A Follow-Up Study to Monitor Therapeutic Response in Transthyretin Cardiac Amyloidosis Using Amyloid Reactive Peptide 124I-evuzamitide (AT01) PET/CT
Phase: PHASE2
Conditions: Transthyretin Amyloidosis
Sponsor: Columbia University

CLINICAL STUDY PROTOCOL 
Title: A Follow-Up Study to Monitor Therapeutic Response in 
Transthyretin Cardiac Amyloidosis Using Amyloid Reactive Peptide 
124I-evuzamitide (AT01) PET/CT 
Protocol Version: 
Protocol Date:  
ClinicalTrials.gov: 
Sponsor: 
Sponsor-Investigator: 
2.0 
October 26, 2023 
NCT05635045 
Columbia University Irving Medical Center 
Clinical Cardiovascular Research Laboratory for the 
Elderly (CCRLE) 
21 Audubon Avenue 
New York, NY 10032, USA 
Mathew Maurer, MD 
212-932-4537
Collaborating Investigators: Andrew Einstein, MD, PhD 
Columbia University Irving Medical Center 
Dia Smiley, DO 
Columbia University Irving Medical Center 

STUDY SYNOPSIS 
Protocol Title 
Title: A Follow-Up Study to Monitor Therapeutic Response in 
Transthyretin Cardiac Amyloidosis Using Amyloid Reactive Peptide 
124I-evuzamitide (AT01) PET/CT 
Protocol Number 1.0 
Design 
This is a single center, prospective cohort study that is evaluating the 
ability of 124I-evuzamitide PET scanning to serially assess and quantify 
TTR stabilizer and TTR silencer response in the heart in ATTR-CA. 10 
subjects will be recruited from our pilot study that have a baseline 124I-
evuzamitide PET/CT showing cardiac uptake, who are on TTR 
stabilizer and/or silencer therapy. Data generated from this study will 
provide amongst the first evidence of changes in myocardial amyloid 
load on PET/CT imaging with disease modifying therapy and provide 
preliminary data to support larger investigations in this arena. 
Consented eligible patients will undergo a single 124I-evuzamitide PET 
scan. Clinically available demographic, clinical and phenotypic data 
that is collected as part of routine clinical care will be used to 
characterize the type, severity, and stage of ATTR-CM. Bloodwork, 
electrocardiograms, and echocardiograms will be performed at the time 
of the scan. 
Study Sites 
This study is to be conducted at Columbia University Irving Medical 
Center.    
Time on Study 
The duration of patient participation in this study is 31 days.  
Primary 
Objective 
To assess and quantify TTR stabilizer and TTR silencer response in the 
heart in ATTR-CA.  
Sample Size 
10 patients will be included in this study. 
Inclusion and 
Exclusion 
Criteria 
10 Participants from the current study on ATTR treatment will be 
recruited to one cohort.  
Overall Inclusion Criteria: 
1. Must have given written informed consent (signed and dated) and 
any authorizations required by local law and be able to comply 
with all study requirements. 
2. Were enrolled in the initial pilot using 124I-Evuzamitide, on ATTR 
stabilizer and/or silencer therapy. Able to understand and sign 
the informed consent document after the nature of the study has 
been fully explained.  
3. TTR genotype shown to be either Val122Ile or wild type.  
The presence of any of the following excludes eligibility for enrollment 
in this study: 

1. Primary amyloidosis (AL) or secondary amyloidosis (AA). 
2. Active malignancy or non-amyloid disease with expected survival 
of less than 1 year. 
3. Heart failure, in the opinion of the investigator, primarily caused by 
something other than amyloidosis.  
4. Ventricular assist device. 
5. Impairment from stroke, injury or other medical disorder that 
precludes participation in the study. 
6. Disabling dementia or other mental or behavioral disease. 
7. Enrollment in a clinical trial not approved for co-enrollment. 
8. Continuous intravenous inotropic therapy. 
9. Inability or unwillingness to comply with the study requirements. 
10. Chronic kidney disease requiring hemodialysis or peritoneal 
dialysis. 
11. Patients taking heparin, or heparin derivatives (e.g. low molecular 
weight heparins) for anticoagulation. 
12. Other reason that would make the subject inappropriate for entry 
into this study. 
 
Aims 
 
 
 
 
 
 
 
The specific aim is to determine if 124I-evuzamitide PET/CT 
scanning can:  
(1) Serially quantify TTR cardiac amyloid load as measured after 1 
year of TTR stabilizer and/or silencer treatment. 
Safety 
Assessments 
 
The safety of study participants will be evaluated by: 
1. Assessment of adverse events (AEs), including serious adverse 
events (SAEs). 
2. Vital sign measurements (blood pressure, pulse rate, and respiratory 
rate). 
3. Physical examinations 

SCHEDULE OF ACTIVITIES 
The following table summarizes the activities to be performed at each of the designated study 
visits. Details of the different procedures can be found in subsequent sections of this manual. 
Procedure 
Screeni
ng 
Historical
ly 
Obtained 
Demogra
phic and 
Clinical 
Informati
on 
124I-
evuzamiti
de PET 
scanning 
 
Day 7 
(+/- 2 
days) 
           
Day 28 
(+/- 4 
days) 
Informed Consent 
X 
 
 
 
 
Inclusion and Exclusion Criteria 
X 
 
 
 
 
Medical History 
 
X 
 
 
 
Co-morbidities 
 
X 
 
 
 
ATTR-CM cardiac stagea 
 
X 
 
 
 
TTR genotype 
 
X 
 
 
 
Height and Weight† 
 
 
X 
 
 
Vitals Signs 
 
 
X 
 
 
Medications 
 
X 
 
 
 
Clinical Examination 
 
 
X 
 
 
Adverse Events Review 
 
 
X 
 
 
KCCQ Questionnaire 
 
 
X 
 
 
Electrocardiogram 
 
 
X 
 
 
Echocardiogram 
 
 
X 
 
 
Bloodwork 
 
 
X 
 
 
99mTc-PYP Scintigraphy 
 
X 
 
 
 
PET scanning 
 
 
X 
 
 
Follow-Up Safety Call 
 
 
 
X 
X 
a Stage of ATTR-CM will be defined by criteria as specific in Cheng, R, JACC CardioOncol 2020 
Sep;2(3):414-424.

TABLE OF CONTENTS 
STUDY SYNOPSIS 
2 
SCHEDULE OF ACTIVITIES 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
7 
1. 
INTRODUCTION 
8 
1.1 Background and Rationale 
8 
2. 
STUDY OBJECTIVES & STUDY DESIGN 
11 
2.1 Primary Objective 
11 
2.1.1 Research Goal 
11 
2.2 Overview of Study Design 
12 
2.2.1 Methods 
12 
2.2.2 Study Sites 
12 
2.2.3 Time on Study 
12 
2.2.4 Sample Size 
12 
2.2.5 Patient Recruitment 
13 
2.2.6 Selection Criteria 
13 
2.2.7 Cardiac PET/CT with 124I-evuzamitide 
13 
2.2.8 Statistical Considerations and Sample Size 
14 
2.2.9 Data Analysis Plan 
14 
 
 
2.3 Limitations and Assumptions 
14 
3.     PATIENT NUMBERING 
14 
4.     ADVERSE AND SERIOUS ADVERSE EVENTS 
15 
4.1 Adverse Events Definition 
15 
4.2 Serious Adverse Event (SAE) Definition 
15 
4.3 Collecting and Reviewing Adverse Event and Outcome Information 
15 
4.4 Stopping Study Procedure Due to Adverse Event 
16 
5.     ADVERSE EVENT REPORTING 
16 
5.1   Reporting to the Sponsor 
16 
5.2 Reporting to the IRB 
16 
5.3 Reporting to the FDA 
17 
5.4 Reporting to Participants 
17 
6. 
   REGULATORY GUIDELINES 
18 
6.1 Institutional Review Board/Independent Ethics Committee 
18 
6.2 Regulatory Authorities 
18 

6.3 Modification of the Protocol 
18 
6.4 Informed Consent Form 
18 
6.5 Study Data Handling 
19 
6.6 Confidentiality 
19 
REFERENCES 
21 

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Specialist 
Term 
Explanation 
99mTc-PYP 
99mTechnetium pyrophosphate 
AE 
Adverse event 
SAE 
Serios adverse event 
TTR 
 
 
 
 
Transthyretin  
ATTRv 
 
 
Variant transthyretin amyloidosis 
ATTRwt 
 
Wild-type Transthyretin amyloidosis 
ATTR-CA 
Transthyretin cardiac amyloidosis 
ATTR-CM 
Transthyretin amyloid cardiomyopathy 
  AT-01(124I-evuzamitide) 
Pan amyloid imaging peptide labeled with Iodine-
124 
 
 

1. INTRODUCTION 
1.1 Background and Rationale  
Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly recognized due to better 
diagnostic imaging and enhanced clinical awareness, as well as the introduction of novel 
treatments [1]. Although there have been great advances in the diagnosis of ATTR-CA using 
nuclear imaging; it has yet to be delineated how myocardial amyloid load changes with disease-
specific treatment. Specifically, it is unclear if the amount of TTR amyloid decreases, increases, 
or remains unchanged after TTR stabilizer and/or silencer treatment. In short, the objective 
monitoring of response to ATTR-CA therapy on imaging is an unmet need. We believe that 
monitoring response to therapy by measuring amyloid load on imaging will be complementary to 
cardiac biomarkers, physical battery tests and quality of life questionnaires -- and will provide 
essential pathophysiologic insights.  
Studies have shown that echocardiography is not sensitive or specific for the diagnosis of ATTR-
CA, but also cannot be used for monitoring with ATTR therapy, since parameters such as LVEF, 
strain, and wall thickness do not consistently change with therapy and are highly variable. 
Cardiac MRI can provide quantification but doesn’t measure amyloid deposits directly. 
Technetium 99m-pyrophosphate (Tc99M-PYP) scintigraphy has no doubt revolutionized the 
diagnosis of ATTR-CA, but it is unclear what PYP is binding to [2,3]. Further, recent TTR 
silencer studies have shown that improvement in Perugini score can occur in some patients after 
TTR silencer treatment, but this is not accompanied by changes in cardiac structure and function. 
We have shown in a pilot study [NCT05635045] evaluating 124I-evuzamitide PET/CT scanning 
for the diagnosis of ATTR-CA, that even with an improvement in baseline Tc99M-PYP with 
Perugini score of 3 to a Perugini score of 1 after <2 years of silencer treatment, there was 
significant and diffuse cardiac uptake of 124I-evuzamitide on PET/CT and no change in 
structure or function on echocardiography, suggesting that Tc99M-PYP may not be reliable for 
monitoring response to ATTR-CA therapy (figure 1) [4].  

 
Figure 1 Post TTR gene silencer therapy 124I-evuzamitide PET-CT scan images. (A) 
Transaxial, (B) coronal and (C) sagittal images demonstrate 124I-evuzamitide uptake in the left 
and right ventricle. Images were obtained 300 minutes after administration of tracer. Tc99-PYP 
imaging was performed approximately 2 years after initiation of TTR gene silencer therapy. 
Images were obtained 3-hours post-infusion of radiotracer. Planar images demonstrate uptake 
over the cardiac silhouette less than rib uptake (Perugini visual grade 1), with heart to 
contralateral ratio (H:CL) of 1.35. (I) SPECT-CT imaging confirmed that radiotracer activity was 
limited to the left ventricular blood-pool, with no myocardial uptake, a significant change from 
the prior scan.  
Results of the APOLLO-B trial, a phase 3, randomized, double-blind, placebo-controlled 
multicenter global study of patisiran, were presented in September 2022. In APOLLO-B, cardiac 
uptake of Tc99M-PYP on scintigraphy was assessed in a subset of patients (37 patisiran and 28 
placebo) at baseline and 12 months after initiation of therapy. All subjects in the patisiran arm 
had reduced or no change in the Perugini grading scale at month 12 relative to baseline, whereas 
no placebo subjects demonstrated a reduction from baseline in Perugini grade at month 12. Of 
the evaluable patients in the patisiran arm, 37.8% demonstrated reduction of ≥1 Perugini grade, 
including 3 (8.1%) patients who reduced by ≥2 Perugini grades at month 12 [5]. However, as 
noted previously the implications of these findings regarding amyloid load are unknown.  

Several recent studies suggest a promising role of PET imaging in cardiac amyloidosis, and 
several PET tracers are now available for in vivo detection of amyloid deposits [6-11]. PET 
imaging has high sensitivity and specificity for amyloid with quantitation and can identify 
cardiac amyloidosis earlier than Tc99M-PYP scans [11]. PET radiotracers C-11–Pittsburgh 
compound-B (C-11–PiB), F-18–florbetapir, F-18–florbetaben, F-18–flutemetamol have been 
approved by the Food and Drug Administration (FDA) for imaging Alzheimer’s disease, and 
have been used successfully in off-label research to image light chain cardiac amyloidosis (AL-
CA) and ATTR-CA. Although they are currently not being used in clinical practice, these 
amyloid PET radiotracers are being investigated for early detection, quantitation, and assessment 
of response to therapy [ 6-13]. Multiple studies demonstrated visual uptake of radiotracer and a 
higher retention index of C-11–PiB in all patients with AL and ATTR compared with control 
subjects but had the limitation of not distinguishing AL-CA from ATTR-CA; and due to the 
short half-life of 20 minutes for C-11–PiB, it requires an onsite cyclotron for production 
[6,14,15]. Further, reports suggested that Tc99M– DPD imaging could be negative despite 
cardiac amyloid deposition diagnosed by C-11–PiB in certain forms of variant (hereditary) 
ATTR-CA, such as with the Val30Met variant, where there is a substitution of a single amino 
acid valine for methionine at position 30 of the TTR gene [15].  
A novel amyloid reactive peptide, 124I-evuzamitide, also known as AT01, has been shown to 
detect various forms of amyloidosis in the liver, spleen, kidney, and bone marrow [16- 18]. We 
conducted a pilot study at our institution (n=25), where we used 124I-evuzamitide for early 
detection of ATTR-CA, the assessment of cardiac involvement in rare TTR variants, and the 
detection and quantification of extra-cardiac amyloidosis [4,19]. PET with molecular imaging 
could provide detailed information on the extent and quantity of systemic amyloid load, which 
could be valuable in tracking serially in the context of emerging therapies.  
Accordingly, we propose a prospective pilot study using amyloid reactive peptide 124I- 
evuzamitide PET/CT scans to serially assess and quantify TTR stabilizer and TTR silencer 
response in the heart in ATTR-CA. 10 subjects will be recruited from our pilot study that have a 
baseline 124I-evuzamitide PET/CT showing cardiac uptake, who are on TTR stabilizer and/or 
silencer therapy. Data generated from this study will provide amongst the first evidence of 
changes in myocardial amyloid load on PET/CT imaging with disease modifying therapy and 
provide preliminary data to support larger investigations in this arena.  
2. STUDY OBJECTIVES & STUDY DESIGN  
2.1 Primary Objective  
To determine if 124I-evuzamitide PET/CT scanning can quantify and detect changes in 
myocardial amyloid load with stabilizers and Silencers in ATTR-CA.  
2.1.1 Research Goal  
The goal of our research is to obtain preliminary data on stabilizer and silencer therapy response 
to the treatment in ATTR-CA by quantitatively comparing cardiac uptake of 124I- evuzamitide 

on PET/CT after one year of disease specific therapy. 
The specific aim is to determine if 124I-evuzamitide PET/CT scanning can:  
(1) Serially quantify TTR cardiac amyloid load as measured after 1 year of TTR stabilizer and/or 
silencer treatment.  
2.2 Overview of Study Design  
We will undertake a prospective cohort study among ATTR-CA subjects that have had 124I- 
evuzamitide PET/CT scan showing cardiac uptake. Eligible subjects, who have already had 
baseline scans (n=10) will undergo a repeat cardiac PET/CT scan using 124I-evuzamitide one 
year after the baseline scans. Additional information regarding demographic and clinical features 
including measures of disease severity and stage and TTR genotype will be obtained from 
previous recent medical encounters. The study will entail a single in-person visit for the whole-
body PET scan.  
Consented eligible patients will undergo a single 124I-evuzamitide PET scan. Cardiac 
biomarkers and basic metabolic panel, along with quality of life questtionaires, which include: 
KCCQ, COMPASS 31, SF-36, and EQ-5D-5Land 6-minute walk, will obtained at the time of the 
1-year follow-up scan. Clinically available demographic, clinical and phenotypic data that is 
collected as part of routine clinical care will be used to characterize the type, severity, and stage 
of ATTR-CM. An echo will also be obtained at the time of the scan.  
2.2.1 Methods  
The subjects that will be enrolled will be of variant ATTR-CA (ATTRv) or wild-type ATTR-CA 
(ATTRwt). Subjects will receive < 1.5 mg of 124I-evuzamitide (1 mCi ± 10%), and this will be 
administered as a single slow IV bolus. PET/CT images will be acquired ~5 hours after dose, as 
has been demonstrated in our previous studies. 20 minutes of cardiac PET acquisition will be 
performed.  
2.2.2 Study sites  
This study is to be conducted at Columbia University Irving Medical Center.  
2.2.3 Time on Study  
The duration of patient participation in this study is 31 days (for one month follow-up to assess 
for safety and 3 days of potassium iodide administration prior to PET scanning).  
2.2.4 Sample size  
10 patients have already been identified who have had baseline scans to be included in this study.  
2.2.5 Patient Recruitment  

The subjects have been selected from among subjects who underwent 124I-evuzamitide PET/CT 
scanning previously. All necessary follow-up care or communication of adverse events or 
incidental findings will either take place as part of the clinical care of the enrolled subjects or be 
communicated in writing and via telephone with the physician.  
2.2.6 Selection Criteria  
Inclusion Criteria  
1. 
Subjects with TTR-CA who had a 124I-evuzamitide PET/CT in our previous pilot study 
(table 1) with PET/CT cardiac uptake. 
2.  
On TTR stabilizer and/or silencer therapy for 12 months between the original 124I- 
evuzamitide PET/CT scan, and the 124I-evuzamitide PET/CT in this study.  
Table 1: Characteristics of Subjects to be scanned. 
 
 
Exclusion criteria:  
Primary amyloidosis (AL) or secondary amyloidosis (AA), Active malignancy or non-amyloid 
disease with expected survival of less than 1 year, Heart failure, in the opinion of the 
investigator, primarily caused by something other than amyloidosis, Ventricular assist device, 
impairment from stroke, injury or other medical disorder that precludes participation in the study, 
disabling dementia or other mental or behavioral disease, enrollment in a clinical trial not 
approved for co-enrollment, continuous intravenous inotropic therapy, inability or unwillingness 
to comply with the study requirements, chronic kidney disease with eGFR 
 
 
2.2.7 Cardiac PET/CT with 124I-evuzamitide  

Eligible subjects will begin therapy with potassium iodide (KI) 130 mg orally daily for 3 days 
prior to receiving 1 mCi 124I-evuzamitide to protect the thyroid. On the day of the scan 124I-
evuzamitide will be administered via intravenous push at a proposed rate of ~1 mL per 5 
seconds. This dose corresponds to <1.5 mg of AT-01 peptide and 1 mCi +/- 10%). This dosage 
of 124I-evuzamitide is approximately 38MBq and should be calculated based on the half-life of 
96 hours and the date and time of calibration.  
Vitals including blood pressure and pulse will be monitored 15 min (+/- 5 minutes) before and 
after the injection. Cardiac PET/CT images will be acquired at approximately 5 hours post-
injection using a low-dose CT (120 kVp, 50 effective mAs). Cardiac PET images will be 
acquired for 20 minutes. PET data will be reconstructed using a 3DOSEM algorithm with 
attenuation weighting and prompt gamma correction. PET/CT images will be evaluated for 
positive radiotracer retention by a nuclear cardiologist blinded to the subjects’ history. The 
retention of 124I-evuzamitide may be quantified from PET/CT images using region-of-interest 
(ROI) analysis employing a 2D freehand ROI placement method. The data will be expressed as 
Bq/cc or as standard uptake value ratios (SUVR) using the lumen of the left atrium (blood pool) 
as the reference tissue.  
2.2.8 Statistical Considerations and Sample Size  
Given the pilot nature of this investigation, normal formal power calculation was performed.  
2.2.9 Data Analysis Plan  
Descriptive statistics will be used to summarize subjects’ demographics and clinical features. 
The subjects will be re-randomized for the readers and for quantification. The quantification will 
be performed using PMOD, and 3 different physicians will be performing quantification 
individually to verify reproducibility. PET scans will be interpreted by two readers blinded to the 
clinical information. The organ-specific radioactivity data will be expressed as the mean and 
standard deviation (SD) of three independent ROIs. The coefficient of variation (COV) will be 
expressed as (SD/mean)*100.  
2.3 Limitations and Assumptions  
This is a pilot study and thus generalizability to the broader population of patients who have 
ATTR-CA and are on stabilizer and/or silencer treatment, is unknown. Further, the patients were 
already on stabilizer and/or silencer therapy at the time of PET/CT scan, for varying duration.  
 
 
3.PATIENT NUMBERING 
Each patient will be uniquely identified in the study by a combination of the site number and 
screening number. The site number will be assigned by the coordinating site.  The screening 
number will be assigned sequentially. 

 
4. 
 
ADVERSE AND SERIOUS ADVERSE EVENTS 
 
4.1 
Adverse Events Definition 
An AE is any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease temporally 
associated with the subject’s participation in the research. 
4.2 
Serious Adverse Event (SAE) Definition 
An SAE is any untoward medical occurrence related to study participation that: 
1. Results in death. 
2. Is life-threatening (an event which places the patient at immediate risk of death from the event 
as it occurred. It does not include an event that had it occurred in a more severe form might 
have caused death). 
3. Requires in-patient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability or incapacity. 
5. Is a congenital abnormality or birth defect. 
6. An important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient and may require intervention to prevent one 
of the other outcomes listed in the definition above (e.g. events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, convulsions, or the development of drug dependency or abuse). 
4.3 
Collecting and Reviewing Adverse Event and Outcome Information 
During7 day and 28 day follow-up visits, whether in person or via telephone, the subjects will be 
asked about medically relevant changes in their health since the previous visit including 
hospitalization, and whether those hospitalizations were related to cardiovascular health. 
The study team will record AE information for start dates/times occurring any time after informed 
consent is obtained until 28 days after the time of imaging agent infusion.   
To assess relationship of an event to study procedure, the following guidelines are used: 
• 
Unrelated 
• 
Unlikely to be related 
• 
Possibly related 
• 
Probably related 
• 
Definitely related 
All adverse events must have their relationship to study participation, expectedness and severity 
of the event assessed by a qualified investigator, upon reporting of the event.  These determinations 
will be made according to the professional opinion of the investigator using the package insert of 

the imaging agent and the investigators assessment will be entered into the Redcap data collection 
software by research staff. All AEs will be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, the condition is stabilized, or the AEs are otherwise 
explained. 
4.4 
Stopping Study Procedure Due to Adverse Event 
In the use of this procedure there have been no reports of serious adverse reactions.  Nevertheless, 
the injection and scan procedure will be stopped, and the results will be marked as incomplete if 
there are any adverse reactions during its administration as part of this study.  The adverse reactions 
that will lead the investigators to stop the 124I-evuzamitide PET scan include but are not limited to 
the following events:  hypotension, fever, chills, nausea, vomiting and dizziness, as well as 
hypersensitivity reactions such as itching and various skin rashes.   
The scan will also be stopped in cases of severe cardiac symptomology such as: chest pain, 
shortness of breath, palpitations, tachycardia. In such cases, other study procedures may be 
continued. 
In addition to the planned 7 day and 28 day follow-up phone visits, subjects will be asked to contact 
the investigators if any additional adverse or allergic reactions are noted within the first 24 hours 
following the injection.  If any such events are reported, the principal investigator will determine 
if they are potentially related to the administration of the imaging agent.  Appropriate clinical care 
will be advised for any events determined by the investigator to be related to the scanning injection, 
and information about the reactions will be reported as described below. 
5.ADVERSE EVENT REPORTING 
5.1 
    Reporting to the Sponsor 
The principal and participating investigator will report every serious adverse event (SAE) to the 
study sponsor, Attralus,  as soon as possible, but no later than 48 hours after becoming aware of 
the event via phone, email or facsimile, and will complete the new SAE field on the Redcap 
database as soon as possible but no later than 48 hours after becoming aware of the event. The 
principal investigator will document the time of their awareness of the SAE in the study subject’s 
binder 
A participating investigator will also provide follow-up information on the SAE once new or 
updated information is available. The follow-up information will be added to the Redcap SAE 
field, as a follow-up to the initial entry. 
Non-serious adverse events will be recorded on the Adverse Event Form.  All non-serious entries 
related to study drug must be completed by the participating investigator within 5 business days. 
5.2 
   Reporting to the IRB 
Unanticipated Problem (UP): 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects’ research that meets all of the following criteria: 

• 
Unexpected (in terms of nature, severity or frequency) given (a) the research procedures that 
are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
• 
Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the 
procedures involved in such research); and  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic or social harm) than was previously known or recognized.  
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the investigator’s acquiring 
knowledge of the unanticipated problem in accordance with IRB policy. Additionally, the 
investigator will submit a summary of all unanticipated problems that occurred since the beginning 
of the study at the time of continuing review. 
5.3 
   Reporting to the FDA 
Suspected Adverse Reaction: 
In accordance with 21 CFR 312.32(a), a suspected adverse reaction (SAR) means any adverse 
event for which there is a reasonable possibility that the drug caused the adverse event. 
The IND Sponsor will be responsible for all communication with the FDA and will report to the 
FDA, any adverse event that is serious, unexpected and for which there is reasonable possibility 
that the drug caused the adverse event. These must be reported to the FDA as soon as possible, but 
no later than 15 calendar days after the Sponsor determines that the information qualifies for 
reporting.  Any fatal or life-threatening SARs will be reported to the FDA as soon as possible, but 
no later than 7 calendar days after the Sponsor determines that the information qualifies for such 
reporting. 
All other serious adverse events will be included in the IND annual reports that are to be submitted 
to the FDA within 60 days of the anniversary date of the IND each year. 
5.4 
   Reporting to Participants 
The study team will notify all participants of any adverse event associated with the use of the drug 
that is both serious and unexpected, as well as any incidental findings.  In addition, the investigator 
will analyze the significance of any above findings to the ongoing clinical care of the subjects. 

REGULATORY GUIDELINES 
This study will be performed in accordance with the protocol, all applicable government laws, 
regulations, and guidance in whatever city and state it in conducted within, including policies with 
the Health Insurance Portability and Accountability Act of 1996 ("HIPAA"), and all other 
applicable medical privacy laws and regulations. 
6.1 
Institutional Review Board/Independent Ethics Committee 
National regulations and ICH require that approval be obtained from an IRB or an IEC prior to 
participation of patients in research studies. Prior to the study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for patient recruitment, and any other written 
information regarding this study to be provided to a patient or patient's legal guardian must be 
approved by the IRB or IEC. 
All IRB and IEC approvals must be dated and contain IRB/IEC Chairman or designee 
authorization and must identify the IRB/IEC (e.g., name and address), the clinical protocol by title 
and/or protocol number, and the date of approval or favorable opinion was granted for the clinical 
research. 
The Investigator is responsible for obtaining continuing review of the clinical research at least 
annually or more often if specified by the IRB or IEC. The Investigator must supply the Sponsor 
with written documentation of the approval of the continued clinical research. 
The Investigator will make all attempts to ensure that the IRB or IEC is constituted and operates 
in accordance with Federal and ICH GCP and any local regulations. 
6.2 
Regulatory Authorities 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the Integrated 
Clinical Trial Report according to national and any local regulations. 
6.3 
Modification of the Protocol 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the IRB that approved the study.  Amendments to 
the protocol must be submitted in writing to the Investigator's IRB for approval prior to patients 
being enrolled under the amended protocol. 
6.4 
Informed Consent Form 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 and ICH 
will be obtained from each patient prior to undergoing any protocol-specific tests or procedures 
that are not part of routine care. 
The study purpose, methods and procedures will be explained to each potential participant, 
including all risks, benefits, compensation and alternatives. Subjects would in all cases be given 
ample time to consider participation and to consult family members or caregivers, if they wish. 
They would be given an opportunity to ask questions and have them answered. The potential 
subjects will have an opportunity to discuss the information provided directly (either in-person, on 
the telephone or on a video call) All forms of consent shall as a whole present information in 
sufficient detail relating to the research study and the circumstances of the consent process in a 
way that minimizes the possibility of coercion or undue influence. 

6.5 
Study Data Handling 
All study results will be recorded upon paper CRFs, and such data will be recorded into a shared 
RedCap electronic database no later than five days following study visit. 
Study data will be reviewed during the study in a systematic manner by a research worker who is 
not performing or administering the study procedures, in order to detect any deviations from 
intended protocol.  Significant protocol exemptions will not be considered. Upon completion of 
the project, all study records will be audited internally once more to assure good clinical practice 
and FDA compliance. 
Essential documents will be retained for the period required by applicable local law. The essential 
documents include the signed and dated final protocol, signed, and dated amendments(s), if 
applicable, signed and dated curriculum vitae of the Investigators, copies of the completed CRFs, 
signed ICFs, IRB approval and all related correspondence, financial agreements, regulatory 
approval, drug accountability, study correspondence, and patient identification codes. 
6.6 
Confidentiality 
The Investigator must ensure that the patients’ anonymity will be maintained. On the CRFs patients 
will not be identified by their names, but by the assigned patient number and initials.   
Following the principles of the Good Clinical Practice, if local regulations specify a patient’s 
number and initials will be used to identify the patient on their study records. Laboratory samples 
may be labeled with an independent numbering code, and the label will not contain any other 
personal identification information. 
 
Please consider including the following sections: 
• 
Describe how participants will be informed about AEs and SAEs, and study-related results on 
an individual or aggregate level. In addition, describe plans for detecting and managing 
incidental findings associated with study procedures.    
• 
Describe the procedures for obtaining and documenting informed consent of study participants. 
In obtaining and documenting informed consent, the investigator must comply with 
applicable regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) 
and should adhere to ICH GCP. Prior to the beginning of the trial, the investigator should 
have the IRB’s written approval for the protocol and the written informed consent form(s) 
and any other written information to be provided to the participants.  
• 
Describe the composition of the SMC or DSMB, frequency of interim data review, final data 
analysis and method of reviews. A separate DSMB Charter will provide further detail of 
DSMB membership, responsibilities and administration of the DSMB. 
• 
Describe how monitoring of the conduct and progress of the clinical investigation will be 
conducted (i.e., who will conduct the monitoring, the type, frequency, and extent of 
monitoring, who will be provided reports of monitoring, if independent audits of the 
monitoring will be conducted).  This section may refer to a separate detailed clinical 
monitoring plan.   

• 
Plans for detecting, reviewing, and reporting deviations/violations from the protocol should be 
described. Provisions for approval of protocol exemptions can be described. 
 
 

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