A Randomized, No-treatment Controlled, Evaluator-blinded, Multi-center Study to Evaluate the Effectiveness and Safety of Restylane Defyne in the Chin for Augmentation and Correction of Chin Retrusion
Phase: NA
Conditions: Chin Retrusion, Chin Augmentation
Sponsor: Galderma R&D

 
 
A randomized, no-treatment-controlled, evaluator-blinded, 
multi-center study to evaluate the effectiveness and safety of 
Restylane® Defyne in the chin for augmentation and correction 
of Chin Retrusion 
 
 
NCT Number: NCT03624816 
 
 
Protocol document date: 11Oct2019 

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A  Randomized,  No-Treatment Controlled,  Evaluator-Blinded, Multi-
Center Study to Evaluate the Effectiveness and Safety of Restylane®
Defyne in the Chin for Augmentation and Correction of Chin Retrusion
Study product:
Restylane® Defyne
Clinical trial number (CTN):
43USCH1702
Sponsor:
Q-Med AB, a Nestle Skin Health affiliate
Confidentiality Statement
This study protocol contains confidential information belonging to Q-Med AB, a Nestle 
Skin Health affiliate. Except as may be otherwise agreed to in writing, by accepting or 
reviewing these materials, you agree to hold such information in confidence and neither 
disclose it to any third parties (except where required by applicable law) nor use it for any 
other purpose than in relation to the clinical study described herein. 
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Investigators and Study Administrative Structure
Sponsor:
Q-Med AB, a Nestle Skin Health affiliate
Medical Expert:
Clinical Project Manager:
Study Statistician:
Further details on all participating Investigators and the complete administrative structure of 
the study are found in the study files. Note that administrative changes are to be documented in 
the study files without requiring a clinical investigational plan (CIP) amendment.
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Signed Agreement of the Clinical Investigational Plan
CTN:
43USCH1702
Title of the CIP:
A  Randomized,  No-Treatment Controlled,  Evaluator-Blinded, Multi-
Center Study to Evaluate the Effectiveness and Safety of Restylane® 
Defyne in the Chin for Augmentation and Correction of Chin Retrusion
I, the undersigned, have read and understand the CIP specified above, and agree on the 
contents. The CIP, the clinical trial agreement (CTA) and the additional information given in 
the Instructions for Use (IFU) and Report of Prior Investigations (ROPI) will serve as a basis 
for co-operation in this study.
Principal Investigator
Printed name 
Signature
Date
Study site name and address
Study site number
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Abbreviations and Definitions of Terms
AE
Adverse event 
BDDE
1,4-butanediol diglycidyl ether
CE
“Conformité  Européenne” the quality and branding mark for products 
made or sold within the European Union.
CFR
Code of Federal Regulations
CIP
Clinical Investigational Plan
Childbearing 
Potential
A female (including pre-menopausal subjects) capable of becoming
pregnant. This includes women on oral, injectable or mechanical
contraception; women who are single, women whose husbands have been
vasectomized or whose husbands have received or utilizing mechanical
contraceptive devices.
CTA
Clinical trial agreement
CTN
Clinical trial number
CV
Curriculum vitae
Device 
deficiency
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance (includes malfunctions, use 
errors, and inadequate labelling)
DMP
Data management plan
eCRF
EOS
Electronic case report form
End of Study
ET
Early termination
FDA
United States Food and Drug Administration
First subject 
in
First subject screened, i.e. who signs the informed consent form
First subject 
out
First subject who completed their last study visit
FST
Fitzpatrick Skin Type
G
Gauge
GAIS
Global aesthetic improvement scale
GCP
Good clinical practice
HA
Hyaluronic acid
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
ICF
Informed Consent Form
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IFU
Instructions for use
IP
Investigational Product. Medical device being assessed for safety or 
performance in a study. “Investigational product” is the same as “study 
device”, “investigational device”, or “investigational medical device”.
Institution
Any public or private entity or agency or medical or dental facility where a 
clinical study is conducted.
Investigator
The Principal Investigator (PI) or other qualified person, i.e. sub-
investigator, designated and supervised by the PI at a study site to perform 
critical study-related procedures or to make important study-related 
decisions as specified on the signature and delegation log
Investigator 
file
Essential documents relating to a clinical study as defined in applicable 
GCP guidance document and maintained by the Investigator.
IPR
Independent Photographic Reviewer
IRB
Institutional review board
ISF
Investigator Study File
ISO
International Organization for Standardization
ITT
Intention-to-treat
Last subject 
in
Last subject who entered the study
Last subject 
out
Last subject who completed their last study visit
MedDRA
Medical dictionary for regulatory activities
NSAID
Non-steroidal anti-inflammatory drugs
PI
Principal Investigator; qualified person responsible for conducting the study 
at a study site
PP
Per protocol
PT
Preferred term
QA
Quality assurance
RA
Regulatory authority
ROPI
Report of Prior Investigations, i.e. compilation of the current clinical and 
non-clinical information on the investigational product, relevant to the 
clinical study
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SDV
Source data verification
SOC
System Organ Class
Sponsor file
Essential documents relating to a clinical study as defined in applicable 
GCP guidance document and maintained by the Sponsor.
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Study files
The Investigator file and the Sponsor file
Study 
products
The investigational product and the reference product under study
Study site
Institution or site where the study is carried out
TC
Telephone Call
Touch-up
Repeated injection to be performed after treatment if necessary to achieve 
optimal correction 
TW
Thin wall
Tx
Treatment
WHO
World Health Organization
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Table of Contents
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
3
SIGNED AGREEMENT OF THE CLINICAL INVESTIGATIONAL PLAN
5
SYNOPSIS
6
ABBREVIATIONS AND DEFINITIONS OF TERMS
16
LIST OF TABLES
22
LIST OF FIGURES
22
LIST OF APPENDICES
22
1.
ETHICAL CONSIDERATIONS
23
1.1
Statement of ethical compliance
23
1.2
Application to independent ethics committee and/or regulatory authorities
23
2.
BACKGROUND INFORMATION
23
2.1
Indication and population description
23
2.2
Investigational and comparator product descriptions
23
2.2.1
Clinical documentation
23
2.3
Study rationale
24
2.4
Justification for the design of the study
24
2.5
Risks and benefits
24
3.
OBJECTIVE(S) AND ENDPOINT(S)
25
3.1.1
Primary objective and endpoint
25
3.1.2
Secondary objectives and endpoints
25
3.1.3
Safety objectives and endpoints
26
3.1.4
Exploratory objectives
26
4.
DESIGN OF THE STUDY
27
4.1
General outline
27
4.2
Number of subjects
29
4.3
Duration of subject participation
29
4.4
Randomization and blinding
29
4.4.1
Randomization
29
4.4.2
Blinding
30
4.4.3
Emergency unblinding
30
4.5
Medical history
30
4.6
Concomitant medications, treatments, and procedures
30
4.7
Schedule of events
32
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8.8
Laboratory Assessments
54
8.9
Adverse events
54
8.9.1
Definition of an adverse event
54
8.9.2
Definition of a serious adverse event
54
8.9.3
Recording instructions
55
8.9.4
Reporting of adverse events
56
8.9.5
Reporting of serious adverse events
56
8.9.6
Stopping Rule
57
8.9.7
Follow up of ongoing related events after termination of the study and events with onset after termination of 
study (subject last visit)
57
8.9.8
Pregnancy
58
8.9.9
Anticipated adverse events
58
8.10
Device deficiencies
58
8.10.1
Definition of a device deficiency
58
8.10.2
Recording instructions
58
8.10.3
Reporting of device deficiencies
59
9.
DATA HANDLING AND MANAGEMENT
59
9.1
Data management
59
9.2
Electronic case report forms
59
9.2.1
Data entry
60
9.2.2
The query process
60
9.2.3
User identification
60
9.2.4
Audit trail
61
9.3
Source documents
61
9.4
Record keeping and access to source data
61
9.5
Document and data retention
61
10.
STATISTICAL METHODS
62
10.1
General
62
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6For male subjects only 
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In cases of doubt, whether an AE fulfils a serious criterion or not, there should be a 
predisposition to report as a SAE rather than not report as such
8.9.3 Recording instructions
Each subject with an AE occurring after randomization and through study exit should be 
fully recorded in the source document for further transcription to the eCRF.  Each subject 
should be questioned about AEs at each study visit following randomization. The question 
asked should be, “Since your last clinical visit have you had any health problems?” 
Information on AEs can also be obtained from signs and symptoms detected during each 
examination.  
When an AE is related to a device deficiency including technical device malfunction, the 
AE should be recorded in the AE eCRF and technical complaint should be reported 
separately on the study complaint form.  
Investigators, or other study site personnel, should record all AEs in the eCRF, including:
a) Event term (recorded in standard medical terminology and avoiding abbreviations)
b) Description of event and affected area 
c) Start date (first day with symptoms)
d) Stop date (last day with symptoms)
e) Intensity (mild, moderate, or severe according to definition in Section 8.9.3.1)
f)
Seriousness (serious or not serious, according to definition in Section 8.9.3.2)
g) Causal relationship to study product or study product injection procedure (yes or no)
h) Action taken (none, medication treatment, non-medication treatment, or other 
procedures/tests, subject withdrawn)
i)
Outcome of the AE (ongoing, recovered, recovered with sequelae, death, chronic/ 
stable, not recovered at the end of the study)
The pre-defined, expected post-treatment events should be assessed separately. These 
events should be collected by subjects in a diary used daily for 28 days after the treatment.
8.9.3.1 Intensity
Intensity will be recorded for each reported AE. The following definitions of intensity are to 
be used:
Mild:
Awareness of symptoms or signs, but easily tolerated (acceptable)
Moderate:
Enough discomfort to interfere with usual activity (disturbing) 
Severe:
Incapacity to work or to do usual activity (unacceptable) 
If the intensity changes within one day, the maximum intensity of the AE during that day 
should be recorded.
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8.9.3.2 Causal relationship and seriousness
Each AE, serious as well as non-serious, should be assessed by the Investigator for causal 
relationship with the study product and its use (the injection procedure) and for seriousness
(Yes or No) of the event. 
A two-point scale (Yes or No response) should be used for the causality assessments. The 
Investigators should be asked to indicate a response to each of the following questions in the 
eCRF:

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the study product?”, and 

“Do you consider that there is a reasonable possibility that the event may have been 
caused by the device injection procedure?”
If any of these questions is answered ‘Yes’, the AE is considered related.
Each AE will also be assessed for causal relationship and seriousness by the Sponsor, in order 
to fulfil regulatory requirements. 
8.9.4 Reporting of adverse events 
Adverse event reporting on each subject should start after the subject has been randomized.  
The reporting should continue during each follow-up visit (including telephone contacts 
and extra visits between planned visits) until the last scheduled visit in the study.
All AEs, non-serious as well as serious, are to be reported as an AE in the eCRF.
8.9.5 Reporting of serious adverse events
The Investigator should report any SAE to the Sponsor immediately but not later than 24 
hours of awareness of the event. This initial report can be made via e-mail.
In case of difficulty to obtain all the required information within 24 hours, an initial report 
can be submitted, with the following information as a minimum, irrespective of whether 
some of it is regarded as preliminary:

CTN: 43USCH1702

Subject identification (age, gender, subject number)

Adverse event description

Date when AE occurred

Date when AE became serious

Name of Investigator and original reporter (if other than the Investigator) 

Name of device: Restylane® Defyne (investigational) 

Treatment specification
Follow-up information and data missing in the initial SAE reporting should be gathered as 
soon as possible and reported immediately but not later than 24 hours of awareness of the 
new data.  Complete and adequate information on each SAE is required.  All attempts to 
obtain this information, including dates for follow-up activities, must be documented by the 
Investigator or designated study staff.
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Supporting documentation to be provided with the SAE report:

Concomitant medication form

Concomitant procedure/treatment form

Study treatment CRF form

AE form

Medical history form

Any other relevant supporting documentation (e.g. hospital notes, death certificate, 
autopsy reports etc.)
_________________________________________________________________________
_________________________________________________________________________
The SAE form must be signed and dated by the Investigator.  If the initial 24-hour SAE 
report does not contain full information or if it is made without using the SAE form the 
fully completed and signed SAE form should be e-mailed to the Sponsor. A copy of the 
fully completed SAE form should be kept at the site.
In addition, the Investigator should report SAEs to the responsible IRB without undue 
delay, if applicable according to national regulations.  The Investigator is responsible for 
checking what reporting procedures are applicable for his/her IRB regarding SAEs and 
final report of the outcome of the study and to comply with such reporting procedures 
during the study period. For non-urgent complementary information not possible to send by 
e-mail or fax, please use surface mail.
8.9.6 Stopping Rule
Enrollment into the study will be temporarily halted if the Sponsor receives a SAE for a 
vascular embolic event that lead to skin necrosis, vison loss, or stroke and is determined by 
the Investigator to be directly or possibly related to the study device or injection procedure.  
The SAE will be investigated by the Sponsor.  If the Sponsor’s investigation concludes:
The SAE was unanticipated, directly related to the study product or device injection 
procedure, and presents an unreasonable risk to study subjects, the study will be 
terminated and the Investigators notified.  The IRB and RA will also be notified if the 
study is prematurely terminated due to safety concerns.  

If the SAE does not meet the above criteria, then enrollment in the study will 
continue.  
8.9.7 Follow-up of ongoing related events after termination of the study and events with 
onset after termination of study (subject last visit)
All serious as well as non-serious AEs with a causal relationship to the study product or 
treatment procedure and ongoing at study end, should be followed up after the subject's 
participation in the study is over.  Such events should be followed-up after the last study 
visit until resolved, or assessed as chronic or stable.  All AEs assessed as related to the 
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study product or treatment procedure, serious as well as non-serious, with onset after the 
study termination (last subject study visit), and that the Investigator becomes aware of, 
should be reported to the Sponsor by email to
8.9.8 Pregnancy
Pregnancy itself is not regarded as an AE.
If there is a pregnancy after the subject has been treated, the subject must continue to be 
followed and the outcome of pregnancy must be reported even if the delivery occurs after 
study completion.
A pregnancy confirmed during the study period after treatment must be reported by the 
Investigator on a pregnancy report form immediately upon acknowledgement and 
submitted to the Sponsor according to contact details specified in Section 8.9.5. The report 
can be prospective or retrospective. Follow-up should be conducted to obtain outcome 
information on all prospective reports. 
Cases that led to fetal distress, fetal death or a congenital abnormality or birth defect are to 
be regarded as SAEs and should be reported on the exposure in utero report form to the 
Sponsor immediately but no later than 24 hours after the Investigators awareness. These 
events should be handled as SAEs during data processing. Other complications during the 
pregnancy that are related to the pregnant woman and fulfils any serious criteria, such as 
pre-eclampsia requiring hospitalization, should be reported and handled as SAEs. Elective 
abortions without complications should not be reported as AEs.
8.9.9 Anticipated adverse events
Information regarding anticipated AEs for Restylane® Defyne (investigational) is included 
in the study specific IFU. 
8.10 Device deficiencies
8.10.1 Definition of a device deficiency
A device deficiency is defined as an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety1, or performance.
Note: Device deficiencies include malfunctions, use errors, and inadequate labelling.
8.10.2 Recording instructions
When a device deficiency is discovered, Part A of the clinical study complaint form should
be completed by the Investigator or qualified designee. The type of complaint should be 
described and injury to the subject or user or unintended exposure to study product should
be reported as applicable. If an injury has occurred, an AE or an SAE form should be 
completed as applicable (refer to Section 8.9.4 and 8.9.5). If no SAE was experienced as a 
result of the device deficiency the Investigator should assess whether or not the device 
deficiency could have led to an SAE if:

Suitable action had not been taken,

Intervention had not been made or,
                                                
1Inadequacy of device safety refers to properties of the device which could have or have led to an AE.
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
Circumstances had been less fortunate
In Part B of the clinical study complaint form the Sponsor will make the same assessment.
8.10.3 Reporting of device deficiencies
The Investigator should send the completed clinical study complaint form to the Sponsor by 
email to 
A device deficiency that led to a SAE and 
any device deficiency that is assessed as it could have led to a SAE should be reported 
within 24 hours after the Investigator’s awareness in accordance to Section 8.9.5.
In order to fulfil regulatory reporting requirements, all deficiencies with the study product 
must be assessed by both the Investigator and the Sponsor to determine if it could have led 
to a SAE.
If a SAE has resulted from a device deficiency or if either the Investigator or the Sponsor 
assesses that the device deficiency could have led to a SAE the Sponsor is responsible for 
reporting the device deficiency to RA and the PI is responsible for reporting it to the IRB.
The deficient study product should be kept by the study site until the Sponsor has 
confirmed whether the product should be returned to Sponsor for further study or if it can 
be destroyed at the study site.
9. Data Handling and Management 
9.1
Data management
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter clinical data information into a database, efficiently and avoiding errors. The data 
management routine includes procedures for handling eCRFs, database set-up and 
management, data entry and verification, data validation, and documentation of the 
performed activities including information of discrepancies in the process. The data 
management process will be described in detail in the data management plan (DMP).
The database, the data entry screens and program will be designed in accordance with the CIP 
and the eCRF. Data validation will be performed by computerized logical checks and manual 
review. Drugs and events will be coded in accordance with World Health Organization 
(WHO) Drug and medical dictionary for regulatory activities (MedDRA) dictionaries as 
specified in the DMP. SAEs in the clinical database will be reconciled against the data in the 
safety database.
When all efforts have been made to ensure that the data recorded in the eCRFs and entered in 
the database is as correct and complete as possible, the clinical database will be locked. Study 
data will be transferred to SAS datasets which thereafter will be write-protected. Statistical 
analyses will be generated in SAS using data from the locked datasets.
9.2
Electronic case report forms
A 21 Code of Federal Regulations Part 11-compliant electronic data capture application will 
be used to collect, modify, maintain, archive, retrieve, and transmit study data.  An eCRF is 
required and should be completed electronically for each screen failure as well as enrolled 
subjects. 
The eCRF includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate.  Study data should
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be entered directly from the source documents, which are to be defined at each site before 
inclusion of the first subject.
Authorized study site personnel designated by the Investigator should complete data 
collection. Appropriate training and security measures should be completed with all 
authorized investigation site personnel prior to the study being initiated and any data being 
entered into the system for any subject.
The study data is the sole property of the Sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate RA, without written 
permission from the Sponsor.  At the end of the study, electronic data are kept at the Sponsor 
and a copy (provided by the vendor) at the study site as part of the Investigator file.
Any delegation of collection of data should be specified in a signature and delegation log.
9.2.1 Data entry
All data should be entered in English. The eCRFs should always reflect the latest 
observations on the subjects participating in the study. Therefore, the eCRFs should be 
completed as soon as possible during or after the subject’s visit. The subject’s identity must 
always remain confidential, i.e. the name and address of the subjects must not be registered 
in the eCRFs or in the database. The Investigator must verify that all data entries in the 
eCRFs are accurate and correct. If some assessments are not done, or if certain information 
is not available, not applicable or unknown, the Investigator should indicate this in the 
eCRF. The Investigator should electronically sign off the study data. By signing, the 
Investigator takes responsibility for the accuracy, completeness, and legibility of the data 
reported to the Sponsor in the eCRF. 
9.2.2 The query process
The monitor should review the eCRFs and evaluate them for completeness and consistency. 
Each eCRF should be compared with the respective source documents to ensure that there 
are no discrepancies between critical data. All entries, corrections, and alterations should be 
made by the PI or his/her authorized designee. The monitor cannot enter data in the eCRFs. 
Once study data have been submitted to the central server via the eCRF, corrections to the 
data fields will be audit trailed, meaning that the reason for change, the name of the person 
who made the change, together with time and date will be logged. Roles and rights of the 
site personnel responsible for entering study data into the eCRF should be determined in 
advance. If discrepant data is detected during review of the data, either by the Sponsor or its 
representatives, the responsible data manager or monitor should raise a query in the 
electronic data capture application. The query should state the question or data to be 
changed and should be resolved in the system by the PI or his/her authorized designee. The 
appropriate study site personnel should answer the queries in the eCRF. This will be audit 
trailed by the electronic data capture application meaning that the name of study site 
personnel, time, and date is logged.
9.2.3 User identification
eCRF records will be automatically appended with the identification of the creator, by 
means of their unique User ID. Specified records should be electronically signed by the 
Investigator to document his/her review of the data and acknowledgement that the data are 
accurate. This will be facilitated by means of the Investigator’s unique User ID and 
password; date and time stamps will be added automatically at time of electronic signature. 
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If an entry in an eCRF requires change, the correction should be made in accordance with 
the relevant software procedures. 
9.2.4 Audit trail
All changes will be fully recorded in a protected audit trail and a reason for the change 
should be stated. Once all data have been entered, verified, and validated, the database will 
be locked.
9.3
Source documents
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, that verifies the existence of the subject, the inclusion and 
exclusion criteria, and all records covering the subject’s participation in the study.  They 
include laboratory notes, memoranda, material dispensing records, subject files, etc.
The Investigator is responsible for maintaining source documents.  These should be made 
available for inspection by the monitor at each monitoring visit.  The Investigator must 
submit a completed eCRF for each subject for whom signed informed consent has been 
collected.  All supportive documentation submitted with the eCRF, such as laboratory or 
hospital records, should be clearly identified with the CTN and subject number. Any personal 
information, including name, should be removed or rendered illegible to preserve individual 
confidentiality.
9.4
Record keeping and access to source data
The Investigator/Institution should permit study-related monitoring, audits, IRB review, and 
RA inspections and should provide direct access to the source data/medical record including 
the identity of all participating subjects (sufficient information to link records, i.e. eCRF, 
medical records, original signed informed consent forms and detailed records of study 
product accountability).  The records should be retained by the Investigator as required by 
local legislation and international guidelines.  Any transfer of responsibility for storage of the 
records should be documented and the Sponsor should be informed in writing.
The Sponsor should verify that each subject has consented in writing to direct access to the 
original medical record/source data (by the use of written subject information and signed 
informed consent).  The data recorded in the eCRFs will be checked for consistency with the 
source documents/medical record by the monitor during monitoring (source data verification; 
SDV).  In order to be able to perform SDV, information about each subject’s participation in 
the study has to be detailed in the medical record. 
9.5
Document and data retention
All records pertaining to the conduct of the study, including signed eCRFs, informed consent 
forms, study product accountability records, source documents, and other study 
documentation must be retained for as long as is specified in the CTA.  Measures should be 
taken to prevent accidental or premature destruction of these documents (e.g. protection 
against damage and unauthorized access, preferably by storage in a fire-proof cabinet). 
It is the Investigator’s responsibility to inform the Sponsor in writing if the Investigator file is 
moved or if the responsibility for the documents is transferred to someone else.
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The Investigator understands that clinical studies conducted under an IDE are exempt
from the study subject identifier confidentiality provisions of the Health Insurance
Portability and Accountability Act of 1996 (HIPAA), and the study subject should be made
aware of this exception in the informed consent.  The Institution and Investigator are jointly
responsible for providing sufficient information to all subjects to enable them to give their
informed consent not only to the participation in the investigation, but also to the processing 
of Personal Data. Such information includes information regarding the purposes of the
processing, the length of time during which Personal Data will be stored, the right of access
to stored Personal Data and the right to correction or purging of incorrect or obsolete
Personal Data.  A subject may also withdraw his or her consent at any time.
A subject who withdraws his or her consent to the processing  of Personal Data must 
be considered to have withdrawn from the investigation but the data collected until the 
consent was withdrawn may be used in the statistical analyses.
Authorized representatives from the Sponsor or a RA may visit the investigational site to 
perform audits/inspections, including  source data verification, i.e., comparing  data in 
the subjects’ medical records and the eCRF.  Data and information will be handled with
strict confidentiality.
12. Quality Control and Quality Assurance
12.1 Quality control
On-site monitoring of the study will be arranged by the Sponsor according to GCP guidelines 
to verify that the rights and well-being of the subjects are protected, the reported data are 
accurate, complete, verifiable from source documents, and that the conduct of the study 
complies with the approved CIP, subsequent amendment(s), GCP and the applicable 
regulatory requirements. 
Any CIP deviation should be reported in the eCRF, which will be verified, discussed, and 
collected, by the monitor and appropriate actions will be taken.  The Investigator is 
responsible for promptly reporting any deviations from the CIP that affects the rights, safety 
or well-being of the subject or the scientific integrity of the study, including those, which
occur under emergency circumstances, to the Sponsor as well as the IRB if required by 
national regulations.  Deviations will be reviewed to determine the need to amend the CIP or 
to terminate the study.  Handling of CIP deviations will be performed as described in the 
monitoring manual.
12.2 Quality assurance
The study site may be subject to quality assurance audit by the Sponsor as well as inspection 
by appropriate RA.  It is important that the Investigator and other relevant study site 
personnel are available during the monitoring visits, possible audits, and inspections, and that 
sufficient time is devoted to the monitoring process.
Each participating member of the study site team should provide a curriculum vitae (CV) or 
equivalent that demonstrates their qualifications to conduct the study.  
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge of and 
training in all procedures to be followed.  All Investigators and other responsible persons 
should be listed together with their function in the study on a signature and delegation log.
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15. Suspension or Premature Termination
The Sponsor will suspend or terminate the study when so instructed by the IRB or FDA, or if
it is judged that the subjects are subjected to unreasonable risks, or for valid scientific or 
administrative reasons.
The Sponsor may also decide to close a single study site due to unsatisfactory subject
enrollment or non-compliance with the CIP, GCP, or applicable regulatory requirements.
In the event of premature termination, the Sponsor will provide information on the handling
of currently enrolled subjects who have not completed the study.
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17. Appendices
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SIGNATURES PAGE
Date
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Approved by Owner
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