A Phase II, Randomized, Double Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of AS012 in Subjects With Non-segmental Vitiligo
Phase: PHASE2
Conditions: Non-segmental Vitiligo
Sponsor: Ache Laboratorios Farmaceuticos S.A.

Official title: A Phase II, Randomized, Double Blind, Placebo-Controlled, Dose-Ranging Study to 
Evaluate the Efficacy and Safety of AS012 in Subjects with Non-segmental Vitiligo   
Document: Study Protocol 
NCT number: NCT04487860 
Document date: 20-May-2022 

 
  
 
 
 
CONFIDENTIAL 
 
 
 
A PHASE II, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DOSE-RANGING STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF AS012 IN SUBJECTS WITH NON-SEGMENTAL 
VITILIGO 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number:  AS012-20-01 
 
 
Protocol Version Date: May 20, 2022 
Study Managing Lead: 
 
  
Sponsor: 
 
Developmental phase of study: II 
 
PROTOCOL APPROVAL: 

 

 
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PRINCIPAL INVESTIGATOR AGREEMENT 
 
I have carefully read and understand the foregoing protocol AS012-20-01 “A PHASE II, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED DOSE-RANGING STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF AS012 IN SUBJECTS WITH NON-SEGMENTAL VITILIGO” and agree that it contains 
all the necessary information for conducting this study safely. I will conduct this study in strict accordance 
with this protocol, ICH guidelines for Good Clinical Practice, the Code of Federal Regulations and local 
regulatory guidelines. I will attempt to complete the study within the time designated. 
 
I will ensure that the rights, safety and welfare, of Subjects under my care are protected. I will ensure 
control of the drugs under investigation in this study. 
 
I will provide copies of the protocol and all other study-related information supplied by the Sponsor to all 
personnel responsible to me who participate in the study. I will discuss this information with them to 
assure that they are adequately informed regarding the drug and conduct of the study. 
 
I agree to keep records on all Subject information (case report forms, shipment and drug return forms and 
all other information collected during the study) and drug disposition in accordance with FDA regulations. 
 
I will not enroll any Subjects into this protocol until IRB approval and Sponsor approval are obtained. 
 
 
 
 
 
 
 
Principal Investigator 
 
Signature, Date 

 
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The following are prohibited during this study: 
1. Use of new or changes in use of hormonal contraceptives 
2. Minocycline 
3. Phototherapy (e.g.  UV-B light phototherapy, PUVA therapy, tanning salon, home-administered 
UVB), or excessive exposure to the sun 
4. Herbal preparations for the treatment of vitiligo [e.g. Rubia cordifolia (manjistha or majith) and 
Psoralea coryfolia (bakuchi or bavanchi) 
5. Oral or injectable corticosteroids  
6. Biologic agents  
7. Immunosuppressive agents (e.g. e.g. Methotrexate, Azahioprine, cyclosporine, 6-thiouganine, 
mercaptopurine, mycophenolate mofetil, hydroxyurea, tacrolimus) 
8. JAK inhibitors 
4.5 Precautions  
If a reaction suggesting Subject’s condition has worsened to the degree that it is unsafe for the 
Subject to continue in the study, the Principal Investigator should assess the Subject’s condition as 
soon as possible (i.e., during an Unscheduled Visit) and determine whether treatment should be 
discontinued. If the Subject is discontinued from the study during an Unscheduled Visit, the visit will 
be referred to as an Early Discontinuation Visit. 
4.6 Subject Disposition and Discontinuation 
Investigators are urged to enroll only those eligible Subjects who are likely to complete the entire 
study and who are willing to comply with the protocol-specified procedures. It is the right and duty of 
the investigator to interrupt the treatment of any Subject whose health or well-being may be 
threatened by continuation in this study, or who may be experiencing unmanageable factors that may 
interfere with the study procedures and/or the interpretation of study results.  Such Subjects should 
be withdrawn from the study rather than continued under a modified regimen. 
Subjects will be removed from the study for any of the following reasons:  
 
If the Subject withdraws his or her consent for any reason; 
 
If the Subject’s condition has worsened to the degree that the Principal Investigator feels it is 
unsafe for the Subject to continue in the study; 
 
If the Subject’s drug code is unblinded (on a case-by-case basis in consultation with the MM); 
 
If an adverse event occurs for which the Subject desires to discontinue treatment or the 
Principal Investigator determines that it is in the Subject’s best interest to be discontinued; 
 
If there is a significant protocol violation; 
 
If the Subject is lost to follow-up;  
 
If the Subject becomes pregnant; 
 
If the Subject becomes a prisoner or become involuntarily incarcerated;  
 
Any other reason that may affect the outcome of the study or the safety of Subjects 
 
Termination of the study by the IRB; or 
 
Termination of the study by the Sponsor. 
Additional reasons for Subjects to be removed from the study:  
 
More than 14 consecutive days of non-compliance to study medication i.e. subjects who have 
missed all doses for more than 14 consecutive days  
Medical Monitor/Sponsor notification is required before removing subjects for any of the reasons 
noted above. 
A significant protocol violation is defined as any Subject or Investigator activity that could have 
possibly interfered with the therapeutic administration of the treatment or the precise evaluation of 

 
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treatment efficacy. 
The reasons for a Subject discontinuation will be documented. Data, in addition to the reason for 
discontinuation and the date of removal, will be documented. 
Before a Subject is considered to be lost to follow-up, the Principal Investigator will document all (at 
least three) attempts to reach the Subject twice by telephone and will send a certified follow-up letter. 
In the event that a Subject discontinues from the study at any time due to an adverse event, the 
reason for discontinuation, the nature of the event and its clinical course must be fully documented. 
For such a Subject, the Principal Investigator must strive to follow the Subject until the adverse event 
has resolved, becomes clinically insignificant, is stabilized or the Subject is lost to follow-up. Should a 
serious adverse event be noted, procedures stated in Section 10.3 must be followed. 
Subjects who drop out after randomization will not be replaced. 
5. 
SAFETY AND TOLERABILITY EVALUATIONS 
5.1 Medical History 
A complete medical history will be obtained for the Subject’s current and past medical conditions. 
Significant medical history should include, but not be limited to, evidence of hypertension, lipid 
disorders, obesity (BMI >/= 30 as per the Metropolitan Index), heart attack, stroke, congestive heart 
failure, kidney disease, auto immune disease and gestational diabetes. Significant surgical history 
should include, but not be limited to, removal of blockage from an artery and gallbladder removal. 
5.2 Physical Examination 
The investigator, sub-investigator or appropriately delegated designee, (Physician’s Assistant, 
Advanced Registered Nurse Practitioner, and Registered Nurse as per local regulations) will perform 
a physical examination, prior to the Subject starting study drug and at the end of treatment.   
The physical examination will include, at a minimum, examination of the Subject’s general 
appearance, comprehensive skin examination, HEENT (head, eyes, ears, nose and throat), heart, 
lungs, musculoskeletal system, neurological system, lymph nodes, abdomen and extremities. 
Height and weight will be measured without shoes. 
At the study visits 1, 2, 6, 10, 11, 12, and 13 (Screening, Baseline, and study weeks 20, 44, 48, 52, 
and 64) the Subject’s body weight will also be measured while the Subject is lightly clothed (e.g., no 
coat or shoes).  
5.3 Vital Signs 
Vital signs, including blood pressure, pulse rate*, respiratory rate and oral body temperature, will be 
documented at every visit. Vital signs will be measured after the Subject has rested in a seated or 
supine position for at least 5 minutes.  
* Pulse rate will be measured once by counting the number of heart beats over 60 seconds (the pulse 
rate should not be extrapolated after counting for part of 60 seconds). 
5.4 Pregnancy Test 
All female Subjects of childbearing potential will undergo serum beta-hCG at Screening. A urine 
pregnancy test will be performed during all Visits.  
All female Subjects are considered to be of childbearing potential unless they are premenarchal, have 
been surgically sterilized (by hysterectomy) or have been postmenopausal for at least 1 year. Tubal 
ligation is not considered equivalent to female sterilization. Women with a history of tubal ligation are 
still considered females able to become pregnant and must complete a urine pregnancy test. Women 
of childbearing potential, in addition to having a negative urine pregnancy test, must be willing to use 
an acceptable form of birth control during the study from the day of the first dose administration to 90 
days after the last administration of study drug. For the purpose of this study the following are 
considered acceptable methods of birth control: oral or injectable contraceptives, contraceptive 

 
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5.6 Concomitant Medications 
Concomitant medications, including the use of non-drug treatments/therapies, in addition to the 
reason for the medication use, will be assessed at baseline and at each subsequent study visit. The 
start and stop date of concomitant medication use during the study should be provided in the data set 
in addition to the reason for the medication use. 
A record of concomitant medications taken by the Subject is to be obtained using generic name, if 
known, with the corresponding indication. The medications to be recorded will include prescription 
and over-the-counter (OTC) medications and dietary supplements. All medications taken on a regular 
basis, including acetaminophen, should be recorded. 
5.7 Adverse Events (AEs)  
Any AEs reported after signing Informed Consent should be reported. An adverse event is defined as 
any untoward medical occurrence (sign, symptom or abnormal laboratory finding) regardless of 
severity in a Subject or clinical-trial Subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with this treatment. All adverse events, whether 
observed by an Investigator or Study Coordinator or reported by the Subject, whether related to study 
drug or not related to study drug, shall be documented on Subject records, together with details, i.e. 
date of onset, description of the AE, the duration and intensity of each episode, the action taken, the 
relationship to the investigational product and the degree of severity, the seriousness, date of 
resolution, and the outcome.  
5.8 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Subject will not be eligible to participate in the study if at Screening Subject responded “yes” within 
the last 12 months to Questions 4 or 5 in the suicidal ideation section, or any positive response in the 
behavioral section of the Columbia Suicide Severity Rating Scale (C-SSRS). 
 
5.9 ECG 
Digital ECG devices will be used to record 12-lead ECGs at the Screening visit to confirm the subject’s 
eligibility criteria as well as at the study visits 4, 7, 9, end of treatment and post treatment follow up 
(study weeks 12, 24, 36, 52, and 64). To avoid impacting results and quality of data, ECG should be 
done before other invasive or stressful procedures. 
The following ECG parameters will be obtained directly from the computerized 12-lead ECG 
recordings: rhythm, ventricular rate, P-R interval (the portion of the ECG between the onset of the P 
wave and the QRS complex), R-R interval, QRS duration and QT. QTcF will be calculated according to 
the Fridericia formula. 
5.10 
Treatment Interruption Guidance for AEs 
The treatment period should not be extended beyond 52 weeks due to missed doses or treatment 
interruption periods. Subjects whose condition worsens (e.g. an increase in VASI score from baseline 
by ≥ 25%, or development of allergic reactions or the development of other potentially serious drug 
reactions) should be re-evaluated by the Investigator and management reconsidered. 
Study drug dosing may be temporarily suspended in the event of: 
 
Clinically important laboratory abnormalities 
 
Other inter-current illnesses or major surgery or AE related or unrelated to the study treatment  
A decision to discontinue IP and/or to resumption of study treatment after temporary discontinuation 
due to illness, AE or laboratory abnormality should be discussed with the Medical Monitor. The 
Investigator may suspend study treatment at any time, without consultation with the medical monitor if 
the urgency of the situation requires immediate action and if this is determined to be in the subject’s 
best interest.  Medical Monitor should be contacted as soon as possible in any case of IP 
discontinuation.  

 
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7 
STUDY VISITS (SEE STUDY VISIT SCHEDULE) 
At all visits the efficacy assessments have to be performed in the order per instructions below: 
- 
AE will be evaluated before application of any assessment questionnaire 
- 
the patient-rated questionnaires like DLQI, 
, VIPs, 
 
 must be completed prior to the Investigator assessments* 
*only at a screening visit the patient rated questionnaires can completed after the investigator assessments 
- 
Physician Global assessment (PGA) for vitiligo, 
 must be completed prior to other 
efficacy assessments (VASI, 
 VES) 
Note: changes in study visit schedules, missed visits, or subject discontinuations may lead to missing 
information (e.g., for protocol-specified procedures). It is important to capture specific information in the 
subject records that explains the basis of the missing data, including the relationship to COVID-19, for 
missing protocol-specified information (e.g., from missed study visits or study discontinuations due to 
COVID-19). 
7.1 Visit 1: Screening Visit (Week ≥ -4 / Day -28 to -1) 
Potential subjects will be screened during a 4-week period prior to randomization. CRO/Sponsor’s 
approval is required on a case-by-case basis for an extension of the Screening Period to obtain all test 
results and to re-screen a subject. Re-screening is allowed once per subject; all assessments should be 
repeated using a new screening number. The new informed consent/assent is not required, unless an 
amended or revised informed consent/assent is introduced during the study. 
The following procedures will be performed at Screening: 
1. Written informed consent will be obtained. Subjects must have provided IRB approved 
written informed consent. Subjects will be given the approved ICF describing the study and 
any risks associated with participation. The Subject will be allowed as much time as needed 
to read and understand the information presented in the consent form. Appropriate study 
personnel will be available to answer any questions the Subject might have regarding the 
study or study-related procedures. If the Subject chooses to participate in the study, he or 
she will be asked to sign and date the consent form and will be provided with a copy for his 
or her records. The ICF must be signed by the Subject before any protocol assessments 
can be undertaken. Subjects participating 
 the study, or those 
having skin biopsies taken, will be asked to sign a separate informed consent form in 
addition to the main study consent. 
2. Demographics will be collected, including date of birth, gender, race and ethnicity. 
3. A compliance with applicable inclusion and exclusion criteria will be reviewed. (See Sections 
4.2, 4.3)  
4. After confirming the eligibility, the Subject will be assigned a screening number. 
5. A complete medical history will be obtained for the Subject’s current and past medical 
conditions, including a complete list of current and past (within the previous 30 days) 
medications. Significant medical history should include, but not be limited to, evidence of 
hypertension, lipid disorders, obesity*, heart attack, stroke, congestive heart failure, kidney 
disease, and auto immune disease and gestational diabetes. Significant surgical history 
should include, but not be limited to, removal of blockage from an artery and gallbladder 
removal. (See Section 5.1) 
* Obesity = BMI ≥30 (as defined by Metropolitan Life Insurance Company Chart) 
6. A urine pregnancy test will be conducted for all females of childbearing potential (see Section 5.4) 
7. A physical examination will be performed. At a minimum, the physical examination will 
include the following: height, weight, assessment of general appearance, comprehensive skin 

 
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Tablets should be swallowed intact and not chewed or crushed. The doses should be taken with 
approximately 240 mL (8 oz.) of water between meals, approximately one hour after and before 
meals. 
Investigational Product will be used for 365 consecutive days. 
Subjects will be required to use diaries to document the date and time of doses, any missed doses 
and the occurrence of all adverse events. 
At each visit during the study, the Investigator or designee should review proper use of the 
Investigational Product. 
In case of vomiting within 30 minutes of taking a dose, the dose shall be repeated. The dose shall not 
be repeated if vomiting occurs more than 30 minutes after ingestion. If vomiting recurs no new doses 
should be taken and the subject should contact the site for instructions.  
Missed doses: 
The dose will be skipped if the subjects realizes more than 2 hours after the scheduled time-point. All 
missed doses should be entered by the subject in the patient diary.  
More than 14 consecutive days of non-compliance to study medication (i.e. subjects who have 
missed all doses for more than 14 consecutive days) will result in subject’s discontinuation from the 
study.  
8.7 Assessment of Compliance  
Compliance with scheduled use of Investigational Product will be determined from the Subject’s diary. 
Subjects will be instructed to bring their daily diary and used and unused study drug containers at all 
scheduled visits or Early Discontinuation Visit to allow for tablet count and compliance checks. 
Subjects will also be asked to record in a daily diary the date and time at which they took the study 
drug. In addition, Subjects will be instructed to document all AEs on the diary.  
If the subject does not return the Diary, Subject-reported dosing compliance will be recorded in the 
source notes and will be used to derive compliance between those visits. 
For scheduled visits greater than 4 weeks apart, subjects will be called (at w8, w32, w40) and asked 
about compliance with study drug. 
8.8 Investigational Product Accountability  
It is the responsibility of the Principal Investigator to ensure that the current disposition of the 
Investigational Product is maintained at each study site where Investigational Product is inventoried 
and dispensed. When a drug shipment is received at a study site, the Principal Investigator or the 
Principal Investigator’s Designee must inventory the drug and sign the receipt form provided with the 
shipment. The receipt form should be emailed as per instructions provided on the receipt.  A copy of 
the receipt should remain at the site. 
The Investigator will not supply study test articles to any person not enrolled in this study, or to any 
physician or scientist except those named as sub-investigators. 
A Drug Accountability Log will assist study site staff in maintaining inventory records of study drug. 
Subjects must return used, partially used or unused Investigational Product so that any remaining 
drug supplies can be accounted for and noted in the Drug Accountability Log.  
8.9 Return of Clinical Supplies  
All used and unused containers of Investigational Product may be returned to the Drug Shipping 
Facility for destruction or be destructed at the site after study close-out and final drug accountability is 
reconciled.  
 

 
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and the AE. Based upon the Principal Investigator’s clinical experience, the association 
of the event with the study drug seems likely.  
 
Definite: The AE occurs following the application of the study drug and it cannot be 
reasonably explained by any known characteristics of the Subject’s clinical state, 
environmental or toxic factors or other modes of therapy administered to the Subject. It 
disappears or decreases upon discontinuation of the study drug and reappears on a re-
challenge of the investigational product.  
10.2 
Pregnancy 
Female Subjects of childbearing potential must have been using and must agree to continue to use 
accepted methods of birth control, throughout the study. All female Subjects are considered to be of 
childbearing potential unless they are premenarchal, have been surgically sterilized or have been 
postmenopausal for at least 1 year. Tubal ligation is not considered equivalent to female sterilization.  
Women with a history of tubal ligation are still considered females able to become pregnant and must 
complete a urine pregnancy test. Alternatively, any of the following methods of birth control are 
acceptable: oral or injectable contraceptives, contraceptive patches, Depo-Provera® (stabilized for at 
least 3 months), NuvaRing® (vaginal contraceptive), Implanon™ (contraceptive implant), double 
barrier methods (e.g. condom and spermicide), IUD, tubal ligation, Essure or abstinence with a 2nd 
acceptable method of birth control should the Subject become sexually active.  Prior to study 
enrollment women of child bearing potential must be advised of the importance of avoiding pregnancy 
during study participation. 
A negative result of a pregnancy test having a minimum sensitivity of at least 50mIU/ml for hCG 
should be obtained, prior to study participation, at Visit 1. Pregnancy testing will also be performed at 
every study visit and the results of all pregnancy tests (positive or negative) will be documented. 
If following initiation of study treatment, it is subsequently discovered that a study Subject is pregnant 
or may have been pregnant at the time of Investigational Product exposure, the Investigational 
Product will be permanently discontinued. The Principal Investigator must immediately notify the CRO 
of this event. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
Subject. Other appropriate pregnancy follow-up procedures should be considered if indicated. In 
addition, the Principal Investigator must report to the sponsor follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome. Infants should be followed for a 
minimum of eight weeks after birth.   
10.3 
Serious Adverse Events  
An Adverse Event or Suspected Adverse Reaction is considered ‘‘serious’’ if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
 
Death  
 
A life threatening adverse event; (Note: the term “life-threatening” as used here refers to an 
event in which the Subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.)  
 
In-Subject hospitalization or prolongation of existing hospitalization 
(A planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health or if the hospitalization is clearly 
not associated with an AE (e.g., hospitalization due to social / logistic reason) are not to be 
considered as SAEs)  
 
A persistent or significant disability/incapacity (substantial disruption of the ability to conduct 
normal life functions) 
 
A congenital anomaly/birth defect 
 
Any “other” important medical event  
Important medical events that may not result in death, be life-threatening or require hospitalization 
may be considered Serious Adverse Events when, based on appropriate medical judgment, they may 

 
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All participating Investigators, IEC/IRB and other stakeholders shall be notified of any SUSAR by 
CRO’s Medical Monitor as per local regulatory requirement. 
10.5 
Post-study Events  
Any AE/SAE that occurs up until the follow-up visit, or if the follow-up visit does not occur within the 
defined time window, then 4 weeks post the end of treatment visit or 4 weeks post the last dose of 
study drug for subjects with early discontinuation, should be reported and included in the safety 
analysis of the study.  
Any AE/SAE which occurs past this date will be reported if it is considered related to study drug by 
the Investigator. 
11. 
ETHICS  
This study will be conducted in accordance with the ethical principles that have their origin in the 
current Declaration of Helsinki and will be consistent with International Council on Harmonisation 
Good Clinical Practice (ICH GCP) and applicable regulatory requirements. The study will be 
conducted in compliance with the protocol. 
The rights, safety and well-being of the study Subjects are the most important considerations and 
should prevail over interests of society and science.   
11.1 
Informed Consent 
The Principal Investigator must ensure that Subjects are clearly and fully informed about the purpose, 
potential risks and other critical issues regarding clinical studies in which they volunteer to participate. 
The principles of Informed Consent, according to FDA Regulations and ICH GCP will be followed.  A 
copy of the proposed consent form must be submitted to the IRB, together with the protocol, for 
approval. Prior to beginning of the study, the Principal Investigator must have the IRB’s written 
approval of the written informed consent form and any other information to be provided to Subjects. 
Informed consent will be obtained from all Subjects using the following procedure: Subjects must 
have provided IRB approved written informed consent. Prior to initiating screening for the study, 
Subjects will be given the approved ICF describing the study and any risks associated with 
participation. The Subject will be allowed as much time as needed to read and understand the 
information presented in the consent form. Appropriate study personnel will be available to answer 
any questions the Subject might have regarding the study or study-related procedures. If the Subject 
chooses to participate in the study, he or she will be asked to sign and date the consent form and will 
be provided with a copy for his or her records. The ICF must be signed by the Subject before any 
protocol assessments can be undertaken. Each Subject’s signed informed consent must be kept on 
file by the Principal Investigator. 
Audio-video (AV) consent in India: 
As per, DCGI regulation (G.S.R. 611 (E), Dated 31st July 2015) AV recording of the informed consent 
process is mandatory for vulnerable subjects participating in clinical trials of new chemical entity 
(NCE) or new molecular entity (NME). Consequently, for patients aged ≥65 years, AV recording of the 
consent process will be done. 
11.2 
Institutional Review Board  
Before study initiation, the Principal Investigator must have written and dated approval from the IRB 
for the protocol, consent form, Subject recruitment materials and any other written information to be 
provided to Subjects.  
Any changes to the protocol as well as a change of the Principal Investigator, which is approved by 
the Sponsor, must also be approved by the site’s IRB and documentation of this approval provided to 
the Sponsor/designee. Records of the IRB review and approval of all documents pertaining to this 
study must be kept on file by the Principal Investigator and are subject to inspection during or after 
completion of the study.  All SAEs must also be reported to the IRB. 

 
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Periodic status reports must be submitted to the IRB at least annually, as well as notification of 
completion of the study and a final report within one (1) month of study completion or discontinuation. 
A copy of all reports submitted to the IRB must be sent to the Sponsor/designee. 
The Principal Investigator will ensure that an IRB that complies with the requirements set forth in 21 
CFR Part 56 will be responsible for the initial and continuing review and approval of the proposed 
clinical study. 
11.3 
Subject Confidentiality  
The monitor(s), the auditor(s), IRB/IEC, and the regulatory authority(ies), will be granted direct access 
to the Subject’s original medical records for verification of the clinical trial procedures and/or data, 
without violating the confidentiality, to the extent permitted by the applicable laws and regulations and 
that by signing a written informed consent form, the Subject or the Subject’s legally acceptable 
representative is authorizing such access. 
The identifying the Subject will be kept confidential and, to the extent permitted by the applicable laws 
and regulations, will not be made publicly available. If the results of the trial are published, the 
Subject’s identity will remain confidential.   
12. 
DOCUMENTATION  
12.1 
Site Regulatory Documents Required for Initiation  
The following documents will be received by the CRO from US sites prior to the initiation of the study:  
1. Completed and signed FDA Form 1572 
2. Current curricula vitae, signed and dated for the Principal Investigator and each Sub-Investigator 
named in the FDA Form 1572 (current within 2 years) 
3. Current medical licenses of the Principal Investigator and Sub-Investigators named in FDA Form 
1572 
4. Documentation of IRB approval of this study protocol, Principal Investigator and informed consent 
form 
5. Current IRB membership list or roster  
6. A copy of the protocol agreement page signed by the Principal Investigator  
7. Non-disclosure Agreements for the Principal Investigator and Sub-Investigators named in FDA 
Form 1572  
8. Financial Disclosure Statement for the Principal Investigator and each Sub-Investigator named in 
FDA Form 1572. 
9. Statement of Non-Debarment 
12.2 
Maintenance and Retention of Records  
It is the responsibility of the Principal Investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation. 
Copies of all pertinent records will be retained by the Principal Investigator for at least two years 
following final approval of the drug and/or notification from the Sponsor. These regulatory documents 
should be retained for a longer period if required by local regulatory authorities. These records 
include documents pertaining to the receipt and return of drug supplies, IRB, informed consent, 
source documents. No documents shall be transferred from the site or destroyed without first 
notifying the Sponsor. If the Principal Investigator withdraws from the study, the records shall be 
transferred to a mutually agreed upon designee. Notice of such transfer will be given in writing to the 
Sponsor. 
The Principal Investigator is required to prepare and maintain adequate and accurate case histories 

 
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designed to document all observations and other data pertinent to the investigation on each individual 
treated with the Investigational Product or entered as a control in the investigation.   
12.3 
Data Collection and Reporting  
Data for individual Subjects will be collected on source documents. The data management system 
will be Electronic Data Capture (EDC). The Investigator and his/her study site personnel will be 
responsible for transferring data to the eCRFs. The Investigator is required to verify that all of the 
requested information is accurately recorded in the eCRFs. All information requested in the eCRFs 
needs to be supplied, including subject identification, date(s), assessment values, etc., and any 
omission or discrepancy will require explanation. All information on eCRFs must be traceable to 
source documents.  
Source documents such as the clinic chart are to be maintained separately from the eCRF in order to 
allow data verification. Because of the potential for errors, inaccuracies and illegibility in transcribing 
data into eCRFs, originals of laboratory and other test results must be kept on file. Source documents 
and copies of test results must be available at all times for inspection by the study monitor. The 
following should also be available for review:  
1. Subject Screening Log – reflecting the reason any Subject screened for the study was found to 
be ineligible 
2. Delegation of Authority / Study Personnel Signature Log – all site personnel will be listed along 
with their responsibilities and signatures; to be maintained at the site throughout the study 
3. Monitoring Log – the date and purpose of all monitoring visits by the Sponsor/Designee will be 
documented 
4. Enrollment Log – documenting Subject initials and start and end dates for all Subjects enrolled 
5. Drug Inventory/Packing Slip – reflecting the total amount of drug shipped to the site and received 
and signed for by the Principal Investigator 
6. Drug Accountability Log – reflecting the total amount of Investigational Product dispensed to and 
returned by each Subject 
7. Informed Consent Form and Assent Form  – which must be available for each Subject and be 
verified for proper documentation 
The study monitor will be responsible for reviewing and verifying the data recorded in the eCRFs, 
utilizing the original source documentation and will query discrepant findings. The Investigator and 
study site personnel will be responsible for answering all queries. All queries issued by the data 
management personnel will be answered by site personnel and verified by the monitor. 
Electronically generated data like laboratory results, ECG results etc. could be directly integrated with 
or transferred to the clinical database. 
The CRO will have an independent CRA(s) and MM to monitor the cardiac monitoring and targeted 
safety lab data. The access to related data will be restricted to other CRO members and Sponsor. 
12.4 
Primary Source Documents  
The Principal Investigator must maintain primary source documents supporting significant data for 
each Subject’s medical notes. These documents, which are considered “source data”, should include 
documentation of:  
 
Demographic information  
 
Evidence supporting the diagnosis/condition for which the Subject is being studied  
 
General information supporting the Subject’s participation in the study  
 
General history and physical findings  
 
Hospitalization or Emergency Room records (if applicable)  
 
Each study visit by date, including any evaluations, relevant  findings/notes by the Principal 
Investigator(s), occurrence (or lack) of adverse events and changes in medication usage, 
including the date the study drug commenced and completed.  

 
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 
Any additional visits during the study  
 
Any relevant  telephone conversations with the Subject regarding the study or possible 
adverse events  
 
An original, signed informed consent form or assent form for study participation  
The Principal Investigator must also retain all Subject specific printouts/reports of tests/procedures 
performed as a requirement of the study.  
12.5 
Study Monitoring  
The study will be monitored by a representative of the Contract Research Organization to assess 
compliance with ICH-GCP and applicable regulations. The Principal Investigator will be visited by a 
monitor prior to the study and at regular intervals during the course of the study. These visits are for 
the purposes of verifying adherence to the protocol. 
The study monitor will review the informed consent/assent forms and verify eCRF entries by 
comparing them with the source documents (hospital/clinic/office records) that will be made available 
for this purpose. The monitor will review the maintenance of regulatory documentation and drug 
accountability. The monitor will review on a regular basis the progress of the study with the Principal 
Investigator and other site personnel.  
eCRF sections may be monitored during these visits. At the end of the study, a closeout monitoring 
visit will be performed. Monitoring visits will be arranged in advance at a mutually acceptable time 
with site personnel. Sufficient time must be allowed by the site personnel for the monitoring of eCRFs 
and relevant source documents. The Study Coordinator and/or Principal Investigator should be 
available to answer questions or resolve data clarifications. Adequate time and space for these visits 
should be made available by the Principal Investigator. 
12.6 
Audits and Inspections  
During the course of the study and/or after it has been completed, one or more site visits may be 
undertaken by auditors as authorized representatives of the Sponsor. The purpose of the audit is to 
determine whether or not the study is being conducted and monitored in compliance with the 
protocol, recognized GCP guidelines and all applicable regulations. 
Additionally, the study may be inspected by regulatory agencies. These inspections may take place at 
any time during the course of the study and/or after it has been completed.  
THE INVESTIGATOR MUST NOTIFY THE CONTRACT RESEARCH ORGANIZATION and 
SPONSOR PROMPTLY OF ANY INSPECTIONS SCHEDULED BY REGULATORY AUTHORITIES, 
AND PROMPTLY FORWARD COPIES OF INSPECTION REPORTS TO THE SPONSOR. 
12.7 
Modifications to the Protocol  
The procedures defined in the protocol will be carefully reviewed to ensure that all parties involved 
with the study fully understand the protocol. In order to ensure the validity of the data, no violations 
from the protocol, with minimal exceptions, may be made unless the issue is broad enough to warrant 
revision of the protocol. Such revisions must be submitted to and have documented approval from the 
Sponsor and the IRB prior to implementation.  
The only circumstance in which an amendment may be initiated without prior IRB approval is to 
eliminate apparent immediate hazards to a Subject or Subjects. However, the Principal Investigator 
must notify the Sponsor immediately and the IRB within 5 working days after implementation.  
All protocol violations will be reported on the protocol violation log and included in the study reports. A 
protocol violation is defined as any change, deviation, or departure from the study design or 
procedures of  research project that is NOT approved by the IRB prior to its initiation or 
implementation, OR deviation from standard operating procedures, Good Clinical Practices (GCPs), 
federal, state or local regulations. 

 
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12.8 
Completion of Study  
The Principal Investigator is required to sign the eCRFs and all other relevant data and records to the 
Contract Research Organization.  
The Principal Investigator is expected to submit a final report to the IRB and the Sponsor within one 
(1) month of study completion or discontinuation.   
13. 
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