1.6 Events of Special Interest................................................................................25
13.1.7 Reporting of Pregnancy...................................................................................25
13.2 Definition of SAE.......................................................................................................25
13.2.1 Reporting of SAE to IRB ..................................................................................26
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-
Investigator]..................................................................................................................26
13.2.3 Reporting of SAE to Eclipse Medical...............................................................26
13.3 AE/SAE Follow Up.....................................................................................................26
13.4 Time Period and Frequency for Event Assessment and Follow Up .........................27
14. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS .........27
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others
(UPIRTSO) ........................................................................................................................27
14.1.2 Unanticipated Problem Reporting ...................................................................24
15. DATA AND SAFETY MONITORING PLAN (DSMP)........................................................24
16. REFERENCES........................................................................................................................ 26
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Statement of Compliance
The trial will be carried out in accordance with International Conference on Harmonisation Good
Clinical Practice (ICH GCP) and the following:
‡ United States (US) Code of Federal Regulations (CFR) applicable to clinical studies
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR
Part 812)
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are
responsible for the conduct, management, or oversight of NIH-funded clinical trials have
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials
will be submitted to the Institutional Review Board (IRB) for review and approval.
Approval of both the protocol and the consent form must be obtained before any participant
is enrolled. Any amendment to the protocol will require review and approval by the IRB
before the changes are implemented to the study. In addition, all changes to the consent
form will be IRB-approved; a determination will be made regarding whether a new consent
needs to be obtained from participants who provided consent, using a previously approved
consent form.
Confidentiality Statement
This document is confidential and is to be distributed for review only to investigators, potential
investigators, consultants, study staff, and applicable independent ethics committees or
institutional review boards. The contents of this document shall not be disclosed to others without
written authorization from WCM, unless disclosure on ClinicalTrials.gov is federally required.
List of Abbreviations
WCM
Weill Cornell Medicine
PGIA
Physician Global Improvement Score
PGA
Physician Global Assessment
AE
Adverse events
ADE
Adverse Device Effect
SAE
Serious Adverse Event
UADE
Unanticipated Adverse Device Effect
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1. Protocol Summary
Full Title:
Short Title:
Clinical Phase:
Principal Investigator:
Study Description:
Sample Size:
Enrollment:
Study Population:
Enrollment Period:
Study Design:
Description of Sites/
Facilities Enrolling
Participants:
Study Duration:
Participant Duration:
Analysis of hydrocodone compared to acetaminophen and
ibuprofen for post-nail procedure analgesia
Hydrocodone for post-nail surgery analgesia
Phase 4
Shari R. Lipner MD, PhD
Nail surgery is associated with moderate to severe postoperative
pain. The purpose of this study is to assess the efficacy and safety
of ropivacaine and hydrocodone for post-nail procedure analgesia.
N = 20 participants.
This study will enroll 20 subjects and screen up to 30
Patients 18 years and older undergoing fingernail biopsies at the
Weill Cornell Medicine, Department of Dermatology, specialty nail
clinic.
07/01/2022 ± 07/01/2023
This is a randomized, open-label study, assessing the efficacy
and safety of: group a: intraoperative ropivacaine 0.75% +
lidocaine 1% and hydrocodone 5 mg + acetaminophen 325 mg
(every 4 hours for 2 days, starting 6 hours after surgery) for nail
procedure-associated analgesia, compared with group b:
intraoperative ropivacaine 0.75% + lidocaine 1% and
acetaminophen 1000 mg + ibuprofen 400 mg (every 6 hours for 6
days, starting 6 hours after surgery). The Wong-Baker scale 0-to-
10 scale will be used to quantitate pain scores prior to surgery, at
3 time points during surgery, and postoperatively (days 0-6).
Subjects will be asked to complete a daily log where they will
record pain twice daily during the postoperative period. Also, the
APS-POQ-R quality of life survey will be completed on
postoperative days 3 and 6. Any side effects will be recorded
throughout the study period.
Weill Cornell Dermatology - 1305 York Avenue, NY, NY 10021
1 year
6 days
Study Agent/Device Name
Intervention Description:
Lidocaine 1% (duration of action: 1-2 hours) and ropivacaine 0.75% (duration of action: 8
hours) are short- and long-acting local anesthetics, respectively. A mix of these will be
used for intraoperative/postoperative anesthesia in both study groups. In addition,
subjects in group a will receive: oral hydrocodone 5 mg (moderate-strength
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opioid)/acetaminophen 325 mg (non-opioid analgesic), every 4 hours for 2 days, starting 6
hours after surgery. On postoperative day 3, subjects in group a will switch to oral
acetaminophen 1000 mg and ibuprofen 400 mg every 6 hours, until postoperative day 6.
Patients in group b will receive: acetaminophen 1000 mg and ibuprofen 400 mg, every 6
hours, for 6 days, starting 6 hours after surgery. Ropivacaine and lidocaine are FDA-
approved for surgical anesthesia. Hydrocodone, acetaminophen, and ibuprofen are
FDA-approved for postoperative analgesia.
Primary Objective:
Secondary Objectives:
Primary Endpoints:
Secondary Endpoints:
The primary objective of this study is to determine the efficacy and
safety of hydrocodone/acetaminophen + acetaminophen and
ibuprofen vs. acetaminophen + ibuprofen, for nail procedure-
associated pain management.
The secondary objective of this study is to determine the impact of
hydrocodone/acetaminophen + acetaminophen and ibuprofen vs.
acetaminophen + ibuprofen on health-related quality of life
associated with pain.
The primary efficacy endpoint will be the change in pain scores
obtained with the Wong-Baker 0-to-10 pain scale between the 2
groups on post-operative day 2.
The secondary endpoint will be the change in health-related
quality of life associated with pain obtained with an adapted
version of the APS-POQ-R between the 2 groups on post-
operative days 3 and 6.
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1.1
Schema
Flow diagram
Screening
Visit: Day 0
At least 24 hours prior to date of procedure:
Screen potential participants by inclusion and exclusion criteria; obtain history, review of medications, document. Sign consent.
Ropivacaine 0.75% + lidocaine 1% is administered to both groups for intraoperative anesthesia
Assess pain using the Wong-Baker 0-to-10 pain scale, pre-surgery and during surgery. Give pain dairies to subjects.
6 hours after
surgery
Day 3
Group a: hydrocodone 5 mg/acetaminophen 325 mg every 4
hours for 2 days.
Group a: Start acetaminophen 1000 mg and ibuprofen 400 mg
every 6 hours for 4 days. Complete quality of life survey
Group b: start acetaminophen 1000 mg and ibuprofen 400 mg,
every 6 hours for 2 days.
Group b: continue acetaminophen 1000 mg and ibuprofen 400
mg, every 6 hours for 4 days. Complete quality of life survey
Day 6
Collection of pain dairies. Complete quality of life survey.
1.2
Study Objectives and End Points
1.2.1 Primary Objectives
The primary objective of this study is to determine the efficacy and safety of
hydrocodone/acetaminophen + acetaminophen and ibuprofen vs. acetaminophen +
ibuprofen, for nail procedure-associated pain management.
1.2.2 Secondary Objectives
The secondary objective of this study is to determine the impact of
hydrocodone/acetaminophen + acetaminophen and ibuprofen vs. acetaminophen +
ibuprofen on health-related quality of life associated with pain.
1.2.4 Primary Endpoints
The primary efficacy endpoint will be the change in pain scores, obtained with the Wong-
Baker 0-to-10 pain scale, between the 2 groups on postoperative day 2.
1.2.5 Secondary Endpoints
The secondary endpoint will be the change in subject reported health-related quality of
life associated with pain, obtained with an adapted version of the APS-POQ-R, between
the 2 groups on postoperative days 3 and 6.
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2. Background
2.1 Disease
Nail procedures are associated with moderate to severe postoperative pain that can be
present up to one week post-op.1 While ropivacaine has been shown to be effective for pain
management after nail surgical procedures in the immediate postoperative (up to 48 hours
following surgery), studies assessing safety and efficacy of pain management regimens have
been limited.2 Research on Mohs micrographic surgery have shown that the combination of
oral acetaminophen 1000 mg + ibuprofen 400 mg, given every 4 hours for up to 4 doses
(non-opioid analgesics) is more effective and has a lower risk of side effects than
acetaminophen + codeine (opioid analgesic) and acetaminophen alone, for postoperative
analgesia.3 However, as opposed to nail surgical procedures, Mohs micrographic surgery is
only associated with mild postoperative pain (2, 1.5 out of 10 on postoperative days 0-1,
respectively).4 It is currently unknown whether this combination is also superior for post-nail
procedure analgesia. Effective postsurgical pain control affects patient satisfaction, reduces
morbidity, and improves return to daily activities and to work.5 It is therefore essential to
determine optimal pain management alternatives for nail procedure-associated pain.
References
1. Ricardo JW, Qiu Y, Lipner SR. Longitudinal perioperative pain assessment in nail
surgery. Jounral of the American Academy of Dermatology. 2021 Nov 26;S0190-
9622(21)02911-X.
2. Di Chiacchio N, Ocampo-Garza J, Villarreal-Villarreal CD, Ancer-Arellano J, Noriega
LF, Di Chiacchio NG. Post±nail procedure analgesia: A randomized control pilot study.
Journal of the American Academy of Dermatology. 2019 Sep 1;81(3):860-2.
3. Sniezek PJ, Brodland DG, Zitelli JA. A randomized controlled trial comparing
acetaminophen, acetaminophen and ibuprofen, and acetaminophen and codeine for
postoperative pain relief after Mohs surgery and cutaneous reconstruction. Dermatologic
surgery. 2011 Jul;37(7):1007-13.
4. Firoz BF, Goldberg LH, Arnon O, Mamelak AJ. An analysis of pain and analgesia after
Mohs micrographic surgery. Journal of the American Academy of Dermatology. 2010 Jul
1;63(1):79-86.
5. Ljungqvist O, Scott M, Fearon KC. Enhanced recovery after surgery: a review. JAMA
surgery. 2017 Mar 1;152(3):292-8.
2.2 Investigational Agent/Device, or Surgical Treatment/Method
Lidocaine 1% (duration of action: 1-2 hours) and ropivacaine 0.75% (duration of action: 8
hours) are short and long-duration of action local anesthetics, respectively. A mix of these
will be used in groups a and b, infiltrated with a wing block (approximately 4 injections into the
nail folds and hyponychium) for intraoperative anesthesia, using a 30-gauge needle, with
approximately 1 ml of solution injected in total. In addition, subjects in group a will receive:
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oral hydrocodone 5 mg (moderate-strength opioid analgesic)/acetaminophen 325 mg (non-
opioid analgesic), every 4 hours for 2 days (12 doses in total), starting 6 hours after surgery.
On postoperative day 3, patients in group a will switch to oral acetaminophen 1000 mg +
ibuprofen 400 mg every 6 hours, until day 6. Patients in group b will receive: acetaminophen
1000 mg + ibuprofen 400 mg every 6 hours, starting 6 hours after surgery, for 6 days.
Ropivacaine and lidocaine are FDA-approved for surgical anesthesia.
Hydrocodone/acetaminophen, acetaminophen and ibuprofen are FDA-approved for
treatment of acute-pain management.
2.3 Rationale
Treatment regimens for nail procedure-associated postoperative pain are not well studied.
While pain management guidelines for cutaneous procedures exist, consensus for nail
surgical procedures is lacking. Randomized controlled trials are the mainstay for
development of safe and effective treatments. Therefore, there is a need for randomized
controlled studies objectively assessing the efficacy and safety of available analgesic
regimens for management of pain associated to nail surgical procedures. We hope that the
UHVXOWVRIWKHSUHVHQWVWXG\ZLOOJXLGHQDLOVXUJHRQVWRLPSURYH quality of life following
nail surgery.
2.4 Risk/Benefit Assessment
2.4.1 Known Potential Risks
Pain associated with anesthetic infiltration, digital ischemia or necrosis. Potential side
effects of opioid analgesic hydrocodone include: nausea, vomiting, constipation,
somnolence, headache, euphoria and agitation. Potential severe-adverse reactions
include life-threatening respiratory depression, addiction, abuse, opioid withdrawal,
serotonin syndrome (when used with serotoninergic agents) and adrenal insufficiency.
Hydrocodone is a controlled substance and classified as a Schedule III drug, indicating
that it has medical usefulness, but also a potential for physical and psychological
dependency abuse. Potential risks of acetaminophen use include skin rash,
hypersensitivity reaction, nephrotoxicity, hepatotoxicity, anemia, leukopenia, neutropenia,
pancytopenia and gastrointestinal reactions such as nausea, stomach pain, loss of
appetite. Severe liver damage may occur if taking more than 4000 mg in 24 hours,
combining with other drugs containing acetaminophen, or consuming 3 or more alcoholic
beverages daily. Potential risks of ibuprofen include gastritis, ulceration, hemorrhage or
perforation, nephrotoxicity, skin rash and other hypersensitive reactions.
2.4.2 Known Potential Benefits
Lidocaine 1% and ropivacaine 0.75% are FDA-approved for intraoperative anesthesia,
adequately controlling pain for up to 8 hours following surgery. Hydrocodone,
acetaminophen and ibuprofen are all FDA-approved for treatment of acute pain, and
may provide adequate control of postoperative pain associated with nail surgical
procedures.
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2.4.3 Assessment of Potential Risks and Benefits
Nail surgical procedures are associated with moderate to severe pain. Although opioid
and non-opioid analgesics are associated with various severe side effects, these are
fortunately rare. Therefore, the benefit of the assessed interventions in the way of pain
reduction may surpass the associated risks.
3. Study Design
3.1 Overall Design
This is a single center, randomized, controlled, open-label study of 20 patients undergoing
fingernail or toenail biopsies. Patients will be consented at least 24 hours prior to their nail
procedure. All other study procedures outside of the nail biopsy can be conducted remotely.
All surgical procedures will be performed by principal investigator Dr. Shari Lipner following
standardized procedure. A mix of ropivacaine 0.75% + lidocaine 1% will be used for
intraoperative anesthesia for all patients. Patients will be randomized into 1 of 2 groups:
Group a: Oral hydrocodone 5 mg (moderate-strength opioid analgesic)/acetaminophen
325 mg (non-opioid analgesic), every 4 hours for 2 days (12 doses in total), starting 6
hours after surgery. On postoperative day 3, patients in group a will switch to oral
acetaminophen 1000 mg + ibuprofen 400 mg every 6 hours, until day 6.
Group b: Patients in group b will receive: acetaminophen 1000 mg + ibuprofen 400 mg
every 6 hours, starting 6 hours after surgery, for 6 days.
The Wong-Baker 0-to-10 pain scale will be used to quantitate pain scores in all participants
prior to surgery, intraoperatively and during postoperative days 0-6 (once in the morning and
evening).
An adapted version of the American Pain Society Patient Outcome Questionnaire for nail
surgical pain will be used to quantitate health-related quality of life associated with pain on
postoperative days 3 and 6.
Adverse Events and Reporting
Adverse events (AE) assessment will be ongoing throughout the study. All adverse events
shall be reported by the clinical Investigator to the IRB as described below.
Adverse Device Effect (ADE)
Any sign, symptom, or disease in a study subject that occurs during the course of a clinical
trial that is determined by the investigator to have a causal relationship or possible causal
relationship with the device under investigation.
Serious Adverse Event (SAE)
Any untoward medical occurrence in a subject, regardless of whether the event is related to
the device that:
a. results in death;
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b. results in a life-threatening illness or injury;
c. results in a permanent impairment of a body structure or body function;
d. requires in-subject hospitalization or prolongation of existing hospitalization
e. requires a medical or surgical intervention that was necessary to preclude permanent
impairment of a body function, or prevent permanent damage to a body structure, either
situation suspected to be due to the use of a medical product.
f. If exposed prior to conception or during pregnancy may have resulted in an adverse
outcome in the child.
g. Does not fit the other outcomes, but the event may jeopardize the patient and may
require medical or surgical intervention (treatment) to prevent one of the other outcomes.
Examples include allergic bronchospasm (a serious problem with breathing) requiring
treatment in an emergency room, serious blood dyscrasias (blood disorders) or
seizures/convulsions that do not result in hospitalization. The development of drug
dependence or drug abuse would also be examples of important medical events.
Serious adverse events (SAEs) and unanticipated adverse device effects (UADEs) must be
reported within 24 hours of knowledge of the event to the IRB.
Unanticipated Adverse Device Effect (UADE) Any serious adverse effect on health and
safety or any life-threatening problem or death caused by, or associated with a device, if that
effect, problem, or death was not previously identified in nature, severity, or degree of
incidence in the investigational plan or application, or any other unanticipated serious
problem associated with a device that relates to the rights, safety, or welfare of subjects.
The Investigator shall be responsible for determination of the causal relationship of all
adverse events to the device and/or procedure. The Principal Investigator is responsible for
monitoring the safety of the subjects enrolled.
Any serious adverse events will be reviewed and analyzed by the Principal Investigator as
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3.2 Scientific Rationale for Study Design
This is a pilot, randomized, controlled, open-label study assessing the use of hydrocodone +
acetaminophen and acetaminophen + ibuprofen vs. acetaminophen + ibuprofen alone for
pain management after nail surgical procedures.
3.3 Justification for Dose
The dosage herein included has been assessed in previous studies on analgesic regimens
for Mohs micrographic surgery. There are currently no guidelines on the preferred analgesic
regimen for post-nail surgery analgesia.
3.4 End of Study Definition
A participant is considered to have completed the study if he or she has completed all
phases of the study. The end of the study is defined as completion of the last visit or
procedure.
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4. Subject Selection
4.1 Study Population
Subjects 18 years and older undergoing fingernail or toenail, excision or shave biopsy at
specialized nail clinic, WCM Department of Dermatology for any diagnosis.
4.2 Inclusion Criteria
1. Patients undergoing fingernail or toenail, excision, or shave biopsy
2. Must understand and voluntarily sign an informed consent form
3. Must be male or female and aged 18-95 years at time of consent
4. Must be able to adhere to the study visit schedule and other protocol requirements
4.3 Exclusion Criteria
1. Subject is unable to provide written informed consent for any reason.
2. Subject has peripheral vascular disease, arterial insufficiency, peripheral neuropathy
3. Subject is on Aspirin, NSAIDs, or consumes a chronic medication for control of any other
chronic pain.
4. Subject has a history of opioid or alcohol use disorder.
5. Subject has a history of peptic ulcer disease, gastritis, chronic renal insufficiency or a
history of kidney disease, or has underlying liver disease
6. Subject has a history of severe constipation.
7. Subject is sensitive or allergic to any of the elements included in this study.
8. Subject is unable to complete the required pain dairy.
9. Subject is pregnant, planning pregnancy, or nursing.
4.4 Lifestyle Considerations
During this study, participants are asked to:
·
Abstain from using any other analgesics different than the ones herein included as well
as any other treatment modality aiming to improve pain after nail surgery.
4.5 Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but
are not subsequently randomly assigned to the study intervention or entered in the study. A
minimal set of screen failure information is required to ensure transparent reporting of
screen failure participants, to meet the Consolidated Standards of Reporting Trials
(CONSORT) publishing requirements and to respond to queries from regulatory authorities.
Minimal information includes demography, screen failure details, eligibility criteria, and any
serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this trial (screen failures) because
of a modifiable factor may be rescreened. Rescreened participants should be assigned the
same participant number as for the initial screening.
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4.6 Strategies for Recruitment and Retention
Patients attending Weil Cornell Medicine, Department of Dermatology, specialized nail clinic
for fingernail or toenail biopsy. 20 participants will be offered to be included in the study and
approximately 30 patients will be screened. All participants will be enrolled in:
Weill Cornell Dermatology - 1305 York Avenue, New York, NY 10021
In the present study, participants will not be compensated or provided any incentives.
5. Registration Procedures
5.1 Subject Registration (WCM only)
Subjects will be registered within the WRG-CT as per the standard operating procedure for
Subject Registration.
6. Study Procedures
6.1 Schedule of Assessments
Table 1. Schedule of trial event
Screening
Visit: Day 0
Day 3
Day 6
Informed consent
X
Demographics
X
Medical history
X
Physical exam
X
Concurrent medications
X
X
X
X
Adverse event evaluation
X
X
X
Ropivacaine + lidocaine administration
X
Hydrocodone/acetaminophen
X
X
Acetaminophen + ibuprofen
X
X
X
Patient quality of life survey
X
X
Efficacy assessment
X
6.1.1 Screening Visit
At the screening visit, all inclusion and exclusion criteria will be reviewed. Obtaining
history and review of medications will take place.
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6.1.2 Treatment Phase
Subjects who fulfill all inclusion and exclusion criteria, and sign informed consent are
eligible to enroll and begin baseline visit procedures 24 hours after signing consent. After
this baseline visit, all other procedures can be conducted remotely, including collection of
pain diaries, medication history, and quality of life survey.
Nail biopsy will be performed under standardized procedure by principal investigator Dr.
Shari Lipner. A mix of ropivacaine 0.75% + lidocaine 1% will be infiltrated for
intraoperative anesthesia.
6 hours after nail surgery:
Patients in group a: start oral hydrocodone 5 mg (moderate-strength opioid
analgesic)/acetaminophen 325 mg (non-opioid analgesic), every 4 hours for 2 days
(12 doses in total)
Patients in group b: start acetaminophen 1000 mg + ibuprofen 400 mg every 6
hours for 2 days.
On postoperative day 3:
Patients in group a: switch to oral acetaminophen 1000 mg + ibuprofen 400 mg
every 6 hours, until postoperative day 6.
Patients in Group b: continue acetaminophen 1000 mg + ibuprofen 400 mg every 6
hours, until postoperative day 6.
7. Study Intervention
7.1 Study Intervention/Device Description
Lidocaine 1% (duration of action: 1-2 hours) and ropivacaine 0.75% (duration of action: 8
hours) are short- and long-acting local anesthetics, respectively. A mix of these will be used
for intraoperative/postoperative anesthesia in both study groups. In addition: subjects in
group a will receive: oral hydrocodone 5 mg (moderate-strength opioid)/acetaminophen 325
mg (non-opioid analgesic), every 4 hours for 2 days, starting 6 hours after surgery. On
postoperative day 3, subjects in group a will switch to oral acetaminophen 1000 mg and
ibuprofen 400 mg every 6 hours, until postoperative day 6. Patients in group b will receive:
acetaminophen 1000 mg and ibuprofen 400 mg, every 6 hours, for 6 days, starting 6 hours
after surgery. Ropivacaine and lidocaine are FDA-approved for surgical anesthesia.
Hydrocodone, acetaminophen, and ibuprofen are FDA-approved for postoperative analgesia.
7.2 Availability
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Ropivacaine 0.75%, lidocaine 1%, hydrocodone 5 mg/acetaminophen 325 mg,
acetaminophen 500 mg and ibuprofen 200 mg are widely available in pharmacies, and will
be purchased by WCM Medicine, Department of Dermatology, for the purpose of this study.
7.3 Acquisition and Accountability
Inventory Records/Device Logs ± The investigator, or a responsible party designated by the
investigator, will maintain a careful record of the inventory and all medications here included.
7.4 Formulation, Appearance, Packaging, and Labeling
Ropivacaine hydrochloride injection 0.75% (150 mg/20 ml) glass vial
Lidocaine hydrochloride injection 1% (300 mg/30 ml) glass vial
Hydrocodone bitartrate and acetaminophen tablets 5 mg/325 mg (12 tablets will be
prescribed; Vicodin)
Acetaminophen 500 mg each tablet (Tylenol Extra Strength)
Ibuprofen 200 mg each tablet (Advil)
7.5 Product Storage and Stability
All medications herein included will be stored in a dry place with temperature 60°F ± 90°F
7.6 Preparation
A mix of 0.5 ml ropivacaine 0.75% and 0.5 ml lidocaine 1% will be used for
intraoperative/postoperative anesthesia.
7.7 Dosing and Administration
Approximately 0.5 ± 1 ml of anesthetic mix will be infiltrated for intraoperative/postoperative
anesthesia with a wing digital block. Dosage of all other medications will be:
·
Oral hydrocodone 5 mg (moderate-strength opioid)/acetaminophen 325 mg (non-
opioid analgesic), every 4 hours for 2 days, starting 6 hours after surgery.
·
Acetaminophen 1000 mg and ibuprofen 400 mg every 6 hours, for 4 or 6 days
(depending on the group)
7.7.1 Dosing Delays/Dose Modifications
Not applicable.
7.8 General Concomitant Medication and Supportive Care Guidelines
All concomitant medications will be recorded and/or updated on subject medication chart
throughout the course of the study and saved in subject binder, if applicable.
7.9 Duration of Therapy and Criteria for Removal from Study
In the absence of treatment delays due to adverse event(s), oral hydrocodone 5 mg
(moderate-strength opioid)/acetaminophen 325 mg (non-opioid analgesic) will be consumed
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for a maximum of 2 days (every 4 hours, 12 doses in total). Acetaminophen 1000 mg and
ibuprofen 400 mg will be consumed for up to 6 days (every 6 hours), depending on the
group.
The treatment may will be discontinued prior to the time specified above in the case of below
events:
·
Intercurrent illness that prevents further administration of treatment,
·
Unacceptable adverse event(s),
·
Subject decides to withdraw from the study, or
·
General or specific changes in the subject¶VFRQGLWLRQUsHuQbjGecHtUWKH
unacceptable for further treatment in the judgment of the investigator.
Study Termination Guidelines: $VXEMHFW¶V-upIRinOtOheRsZtudy will end after one of the
following applies:
·
6XEMHFW¶VYROXQWDU\ZLWKGUDZDO ·
Subject lost to follow-up
·
Subject death
·
Completion of all scheduled study follow-up appointments
·
Any other rules specific to your study
7.10 Duration of Follow Up
Subjects will be followed for 3 days after their last dose. Subjects removed from study for
unacceptable adverse events will be followed until resolution or stabilization of the adverse
event.
7.11 Measures to Minimize Bias: Randomization and Blinding
This is a pilot open label study. A randomization table will determine subject allocation to
each group (10 subjects in group a and 10 subjects in group b).
7.12 Study Intervention/Follow-up Compliance
During the baseline visit (standard of care visit), participants will be asked to provide their
best way of contact. All other study procedures will be conducted remotely. There are no
more in-person visits required for this study.
8. Study Intervention Discontinuation and Participant Discontinuation/Withdrawal
Participants may withdraw voluntarily from the study or the PI may discontinue a participant
from the study. Participants will be excluded if they have/develop peripheral neuropathy or any
other condition precluding the accurate measurement of pain. The subject gets pregnant, is
planning pregnancy, or is nursing. The subject has/develops peripheral vascular disease or
arterial insufficiency.
8.1 Discontinuation of Study Intervention
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Discontinuation from treatment regimens means discontinuation from the study. However, if
a clinically significant finding is identified (including, but not limited to changes from baseline)
after enrollment, the investigator or qualified designee will determine if any change in
participant management is needed. Any new clinically relevant finding will be reported as an
adverse event (AE).
The data to be collected at the time of study intervention discontinuation will include the
following:
·
Reason(s) for discontinuation, take digital photographs, assessment of
concomitant medications.
8.2 Participant Discontinuation/Withdrawal from the Study
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the following
reasons:
·
Pregnancy
·
Significant study intervention non-compliance
·
If any clinical adverse event (AE), laboratory abnormality, or other medical
condition or situation occurs such that continued participation in the study would
not be in the best interest of the participant
·
If the participant meets an exclusion criterion (either newly developed or not
previously recognized) that precludes further study participation
·
Participant unable to receive study intervention(s)
·
Participant lost to follow-up after several attempts to contact subject to schedule
study visit.
The reason for participant discontinuation or withdrawal from the study will be recorded on
the Case Report Form (CRF). Subjects who sign the informed consent form and are
randomized but do not receive the study intervention may be replaced. Subjects who sign
the informed consent form, and are randomized and receive the study intervention, and
subsequently withdraw, or are withdrawn or discontinued from the study, will be replaced.
8.3 Lost to Follow Up
A participant will be considered lost to follow-up if he or she fails to return for one or more
scheduled visits and is unable to be contacted by the study site staff.
The following actions must be taken if a participant fails to return to the clinic for a required
study visit:
·
The site will attempt to contact the participant and reschedule the missed visit up
to 7 days after the 4 weeks from the previous visit and counsel the participant on
the importance of maintaining the assigned visit schedule and ascertain if the
participant wishes to and/or should continue in the study.
·
Before a participant is deemed lost to follow-up, the investigator or designee will
make every effort to regain contact with the participant (where possible, 3
telephone calls and if possible, 1 email). These contact attempts should be
GRFXPHQWHGLQWKHSDUWLFLSDQW¶VPHGLFDOUHFRUGRUVWXG\IL
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·
Should the participant continue to be unreachable, he or she will be considered
to have withdrawn from the study with a primary reason of lost to follow-up.
9. Correlative/Special Studies
Not applicable
10. Measurement of Effect
Pain levels will be measured using the Wong-Baker FACES 0-to-10 pain scale:
Health-related quality of life associated with pain will be measured using an adapted version of
the American Pain Society Patient Outcome Questionnaire:
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10.1 Response Criteria
Change in the pain level from baseline to postoperative days 2 and 6.
10.2 Duration of Response
Duration of overall response: The duration of overall response is measured from the time
measurement criteria are met for CR or PR (whichever is first recorded) until the first date
that recurrent or progressive disease is objectively documented (taking as reference for
progressive disease the smallest measurements recorded since the treatment started).
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The duration of overall CR is measured from the time measurement criteria are first met for
CR until the first date that recurrent disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until
the criteria for progression are met, taking as reference the smallest measurements
recorded since the treatment started.
10.3 Progression-Free Survival
Not Applicable.
10.4 Other Response Parameters
Please see section 12.5 Secondary Endpoints.
11. Data Reporting / Regulatory Considerations
11.1 Data Collection
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity,
efficacy, and adverse event data for all enrolled subjects.
11.1.1 REDCap
REDCap (Research Electronic Data Capture) is a free data management software
system that is fully supported by the Weill-Cornell Medical Center CTSC. It is a tool for
the creation of customized, secure data management systems that include Web-based
data-entry forms, reporting tools, and a full array of security features including user and
group-based privileges, authentication using institution LDAP system, with a full audit
trail of data manipulation and export procedures. REDCap is maintained on CTSC-
owned servers that are backed up nightly and support encrypted (SSL-based)
connections. Nationally, the software is developed, enhanced and supported through a
multi-institutional consortium led by the Vanderbilt University CTSA.
11.2 Regulatory Considerations
11.2.1 Institutional Review Board/Ethics Committee Approval
As required by local regulations, the Investigator will ensure all legal aspects are covered,
and approval of the appropriate regulatory bodies obtained, before study initiation.
Before initiation of the study at each study center, the protocol, the ICF, other written
material given to the patients, and any other relevant study documentation will be
submitted to the appropriate Ethics Committee. Written approval of the study and all
relevant study information must be obtained before the study center can be initiated or the IP
is released to the Investigator. Any necessary extensions or renewals of IRB approval must
be obtained for changes to the study, such as amendments to the protocol, the ICF,
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or other study documentation. The written approval of the IRB together with the approved
ICF must be filed in the study files.
The Investigator will report promptly to the IRB any new information that may adversely
affect the safety of the patients or the conduct of the study. The Investigator will submit
written summaries of the study status to the IRB as required. On completion of the study,
the IRB will be notified that the study has ended.
All agreed protocol amendments will be clearly recorded on a protocol amendment form
and will be signed and dated by the original protocol approving signatories. All protocol
amendments will be submitted to the relevant institutional IRB for approval before
implementation, as required by local regulations. The only exception will be when the
amendment is necessary to eliminate an immediate hazard to the trial participants. In this
case, the necessary action will be taken first, with the relevant protocol amendment
following shortly thereafter.
Once protocol amendments or consent form modifications are implemented at the lead
site, Weill Cornell Medicine, updated documents will be provided to participating sites, as
applicable. Weill Cornell Medicine must approve all consent form changes prior to local
IRB submission.
Relevant study documentation will be submitted to the regulatory authorities of the
participating countries, according to local/national requirements, for review and approval
before the beginning of the study. On completion of the study, the regulatory authorities
will be notified that the study has ended.
11.2.2 Ethical Conduct of the Study
The Investigators and all parties involved should conduct this study in adherence to the
ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines and the
applicable national and local laws and regulatory requirements.
This study will be conducted under a protocol reviewed and approved by the applicable
ethics committees and investigations will be undertaken by scientifically and medically
qualified persons, where the benefits of the study are in proportion to the risks.
11.2.3 Informed Consent
The investigator or qualified designee must obtain documented consent according to ICH-
*&3DQGORFDOUHJXODWLRQVDVDSSOLFDEOHIURPHDFKSRWHQWLDO legally authorized
representative prior to participating in the research study. Subjects who
agree to participate will sign the approved informed consent form and will be provided a
copy of the signed document.
The initial ICF, any subsequent revised written ICF and any written information provided to
the subject must approved by IRB prior to use. The ICF will adhere to IRB requirements,
applicable laws and regulations.
11.2.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the
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Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the
trial is solely responsible for determining whether the trial and its results are subject to the
requirements for submission to http://www.clinicaltrials.gov. Information posted will allow
subjects to identify potentially appropriate trials for their disease conditions and pursue
participation by calling a central contact number for further information on appropriate trial
locations and trial site contact information.
11.2.5 Record Retention
Essential documents are those documents that individually and collectively permit
evaluation of the study and quality of the data produced. After completion of the study, all
documents and data relating to the study will be kept in an orderly manner by the
Investigator in a secure study file. Essential documents should be retained for 2 years
after the final marketing approval in an ICH region or for at least 2 years since the
discontinuation of clinical development of the IP. In addition, all subjects medical records
and other source documentation will be kept for the maximum time permitted by the
hospital, institution, or medical practice.
12. Statistical Considerations
12.1 Study Design/Endpoints
For study design, please see section 3. Study Design.
Endpoints
The Primary efficacy endpoint will be the change in pain scores obtained with the Wong-
Baker 0-to-10 pain scale between the 2 groups.
The secondary endpoint will be the change in health-related quality of life associated
with pain between the 2 groups.
12.2 Sample Size/Accrual Rate
20 patients undergoing fingernail or toenail, excision or shave biopsy will be included.
12.3 Stratification Factors
Not applicable.
12.4 Analysis of Endpoints
12.4.1 Analysis of Primary Endpoints
Please see section 12.1 Study design/Endpoints
12.4.2 Analysis of Secondary Endpoints
Please see section 12.1 Study design/Endpoints
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12.5 Interim Analysis
Not applicable.
12.6 Reporting and Exclusions
12.6.1 Evaluation of Toxicity
All subjects will be evaluable for toxicity from the time of anesthesia infiltration, until
follow-up is completed (3 days after postoperative day 6).
12.6.2 Evaluation of Response
All subjects included in the study will be assessed for response to treatment if they have
received one treatment.
13. Adverse Event Reporting Requirements
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The
investigator will be required to provide appropriate information concerning any findings that
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe
use of the drug or device under investigation. Safety will be monitored by evaluation of adverse
events reported by subjects or observed by investigators or research staff, as well as by other
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc.
13.1 Adverse Event Definition
An adverse event (also referred to as an adverse experience) can be any unfavorable
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease
temporally associated with the use of a drug, and does not imply any judgment about
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use in
combination with another drug) and with any route of administration, formulation, or dose,
including an overdose.
13.1.1 Investigational Agent or Device Risks (Expected Adverse Events)
Pain associated with anesthetic infiltration, digit ischemia or necrosis. Potential side
effects of opioid analgesic hydrocodone include: nausea, vomiting, constipation,
somnolence, headache, euphoria and agitation. Potential severe-adverse reactions
include life-threatening respiratory depression, addiction, abuse, opioid withdrawal,
serotonin syndrome (when used with serotoninergic agents) and adrenal insufficiency.
Hydrocodone is a controlled substance and classified as a Schedule III drug, indicating
that it has medical usefulness, but also a potential for physical and psychological
dependency abuse. Potential risks of acetaminophen use include skin rash,
hypersensitivity reaction, nephrotoxicity, hepatotoxicity, anemia, leukopenia,
neutropenia, pancytopenia and gastrointestinal reactions such as nausea, stomach pain,
loss of appetite. Severe liver damage may occur if taking more than 4000 mg in 24 hours,
combining with other drugs containing acetaminophen, or consuming 3 or more alcoholic
beverages daily. Potential risks of ibuprofen include gastritis, ulceration,
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hemorrhage or perforation, nephrotoxicity, skin rash and other hypersensitive reactions.
13.1.2 Adverse Event Characteristics and Related Attributions
CTCAE term (AE description) and grade: The descriptions and grading scales found
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
5.0 will be utilized for AE reporting. A copy of the CTCAE version 5.0 can be
downloaded from the CTEP web site (http://ctep.cancer.gov).
·
Attribution of the AE:
o Definite ± The AE is clearly related to the study treatment.
o Probable ± The AE is likely related to the study treatment. o
Possible ± The AE may be related to the study treatment.
o Unlikely ± The AE is doubtfully related to the study treatment.
o Unrelated ± The AE is clearly NOT related to the study treatment.
13.1.3 Recording of Adverse Events
All adverse events will be recorded on a subject specific AE log. The AE log will be
maintained by the research staff and kept in the subject¶VUHVHDUFKFKDUW
13.1.4 Reporting of AE to WCM IRB
All AEs occurring on this study will be reported to the IRB according to the IRB policy,
which can be accessed via the following link:
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.
13.1.5 Reporting Events to Participants
Not applicable.
13.1.6 Events of Special Interest
Not applicable
13.1.7 Reporting of Pregnancy
Discontinuation of study intervention, while continuing safety follow-up, requesting
permission to follow pregnant women to pregnancy outcome.
13.2 Definition of SAE
SAEs include death, life threatening adverse experiences, hospitalization or
prolongation of hospitalization, disability or incapacitation, overdose, congenital
anomalies and any other serious events that may jeopardize the subject or require
medical or surgical intervention to prevent one of the outcomes listed in this
definition.
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13.2.1 Reporting of SAE to IRB
All SAEs occurring on this study will be reported to the IRB according to the IRB policy,
which can be accessed via the following link:
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting
_Policy.pdf.
13.2.2 Reporting of SAE to FDA [For Protocols Where WCMC is the Sponsor-
Investigator]
IND application sponsor must report any suspected adverse reaction or adverse reaction
to study treatment that is both serious and unexpected. Unexpected fatal or life-
threatening suspected adverse reactions represent especially important safety
information and must be reported to FDA as soon as possible but no later than 7
FDOHQGDUGD\VIROORZLQJWKHVSRQVRU¶VLQLWLDOUHFHLSWRIWKHLQ i. death,
ii. a life-threatening adverse event,
iii. in-patient hospitalization or prolongation of existing hospitalization,
iv. a persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions, or
v. a congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the patient or research subject and may require medical
or surgical intervention to prevent one of the outcomes listed as serious
CDER-only Biologic INDs:
Food and Drug Administration
Center for Drug Evaluation and Research
Therapeutic Biologic Products Document Room
5901-B Ammendale Road
Beltsville, MD 20705-1266
13.2.3 Reporting of SAE to KeryFlex, Pod-Advance, Inc
Institution will send KeryFlex, Pod-Advance, Inc copies of any and all serious adverse
event reports filed with the FDA or other applicable regulatory authorities, as well as
copies of any correspondence with the FDA or other applicable regulatory authorities,
regarding any and all serious adverse events, irrespective of association with the Study
Drug(s) in the course of the Clinical Trial, within 30 business days of such report or
correspondence being sent to the FDA or other applicable regulatory authorities. Copies
should be faxed directly to Eclipse Medical at (866)-558-0415.
13.3 AE/SAE Follow Up
All SAEs and AEs reported during this study will be followed until resolution or until the
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This
requirement indicates that follow-up may be required for some events after the subject
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discontinues participation from the study.
13.4 Time Period and Frequency for Event Assessment and Follow Up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the
attention of study personnel during study visits and interviews of a study participant
presenting for medical care, or upon review by a study monitor.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be
captured on the appropriate case report form (CRF). Information to be collected includes
HYHQWGHVFULSWLRQWLPHRIRQVHWFOLQLFLDQ¶VDVVHVVPHQWRIVHYHU product (assessed
only by those with the training and authority to make a diagnosis), and
time of resolution/stabilization of the event. All AEs occurring while on study must be
documented appropriately regardless of relationship. All AEs will be followed to adequate
resolution.
Any medical condition that is present at the time that the participant is screened will be
considered DVEDVHOLQHDQGQRWUHSRUWHGDVDQ$(+RZHYHULIWKH condition deteriorates at any
time during the study, it will be recorded as an AE.
Changes in the severity of an AE will be documented to allow an assessment of the duration
of the event at each level of severity to be performed. AEs characterized as intermittent
require documentation of onset and duration of each episode.
Jonathan Hwang or Jose Ricardo will record all reportable events with start dates occurring
any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for
SAEs) after the last day of study participation. At each study visit, the investigator will
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for
outcome information until resolution or stabilization.
14. Unanticipated Problems Involving Risks to Subjects or Others
14.1 Definition of Unanticipated Problems Involving Risks to Subjects or Others
(UPIRTSO)
This definition could include an unanticipated adverse device effect, any serious adverse
effect on health or safety or any life-threatening problem or death caused by, or associated
with, a device, if that effect, problem, or death was not previously identified in nature,
severity, or degree of incidence in the investigational plan or application (including a
supplementary plan or application), or any other unanticipated serious problem associated
with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).
14.1.2 Unanticipated Problem Reporting
An investigator shall submit to the sponsor and to the reviewing Institutional Review
Board (IRB) a report of any unanticipated adverse device effect occurring during an
investigation as soon as possible, but in no event later than 10 working days after the
investigator first learns of the effect (21 CFR 812.150(a)(1)), A sponsor who conducts an
evaluation of an unanticipated adverse device effect under 812.46(b) shall report the
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results of such evaluation to the Food and Drug Administration (FDA) and to all
reviewing IRB's and participating investigators within 10 working days after the sponsor
first receives notice of the effect. Thereafter the sponsor shall submit such additional
reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).
15. Data and Safety Monitoring Plan (DSMP)
In this section, please include a written plan of the measures that will be taken to ensure the safety of
clinical research subjects and protect the validity and integrity of research data. The following
questions should be addressed as a part of the DSMP and must be incorporated into your WCM
eIRB application:
·
Include a description of the proposed monitoring entity (i.e. WCM DSMB, Independent
Medical Monitor) and rationale for choosing the specified monitoring entity. If you are
using an independent medical monitor or study monitoring committee/group, please
specify their qualifications.
·
Describe the data/events that will be captured and submitted to the monitoring entity.
Specify what data will be collected during the course of the study to assess both safety
and efficacy.
·
Describe what adverse events may cause the subject to terminate protocol treatment.
Specifically, describe treatment stopping rules for an individual subject.
·
How will adverse events and unanticipated problems be reported to the monitoring
entity and with what frequency?
·
How often will the monitoring entity review data/events (i.e. annually, semi-annually,
etc.)
·
Describe the complete study stopping rules (criteria for study suspension and potential
study termination) statistical considerations. If there are no defined stopping rules,
please provide a rationale. Also, state any specific triggers for action.
·
All dose escalation trials are required to define dose limiting toxicities, rules for
escalation of dose, and criteria for stopping the trial and defining the Maximum
Tolerated Dose.
·
How will the monitoring HQWLW\¶VFRPPHQWVUHYLHZEHGLVVHPLQDWHG"HJ
the IRB at the time of continuing review and submitted to participating sites upon receipt
of review comments.)
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