Clinical trial NCT05408663
Conditions: Safety Issues
Sponsor: Extend Biosciences Inc.
Start date: 2022-07-21; Completion date: 2023-06-13
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose safety and tolerability study of EXT608 in healthy subjects. There will be up to 6 sequential dose escalation cohorts of 4 participants. In each cohort 3 participants will receive EXT608 and 1 participant will receive placebo.

Detailed description:
This is a randomized, double-blind, first-in-human, placebo-controlled single ascending dose study to study the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EXT608 in healthy adult participants.

Participants will be enrolled into 1 of up to 6 planned single dose cohorts in ascending fashion.

Each cohort will consist of 4 participants randomized to receive either EXT608 or placebo, whereby 3 will receive a single injection of EXT608 and 1 will receive matching placebo.

Up to 6 dosing cohorts are planned with no single dose escalation to exceed a 3-fold dose increment. A Data Monitoring Board will review the seven-day safety data in each cohort before authorizing the initiation of the next cohort.

A screening visit will take place within 28 days of dosing. Eligible participants for each cohort will be admitted to the Clinical Research Unit (CRU) 1 day prior to dosing and remain in the CRU through at least 72 hours after dosing for safety and PK assessments before discharge. The total confinement period will be 4 nights, unless extended for management of Adverse Events (AEs) at the discretion of the Investigator

Arms: arm 1: Up to 6 sequential dose escalation cohorts will receive a single dose of EXT608 administered as a subcutaneous injection arm 2: Up to 6 participants will receive matching placebo administered as a subcutaneous injection
Interventions: intervention 1: EXT608 intervention 2: Placebo
Intervention descriptions: intervention 1: EXT608 is an investigational drug administered via subcutaneous injection intervention 2: matching placebo administered via subcutaneous injection

Protocol documents:
ICF_002.pdf: 
Screening # _______________ 
 
PRA LNX – Version 1_25May2022 
 
 
INFORMED CONSENT FORM 
AND AUTHORIZATION TO USE AND DISCLOSE  
PROTECTED HEALTH INFORMATION 
 
 
 
Study Title: 
  
EXT608 in Human Healthy Adults; A First-in-Human, 
Randomized, Double-blind, Placebo-controlled, Single 
Dose Escalation Study 
 
Sponsor:  
 
Protocol Number: 
 
Extend Biosciences Inc. 
 
EXT608-101 
 
Principal 
Investigator: 
(Study Doctor) 
 
Daniel Dickerson, MD, PhD, FAAFP 
Telephone: 
 
913-205-4397 (24-Hour Number) 
Address: 
Pharmaceutical Research Associates, Inc. 
9755 Ridge Drive, Lenexa  KS, 66219 
 
 
 
KEY INFORMATION  
 
You are invited to take part in a research study because you are a healthy adult man or 
woman 18 to 55 years of age who might meet the study participation requirements. This 
research study involves the use of a new investigational drug called EXT608. An 
investigational drug is one that is not approved by the United States Food and Drug 
Administration (FDA) for human use. It is not available for sale or prescription and can 
only be used in a study like this one. The study has received approval from the 
institutional review board.  EXT608 is a version of a hormone found naturally in the body 
called parathyroid hormone that is being studied as a possible treatment for a rare 
clinical syndrome called hypoparathyroidism. This is the first time that EXT608 will be 
used in humans. 
 
Extend Biosciences Inc. is sponsoring this research study, and has contracted 
Pharmaceutical Research Associates Inc. (PRA) to conduct the research.  
 
Please read this form carefully. Take your time to ask the study doctor or study staff as 
many questions about the study as you would like. The study doctor or study staff can 
explain words or information that you do not understand. Reading this form and talking 


 
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to the study doctor or study staff may help you decide whether to take part or not. If you 
decide to take part in this study, you must sign your name at the end of this form and 
date it.  
 
 
BACKGROUND AND PURPOSE  
 
Extend Biosciences Inc. is developing the study drug EXT608.   
 
The purpose of this research study is to: 
• Determine the safety and tolerability of a single dose of EXT608 
• Determine how EXT608 is absorbed and eliminated by your body; also known as 
pharmacokinetics 
• Determine the effect(s) of EXT608 on your body, particularly changes in calcium 
levels in the blood and urine; also known as pharmacodynamics 
• Determine the effect of EXT608 on vitamin D metabolism 
• Determine if there is an immune system effect from EXT608 
 
 
WHAT WILL HAPPEN DURING THE STUDY 
 
The study will enroll up to approximately 30 healthy adult male and female participants 
in 6 groups with approximately 4 participants in each group. In each group, 3 
participants will be given one dose of EXT608 in a subcutaneous (under the skin) 
injection, and 1 participant will be given one dose of the placebo in a subcutaneous 
injection. The placebo will look the same as EXT608 but will not have any active 
ingredients in it. Whether you receive EXT608 or placebo will be decided by 
randomization, in other words, by chance (like flipping a coin). Neither you nor the study 
staff directly involved in your care will know whether you are assigned to receive the 
study drug or the placebo, although in an emergency, if needed, the study staff can find 
out. 
 
The planned doses of EXT608 for each group of participants will be determined based 
on the safety information (blood tests results and any adverse reactions) of the prior 
dose level. The starting dose will be 4 micrograms, and each participant will receive 
only one dose of EXT608 or matching placebo. The dose levels for the subsequent 
groups are planned to be higher than the starting dose, but based upon the review of 
safety information, may be the same or lower than the previous group’s dose. 
 
Your participation in this study will last up to approximately 8 weeks, depending on the 
duration of the screening period: 
• Screening visit: Will occur within 28 days prior to receiving your dose. You will 
undergo assessments to determine whether you are eligible for the study. 


 
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• Admission, study treatment and in-patient period: You will be required be 
admitted to the study clinic 1 day prior to your scheduled dosing (before 9pm) 
and remain there for a 4-night/3-day inpatient stay. 
• Follow-up out-patient visits: Will occur on Days 5, 7, 14, 21 and 28 post-dose.  
You will need to arrive at the study clinic before 10am for these visits. 
 
Screening visit 
Before any study-related tests and procedures are performed, you will be asked to read, 
sign, and date this informed consent document. The following screening tests and 
procedures will then be performed to determine if you qualify to take part in this study:  
 
• A negative SARS-CoV-2 test or proof of vaccination may be required prior to your 
study screening procedures per the site’s procedures at the time of your visit. 
• You will be asked about your medical history  
o For females of current reproductive potential, this history will include 
current or plans of pregnancy, and for males of current reproductive 
potential, plans of conceiving or donating sperm during the course of or 
within 3 months of completing this study.   
• You will be asked about all medications, including over-the-counter, vitamin and/or 
herbal medications, that you have been, or are currently taking. 
o If you are taking certain medications that, in the opinion of the study 
doctor, cannot be discontinued or avoided for 4 weeks prior to receiving 
the study treatment through 1 month after, you will not be eligible for 
participation. 
• You will be asked to confirm your age, month and year of birth, race and ethnicity. 
• You will be asked about your drug, alcohol, and smoking history. 
• Your blood pressure, pulse rate, breathing rate, and body temperature will be 
measured.  
• You will have a full physical examination. 
• Your height and weight will be measured to determine your body mass index. 
• An electrocardiogram (recording of your heart’s electrical activity and rhythm) will 
be done  
• Blood and urine samples will be collected to assess your general health.  
o Part of the blood test will include a test for the HIV virus (which causes 
AIDS), and hepatitis B and C viruses. If the test shows you are positive for 
HIV or hepatitis, you will not be included in this study, but you will have 
follow-up counseling and medical advice. If your test results are positive, 
the study doctor may be required by state law to notify the local health 
department.  Signing and dating the consent form means you agree to have 
this testing. It will not be done without your consent. 
• A urine sample will be collected to assess your general health and to test for drugs 
of abuse and cotinine (a test for nicotine use). If you are female it will also be used 
to check if you are pregnant. 


 
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o This is a study requirement and the results will remain confidential. The 
tests may reveal that you have previously used illegal drugs. That 
information will be stored in a re-identifiable (or coded) format. If you test 
positive for any of these substances, you will be excluded from further 
participation in this study. 
 
It is possible that more participants will be screened in this study than are needed. This 
means that it is possible that you could successfully complete the screening phase and 
are ready to begin the study, but would not be admitted in the study if the target number 
of participants is achieved and your participation will then not be necessary anymore.  
 
Study Treatment  
The study treatment period will include an admission, study treatment, and in-patient 
follow up period. 
 
If you are eligible to enter the study, you will be admitted (prior to 9pm) to the study site 
the day before the planned dosing day (Day -1). On Day-1, you will undergo a number 
of procedures to confirm that you still qualify for participation in the study. 
 
You will be required to stay in the clinical unit for 4 consecutive nights and you will be 
discharged to return home on Day 3. 
 
You will have the following study visits and undergo the following procedures:  
 
Day -1 (Check-in)  
• You will be asked about your current health status and all medications, including 
over-the-counter, vitamin and/or herbal medications, that you have been, or are 
currently taking. 
• Your blood pressure, pulse rate, breathing rate, and body temperature will be 
measured.  
• You will have a physical examination and your weight will be measured. 
• An electrocardiogram will be done.   
• You will have blood and urine samples collected. If you are a female, a urine 
pregnancy test will be performed. The urine sample will test for general health, and 
will also be used to test for drugs of abuse and cotinine.   
 
During the time that you are in-patient, you will be given standardized (identical) meals 
that are given to all study participants, and will stay in the clinic overnight. 
 
Day 0 
Before you are given the study treatment, the following procedures will be done starting 
about 2 hours before you receive the study treatment: 
• You will be asked questions to confirm that you are still eligible for the study. 


 
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• Your blood pressure, pulse rate, breathing rate, and body temperature (vital signs) 
will be measured.  
• A cannula (a small flexible tube) will be inserted into a vein in one of your arms. 
This is a safety precaution so in the case of an emergency, the study site staff 
could quickly utilize it. Additionally, a second cannula may be placed that will allow 
blood to be collected easily and prevent the need for repeated needles to be 
inserted in your vein to collect each sample. The location of the cannula(s) may 
need to be changed if deemed necessary by the study site staff. 
• Blood and urine samples will be collected at various times during the study to 
check your general health and to: 
o measure the amount of EXT608 in your blood (a pharmacokinetic or 
PK test), and 
o to see the effects the study treatment has on your body (a 
pharmacodynamic or PD test) 
• A photograph of the planned injection site will be taken.  
 
Study treatment administration: You will be given either the study drug EXT608 or 
placebo by subcutaneous injection (an injection into the tissue layer between the skin 
and muscle). 
 
After dosing on Day 0, the following procedures will be done at different times as 
indicated: 
• Vital signs (1, 4, 8, 12 and 18 hours) 
• PK blood sample (15 and 30 minutes, 1, 1.5, 2, 4, 8, 12 and 18 hours) 
• PD blood sample (1, 4, 8, 12 and 18 hours) 
• You will be asked how you are feeling to assess for adverse reactions  
• Urine sample (1, 4, 8, 12 and 18 hours) 
• Your injection site will be examined for any redness, swelling, or tenderness.  A 
photograph may be taken if there is a reaction noted upon examination (15 
minutes and 1, 4 and 12 hours) 
 
Day 1-3 (24-72 hours) post-injection 
On each day, the following procedures will be done: 
• Vital signs (24, 36, 48 and 72 hours) 
• Blood samples for PK, PD and/or to assess your general health (24, 36, 48 and 72 
hours) 
• You will be asked how you are feeling and if there have been any changes in your 
health  
• Urine sample (24, 36, 48 and 72 hours) 
• Electrocardiogram (24, 48 and 72 hours) 
• Physical exam (24, 48 and 72 hours) 
• Weight (72 hours) 


 
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• Your injection site will be examined for any redness, swelling, or tenderness.  A 
photograph will be taken if there is a reaction noted upon examination (24 and 72 
hours) 
 
You will be discharged from the clinical unit on Day 3 once all study procedures are 
complete and the study staff sees no changes in your health that would prevent your 
discharge from the clinical unit. 
 
Day 5, 7, 14, 21, 28 post-injection 
On each of these days, you will be asked to arrive at the study site before 10am and the 
following procedures will be done: 
• You will be asked if you have taken any medications  
• Vital signs  
• Blood samples for PK, PD and to assess your general health  
• You will be asked how you are feeling and if you have had any changes in your 
health 
• Urine sample (Days 5, 7 and 28 only) 
• Blood sample to assess general health. On Day 28 this will also include a urine 
pregnancy test 
• 
Physical exam  
• Weight (Day 7 and 28 only) 
• Your injection site will be examined for any redness, swelling, or tenderness.  A 
photograph may be taken if there is a reaction noted upon examination   
 
If you choose to withdraw from the study early, or are asked to discontinue by the study 
doctor, you will be asked to complete all the procedures noted above that would have 
been performed on Day 28.   
 
Blood Samples 
The total amount of blood drawn for tests will be about 435 ml (1¾ cups). For 
comparison, the standard blood donation is about 480 mL. This does not include other 
blood samples that may need to be taken if the study doctor thinks it is necessary for 
your safety.   
 
 
EXPECTATIONS  
 
If you participate in this study, you must:  
• Stay in the clinical unit for 4 consecutive nights.  
• Attend all scheduled visits on time. 
• Avoid using the NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen.  
Please check with the study doctor first if you need to take any medications during 
the study.   


 
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• Males and females of child-bearing age be willing to use an approved double-barrier 
contraceptive method during and for 3 months after study drug administration. 
• Be willing to eat only the standardized meals during the in-patient stay.  
• Be willing to abstain from alcohol and drug use during study duration.    
• If male, abstain from donating sperm during the course of the study. 
• Abstain from intensive exercise during the study (e.g., high impact aerobics, 3-5K 
runs, marathon training/running, doubles tennis, CrossFit training or weightlifting). 
• Abstain from using nicotine-containing products (including but not limited to 
cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch or 
nicotine gum) within 28 days prior to Inpatient Check-in (Day -1) and throughout the 
study. 
• Inform the staff if you decide to withdraw from the study.  
 
You cannot be in this study if you are currently in another research study or if you have 
been in another research study in the last 30 days. You cannot be in this study if you 
are taking any illicit drugs (testing will be performed to check for use of drugs) or if you 
have used prescription drugs in the last 30 days. You may have to wait longer 
depending upon the type of prescription medication used. You cannot be in this study if 
you have been a smoker in the last 28 days or have a history of drug or alcohol abuse 
within the past year.  
 
 
RISKS, SIDE EFFECTS, AND/OR DISCOMFORTS  
 
This will be the first time that EXT608 will be given to humans. All known potential risks 
for EXT608 are based on animal data and on the mechanism of action (the proposed 
way the drug works in the body). The side effects in humans are still unknown.  
 
Potential risks  
Based on the mechanism of action of EXT608 and results found in animal studies on 
EXT608 performed in the laboratory, as well as potential side effects described by 
patients who were treated with multiple injections of a similar drug, risks may include: 
• Nausea 
• Constipation 
• Vomiting 
• Dehydration/increased thirst 
• Frequent urination 
• Joint pain 
• Depression 
• Confusion 
• Fatigue 
• Administration site reactions 
• Renal failure or altered kidney function 
• Changes to bone marrow 


 
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• Altered lab values, such as increases in ALT, AST, as well as changes to liver 
function, changes to levels of vitamin D, serum alkaline phosphatase, and serum 
calcium 
• Bone lesions 
• Changes in red blood cells lymphocytes and eosinophils 
• Muscle Weakness 
• Sleepiness 
• Loss of Appetite 
• Dry Mouth 
• Metallic Taste 
• Headache 
• Diarrhea 
• Extremity pain 
• Upper respiratory infection 
• Pre-syncope (feeling light headed, faint) 
• Back pain 
• Neck pain 
• Dizziness 
• Increased heart rate 
• Heart palpitations (sensation of heart beating fast and/or irregularly) 
• Increased calcium in the blood 
• Increased calcium in the urine 
• Orthostatic hypotension (low blood pressure upon standing from a sitting or lying 
position) 
 
As with taking any drug, there is a risk of having an allergic reaction. Symptoms of an 
allergic reaction may include: 
• Rash 
• Flushing (redness) 
• Swelling 
• Shortness of breath 
 
Severe allergic reactions can cause dizziness, difficulty breathing or swallowing, a 
decrease in blood pressure, and could be life threatening. If you feel that you are having 
symptoms of an allergic reaction, you should notify the study doctor or the study staff 
immediately.  
 
You should be aware that in laboratory studies of male and female rats, repeated 
dosing of the parathyroid hormone found naturally in your body caused an increase in 
the incidence of osteosarcoma (a malignant bone tumor). The osteosarcoma 
occurrence was dependent on the dose and duration of treatment. An increase in 
osteosarcoma risk has not been observed with repeat dosing of parathyroid hormone in 
humans. The risk of osteosarcoma with EXT608 has not been studied. Therefore, 


 
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participants who are at increased risk for osteosarcoma are excluded from the study. If 
you have concerns about your risk, please discuss this with the study staff.  
 
The possible risks and/or discomforts associated with the procedures described in 
this study include: 
• Blood samples: You may experience discomfort from blood sampling, and/or 
placement of the canula, including pain, bleeding, burning swelling, infection or a 
bruise at the site of the blood draw/canula placement.  You could also experience 
dizziness or faint. 
o In the rare event a PRA employee is accidentally exposed to your blood, we 
will draw about ½ tablespoon of blood from you and have it tested for HIV, 
Hepatitis B, and Hepatitis C at a local clinic. The results of the test will be 
shared with you, the PRA employee involved and the medical team 
counseling/treating the employee. 
• Electrocardiogram (ECG): The ECG procedure may cause discomfort during the 
attachment and removal of the leads to and from your chest, including mild 
irritation, slight redness, or itching. To reduce discomfort, the study staff may need 
to shave the hair at the attachment sites. 
 
Unforeseen or Unexpected Risks 
Because the study drug EXT608 is investigational and has not previously been 
administered to humans, there may be other risks that are unknown. Some of these 
may be life threatening. You will be informed of any changes in the way the study will be 
done and any additional identified risks to which you may be exposed. 
 
Reproductive Risks 
The risks to a pregnancy, embryo, or unborn baby (fetus) are unknown. This is why all 
females of child-bearing age and all males must agree to use approved double barrier 
contraception during the study and for 3 months after study drug administration.  Male 
participants must also refrain from donating sperm for the duration of the study.  
 
 
ALTERNATIVES TO PARTICIPATION  
 
This study is for research purposes only. The only alternative is to not participate in this 
study. 
 
 
NEW FINDINGS  
 
Any new important information that is discovered during the study that may influence 
your willingness to continue participation in the study will be provided to you, and in 
which case, you may be asked to sign a new consent form. 
 
 


 
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BENEFITS 
 
This study is for research purposes only. There is no direct benefit to you from your 
participation in the study. Information learned from the study may help other people in 
the future. 
 
 
COMPENSATION FOR PARTICIPATION  
 
You will be compensated for being in this study. There will be no compensation for the 
screening visit. Compensation for your participation in the study will be up to a total of 
$5,400.00 for successful completion of all study procedures. These amounts are based 
on $250.00 for each overnight stay prior to dosing (1); $550.00 for each overnight stay 
after dosing (3), and $400.00 for each out-patient visit (4). You will be compensated 
$820.00 for the follow-up visit and $1080.00 for the end-of-study completion stipend.   
 
The stipend will be paid out on the following schedule: 
• 
Day 3 Check-out: $1900.00 
• 
Day 7 Out-patient: $800.00 
• 
Day 14 Out-patient:$400.00 
• 
Day 21 Out-patient: $400.00 
• 
Follow-Up: $820.00 
• End-of Study: $1080.00 
The $1080.00 end-of-study completion stipend will be provided only after participation is 
completed, including any required repeat labs or other procedures. This stipend will be 
provided to you within 3 business days of your last visit 
 
Compensation will be issued in the form of a ClinCard. With the exception of the end-of-
study completion stipend, these stipends are usually loaded to your ClinCard by the 
evening of the visit; however, the maximum amount of time it may take is two business 
days. 
 
Should you stop participating in the study early or be taken out of the study by 
the PRA medical team or the Sponsor, you will be compensated for the stays and 
visits that you have completed in the amounts indicated above. 
 
If you are released from the study on Day 1 due to being a qualified alternate, you will 
be paid the stipend for the completed overnight stay(s) in the amount indicated above. 
As a qualified alternate, you will have completed all predose procedures that would 
have allowed you to be dosed in the study had a dosing spot been available.  In addition 
to the nightly stipend, you will receive $100 for successful completion of predose 
assessments. 
 
If you are required to return to the clinic for an additional visit for a repeat procedure 


 
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during the screening process, you may be compensated $50.00 to $100.00 for your 
time and travel, depending on the reason for the additional visit. If you are required to 
return to the clinic for an additional visit for a repeat procedure after you are enrolled in 
the study, you will be compensated $50.00 to $100.00 for your time and travel. 
 
If you do not follow the study guidelines, you may be dismissed from the study. If this 
occurs, you will only be compensated for the procedures which you have completed. 
 
You must read and agree to follow the PRA House Rules if you want to take part in this 
study. The House Rules discuss proper behavior at PRA. House Rules must be 
followed to make sure the study results are accurate. You may be fined or withdrawn 
from the study if you do not follow the House Rules. 
 
According to the IRS (Internal Revenue Service) guidelines, you will be responsible for 
paying taxes on any compensation that you receive from your study participation. PRA 
will send you a 1099-form for this purpose. PRA will also report to the IRS any 
compensation that you receive that total $600.00 or more for the calendar year (January 
to December). You should tell PRA of your new mailing address if you move after your 
participation in a study. This is to make sure you receive your 1099 for your year-end 
tax reporting. 
 
Your participation in this study may contribute to the development of commercial 
products from which the Sponsor or others may receive economic benefit. You will have 
no rights to any patents, discoveries or products arising from this research, and you will 
receive no financial benefit or payments relating to these potential products. 
 
 
 
CONFIDENTIALITY   
 
Records of your participation in this study will be held confidential except when sharing 
the information is required by law or as described in this informed consent form. The 
study doctor, the Sponsor or persons working on behalf of the Sponsor, and under 
certain circumstances, the United States Food and Drug Administration (FDA) and the 
Institutional Review Board (IRB) will be able to inspect and copy confidential study-
related records that identify you by name. This means that absolute confidentiality 
cannot be guaranteed. If the results of this study are published or presented at 
meetings, you will not be identified. 
 
Photographs 
Some medical conditions are documented by taking digital photographs. If any changes 
occur anytime during this study, digital photographs of the affected area(s) may be 
taken to document the condition. If photographs are taken, the photos will be identified 
only by your subject number and initials and only involve the area where the condition is 
located. Your face will not be visible. 


 
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COMPENSATION FOR INJURY  
 
If you become ill or are injured while you are in the study, get the medical care that you 
need right away. You should inform the healthcare professional treating you that you 
are participating in this study. Tell the study staff that you think you are ill or have been 
injured so that they will help you get the care you need.  
 
If you are injured as a result of the proper administration of the study drug(s) or from 
properly performed procedures done for the purpose of this study, the Sponsor will pay 
for those medical expenses necessary to treat your injury that are not covered by your 
medical insurance or any other third-party coverage. The Sponsor will not pay the cost 
of your medical care that is unrelated to the clinical study drug or the procedures in the 
treatment plan, or that are pre-existing medical conditions.  
 
Neither PRA nor the Sponsor assumes any independent liability for any injury suffered 
which is the result of any of the following: pre-existing condition or illness (whether or 
not the condition or illness has been previously diagnosed); substance abuse or 
withdrawal from any addictive substance; an accident in the parking lot of PRA; travel to 
or from PRA for screening, admission, study procedures; any other factor outside the 
control of the Sponsor, PRA, and their respective employees or agents. 
 
By signing this consent form, you will not lose any of your legal rights or release 
the Sponsor, the study doctor, the study staff, or study site from liability for 
mistakes. 
 
COSTS  
 
There will be no charge to you for your participation in this study. The study treatment, 
study-related procedures, and study visits will be provided at no charge to you or your 
insurance company. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a study-related injury, 
or have questions, concerns or complaints about the study, please contact the study 
doctor at the telephone number listed on the first page of this consent document. If you 
seek emergency care, or if hospitalization is required, alert the treating physician that 
you are participating in this research study.  
 
An Institutional Review Board (IRB) is an independent committee established to help 
protect the rights of research participants. If you have any questions about your rights 


 
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as a research participant, and/or concerns or complaints regarding this research study, 
contact: 
 
• By mail:   
o WCG IRB 
1019 39th Avenue SE 
Suite 120 
Puyallup, WA 98374 
 
• call toll free:   
o 855-818-2289 
   
• or by email: 
o researchquestions@wcgirb.com       
 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
 
Your decision to participate in this study is voluntary. You may choose to not participate, 
or you may withdraw from the study for any reason without penalty or loss of benefits to 
which you are otherwise entitled, and without any effect on your future medical care. 
However, please note that the FDA requires that any information collected up to the 
point of your withdrawal cannot be removed from the study and can continue to be 
used. 
 
If you decide to withdraw from the study, please notify your study doctor or study staff 
before you withdraw. This notice will allow the study doctor to discuss any health risks 
or special requirements linked to withdrawing. 
 
The study doctor or the Sponsor can stop your participation at any time without your 
consent for the following reasons: 
 
• If it appears to be medically harmful to you 
• If you fail to follow directions for participating in the study 
• If it is discovered that you do not meet the study requirements 
• If the study is canceled 
• For administrative reasons 
 
If you leave the study for any reason, the study doctor may ask you to have some end-
of-study tests for your safety.  
 
 
 
 


 
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PRIMARY HEALTH CARE PROVIDER NOTIFICATION OPTION  
 
I consent to having my family doctor or primary health care provider notified by the 
study site of my participation in this study and/or any significant findings related to my 
health (please check yes or no). 
!YES (If yes, please complete the information below) 
!NO  
 
Name and address of family 
doctor or primary health care 
provider: 
Name: 
Address: 
 
Telephone and Fax Number: 
Tel: 
Fax: 
 
 
 
 


 
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CONSENT  
 
I have read and understand the information in this informed consent document. I 
have had an opportunity to ask questions and all of my questions have been 
answered to my satisfaction. I voluntarily agree to participate in this study until I 
decide otherwise. I do not give up any of my legal rights by signing this consent 
document. I will receive a copy of this signed and dated consent document. 
 
 
________________________________________ 
 
___________ 
Participant’s Printed Name                                                       Time 
 
 
________________________________________ 
 
___________  
Participant’s Signature 
 
 
 
 
 
Date 
 
 
________________________________________ 
 
___________ 
Printed Name of the Person Conducting the  
 
 
Time 
Consent Discussion  
 
 
________________________________________ 
 
___________ 
Signature of the Person Conducting the   
 
           Date  
Consent Discussion  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 16 of 17 
 
PRA LNX – Version 1_25May2022 
 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and study team will use and share 
health data about you to conduct the study. Health data may include: 
• Your name 
• Address 
• Phone number 
• Date of birth 
• Medical history 
• Information from your study visits, including all test results  
 
Health data may come from your study records or from existing records kept by your 
doctor or other health care workers.  
 
For this study, the study team may share health data about you with authorized users. 
Authorized users may include: 
• The Sponsor of the study, Extend Biosciences, Inc. 
• Extend Biosciences’ research collaborators, business partners, subcontractors 
and agent(s), in the United States or in other countries, working to conduct the 
study, to monitor the study, or to analyze the study information for this study or 
for other research about the study drug. 
• Other qualified researchers, approved by Extend Biosciences, Inc., who may 
receive individual research results that do not identify you  
• Representatives of the Clinical Research Organization (CRO) conducting the 
study, ICON. 
• Representatives of the IRB (an Institutional Review Board that reviews this 
study). 
• The Food and Drug Administration (FDA) and other US federal and state 
agencies. 
• Government agencies to whom certain diseases (like HIV and hepatitis) must be 
reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data storage 
companies, that work with the study team and Sponsor and need to access your 
information to conduct this study. 
• Other study doctors and medical centers participating in this research, if 
applicable.  
• A data monitoring board which oversees this research, if applicable. 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways other 
than those listed here.  


 
Page 17 of 17 
 
PRA LNX – Version 1_25May2022 
 
 
Your health data will be used to conduct and oversee the research, including for 
instance: 
• To conduct the study, to monitor your health status, to measure the effects of the 
study drug being studied, and to determine the research results.  
• To compare the study drug to other drugs 
• For other research activities related to the study drug 
• To ensure that the research meets legal and institutional requirements 
• To develop new tests, procedures, and commercial products  
• For regulatory filing purposes  
• To enhance research databases, so that scientists can design better research 
studies to develop new therapies for patients and to gain a better understanding 
of disease 
Your permission to use and share health data about you will not end unless you revoke 
it (take it back).  
 
You may revoke your permission to use and share health data about you at any time by 
writing to the study doctor at the address listed on the first page of this form. If you do 
this, you will not be able to stay in this study. No new health data that identifies you will 
be gathered after your written request is received. However, health data about you that 
has already been gathered may still be used and given to others as described in this 
form.  
 
Your right to access your health data in the study records will be suspended during the 
study to keep from changing the study results. When the study is over, you can access 
your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use and share my health 
data as specified in this form. I will receive a signed and dated copy of this form for my 
records. I am not giving up any of my legal rights by signing and dating this form.  
 
________________________________________ 
 
___________ 
Participant’s Printed Name                                                       Time 
 
 
__________________________________ 
 
 
__________ 
Signature of Participant 
 
 
 
 
 
Date 
 
 

Prot_000.pdf: 
 
 
Clinical Study Protocol 
EXT608 in Human Healthy Adults; A First-in-Human, 
Randomized, Double-blind, Placebo-controlled, Single Dose 
Escalation Study 
 
Protocol Number:  EXT608-101  
Version Number:  
3.0; 24 October 2022 
Compound:   
EXT608  
IND Number:  
IND 146180  
Study Phase:   
Phase 1  
 
Short Title: Safety and Tolerability Study of EXT608 in Healthy Participants  
 
Regulatory Sponsor: Extend Biosciences Inc., 90 Bridge St., Suite 100, Newton, 
Massachusetts, 02458 United States of America 
 
Sponsor Contact: 
Laura Hales 
 
 
 
Cell phone (732) 599-8581 
 
Medical Monitor:  
Poul Strange, MD, PhD 
Cell phone (609) 897-0505 x7114 
 
 
 


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Digitally signed by LEI SHI 
Date: 2022.10.24 15:44:20 
-04'00'


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INVESTIGATOR SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable regulatory and ICH 
guidelines. 
 
Principal Investigator: 
 
 
Signature: 
 
Date: 
 
 
Print Name: 
 
______________________________________ 
 
 
 
 
 


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DESCRIPTION OF CHANGES to Protocol v.3.0 
The protocol was amended per recommendation of FDA to state that all Injection Site 
Reactions, serious and non-serious, will be recorded as Adverse Events. 
Changed text is indicated by strikethrough (deleted text). 
Section. 6.4   Injection Site Assessment 
Positive events will furthermore be recorded as AEs. only if they are determined to be 
Serious Adverse Events. 
DESCRIPTION OF CHANGES to Protocol v.2.0 
The protocol was amended to clarify discrepancies between the schedule of procedures 
(Tables 7.1 and 7.1.1) and the text, to correct minor errors and to add a Visual Analog Scale 
for evaluation of injection site pain.  
Changed text is indicated by boldface type (new text) or strikethrough (deleted text). In 
addition to the changes shown below, clarifications, minor editorial and formatting changes 
have been made. 
Section 4.1 Participant inclusion criteria 
3.  Male or female between 18 and 55 years of age. Male subjects with female partners of 
child bearing potential must agree to use barrier contraception, e.g., condoms plus 
spermicide, from administration of the study drug until at least 3 months after 
administration of the study drug. Abstinence from heterosexual intercourse from 
administration of study drug until at least 3 months after administration of study drug is 
acceptable if it is in accordance with the subject’s lifestyle. Female subjects should be 
surgically sterile (had a bilateral tubal ligation, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, or hysterectomy), postmenopausal (defined as 12 months with 
no menses prior to Screening and a serum follicle stimulating hormone in the 
postmenopausal range at Screening), or, if of child bearing potential, must be non-
lactating and willing to use a highly effective method of birth control for 30 days prior 
to administration of study drug and agree to continued use of this method until at least 1 
month after administration of study drug. Abstinence from heterosexual intercourse for 
30 days prior to administration of study drug until at least 1 month after the 
administration of study drug is acceptable if it is in accordance with subject’s lifestyle. 
May also consider including wording on male sterilization (vasectomy) and sole male 
partner of female subject sterilization (vasectomy). 
Reason for change: The deleted text was included in error in the original protocol. 
Section 6.2.2 Medical History 
The medical history will include: disorders of head, eyes, ears, nose and throat; neoplastic 
and hematological disorders; infectious diseases; disorders of the cardiovascular system 
including hypertension and hyperlipidemia, each with duration; disorders of the 


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respiratory system; disorders of the kidney and urinary tract; disorders of the 
gastrointestinal system; disorders of the immune system, connective tissue and joints; 
endocrinology and metabolism with a subcategory for diabetes including year of 
diagnosis, treatment, complications including nephropathy, neuropathy, and retinopathy; 
neurological disorders; and finally alcohol, illicit drug and smoking history including 
duration in years and 20-pack equivalents a day number of pack years. 
Reason for change: Correction 
 
Section 6.4 Injection Site Assessment 
A Visual Analog Scale (VAS) will be used for evaluation of injection site pain. A 
copy of the VAS is in Appendix 2. 
 
Reason for change: To provide a standardized measurement of tenderness.  
 
Positive events that are deemed clinically relevant will furthermore be recorded as AEs 
only if they are determined to be Serious Adverse Events.  
 
Reason for change: Potential injection site reactions are of special interest and thus 
carefully assessed as described above. As asking participants to rate injection site pain 
is a form of solicitation, which results in biased reporting frequencies, non-serious 
injection site reactions will not additionally be reported as AEs in the present study.   
  
Section 6.8.2.2 Urine PD 
Additional pooled urine collections will take place at the following intervals:  
• Day 1 0: a 4-hour urine collection will begin after dosing. 
• Day 1 0: from 4 hours post-dose until bedtime. Participants will be instructed to 
empty their bladders prior to sleep.  If the participant voids during the night, the 
urine will be collected and pooled with the first morning void. The time and 
volume of urine must be recorded. 
• Day 2 1 through Day 3: 12- hour urine collections.  
 
Reason for change: To be consistent with the Schedule of Procedures with regards to 
naming conventions for study days. 
 
Section 7.1.1: Sequestered Schedule- Footnote 4 and Section 7.2.5.3 
Time 4 hours 
C-telopeptide of type I collagen 
Reason for change: This test is not required and was included in the original protocol 
in error. 
 
Section 7.2.3.2 – 90 minutes prior to planned delivery of study product:  


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a. Clinical Chemistry panel and Complete Blood Count 
Sections 7.2.6.1- Day 1, 7.2.6.3- Day 2 and 7.2.6.4- Day 3:  
Added: Review of concomitant medication 
Reason for change: To be consistent with the Schedule of Procedures in Table 7.1.1. 
 
Added: Appendix 2 Visual Analog Scale 
Synopsis 
 
Protocol Title:  
EXT608 in Human Healthy Adults; A First-in-Human, Randomized, Double-blind, 
Placebo-controlled, Single Dose Escalation Study 
 
Study Center(s): 
Pharmaceutical Research Associates, Inc. 
9755 Ridge Drive, Lenexa  KS, 66219 
 
Investigational Product:  
EXT608 dissolved in a buffered isotonic saline solution 
Starting Dose and Dose Escalation Scheme:  
The starting dose will be 4 µg in a volume of 10 ul. Up to 6 dosing cohorts are planned 
with no single dose escalation to exceed a 3-fold dose increment. 
 
Route of Administration:  
Subcutaneous (SC) injection 
 
Objectives and Endpoints:  
The primary objective is to characterize the safety and tolerability profile of escalating 
dose levels of EXT608 when administered to healthy adult participants as a single 
injection as assessed by:  
1. Incidence, nature, and severity of adverse events (AEs) and withdrawals due to 
treatment emergent AEs (TEAEs) [Time Frame: Day 0 up to Day 28]  
2. Frequency and severity of post-dose change from baseline in hematology, serum 
chemistries, urinalysis, electrocardiogram (ECG), vital signs, and physical 
examination (Exam) findings [Time Frame: Day 0 up to Day 28]  
3. Percentage of participants with injection site reactions [Time Frame: Day 0 to 
Day 7] 
The secondary objectives are to assess: 


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1. Single dose PK including AUC0-24h, AUC0-48h, AUC0-28d, AUC0-≈, Cmax, Tmax, T½, 
ƛz, Cl/F and Vz/F. 
2. Single dose PD by post-dose change from baseline in serum chemistries with 
particular attention to Se-Ca, phosphate, magnesium, and creatinine. Urinalysis 
will also be performed. 
Furthermore, the exploratory objectives are to assess: 
1. Single dose Immunogenicity by anti-drug antibodies (ADA) and any neutralizing 
subset (NAb), 
2. Single dose effect on vitamin D metabolism by serum 25-hydroxy-vitamin D and 
1,25-dihydroxy-vitamin D concentrations. 
 
Number of Patients: 
Up to approximately 30 participants may be enrolled to the study intervention, such that 
approximately 24 evaluable participants complete the study.  
Additional participants and cohorts may be enrolled pending review of study data and 
recommendation by a Data Monitoring Board (DMB) and ratification by the Sponsor.  
Study Design 
This is a randomized, double-blind, first-in-human (FIH), placebo-controlled single 
ascending dose (SAD) study to study the safety, tolerability, PK, and PD of EXT608 in 
healthy adult participants. Each participant will provide written informed consent and 
must meet all of the eligibility criteria prior to being randomized and administered study 
product. Participants who discontinue prematurely will be replaced at the discretion of 
the Sponsor. 
Participants will be enrolled into 1 of up to 6 planned single dose cohorts (designated as 
S1 through S6, respectively) in ascending fashion.  
Each cohort will consist of 4 participants randomized to receive either EXT608 or 
placebo, whereby 3 will receive a single injection of EXT608 and 1 will receive matching 
placebo.  
A safe clinical starting dose will be targeted to have a <10% of maximal effect (Emax) 
based on allometric scaling of pharmacokinetics (PK) and pharmacodynamics (PD), and 
will be less than the threshold derived from 1/10 of the human equivalent of the No 
Adverse Effect Level (NOAEL) established in GLP toxicology studies. Up to 6 dosing 
cohorts are planned with no single dose escalation to exceed a 3-fold dose increment. 
Following a dose escalation, participant dosing for the second and third participant will 
be staggered at least 72 hours post-dosing pending review of safety data including Se-Ca 
and adverse events (AEs) by the Investigator and Medical Monitor.  
A potential DLT is defined as any of the following EXT608 TEAEs that occurs during 
the DLT period, graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0 (2):  
• Grade = 3 TEAE  
• Grade = 3 anemia  
• Grade = 3 AST/ALT elevation; and/or  
• Grade = 2 AST/ALT elevation and Grade = 2 Bilirubin elevation  


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• Grade = 3 QTc prolongation  
• Grade = 3 Hyper- and/or Hypotension  
• Grade = 2 Hyperparathyroidism  
• Grade = 2 Hyperthyroidism  
• Grade = 3 Hypercalcemia  
• Grade = 3 Hypocalcemia  
• Grade = 3 Hypophosphatemia  
• Grade = 3 Hypomagnesemia  
• Grade = 3 Creatinine increased 
Dose escalation decisions will be based on the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0 (2) and Se-Ca levels. 
The DMB will review the seven-day safety data in each cohort before authorizing the 
initiation of the next cohort according to the following decision tree: 
1. No Grade 3 AEs suspected related to study drug and no indication of effect 
observed from Se-Ca will result in the next dose at 3x the previous cohort dose. 
2. No Grade 3 AEs suspected related to study drug and clear indication of effect on 
Se-Ca will result in the next dose at 2x the previous cohort dose.  
3. A Grade 3 AE suspected related to study drug in a single (n=4) cohort and the 
absence of prohibitive effects on Se-Ca will result in an additional cohort at the 
same dose. 
4. A single Grade 3 AE suspected related to study drug in 2 cohorts at the same dose 
(n=8) cohort and the absence of prohibitive indication of effects on Se-Ca will 
result in a dose escalation to 1.5x the previous dose. 
5. Two or more of the same Grade 3 AE within the same cohort suspected related to 
study drug, or average peak Se-Ca > 1.5 mg/dl above the Upper Limit of Normal 
(ULN) range will terminate dose escalation.  
a. If the last dose escalation was 50% and by implication 2 cohorts received 
the previous dose for an n=8, the study will stop. 
b. If the last dose escalation was >50%, the next cohort should receive a dose 
2/3x the previous dose.  
Any DMB recommendation that deviates from the decision tree will be ratified by the 
Sponsor prior to implementation. 
The study schematic is presented in Section 3.2. 
Pending the outcomes of the GLP toxicology and other nonclinical pharmacology studies, 
planned dose levels will be administered by subcutaneous injection.  
A screening visit will take place within 28 days of dosing. 
Participants for each cohort will be admitted to the study unit 1 day prior to dosing and 
remain in the unit through at least 72 hours after dosing for safety and PK assessments 
before discharge. The total confinement period will be 4 nights, unless extended for 
management of AEs at the discretion of the Investigator. The schedule of events while 
inpatient is provided in Section 7.1.1. Follow-up visits to the clinic will occur on/about 
days 5, 7, 14, 21 and 28. Participants will be monitored closely during the duration of the 


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study for safety, PK, and PD assessments as described in Section 3.2. The total duration 
of follow-up period may be modified in the final study design based on safety and PK 
data from non-clinical studies, anticipated PK/PD response and extended in individual 
participants as needed to observe their calcium levels return to concentrations deemed not 
needing further follow up.  
Additional/Alternative PK/PD time points may be implemented if the Sponsor determines 
this is necessary to fully characterize the PK profile of EXT608.  
 
Eligibility Criteria 
Inclusion Criteria:  
Participants must meet each of the following inclusion criteria to be eligible for 
randomization:  
1. Ability to personally provide written, signed, and dated informed consent to 
participate in the study.  
2. An understanding, ability, and willingness to fully comply with study procedures 
and restrictions.  
3. Male or female between 18 and 55 years of age. Male subjects with female 
partners of child bearing potential must agree to use barrier contraception, e.g., 
condoms plus spermicide, from administration of the study drug until at least 3 
months after administration of the study drug. Abstinence from heterosexual 
intercourse from administration of study drug until at least 3 months after 
administration of study drug is acceptable if it is in accordance with the subject’s 
lifestyle. Female subjects should be either surgically sterile (had a bilateral tubal 
ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy), postmenopausal (defined as 12 months with no menses prior to 
Screening and a serum follicle stimulating hormone in the postmenopausal range 
at Screening), or, if of child bearing potential, must be non-lactating and willing 
to use a highly effective method of birth control for 30 days prior to 
administration of study drug and agree to continued use of this method until at 
least 1 month after administration of study drug. Abstinence from heterosexual 
intercourse for 30 days prior to administration of study drug until at least 1 month 
after the administration of study drug is acceptable if it is in accordance with 
subject’s lifestyle.  
4. Body mass index between 18.5 and 32 kilogram per square meter (kg/m2), 
inclusive, with a body weight greater than or equal to (>=) 45 kg (99 pounds 
[lbs]). This inclusion criterion will only be assessed at the first screening visit.  
5. The participant is in general good medical health with no clinically significant or 
relevant abnormalities, including medical history, physical exam, vital signs, 
ECG, and laboratory evaluations (hematology, chemistry, and urinalysis) as 
assessed by the Investigator.  
6. Willing and able to consume standardized meals during the confinement period of 
the study. All participants will be required to consume the similar meals and 


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amounts as practicable on study days when serial pharmacokinetic (PK) and 
pharmacodynamic (PD) blood samples are collected.  
7. A clinical safety laboratory parameter of hemoglobin greater than (>) 11.7 gram 
per deciliter (g/dl) (females) or 13.1 g/dl (males) and less than (<) 16 g/dl 
(females) or 17.4 g/dl (males) or, if out of this range, deemed not clinically 
significant by the Investigator.  
8. Total Se-Ca within laboratory normal limits.  
9. Serum parathyroid hormone (PTH) concentration within normal laboratory limits 
at the screening visit only.  
 
Exclusion Criteria:  
Participants are excluded from the study if any of the following exclusion criteria are 
met:  
1. Participant has received any investigational compound within 30 days prior to the 
first dose of study product, or within 5 half-lives, whichever is greater.  
2. Participant is a study site employee or an immediate family member of a study 
site employee.  
3. Participant has evidence of clinically significant (CS) neurologic, cardiovascular, 
pulmonary, hepatic, hematopoietic disease, renal, metabolic, gastrointestinal, 
urologic, immunologic, endocrine disease, serious allergy, allergic skin rash, 
psychiatric disorder, or other abnormality that may impact the ability of the 
participant to participate or potentially confound the study results.  
4. There is any finding in the participant’s medical history, physical exam, or safety 
laboratory tests giving reasonable suspicion of a disease that would contraindicate 
taking EXT608, or a similar drug in the same class, or that might interfere with 
the conduct of the study.  
5. Participant has a known hypersensitivity to any component of the formulation of 
EXT608.  
6. Participant has a positive urine result for drugs of abuse at Screening or Inpatient 
Check-in (Day -1).  
7. Participant has a history of drug abuse (defined as any illicit drug use) or alcohol 
abuse within 1 year prior to the Screening Visit or is unwilling to agree to abstain 
from alcohol and drugs throughout the study.  
8. Participant is currently using any medication (including over-the-counter [OTC], 
herbal or homeopathic preparations), that, in the opinion of the Investigator, 
cannot be discontinued and avoided for 4 weeks (or other time period as noted 
below) prior to the first dose through 1 month after dose administration. 
Specifically:  
a. 14 days - thiazide diuretics  
b. 30 days - loop diuretics, lithium, systemic corticosteroids (medical 
judgment is required by the Investigator). Primarily high doses of systemic 
corticosteroids (i.e., prednisone) should be excluded  
c. 3 months - calcitonin, cinacalcet hydrochloride, treatment with rhPTH (1-
84) or N-terminal PTH or PTH-related peptide fragments or analogs  


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d. For females: changes in hormone replacement therapy within 3 months are 
excluded. Stable (>=3 months) hormone replacement therapy is acceptable  
e. 6 months - fluoride tablets, oral bisphosphonates, methotrexate, growth 
hormone, digoxin, raloxifene or similar selective estrogen receptor 
modulators (SERMs)  
f. 12 months - intravenous bisphosphonates 
9. Participant is pregnant, nursing, or planning a pregnancy during the course of or 
within 3 months of completing this study.  
10. Participant is male and intends to donate sperm before 90 days after study drug 
administration.  
11. Participant has a history of cancer or other malignancy, with the exception of 
basal cell carcinoma that has been in remission for at least 5 years prior to Day -1.  
12. Participant has a positive test result for hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) antibody or a human immunodeficiency virus (HIV) 
infection at Screening.  
13. Participant has used nicotine-containing products (including but not limited to 
cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch or 
nicotine gum) within 28 days prior to Inpatient Check-in (Day -1) or a positive 
urine cotinine test at Screening or Inpatient Check-in (Day -1).  
14. Participant has poor peripheral venous access.  
15. Participant has donated or lost 450 mL or more of their blood volume (including 
plasmapheresis) or had a transfusion of any blood product, within 45 days prior to 
Day 0.  
16. Participant has a Screening or Inpatient Check-in (Day -1) abnormal (CS) ECG. 
Entry of any participant with an abnormal (NCS) ECG must be approved and 
documented by signature by the Investigator or medically qualified sub-
investigator.  
17. Participant has a resting blood pressure outside the ranges of 90 to 140 mm Hg for 
systolic and 55 to 90 mm Hg for diastolic, confirmed with repeat per Investigator 
discretion, at the Screening Visit or Inpatient Check-in (Day -1).  
18. Participant has a resting heart rate outside the range 40 to 90 bpm, confirmed with 
repeat per Investigator discretion, at the Screening Visit or Inpatient Check-in 
(Day -1).  
19. Participant has increased CV proarrhythmic potential (3): 
a. Participant has a QT interval with Fridericia’s correction method (QTcF) 
>450 ms or PR outside the range of 120 to 220 ms, confirmed with one 
repeat testing, at the Screening Visit or Inpatient Check-in (Day -1) Visit.  
b. A history of additional risk factors for TdP (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
c. The use of concomitant medications that prolong the QT/QTc interval. 
20. Participant has abnormal Screening or Inpatient Check-in (Day -1) laboratory 
values that suggest a CS underlying disease or participant with the following 
laboratory abnormalities: ALT and/or AST >1.5 the ULN, confirmed with one 
repeat testing.  
21. Participant is at increased baseline risk for osteosarcoma such as participant with 
Paget's disease of bone or unexplained elevations of alkaline phosphatase, young 


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adult participants with open epiphyses, participants with hereditary disorders 
predisposing to osteosarcoma or participant with a prior history of external beam 
or implant radiation therapy involving the skeleton are excluded.  
 
Study duration 
Subject participation in the study includes:  
• Up to a 4-week screening period  
• Approximately a 5-day inpatient dosing period  
• An additional outpatient monitoring of 25 days, for a total study duration of 
approximately 58 days  
 
Statistical Methods 
Sample Size 
The sample size is not determined for inferential testing purposes. The sample size of 
4 participants per cohort (3 active: 1 placebo) is considered sufficient for evaluation of 
safety, tolerability, and PD of EXT608 prior to making a decision about dose escalation 
as Se-Ca is very tightly regulated and determination of effect based on simulations can 
therefore reliably be made with the small sample. 
 
Statistical Analyses 
AEs will be presented in listings and TEAEs will be summarized. Individual results of 
laboratory tests (hematology, chemistry, and urinalysis) will be listed and change from 
baseline will be summarized using shift tables. Individual results of vital signs will be 
listed and observed values and changes from baseline will be summarized.  
Individual results of quantitative ECG parameters from the 12-lead safety ECGs will be 
listed and observed values and changes from baseline will be summarized and analyzed 
consistent with the ICH E14 (3).  
All summaries will be performed by placebo and each EXT608 dose level. Placebo data 
will be pooled across cohorts. Physical exam findings will be presented in data listings.  
Concentrations of EXT608 will be summarized by dose over each scheduled sampling 
time using descriptive statistics. Individual plasma concentration data versus time will be 
presented in a data listing. PK parameters will be summarized by dose using descriptive 
statistics. Dose proportionality will be assessed graphically and using a power model. PD 
will be presented in listings and summarized by dose and time point.  
Detection of ADA and NAbs will be presented in listings and summarized by dose and 
time point.  
No formal hypothesis testing will be conducted as part of this study.  
DMB data packages will be based on the FAS for safety and PP for PK/PD. 
 
 


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Table of Contents 
 
EXT608 in Human Healthy Adults; A First-in-Human, Randomized, Double-blind, 
Placebo-controlled, Single Dose Escalation Study ............................................................. 1 
DESCRIPTION OF CHANGES to Protocol v.2.0 ............................................................. 4 
Synopsis .............................................................................................................................. 6 
Table of Contents .............................................................................................................. 13 
Abbreviations and Definitions .......................................................................................... 17 
1 
Background Information ........................................................................................... 20 
1.1 
Hypoparathyroidism ......................................................................................... 20 
1.1.1 
Hypoparathyroidism standard of care ......................................................... 20 
1.2 
Extend Biosciences’ EXT608 .......................................................................... 20 
1.3 
Rationale for Dose Selection ............................................................................ 21 
2 
Trial Objectives and Purpose .................................................................................... 21 
2.1 
Primary Objective ............................................................................................. 21 
2.2 
Secondary Objectives ....................................................................................... 21 
2.3 
Exploratory Objectives ..................................................................................... 21 
3 
Trial Design .............................................................................................................. 22 
3.1 
Design Description ........................................................................................... 22 
3.1.1 
Numbers of Cohorts and Participants, and Treatment Allocation .............. 22 
3.1.2 
Starting Dose ............................................................................................... 22 
3.1.3 
Staggering of Participants after Dose Escalation (Sentinel Participants) ... 22 
3.1.4 
Dose Limiting Toxicity (DLT) Criteria ...................................................... 22 
3.1.5 
Dose Escalation ........................................................................................... 23 
3.1.6 
Individual Participant Schedule .................................................................. 23 
3.2 
Trial schematic ................................................................................................. 24 
3.3 
Design rationale ................................................................................................ 25 
3.3.1 
Population ................................................................................................... 25 
3.3.2 
Control ........................................................................................................ 25 
3.3.3 
Intervention ................................................................................................. 25 
3.3.4 
Stratification, randomization and adaptive treatment allocation based on 
baseline covariates with strata .................................................................................. 25 
3.3.5 
Blinding....................................................................................................... 25 
3.3.6 
Endpoint ...................................................................................................... 25 
4 
Selection and Withdrawal of Participants ................................................................. 25 
4.1 
Participant inclusion criteria ............................................................................. 25 
4.2 
Participant exclusion criteria ............................................................................ 26 
4.3 
Participant withdrawal criteria ......................................................................... 28 


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4.3.1 
Originator of withdrawal request ................................................................ 28 
4.3.2 
Withdrawal documentation ......................................................................... 29 
4.3.3 
Follow up on withdrawn participants ......................................................... 29 
4.4 
Non-completer replacement policy .................................................................. 29 
5 
Treatment of Participants .......................................................................................... 29 
5.1 
Lifestyle ............................................................................................................ 29 
5.2 
Concomitant medications ................................................................................. 29 
5.2.1 
Medications for the investigated condition ................................................. 29 
5.2.2 
Other concomitant medications and dietary supplements .......................... 29 
5.2.3 
Prohibited medications ................................................................................ 30 
5.3 
Test and control product ................................................................................... 30 
5.3.1 
General principles ....................................................................................... 30 
5.3.2 
Test treatment.............................................................................................. 30 
5.3.3 
Control treatment ........................................................................................ 30 
5.3.4 
Drug Accountability.................................................................................... 30 
5.3.5 
Disposal, Return or Retention of Study Drug ............................................. 30 
5.4 
Blinding ............................................................................................................ 31 
5.4.1 
Treatment blinding ...................................................................................... 31 
5.4.2 
Endpoint blinding........................................................................................ 31 
5.4.3 
Breaking the blind ....................................................................................... 31 
5.5 
Treatment assignment, stratification, and randomization ................................ 31 
5.6 
Supply, storage and accountability ................................................................... 31 
5.6.1 
Test and Control Treatment and Labeling .................................................. 31 
5.6.2 
Study Product Preparation .......................................................................... 31 
5.6.3 
Concomitant medications............................................................................ 32 
5.6.4 
Ancillary supplies ....................................................................................... 32 
5.7 
Participant Compliance .................................................................................... 32 
6 
Procedures and Assessments Description ................................................................. 32 
6.1 
Collection Methodology and Data Flow .......................................................... 32 
6.1.1 
Case Report Form (CRF) ............................................................................ 32 
6.1.2 
Electronically uploaded data ....................................................................... 32 
6.2 
Demographic Variables .................................................................................... 32 
6.2.1 
Participant identification ............................................................................. 33 
6.2.2 
Medical History .......................................................................................... 33 
6.2.3 
Concomitant medication ............................................................................. 33 
6.3 
Physical Exam .................................................................................................. 33 
6.3.1 
Complete Physical Exam ............................................................................ 33 
6.3.2 
Directed Physical Exam .............................................................................. 33 


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6.4 
Injection Site Assessment ................................................................................. 33 
6.5 
Vital Signs: Pulse, Blood Pressure, Respiratory Rate and Temperature .......... 34 
6.6 
Weight, Height and Body Mass Index (BMI) .................................................. 34 
6.7 
Electrocardiogram (ECG) ................................................................................. 34 
6.8 
Urine Sample Laboratory Variables ................................................................. 35 
6.8.1 
Urine Pregnancy Test .................................................................................. 35 
6.8.2 
Urinalysis .................................................................................................... 35 
6.9 
Blood Sample Laboratory Variables ................................................................ 36 
6.9.1 
Blood Sample Draw .................................................................................... 36 
6.9.2 
Total Amount of Blood Drawn for Sampling ............................................. 36 
6.9.3 
Screening and Safety Laboratory Tests ...................................................... 36 
6.9.4 
Pharmacokinetics (PK) ............................................................................... 36 
6.9.5 
Pharmacodynamic (PD) variables............................................................... 36 
6.10 
Safety Variables and Safety Reporting ............................................................ 37 
6.10.1 Adverse Events ........................................................................................... 37 
7 
Study Procedures ...................................................................................................... 40 
7.1 
Schedule of procedures .................................................................................... 40 
7.1.1 
Sequestered Schedule .................................................................................. 41 
7.2 
Chronological Description of Study Activities ................................................ 42 
7.2.1 
Screening..................................................................................................... 42 
7.2.2 
Day -1, Check-in for Inpatient Period ......................................................... 43 
7.2.3 
Day 0 of Inpatient Period, before and including Injection .......................... 43 
7.2.4 
Day 0, the First Hour after Injection ........................................................... 44 
7.2.5 
Day 0 from 1 Hour after Injection .............................................................. 45 
7.2.6 
Days 1 through 3 of the Inpatient Period .................................................... 46 
7.2.7 
Outpatient Follow-up .................................................................................. 47 
7.2.8 
Early Termination from Study .................................................................... 49 
7.3 
Data Monitoring Board and Dose Escalations ................................................. 50 
7.3.1 
Data Monitoring Board ............................................................................... 50 
7.3.2 
Dose Escalations ......................................................................................... 50 
8 
Statistical Methods .................................................................................................... 50 
8.1 
Sample size ....................................................................................................... 50 
8.2 
Analysis populations ........................................................................................ 50 
8.3 
Data Analysis ................................................................................................... 50 
9 
Direct Access to Source Data/Documents ................................................................ 51 
10 
Quality Control and Quality Assurance ................................................................. 51 
10.1 
Monitoring ........................................................................................................ 51 
10.2 
Data Management ............................................................................................. 51 


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10.2.1 Audits .......................................................................................................... 52 
11 
Ethics...................................................................................................................... 52 
11.1 
Informed Consent ............................................................................................. 52 
12 
Data Handling and Recordkeeping ........................................................................ 52 
13 
Publication Policy .................................................................................................. 52 
14 
References .............................................................................................................. 53 
15 
Appendix 1 ............................................................................................................. 54 
16 
Appendix 2 ............................................................................................................. 55 
 
 
 


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Abbreviations and Definitions 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-24h 
Area under the curve, zero to 24 hours 
AUC0-48h 
Area under the curve, zero to 48 hours 
AUC0-28d 
Area under the curve, zero to 28 days 
AUC0-≈ 
Area under the curve, zero to infinity 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl/F 
Apparent clearance 
CRA 
Clinical Research Associate 
(e)CRF 
(Electronic) Case Report Form. Refers to the online form part of 
the EDC that directly reflects data that is manually entered by the 
investigational site staff. 
CRU 
Clinical Research Unit 
CS 
Clinically significant 
CTCAE 
NCI Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DLT 
Dose limiting toxicity 
DMB 
Data Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture (application). In addition to the eCRF, 
the EDC may include other items including uploaded files, 
treatment allocation and supply management. 
EDTA 
Ethylenediaminetetraacetic acid 
eID 
Electronic ID 
Emax 
Estimated maximal value of drug levels in an Emax model 
EoS 
End of Study 
Exam 
Examination 
F 
Bioavailability 
FAS 
Full Analysis Set (statistical analysis population) 
FIH 
First-in-human 


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GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
Hg 
Mercury; a measurement of pressure 
HIV 
Human immunodeficiency virus 
ICMJE 
Internal Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ITT 
Intent to Treat (statistical analysis population) 
iv 
Intravenous 
ƛz 
Elimination constant 
NAb 
Neutralizing antibody 
NCS 
Non-clinically significant 
NOAEL 
No Adverse Effect Level 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over the counter 
PD 
Pharmacodynamics 
PDF 
Portable Document Format 
Pbo 
Placebo 
PK 
Pharmacokinetics 
PP 
Per Protocol (statistical analysis population) 
PR 
A measurement on an ECG of the conduction of the impulse from 
the upper part of the atrium to the ventricle 
PTH 
Parathyroid hormone - amino acids 1-84 (full length) 
QRS 
A measurement on an ECG of ventricular depolarization 
QTc  
A measurement on an ECG of the duration of ventricular 
depolarization 
QTcF 
QTc measurement using Fridericia’s formula 
RBC 
Red Blood Cell count 
RR 
A measurement on an ECG of the function of the intrinsic 
properties of the sinus node (the time between heart beats) 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
sc 
Subcutaneous 
Se-Ca 
Serum calcium 
SERM 
Selective estrogen receptor modulator 


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Study product 
The formulated product as delivered to the participant containing 
either test (active) drug or control (placebo). The term may refer 
to either.  
T1/2 
Serum half-life of a drug; the time it takes for the concentration of 
the drug to be reduced by half 
TEAE 
Treatment Emergent Adverse Event 
TdP 
Torsade de pointes; refers to a specific abnormal heart rhythm 
Tmax 
The time it takes to reach maximum drug concentration 
ULN 
Upper Limit of Normal 
VAS 
Vz/F 
Visual Analog Scale 
Apparent distribution volume 
WBC 
White Blood Cell count with differential count 
 


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1 Background Information 
1.1 Hypoparathyroidism 
Hypoparathyroidism is a rare clinical syndrome that results from reduced or absent 
parathyroid gland function and is characterized by low serum calcium (Se-Ca) levels, 
elevated serum phosphorus levels, and absent or inappropriately low levels of parathyroid 
hormone (PTH) in circulation. Hypoparathyroidism is most often caused by inadvertent 
removal or destruction (i.e., radiation treatment) of the parathyroid glands, the presence 
of autoimmune or congenital diseases, or low blood plasma magnesium levels. The low 
production of PTH in hypoparathyroidism patients leads to abnormally low calcium 
levels in blood, and an increase of phosphorus in the blood. 
PTH is secreted in response to low blood Se-Ca levels. To release more ionic calcium 
into the blood, PTH indirectly stimulates bone matrix turnover, enhances renal tubular 
calcium reabsorption, as well as intestinal calcium absorption. 
Patients with hypoparathyroidism most often present with paresthesia, cramps, or tetany, 
but the disorder may also manifest acutely with seizures, bronchospasm, laryngospasm, 
or cardiac rhythm disturbances. In the postsurgical setting, the presentation can be acute 
with tetany, cramping, tachycardia, and altered mental status predominating. Affected 
individuals are most often diagnosed with low blood calcium, magnesium and PTH 
levels, but high phosphorus levels, and frequently show increased urinary calcium 
excretion, which can lead to nephrocalcinosis and kidney stones. Hyperphosphatemia can 
be associated with deposition of calcium-phosphate complexes in other soft tissues.  
1.1.1 Hypoparathyroidism standard of care 
Current standard of care for hypoparathyroidism includes oral calcium carbonate 
supplements and active forms of vitamin D. Under restrictions, alternative treatment with 
once-daily injections of Parathyroid hormone (rhPTH (1-84), Natpara®) has been 
approved by the FDA only for patients whose calcium levels can't be controlled with 
calcium and vitamin D supplements.  
1.2 Extend Biosciences’ EXT608 
EXT608 is under development as an extended half-life hPTH(1-34), covalently attached 
to a derivative of vitamin D using the D-VITylation® technology, which results in an 
extended half-life and improved absorption and bioavailability of PTH, aimed at reducing 
the rate and/or doses of injections. For more information refer to the Investigator’s 
Brochure (1). 
The purpose of this study is to characterize the safety, tolerability, pharmacokinetic (PK), 
and pharmacodynamic (PD) profiles of EXT608 when administered as a single dose to 
healthy adult participants. EXT608 has undergone a full non-clinical testing program as 
recommended by the FDA and is therefore ready to be studied in humans to further its 
development. Data from this study are intended to identify and select pharmacologically 
active dose levels for subsequent dose ranging and other studies in patients with 
hypoparathyroidism.  


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1.3 Rationale for Dose Selection 
A safe clinical starting dose will be targeted to have a <10% of maximal effect (Emax) 
based on allometric scaling of pharmacokinetics (PK) and pharmacodynamics (PD), and 
will be less than the threshold derived from 1/10 of the human equivalent of the No 
Adverse Effect Level (NOAEL) established in GLP toxicology studies. Up to 6 dosing 
cohorts are planned with no single dose escalation to exceed a 3-fold dose increment. 
 
2 Trial Objectives and Purpose 
The purpose of this first-in-human study is to obtain initial safety, tolerability, PK, and 
PD information about EXT608 to facilitate optimal design of the first clinical study 
conducted in participants with the target indication. 
2.1 Primary Objective 
The primary objective is to characterize the safety and tolerability profile of escalating 
dose levels of EXT608 when administered to healthy adult participants as a single 
injection as assessed by:  
1. Incidence, nature, and severity of adverse events (AEs) and withdrawals due to 
treatment emergent AEs (TEAEs) [Time Frame: Day 0 up to Day 28]  
2. Frequency and severity of post-dose change from baseline in hematology, serum 
chemistries, urinalysis, electrocardiogram (ECG), vital signs, and physical 
examination (Exam) findings [Time Frame: Day 0 up to Day 28]  
3. Percentage of participants with injection or infusion site reactions [Time Frame: 
Day 0 to Day 7] 
2.2 Secondary Objectives 
The secondary objectives are to assess: 
1. Single dose PK including AUC0-24h, AUC0-48h, AUC0-28d, AUC0-≈, Cmax, Tmax, T½, 
ƛz, Cl/F and Vz/F. 
2. Single dose PD by post-dose change from baseline in serum chemistries with 
particular attention to Se-Ca, phosphate, magnesium, and creatinine. Urinalysis 
will also be performed. 
2.3 Exploratory Objectives 
Furthermore, the exploratory objectives are to assess: 
1. Single dose Immunogenicity by anti-drug antibodies (ADA) and any neutralizing 
subset (NAb), 
2. Single dose effect on vitamin D metabolism by serum 25-hydroxy-vitamin D and 
1,25-dihydroxy-vitamin D concentrations. 


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3 Trial Design 
3.1 Design Description 
This is a randomized, double-blind, first-in-human (FIH), placebo-controlled single 
ascending dose (SAD) study to study the safety, tolerability, PK, and PD of EXT608 in 
healthy adult participants. Each participant will provide written informed consent and 
must meet all of the eligibility criteria prior to being randomized and administered study 
product. Participants who discontinue prematurely will be replaced at the discretion of 
the Sponsor. 
3.1.1 Numbers of Cohorts and Participants, and Treatment Allocation 
Up to approximately 30 participants may be enrolled to the study intervention such that 
approximately 24 evaluable participants complete the study.  
Additional participants and cohorts may be enrolled pending review of study data and 
recommendation by a Data Monitoring Board (DMB) and ratification by the Sponsor.  
Participants will be enrolled into 1 of up to 6 planned single dose cohorts (designated as 
S1 through S6, respectively) in ascending fashion.  
Each cohort will consist of 4 participants randomized to receive either EXT608 or 
placebo, whereby 3 will receive a single injection of EXT608 and 1 will receive matching 
placebo.  
3.1.2 Starting Dose 
The starting dose will be 4 µg in a volume of 10 ul.  Up to 6 dosing cohorts are planned 
with no single dose escalation to exceed a 3-fold dose increment. 
3.1.3 Staggering of Participants after Dose Escalation (Sentinel Participants) 
For the first cohort, one participant will be dosed initially. A review of safety data, 
including Se-Ca and adverse events (AEs) for the first 72 hours post-dose will be 
conducted by the Investigator and Medical Monitor. If there are no safety concerns, a 
second participant will be dosed and the same safety review will be conducted to review 
data up to 72-hrs post-dose. If there are no safety concerns, the last two participants in the 
cohort will be dosed.  
For subsequent cohorts, this staggering requirement only applies to cohorts for doses 
higher than previously experienced in the study.  
3.1.4 Dose Limiting Toxicity (DLT) Criteria 
A potential DLT is defined as any of the following EXT608 TEAEs that occurs during 
the DLT period, graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0 (2):  
• Grade = 3 TEAE  
• Grade = 3 anemia  
• Grade = 3 AST/ALT elevation; and/or  
• Grade = 2 AST/ALT elevation and Grade = 2 Bilirubin elevation  


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• Grade = 3 QTc prolongation  
• Grade = 3 Hyper- and/or Hypotension  
• Grade = 2 Hyperparathyroidism  
• Grade = 2 Hyperthyroidism  
• Grade = 3 Hypercalcemia  
• Grade = 3 Hypocalcemia  
• Grade = 3 Hypophosphatemia  
• Grade = 3 Hypomagnesemia  
• Grade = 3 Creatinine increased 
3.1.5 Dose Escalation 
Dose escalation decisions will be based on the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), Version 5.0 (2) and Se-Ca levels. 
The DMB will review the seven-day safety data in each cohort before authorizing the 
initiation of the next cohort according to the following decision tree: 
1. No Grade 3 AEs suspected related to study drug and no indication of effect 
observed from Se-Ca will result in the next dose at 3x the previous cohort dose. 
2. No Grade 3 AEs suspected related to study drug and clear indication of effect on 
Se-Ca will result in the next dose at 2x the previous cohort dose.  
3. A Grade 3 AE suspected related to study drug in a single (n=4) cohort and the 
absence of prohibitive effects on Se-Ca will result in an additional cohort at the 
same dose. 
4. A single Grade 3 AE suspected related to study drug in 2 cohorts at the same dose 
(n=8) cohort and the absence of prohibitive indication of effects on Se-Ca will 
result in a dose escalation to 1.5x the previous dose. 
5. Two or more of the same Grade 3 AE within the same cohort suspected related to 
study drug, or average peak Se-Ca > 1.5 mg/dl above the Upper Limit of Normal 
(ULN) range will terminate dose escalation.  
a. If the last dose escalation was 50% and by implication 2 cohorts received 
the previous dose for an n=8, the study will stop. 
b. If the last dose escalation was >50%, the next cohort should receive a dose 
2/3x the previous dose.  
Any DMB recommendation that deviates from the decision tree will be ratified by the 
Sponsor prior to implementation. 
The study schematic is presented in Section 3.2. 
3.1.6 Individual Participant Schedule 
A screening visit will take place within 28 days of dosing. Eligible participants for each 
cohort will be admitted to the Clinical Research Unit (CRU) 1 day prior to dosing and 
remain in the CRU through at least 72 hours after dosing for safety and PK assessments 
before discharge. The total confinement period will be 4 nights, unless extended for 
management of AEs at the discretion of the Investigator. The schedule of events while 


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inpatient is provided in Section 7.1.1. Follow-up visits to the CRU will occur on/about 
days 5, 7, 14, 21 and 28. Participants will be monitored closely during the duration of the 
study for safety, PK, and PD assessments as described in Section 3.2. The total duration 
of follow-up period may be modified in the final study design based on safety and PK 
data from non-clinical studies, anticipated PK/PD response and extended in individual 
participants as needed to observe their calcium levels return to concentrations deemed not 
needing further follow up.  
Additional/Alternative PK/PD time points may be implemented if the Sponsor determines 
this is necessary to fully characterize the PK profile of EXT608.  
 
3.2 Trial schematic  
 
 


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3.3 Design rationale 
3.3.1 Population 
PK modeling of various approaches to extend the half-life of compounds in animals is 
generally not a good predictor of half-life in humans. Knowledge of single dose PK and 
indications of PD in humans are usually sufficient to model multiple dose PK accurately 
and with reasonable precision, and can give good indications of plasma drug 
concentrations. This enables the accurate determination of target dose range for 
therapeutic effect and therefore guides optimal design choice for studies in patients with 
hypoparathyroidism. 
The safest population in which to obtain the single dose PK is healthy participants.  
3.3.2 Control 
To study the PD, the most appropriate comparator is placebo, and as the participants do not 
have a parathyroid hormone deficiency, there are no concerns associated with that. 
3.3.3 Intervention 
EXT608 is the compound under development.  
3.3.4 Stratification, randomization and adaptive treatment allocation based 
on baseline covariates with strata 
In the modest planned cohort size, the DMB needs evaluable data up to and including 
Day 7 for a reliable dose escalation decision. Any participants for whom such data are not 
available will be replaced with a new participant receiving the same treatment assignment 
as the original participant to ensure the 3:1 ratio of active compound to control. 
3.3.5 Blinding 
The primary outcome is safety and tolerability. The assessment relies partly on adverse 
events evaluations that are prone to reporting bias and can be effectively mitigated with 
the double-blind design.  
3.3.6 Endpoint 
Dose limiting toxicity is routinely determined by AEs related to the intervention under 
investigation. Acute effects of parathyroid hormone analogues can be monitored by 
changes Se-Ca, which is tightly regulated in normal physiology with a narrow normal 
range. Furthermore, the relationship between elevated Se-Ca and adverse effects is well 
established. The combination of the limiting toxicity guided by PD therefore appears 
optimal in this situation.  
4 Selection and Withdrawal of Participants 
4.1 Participant inclusion criteria 
Participants must meet each of the following inclusion criteria to be eligible for 
randomization:  


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1. Ability to personally provide written, signed, and dated informed consent to 
participate in the study.  
2. An understanding, ability, and willingness to fully comply with study procedures 
and restrictions.  
3. Male or female between 18 and 55 years of age. Male subjects with female 
partners of child bearing potential must agree to use barrier contraception, e.g., 
condoms plus spermicide, from administration of the study drug until at least 3 
months after administration of the study drug. Abstinence from heterosexual 
intercourse from administration of study drug until at least 3 months after 
administration of study drug is acceptable if it is in accordance with the subject’s 
lifestyle. Female subjects should be surgically sterile (had a bilateral tubal 
ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy), postmenopausal (defined as 12 months with no menses prior to 
Screening and a serum follicle stimulating hormone in the postmenopausal range 
at Screening), or, if of child bearing potential, must be non-lactating and willing 
to use a highly effective method of birth control for 30 days prior to 
administration of study drug and agree to continued use of this method until at 
least 1 month after administration of study drug. Abstinence from heterosexual 
intercourse for 30 days prior to administration of study drug until at least 1 month 
after the administration of study drug is acceptable if it is in accordance with 
subject’s lifestyle.  
4. Body mass index between 18.5 and 32 kilogram per square meter (kg/m2), 
inclusive, with a body weight greater than or equal to (>=) 45 kg (99 pounds 
[lbs]). This inclusion criterion will only be assessed at the first screening visit.  
5. The participant is in general good medical health with no clinically significant or 
relevant abnormalities, including medical history, physical exam, vital signs, 
ECG, and laboratory evaluations (hematology, chemistry, and urinalysis) as 
assessed by the Investigator.  
6. Willing and able to consume standardized meals during the confinement period of 
the study. All participants will be required to consume similar meals and amounts 
as practicable on study days when serial pharmacokinetic (PK) and 
pharmacodynamic (PD) blood samples are collected.  
7. A clinical safety laboratory parameter of hemoglobin greater than (>) 11.7 gram 
per deciliter (g/dl) (females) or 13.1 g/dl (males) and less than (<) 16 g/dl 
(females) or 17.4 g/dl (males) or, if out of this range, deemed not clinically 
significant by the Investigator.  
8. Total Se-Ca within laboratory normal limits.  
9. Serum parathyroid hormone (PTH) concentration within normal laboratory limits.  
4.2 Participant exclusion criteria 
Participants are excluded from the study if any of the following exclusion criteria are 
met:  
1. Participant has received any investigational compound within 30 days prior to the 
first dose of study product, or within 5 half-lives, whichever is greater.  


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2. Participant is a study site employee or an immediate family member of a study 
site employee.  
3. Participant has evidence of clinically significant (CS) neurologic, cardiovascular, 
pulmonary, hepatic, hematopoietic disease, renal, metabolic, gastrointestinal, 
urologic, immunologic, endocrine disease, serious allergy, allergic skin rash, 
psychiatric disorder, or other abnormality that may impact the ability of the 
participant to participate or potentially confound the study results.  
4. There is any finding in the participant’s medical history, physical exam, or safety 
laboratory tests giving reasonable suspicion of a disease that would contraindicate 
taking EXT608, or a similar drug in the same class, or that might interfere with 
the conduct of the study.  
5. Participant has a known hypersensitivity to any component of the formulation of 
EXT608.  
6. Participant has a positive urine result for drugs of abuse at Screening or Inpatient 
Check-in (Day -1).  
7. Participant has a history of drug abuse (defined as any illicit drug use) or alcohol 
abuse within 1 year prior to the Screening Visit or is unwilling to agree to abstain 
from alcohol and drugs throughout the study.  
8. Participant is currently using any medication (including over-the-counter [OTC], 
herbal or homeopathic preparations), that, in the opinion of the Investigator, 
cannot be discontinued and avoided for 4 weeks (or other time period as noted 
below) prior to the first dose through 1 month after dose administration. 
Specifically:  
a. 14 days - thiazide diuretics  
b. 30 days - loop diuretics, lithium, systemic corticosteroids (medical 
judgment is required by the Investigator). Primarily high doses of systemic 
corticosteroids (i.e. prednisone) should be excluded  
c. 3 months - calcitonin, cinacalcet hydrochloride, treatment with rhPTH 
(1-84) or N-terminal PTH or PTH-related peptide fragments or analogs  
d. For females: changes in hormone replacement therapy within 3 months are 
excluded. Stable (>=3 months) hormone replacement therapy is acceptable  
e. 6 months - fluoride tablets, oral bisphosphonates, methotrexate, growth 
hormone, digoxin, raloxifene or similar selective estrogen receptor 
modulators (SERMs)  
f. 12 months - intravenous bisphosphonates 
9. Participant is pregnant, nursing, or planning a pregnancy during the course of or 
within 3 months of completing this study.  
10. Participant is male and intends to donate sperm before 90 days after study drug 
administration.  
11. Participant has a history of cancer or other malignancy, with the exception of 
basal cell carcinoma that has been in remission for at least 5 years prior to Day -1.  
12. Participant has a positive test result for hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV) antibody or a human immunodeficiency virus (HIV) 
infection at Screening.  
13. Participant has used nicotine-containing products (including but not limited to 
cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch or 


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nicotine gum) within 28 days prior to Inpatient Check-in (Day -1) or a positive 
urine cotinine test at Screening or Inpatient Check-in (Day -1).  
14. Participant has poor peripheral venous access.  
15. Participant has donated or lost 450 mL or more of their blood volume (including 
plasmapheresis) or had a transfusion of any blood product, within 45 days prior to 
Day 0.  
16. Participant has a Screening or Inpatient Check-in (Day -1) abnormal (CS) ECG. 
Entry of any participant with an abnormal (NCS) ECG must be approved and 
documented by signature by the Investigator or medically qualified sub-
investigator.  
17. Participant has a resting blood pressure outside the ranges of 90 to 140 mm Hg for 
systolic and 55 to 90 mm Hg for diastolic, confirmed with repeat per Investigator 
discretion, at the Screening Visit or Inpatient Check-in (Day -1).  
18. Participant has a resting heart rate outside the range 40 to 90 bpm, confirmed with 
repeat per Investigator discretion, at the Screening Visit or Inpatient Check-in 
(Day -1).  
19. Participant has increased CV proarrhythmic potential (3): 
a. Participant has a QT interval with Fridericia’s correction method (QTcF) 
>450 ms (males) or >450 ms (females) or PR outside the range of 120 to 
220 ms, confirmed with one repeat testing, at the Screening Visit or 
Inpatient Check-in (Day -1) Visit.  
b. A history of additional risk factors for TdP (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
c. The use of concomitant medications that prolong the QT/QTc interval. 
20. Participant has abnormal Screening or Inpatient Check-in (Day -1) laboratory 
values that suggest a CS underlying disease or participant with the following 
laboratory abnormalities: ALT and/or AST >1.5 the ULN, confirmed with one 
repeat testing.  
21. Participant is at increased baseline risk for osteosarcoma such as participant with 
Paget's disease of bone or unexplained elevations of alkaline phosphatase, young 
adult participants with open epiphyses, participants with hereditary disorders 
predisposing to osteosarcoma or participant with a prior history of external beam 
or implant radiation therapy involving the skeleton are excluded.  
4.3 Participant withdrawal criteria 
4.3.1 Originator of withdrawal request 
4.3.1.1 Participant choice 
Study participants are free to withdraw from the study at any time at their own initiative.  
Participants should be instructed in the importance of notifying the site of such a 
decision. 
4.3.1.2 Investigator determination 
The Investigator may withdraw the participant at his or her discretion should further 
participation for medical reasons not be in the participant's best interest, or for non-


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compliance with the CRU rules and requirements. If possible, the Medical Monitor for 
the study should be contacted to discuss the individual case before withdrawal. 
4.3.1.3 Data Monitoring Board Recommendation 
Potential DLTs as listed in Section 3.1.4 are evaluated by the DMB per the procedures 
outlined in the Safety Plan. 
4.3.1.4 Sponsor request 
The Sponsor may request discontinuation of any participant for non-compliance with 
study procedures or other significant protocol violations, and may discontinue the study 
in the case that significant new information becomes available that renders the study 
unsafe or of questionable medical and scientific value to continue. 
4.3.2 Withdrawal documentation 
In case of withdrawal, the end of study Case Report Form (CRF) must be filled out 
including the reasons for the withdrawal, and if possible, a full end of study visit should 
be completed, and as a minimum the Investigator must evaluate that the participant is 
clinically stable for release from the study.   
4.3.3 Follow up on withdrawn participants 
Early discontinuation does not nullify the need to follow adverse events up until 
resolution or stabilization.  
4.4 Non-completer replacement policy 
Any participants who do not complete and deliver data for a reliable Day 7 assessment 
for review by the DMB for dose escalation decisions will be replaced with a new 
participant receiving the same treatment assignment as the original participant after 
discussion and approval by the Sponsor’s Medical Monitor.  
5 Treatment of Participants 
5.1 Lifestyle 
Participants will be instructed to continue to lead their normal lifestyle except they should 
refrain from high intensity aerobic and anaerobic exercise for the duration of the study.  
5.2 Concomitant medications 
5.2.1 Medications for the investigated condition  
Not applicable. 
5.2.2 Other concomitant medications and dietary supplements 
Except as noted in Section 5.2.3, and Section 4.2 (Exclusion criterion #8) all medication 
and dietary supplements should be discontinued at least 4 weeks prior to investigational 
product dosing, and if possible, no new medications should be started.  If any changes of 


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products or doses occur, the Investigator must be notified by the participant to ensure 
adequate documentation. 
5.2.3 Prohibited medications 
To the degree possible, NSAIDs should be avoided due to their effect on coagulation. 
5.3 Test and control product  
The test and control products are dissolved in a buffered isotonic saline and have 
indistinguishable appearances. EXT608 injectable solution is stored frozen (-20°C) and 
thawed when ready to use. Thawing should take place at room temperature (~25°C), but 
no higher than body temperature (~37°C), protected from light if possible. It is supplied 
as a clear solution in a ready-to-use concentration, single use, glass vial at a concentration 
of 0.4 mg/mL (pH 4.8-6.2).  The vehicle/placebo solution consists of sterile saline. 
EXT608 is provided as a single dose, glass vial containing a sterile, clear injectable 
solution in one strength of 0.4 mg/mL.   
5.3.1 General principles  
Storage is frozen at -20 ⁰C or less. 
5.3.2 Test treatment 
EXT608 dissolved in a buffered isotonic saline solution. 
5.3.3 Control treatment  
Buffered isotonic saline solution. 
5.3.4 Drug Accountability 
Accountability for the study drug at the CRU is the responsibility of the Investigator. The 
investigator will ensure that the study drug is used only in accordance with this protocol. 
Where allowed, the Investigator may choose to assign some of the drug accountability 
responsibilities to a pharmacist or other appropriate individual. Drug accountability records 
indicating the drug’s delivery date to the CRU, inventory at the CRU, use by each subject, 
and return to the Sponsor (or destruction, if approved by the Sponsor) will be maintained 
by the CRU. These records will adequately document that the subjects were provided the 
doses as specified in the protocol and should reconcile all study drug received from the 
Sponsor or its designee. Accountability records will include dates, quantities, batch/serial 
numbers, and subject identification numbers. The site monitor will review drug 
accountability at the site on an ongoing basis during monitoring visits. 
5.3.5 Disposal, Return or Retention of Study Drug 
All unused and used study drug will be retained at the CRU until inventoried by the site 
monitor. All used, unused or expired study drug will be returned to the Sponsor or if 
authorized, disposed of at the study site in accordance with governing regulations and 
documented.  


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5.4 Blinding 
5.4.1 Treatment blinding  
Two Unblinded pharmacy staff members including at least one pharmacist trained to 
prepare sterile injectables will prepare the doses. The pharmacy staff can have no other 
role in the study. The doses will be administered by qualified staff trained to administer 
subcutaneous injections.  
With the exception of the DMB members, all other parties remain blinded to the 
treatment results, until periodic reviews are performed by the DMB. 
5.4.2 Endpoint blinding 
For safety reasons, no outcomes are blinded. 
5.4.3 Breaking the blind 
In case of a medical emergency for a participant, the Investigator and Medical Monitor 
have the capability to obtain the treatment code from the EDC. The reason for this action 
must be documented in the EDC. 
5.5 Treatment assignment, stratification, and randomization 
Treatment allocation is performed in the EDC in a manner that ensures only the 
unblinded pharmacist or equivalent knows the treatment code.   
The treatment assignment is computer generated by the EDC at the point of 
randomization. Participants are randomized 3:1 active:control in blocks of 4.  
5.6 Supply, storage and accountability 
5.6.1 Test and Control Treatment and Labeling 
Extend Biosciences, Inc. will supply test and control product. The products will be 
supplied bulk in 2 ml vials each labeled individually with a label that includes: 
1. Product identity 
2. Lot no. and manufacturing date 
3. Recommended storage (protect from light) 
4. The text: “Caution – for Investigational Use Only.” 
5. Manufacturer and address. 
Storage for both is frozen at -20⁰C or less.  
The products will be logged by the site pharmacy or equivalent, and accounting of all 
dispensed product will be performed. 
5.6.2 Study Product Preparation 
Study product is thawed in a room temperature water bath and has to be administered 
within 4 hours of thawing.  


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5.6.3 Concomitant medications 
No concomitant medications are supplied. 
5.6.4 Ancillary supplies 
Not applicable. 
5.7 Participant Compliance 
Participant compliance will be assessed by planned versus delivered medication, and 
completeness of data acquisition.  
6 Procedures and Assessments Description 
This section describes how to collect and transfer the individual data to the 
Sponsor/CRO. The tables in Section 7.1 describe what data has to be collected when, and 
Section 7.2 outlines the activities in a logical but not mandatory sequence for ease of 
execution.  
6.1 Collection Methodology and Data Flow 
6.1.1 Case Report Form (CRF) 
An electronic CRF (eCRF) will be supplied to the investigational site for collection of 
information.  The eCRF is not considered source information and the investigational site 
must have the information available in source documentation. 
6.1.2 Electronically uploaded data 
6.1.2.1 Participant Files and Documents 
Participant files are uploaded in the EDC under the specific participant ID. These files 
may include:  
1. photographs of the injection sites or  
2. lesion from other AEs, or  
3. files from other data collection devices, or 
4. requested copies of source documents for remote source document verification 
(SDV) 
6.1.2.2  Laboratory Data 
Data from the local laboratory will be uploaded to the Sponsor/CRO directly. A test 
report will be sent to the site for inclusion in the participant chart; this will be considered 
source data. 
6.2 Demographic Variables 
Demographic variables including the medical history and current medications will be 
obtained at the screening visit.  All demographic data are entered into the EDC. 
The data to be collected include: 


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6.2.1 Participant identification 
Participant sex, month and year of birth, and ethnic origin with the categories Caucasian, 
African-American, Hispanic, Asian and “other” with a text input field.  
6.2.2 Medical History 
A medical history will be taken at screening. While serious conditions in the past have to 
be recorded, the emphasis will be on conditions within the last two years including 
completeness of currently ongoing conditions.   
The medical history will include: disorders of head, eyes, ears, nose and throat; neoplastic 
and hematological disorders; infectious diseases; disorders of the cardiovascular system 
including hypertension and hyperlipidemia, each with duration; disorders of the 
respiratory system; disorders of the kidney and urinary tract; disorders of the 
gastrointestinal system; disorders of the immune system, connective tissue and joints; 
endocrinology and metabolism with a subcategory for diabetes including year of 
diagnosis, treatment, complications including nephropathy, neuropathy, and retinopathy; 
neurological disorders; and finally alcohol, illicit drug and smoking history including 
duration in years and number of pack years. 
6.2.3 Concomitant medication 
A complete listing of current medications within the last three months including vitamins, 
herbal and dietary supplements with dose and frequency will be obtained at screening.  
Any medications taken throughout the study must be recorded in the eCRF. 
Acetaminophen may be given at the discretion of the Investigator. 
6.3 Physical Exam 
6.3.1 Complete Physical Exam 
A complete physical exam will be performed at the screening and the last visit either 
when the participant has completed the full study or at an early termination.  The physical 
exam will include: general appearance; head, eyes, ears, nose, throat, chest, lungs, heart, 
abdomen, musculoskeletal, skin neurological including reflexes.  At the screening exam, 
any abnormalities found will be recorded in the eCRF under the medical history in the 
appropriate category. Any new findings at the last visit will be captured as an adverse 
event on the CRF for adverse events.  The eCRF will thus not include any specific pages 
for physical exam. 
6.3.2 Directed Physical Exam 
A directed physical exam based on reported symptoms will be conducted at the scheduled 
time points except for the first and last visit with the complete physical exam described 
above. Any new findings at the last visit will be captured as an adverse event on the CRF 
for adverse events.   
6.4 Injection Site Assessment 
The intended injection site in the abdomen will be photographed prior to injection. 


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The injection site assessment includes evaluation of erythema, edema and any tenderness. 
The size of any erythema is measured with shortest and longest size in mm, and edema 
similarly in size and in addition the tallest height above surrounding skin. The 
measurement data are recorded in the EDC.  
Any positive finding will photographed with clear labeling next to the lesion of 
participant ID, date and time.  
Following a positive finding the injection site will be photographed daily in the inpatient 
period, and subsequently at the clinics visits until resolved. 
Minimally, the photographs  
1. prior to injection,  
2. when the event is at highest intensity, and  
3. when resolved or stabilized  
will be uploaded in the EDC.  
A Visual Analog Scale (VAS) will be used for evaluation of injection site pain. A copy of 
the VAS is in Appendix 2. 
Positive events will furthermore be recorded as AEs. 
6.5 Vital Signs: Pulse, Blood Pressure, Respiratory Rate and 
Temperature 
Pulse, diastolic and systolic blood pressure are measured sitting after five minutes rest. 
Automated instruments may be used. 
Respiratory rate will be measured over at least 30 seconds if regular, if irregular, at least 
1 minute. 
Temperature will be measured orally. 
These data are recorded in the EDC. 
6.6 Weight, Height and Body Mass Index (BMI) 
Weight is measured with empty pockets and normal indoor clothes without shoes. Weight 
is measured at several time points according to the schedule and entered in the EDC. 
Height is measured without shoes and is only measured at screening and entered in the 
EDC. 
The BMI is calculated by the EDC. 
6.7 Electrocardiogram (ECG) 
Equipment for recording the ECG should be recently serviced and calibrated. Machine 
calibration records and performance data should be maintained on file.  
A standard 12-lead ECG will be obtained in supine position after at least 5 minutes at 
rest. A copy of the recording will be made available for the Sponsor.  
At screening, any abnormalities or normal variants will be assessed for clinical relevance 
and recorded in the medical history. Subsequent changes will be recorded in the EDC 
description text field and deemed clinically relevant or not (separate files). Changes that 
are deemed clinically relevant are furthermore recorded as AEs.  


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In addition to the description above, the ECG intervals PR, QRS, RR and QT will be 
measured and recorded in the eCRF for QTc assessment. 
6.8 Urine Sample Laboratory Variables 
Tests on urine are conducted on a fresh midstream urine sample obtained from the 
participant. 
6.8.1 Urine Pregnancy Test 
All females irrespective of reproductive potential will be tested for pregnancy.  
The tests at screening and end of study will be sent to the local laboratory with the 
sample for urinalysis described in Section 6.8.2. 
The test at Day -1 is performed in the CRU using a commercially available pregnancy kit 
and documented with a photograph. The binary negative/positive result will be recorded 
in the EDC. Alternatively, if the turnaround time allows, the test may be sent to the local 
lab. 
6.8.2 Urinalysis 
The sample for urinalysis will be sent to the local laboratory for testing.  
6.8.2.1 Screening 
At screening, at Day -1, and at the end of study, a complete urinalysis will be done 
including visual inspection of color and clarity, chemical testing for specific gravity, pH, 
bilirubin, urobilinogen, protein, glucose, ketones, blood, leukocytes, nitrite, and 
creatinine.  
6.8.2.2 Urine PD 
Participants will be instructed to empty their bladder prior to sleep. If the participant 
voids during the night, the urine will be collected and pooled with the first morning void. 
The time and volume of urine must be recorded. On Day 0 a first morning void will be 
collected prior to dosing, and pooled with any urine collected during the night. An aliquot 
will be sent for urine PD. The time on collection and total volume must be recorded.  
Additional pooled urine collections will take place at the following intervals:  
• Day 0: a 4-hour urine collection will begin after dosing. 
• Day 0: from 4 hours post-dose until bedtime. Participants will be instructed to 
empty their bladders prior to sleep.  If the participant voids during the night, the 
urine will be collected and pooled with the first morning void. The time and 
volume of urine must be recorded. 
• Day 1 through Day 3: 12- hour urine collections.  
  For each collection period an aliquot of the pooled samples will be collected and tested 
for concentration of u-calcium, u-phosphate, u-magnesium, u-bicarbonate, u-sodium, and 
u-chloride and u-creatinine. The times of each void and total volume collected for each 
collection period must be recorded. 
Participants will be provided with a 12-hr. urine collection container and instructed to 
collect all urine for 12 hours leading up to the out-patient visits on Days 5, 7, 14 and 28.  


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Results will be sent to the CRU and transferred periodically to data management. 
 
6.9 Blood Sample Laboratory Variables 
6.9.1 Blood Sample Draw 
Blood is drawn either from a phlebotomy, or an indwelling catheter during the inpatient 
period after drawing out minimally 1 ml blood that is discarded per the investigational 
site’s procedures. 
Samples are drawn into appropriate sample container and processed according to the 
laboratory’s instructions. 
6.9.2 Total Amount of Blood Drawn for Sampling 
The total amount drawn from screening to last visit, which is a period of time of 
approximately 60 days, is well under 500 ml, including potentially discarded blood from 
the indwelling catheter sampling procedure described in Section 6.9.1.  
6.9.3 Screening and Safety Laboratory Tests 
See Sections 7.1 and 7.1.1 for timing of lab tests.  
1. Serum PTH at screening. 
2. Complete blood count (CBC) including RBCs, hemoglobin, hematocrit, WBC, 
and platelets, at all scheduled time points.  
a. At screening and end of study, the CBC will also include a differential 
count. 
3. Clinical chemistry comprehensive metabolic panel including serum glucose, 
calcium, albumin, total protein, sodium, potassium, bicarbonate, chloride, blood 
urea nitrogen (BUN), creatinine, alkaline phosphatase, alanine amino transferase 
(ALT), aspartate aminotransferase (AST), total bilirubin. 
4. Hepatitis B, C and HIV will be tested for at screening.  
a. Hepatitis B surface antigen 
b. Hepatitis C antibody screening test 
c. HIV-1 and HIV-2 antigen and antibody routine screen.  
Anti-Drug Antibody and Neutralizing Antibody development Lab reports will be 
reviewed by the investigator for clinical relevance and possible clinical laboratory 
adverse event reporting. 
6.9.4 Pharmacokinetics (PK)  
 One 5 ml serum sample will be collected at the time points noted in Section 7.1.1 and 
divided into 2 aliquots of 1ml each for determination of EXT608 concentrations. Samples 
will be shipped to the laboratory in batches, with one of the samples retained at the site in 
case of transfer problems. 
6.9.5 Pharmacodynamic (PD) variables 
See Sections 7.1 and 7.1.1 for timing PD labs. Laboratory PD variables include:  


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1. Serum total calcium (corrected for albumin), phosphate, magnesium at all marked 
time points,  
2. Serum PTH, creatinine with estimated GFR, 25-hydroxy-vitamin D (25-OH-D) 
and 1,25-dihydroxy-vitamin D (1,25-OH-D). 
See Section 6.8.2.2 for urine PD variables. 
6.10    Safety Variables and Safety Reporting 
6.10.1 Adverse Events 
6.10.1.1 Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or 
clinical investigation participant administered a pharmaceutical product and which does 
not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not it is considered related to the medicinal product.  
Adverse events will be collected from the time informed consent is signed and until the 
Follow-Up or Early Termination visit.  
All participants will be queried, using non-leading questions, about the occurrence of AEs 
at each study visit. When possible, a constellation of signs and/or symptoms should be 
identified as one overall event or diagnosis. All AEs for randomized subjects will be 
recorded in the eCRF and the subject's source documents. Adverse events for subjects who 
are screened but not subsequently randomized in the study will be recorded only in the 
subject's source documents. The following data should be documented for each AE: 
• Description of the events 
• Classification of “serious” or “not serious” 
• Date of first occurrence and date of resolution (if applicable) 
• Severity 
• Causal relationship to study drug 
• Action taken 
• Outcome 
• Concomitant medication or other treatment given 
Adverse events will be rated a mild, moderate or severe intensity using the following 
definitions: 
• Mild: “Mild” events are usually transient and do not interfere with the 
participant’s daily activities. 
• Moderate: “Moderate” events introduce a low level of inconvenience or concern 
to the participant and may interfere with daily activities. 
• Severe: “Severe” events interrupt the participant’s usual daily activities. 
 


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The causality will be rated in the following categories: 
• Unlikely: An “unlikely” relationship suggests that only a remote connection exists 
between the investigational study product and the reported AE. Other conditions, 
including chronic illness, progression or expression of the disease state or reaction 
to concomitant medication, appear to explain the reported AE. 
• Possible: A “possible” relationship suggests that the association of the AE with 
the investigational study product is unknown; however, the AE is not reasonably 
supported by other conditions. 
• Probable: A “probable” relationship suggests that a reasonable temporal 
association of the AE with study product functionality exists and, in the 
Investigator’s clinical judgment, it is likely that a causal relationship exists 
between the study product’s functionality and the AE, and other conditions 
(concurrent illness, progression or expression of disease state or concomitant 
medication reactions) do not appear to explain the AE. 
6.10.1.2 Adverse Event Outcome 
An AE should be followed until the Investigator has determined and provided the final 
outcome. The outcome should be classified according to the following categories: 
• Recovered/resolved: Resolution of an AE with no residual signs or symptoms 
• Recovered/resolved with sequelae: Resolution of an AE with residual signs or 
symptoms 
• Not recovered/not resolved (continuing): Either incomplete improvement or no 
improvement of an AE, such that it remains ongoing 
• Fatal: Outcome of AE is death. “Fatal” should be used when death is at least 
possibly related to the AE 
• Unknown: Outcome of an AE is not known (e.g., subject lost to follow-up) 
6.10.1.3 Serious Adverse Events 
A serious adverse event is any adverse event that: 
• Results in death 
• Is life-threatening (the term “life-threatening” here refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might cause death if it were more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Would in the opinion of the Investigator jeopardize the participant 
• May require medical or surgical intervention to prevent one of the outcomes listed 
above 


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6.10.1.4 SAE Reporting Procedure 
Serious adverse events will be collected over the same time period as stated above for 
AEs. All SAEs must be reported regardless of the relationship to the drug. The initial 
report should include at least the following information: 
• Subject’s study ID number 
• Protocol number 
• Description of the event 
• Criterion for categorizing the AE as serious 
• Preliminary assignment of causality to study drug 
Any new information should be provided as it becomes available. Copies of discharge 
summaries, consultant reports, autopsy reports, and any other relevant documents may 
also be requested. 
Appropriate remedial measure should be taken by the Investigator using his/her best 
medical judgment to treat the SAE. These measures and the subject’s response to these 
measures should be recorded. All SAEs, regardless of relationship to study drug, will be 
followed by the Investigator until satisfactory resolution or the investigator deems the 
SAE to be chronic or stable. Clinical, laboratory, and diagnostic measures should be 
employed by the Investigator as needed to adequately determine the etiology of the event.  
The Investigator will be responsible for reporting all SAEs to the Institutional Review 
Board (IRB)/Ethics Committee (EC). The Sponsor will be responsible for reporting to the 
regulatory authorities. 
Serious adverse events must be reported to the Sponsor within 24 hours of coming to the 
Investigator's attention Any serious adverse event that occurs any time after the 
participant has signed the informed consent form for the study, up to the participant’s 
final study visit, inclusive, is to be reported to Product Safety within 24 hours following 
when the event was first recognized, discovered, or reported, regardless of severity or 
relationship to the study product. If unable to enter the SAE information in the EDC (e.g., 
internet connection is down), the report may be reported by telephone to the Medical 
Monitor directly via cell phone at (609) 897-0505 x7114.  
Serious adverse events must be followed up by the Investigator until resolution or 
stabilization.  


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7 Study Procedures 
7.1 Schedule of procedures 
Period:
Screening
Check-in8
Day -28 to 
Day-2
Day -1
Day 5
 Day 7
Day 14
Day 21
Day 28
Early 
Termination
0
0
1
1
2
2
X
X
X
X
X
X
X
X
X
X
X
X
X
X1
X1
X1
X1
X1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
X3
X4
X4
X3
X3
X5
X
X
X
X
X
X5
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SARS-CoV-2 screen
X
Urine cotinine test
X
X
Urine drug screen
X
X
X
12 hr urine collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See In-patient sch.
 Tolerance (days)
Procedure
Inpatient Observation
Outpatient Follow-up
Days 0-3
See In-patient sch.
Informed consent 
Inclusion/exclusion criteria
Demography and medical history
Concomitant medications
Physical examination 
Height
Weight
Vital signs
ECG
Urine pregnancy test
Urinalysis2
Complete blood count
Clinical chemistry
Injection site assessment
Adverse Events
Hepatitis B, C and HIV  screening
Blood samples for PD6
Blood samples for PK
Blood sample for ADA/NAb
Check in to clinic
 Urine PD7
 
1  Directed physical exam only 
2  u-calcium, u-phosphate, u-magnesium, u-bicarbonate, u-sodium, and u-chloride 
3  Additionally, complete urinalysis will be done including visual inspection of color and clarity, chemical testing for specific gravity, pH, bilirubin, urobilinogen, protein, glucose, 
ketones, blood, leukocytes, nitrite, and creatinine 
4 Additionally, u-creatinine 
5 With differential count 
6 All PD variables 
7 The participant will be instructed to empty their bladder prior to sleep. If the participant voids during the night, the urine will be collected and pooled with the first morning void.  
8 Additional screening visits for exclusion of SARS-CoV-2 positivity prior to this visit may be added per the site's procedures 


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7.1.1 Sequestered Schedule 
Period
Dose
Day
Day 0
Day 2 Day 3
Time Unit
Time
-120
-90
-30
0
0.25
0.5
1
1.5
2
4
8
12
18
24
36
48
72
15
10
5
0
1
2
5
5
5
10
15
30
30
60
60
60
60
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
X
X
X
X1
X1
X1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
X
X4
X
X
X
X4
X
X4
X4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood samples for PK
Blood sample for ADA/NAb
X
Injection of study product
Injection site assessment
Adverse event(s)
Blood samples for PD3
Sequentered in clinic
Insertion of indwelling catheter
Inclusion/exclusion criteria
Concomitant medication(s)
Physical examination
Weight
Vital signs
ECG
CBC
Clinical Chemistry
Pooled urine for PD2
+/- Tolerance (minutes)
Procedure
Pre-Dose
Post-Dose
Minutes
Hour
Day 1
 
 
1 Directed physical exam only 
2 u-calcium, u-phosphate, u-magnesium, u-bicarbonate, u-sodium, u-chloride and u-creatinine. See Section 6.8.2.2 for collection times 
3 Total calcium (corrected for albumin), phosphate, magnesium 
4 Additionally, PTH, serum creatinine, 25-hydroxy-vitamin D (25-OH-D), 1,25-dihydroxy-vitamin D (1,25-OH-D).


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7.2 Chronological Description of Study Activities 
This section describes the schedule of activities per assessment time point. Details of 
each procedure may be found in Section 6. 
The timing of all activities for a specific participant are counted in minutes, hours or days 
relative to the receipt of the study product on minute, hour, Day 0. Unless otherwise 
noted, the maximal time tolerances on task execution is noted in the Schedules in 
Sections 7.1 and 7.1.1.  Priority will be for the PK and PD assessments to be as close to 
the target time as possible. Deviation from this time window is not considered sufficient 
to disqualify the participant from per protocol analysis.  
The sequence of activities within each visit as described below is not fixed, but may be 
modified to optimize clinic workflow.  
7.2.1 Screening 
Prior to screening for the protocol, the potential participant must be screened for SARS-
CoV-2 per investigational site procedures.  
1. Informed consent including a signed IRB-approved informed consent form must 
be obtained before any other study procedures involving the participant are 
undertaken. The nature of the risks involved and the tasks the participant will do 
will be explained. 
2. Throughout the screening process as outlined below, preliminary assessments of 
eligibility are performed whenever new information is available and further 
screening abandoned, if the participant is no longer eligible. 
3. The participant’s medical history including current conditions will be obtained. 
For females of current reproductive potential, the history will include current or 
plans of pregnancy, and for males of current reproductive potential, plans of 
conceiving or donating sperm during the course of or within 3 months of 
completing this study. 
4. The participant’s complete use of concomitant medications including vitamins, 
herbal supplements and illicit substances will be obtained (Section 6.2.3). 
5. A physical exam including temperature, vital signs, weight and height will be 
performed (Sections 6.3.1, 6.5, and 6.6). 
6. An ECG will be obtained (Section 6.7). 
7. A fresh midstream urine sample will be obtained and 
a. Sample preparation for laboratory urinalysis done (Sections 6.8.2.1 and 
6.8.2.2) 
b. In all females, a urine pregnancy test performed (Section 6.8.1). 
c. A drug and cotinine screen will be performed 
8. A phlebotomy and samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. HBsAg, HCV antibody and HIV screening (Section 6.9.3) 
d. PD variables (Section 6.9.5) 
e. ADA/Nab (Section 6.9.3) 
will be drawn and processed (Section 6.9.1).  


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9. The next visit for the check in to the Inpatient Period will be scheduled when all 
the screening data are anticipated to be available. If the site’s procedures for 
mitigating risk of contagious diseases, including SARS-CoV-2, require additional 
screening and visits prior to the check-in day -1, these are scheduled at the site’s 
discretion. 
7.2.2 Day -1, Check-in for Inpatient Period 
1. The participant checks into the CRU before 9 pm. 
2. All inclusion and exclusion criteria are assessed and participants who do not 
qualify will exit the study.  
3. The participant will now be sequestered until 3 days after the injection of the 
study product. 
4. Review of concomitant medication. 
5. A directed physical exam (Section 6.3.2) including temperature, vital signs, and 
weight will be performed (Section 6.5 and 6.6) 
6. An ECG will be obtained (Section 6.7) 
7. A fresh midstream urine sample will be obtained and 
a. Sample preparation for laboratory urinalysis done (Section 6.8.2.1 and 
6.8.2.2) 
b. In all females, a urine pregnancy test performed (Section 6.8.1) 
c. A drug and cotinine screen will be performed 
8. A phlebotomy for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3), and 
b. Clinical Chemistry panel (Section 6.9.3)  
will be drawn and processed.  
9. The participant will remain in the CRU, if qualified/ eligible to continue in the 
study. 
10. The participant will be instructed to empty their bladder prior to sleep. If the 
participant voids during the night, the urine will be collected and pooled with the 
first morning void. The time and volume of urine must be recorded.  
7.2.3 Day 0 of Inpatient Period, before and including Injection  
The participant will have been sequestered in the CRU overnight. A first morning void 
will be collected for urine PD prior to dosing, and pooled with any urine collected during 
the night. An aliquot will be sent for urine PD. The time on collection and total volume 
must be recorded.  
7.2.3.1 Minimally 2 hours prior to planned delivery of study product 
1. The study staff will place an indwelling intravenous (iv) catheter in minimally one 
arm and keep it functional per the site’s procedures.  
a. The iv catheter in the primary arm is to ensure iv access availability 
should this be needed in case of something unexpected happening in this 
first-in-human study. 
b. The iv catheter in the secondary is for blood sampling, should this method 
be preferred over repetitive phlebotomies. 


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2. Eligibility criteria are checked and if all are met the participant is randomized 
(Section 5.5) 
3. Study product made ready for injection at the scheduled time. 
7.2.3.2  90 minutes prior to planned delivery of study product (+/- 10 min) 
1. Vital signs are measured (Section 6.5) 
2. Blood samples for testing of: 
a. Clinical Chemistry panel and Complete Blood Count (Section 6.9.3) 
b. PK (Section 6.9.4) 
c. PD variables (Section 6.9.5) 
d. ADA/Nab (Section 6.9.3) 
will be drawn, processed and date and time stamp for draw time noted.  
3. The participant will remain in the CRU. 
7.2.3.3   30 minutes prior to planned delivery of study product (+/- 5 min) 
1. A blood sample for testing of: 
a. PK (Section 6.9.4) 
will be drawn, processed and date and time stamp for draw time noted. 
2. The participant will remain in the CRU. 
7.2.3.4 Time 0 
1. The planned injection site in the abdomen is assessed for any abnormalities or 
unusual appearance and a baseline photograph taken (Section 6.4). This may be 
performed within 5 minutes prior to injection of study drug.  
2. The planned injection site is prepared for injection swabbing with alcohol. 
3. Study product is injected subcutaneously by qualified staff, and the actual date 
and time noted. 
4. The participant is under observation and will remain in the CRU. 
5. A 4-hr urine sample collection will begin. The time of each void and total volume 
must be recorded.  
7.2.4 Day 0, the First Hour after Injection 
7.2.4.1 Time 15 minutes (+/- 1 min) 
1. A blood sample for testing of: 
a. PK (Section 6.9.4) 
will be drawn, processed and date and time stamp for draw time noted. 
2. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4) 
3. Any adverse events will be recorded (Section 6.10.1) 
4. The participant remains under observation in the CRU. 
7.2.4.2 Time 30 minutes (+/- 2 min) 
1. A blood sample for testing of: 
b. PK (Section 6.9.4) 
will be drawn, processed and date and time stamp for draw time noted 


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2. Any adverse events will be recorded (Section 6.10.1) 
3. The participant remains under observation in the CRU. 
7.2.4.3 Time 1 hour (+/- 5 min) 
1. Vital signs are measured (Section 6.5) 
2. A fresh midstream urine sample will be obtained and 
a. sample preparation for laboratory urinalysis done (Section 6.8.2.2 item 1 
only) 
3. Blood samples for testing of: 
a. PK (Section 6.9.4) 
b. PD variables (Section 6.9.5, item 1 only) 
will be drawn, processed and date and time stamp for draw time noted.  
4. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4) 
5. Any adverse events will be recorded (Section 6.10.1) 
6. The participant will remain in the CRU. 
7.2.5 Day 0 from 1 Hour after Injection 
7.2.5.1 Time 1.5 hours (+/- 5 min) 
The analogous procedures to the visit at time = 30 minutes are executed. 
7.2.5.2 Time 2 hours (+/- 5 min) 
The analogous procedures to the visit at time = 30 minutes are executed. 
7.2.5.3 Time 4 hours (+/- 10 min) 
The analogous procedures to the visit at time = 1 hour are executed, with the addition of 
25-hydroxy-vitamin D (25-OH-D), 1,25-dihydroxy-vitamin D (1,25-OH-D). 
A pooled urine collection will begin and continue until bedtime. The time of each void 
and total volume will be recorded.  
7.2.5.4 Time 8 hours (+/- 15 min) 
The analogous procedures to the visit at time = 1 hour are executed with the exception of 
the injection site assessment.  
7.2.5.5 Time 12 hours (+/- 30 min) 
The analogous procedures to the visit at time = 1 hour are executed.  
Prior to bedtime the participant will be instructed to empty their bladder. If the participant 
voids during the night, the urine will be collected and pooled with the first morning void. 
The time and volume of urine must be recorded. 
7.2.5.6 Time 18 hours (+/- 30 min) 
The analogous procedures to the visit at time = 8 hours are executed.  


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7.2.6 Days 1 through 3 of the Inpatient Period 
7.2.6.1 Day 1, 24 hours after the injection (+/- 1 hr) 
1. A directed physical exam (Section 6.3.2) including temperature and vital signs 
will be performed (Section 6.5 and 6.6) 
2. Review of concomitant medication 
3. An ECG will be obtained (Section 6.7) 
4. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4) 
d. PD variables (Section 6.9.5) 
will be drawn, processed and date and time stamp for draw time noted.  
5. A 12-hour urine sample collection will begin. The time of each void and total 
volume must be recorded. 
6. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4) 
7. Any adverse events will be recorded (Section 6.10.1) 
8. The participant will remain in the CRU. 
7.2.6.2 Day 1, 36 hours after the injection (+/- 1 hr) 
1. Vital signs are measured (Section 6.5), 
2. Blood samples for testing of: 
a. PK (Section 6.9.4) 
b. PD variables (Section 6.9.5, item 1 only) 
will be drawn, processed and date and time stamp for draw time noted.  
3. A 12-hour urine sample collection will begin. The time of each void and total 
volume must be recorded. 
4. Any adverse events will be recorded (Section 6.10.1) 
5. The participant will remain in the CRU. 
7.2.6.3 Day 2, 48 hours after Injection (+/- 1 hr) 
1. A directed physical exam (Section 6.3.2) including temperature, and vital signs 
will be performed (Section 6.5 and 6.6) 
2. Review of concomitant medication 
3. An ECG will be obtained (Section 6.7) 
4. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4) 
d. PD variables (Section 6.9.5) 
will be drawn, processed and date and time stamp for draw time noted.  
4. A 12-hour urine sample collection will be collected from 48 hours post-dose to 60 
hours and from 60 hours to 72 hours. The time of each void and total volume 
must be recorded. 
5. Any adverse events will be recorded (Section 6.10.1). 


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The participant will remain in the CRU. 
7.2.6.4 Day 3, 72 hours after Injection (+/- 1 hr) 
1. A directed physical exam (Section 6.3.2) including temperature, vital signs and 
weight will be performed (Section 6.5 and 6.6) 
2. Review of concomitant medication 
3. An ECG will be obtained (Section 6.7) 
4. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4) 
d. PD variables (Section 6.9.5) 
e. ADA/Nab (Section 6.9.3) 
will be drawn, processed and date and time stamp for draw time noted. 
5. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4) 
6. Any adverse events will be recorded (Section 6.10.1) 
7. If the participant’s Se-Ca increased ≤5%, or increased >5% and no longer 
increases, and their clinical condition is stable, the participant is discharged from 
the clinic at the investigator’s discretion after:  
a. If not scheduled already, an appointment from the Day 5 visit is 
scheduled, and  
b. The participant has been instructed to contact the CRU should any health 
problems emerge. 
8. Upon discharge, the participant will be provided with a 12-hr urine collection 
container and instructed to collect all urine for 12-hours prior to the next 
outpatient visit. 
7.2.7 Outpatient Follow-up 
7.2.7.1 Day 5 
1. The participant checks into the CRU before 10 am. 
2. Review of concomitant medication  
3. A directed physical exam (Section 6.3.2) including temperature, and vital signs 
will be performed (Section 6.5 and 6.6). 
4. A fresh midstream urine sample will be obtained and 
a. Sample preparation for laboratory urinalysis done (Section 6.8.2.2 only) 
5. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4) 
d. PD variables (Section 6.9.5) 
will be drawn, processed and date and time stamp for draw time noted.  
6. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4). 
7. Any adverse events will be recorded (Section 6.10.1). 


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8. If the participant’s condition is stable, the participants is discharged from the 
clinic at the investigator’s discretion after  
a. if not scheduled already, an appointment from the Day 7 visit is scheduled, 
and  
b. the participant has been instructed to contact the CRU should any health 
problems emerge. 
9. The participant will be provided with a 12-hr urine collection container and 
instructed to collect all urine for 12-hours prior to the next outpatient visit. 
 
7.2.7.2 Day 7 (+/- 1 day) 
1. The participant checks into the CRU before 10 am. 
2. Changes in concomitant medication are reviewed. 
3. A directed physical exam (Section 6.3.2) including temperature, vital signs and 
weight will be performed Section 6.5 and 6.6). 
4. A fresh midstream urine sample will be obtained and 
a. Sample preparation for laboratory urinalysis done (Section 6.8.2.2 only) 
5. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4), 
d. PD variables (Section 6.9.5) 
e. ADA/Nab (Section 6.9.3) 
will be drawn, processed and date and time stamp for draw time noted.  
6. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4). 
7. Any adverse events will be recorded (Section 6.10.1). 
8. If the participant’s condition is stable, the participants is discharged from the 
clinic at the investigator’s discretion after  
a. if not scheduled already, an appointment from the Day 14 visit is 
scheduled, and  
b. The participant has been instructed to contact the CRU should any health 
problems emerge. 
9. The participant will be provided with a 12-hr urine collection container and 
instructed to collect all urine for 12-hours prior to the next outpatient visit. 
 
7.2.7.3 Day 14 (+/- 1 day) 
1. The participant checks into the CRU before 10 am. 
2. Changes in concomitant medication are reviewed. 
3. A directed physical Exam (Section 6.3.2) including temperature, and vital signs 
will be performed (Section 6.5 and 6.6). 
4. Blood samples for testing of: 
a. Complete Blood Count (CBC) (Section 6.9.3) 
b. PK (Section 6.9.4) 
c. PD variables (Section 6.9.5) 


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will be drawn, processed and date and time stamp for draw time noted.  
5. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4). 
6. Any adverse events will be recorded (Section 6.10.1). 
7. If the participant’s condition is stable, the participants is discharged from the 
clinic at the investigator’s discretion after  
a. if not scheduled already, an appointment from the Day 21 visit is 
scheduled 
b. The participant has been instructed to contact the CRU should any health 
problems emerge. 
7.2.7.4 Day 21 (+/- 2 days) 
The analogous procedures to the visit at day 14 are executed. 
The participant will be provided with a 12-hr urine collection container and instructed to 
collect all urine for 12-hours prior to the next outpatient visit 
7.2.7.5 Day 28 (+/- 2 days) Last visit to clinic or Early Termination Visit 
1. The participant checks into the CRU before 10 am. 
2. Changes in concomitant medication are reviewed. 
3. A complete physical exam (Section 6.3.1) including temperature, vital signs and 
weight will be performed (Section 6.5 and 6.6). 
4. A fresh midstream urine sample will be obtained and 
a. sample preparation for laboratory urinalysis done (Section 6.8.2), 
a. and, in females of reproductive potential only, a urine pregnancy test 
performed (Section 6.8.1). 
5. Blood samples for testing of: 
a. Complete Blood Count (CBC) including differential count (Section 6.9.3) 
b. Clinical Chemistry panel (Section 6.9.3) 
c. PK (Section 6.9.4) 
d. PD variables (Section 6.9.5) 
e. ADA/Nab (Section 6.9.3) 
will be drawn, processed and date and time stamp for draw time noted.  
6. The injection site in the abdomen is assessed for any reactions and a photograph 
taken, if there is any reaction (Section 6.4). 
7. Any adverse events will be recorded (Section 6.10.1). 
8. The participant is discharged from the study. 
7.2.8 Early Termination from Study  
In case of early termination from the study, the last visit to the CRU will include the same 
assessment as the Day 28 visit plus a careful assessment of the reason for the early 
termination. 


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7.3 Data Monitoring Board and Dose Escalations 
7.3.1 Data Monitoring Board 
A DMB will be formed to monitor safety and dose cohort choices and provide 
recommendations to the Sponsor for implementation in the study. The DMB will 
minimally include an independent Safety Monitor, the Medical Monitor, the 
Investigator(s), and an independent statistician as voting members, as well as a non-
voting coordinator. Operational details will be described in a Safety Plan. 
7.3.2 Dose Escalations 
When the last participant of a cohort has completed Day 7 and evaluable data are 
available, statistics will provide a data summary of the cohort data for the DMB. The 
DMB will meet and decide further actions as described in the Safety Plan. 
 
8 Statistical Methods 
8.1 Sample size 
The sample size is not determined for inferential testing purposes. The sample size of 4 
participants per cohort (3 active: 1 placebo) is considered sufficient for evaluation of 
safety, tolerability, and PD of EXT608 prior to making a decision about dose escalation 
as Se-Ca is very tightly regulated and determination of effect based on simulations can 
therefore reliably be made with the small sample.  
8.2 Analysis populations 
Two participant populations will be defined. The Safety of Full Analysis Set population 
(FAS) will be defined as all participants who are randomized. The Per-Protocol (PP) 
population will be participants for whom evaluable data to and including Day 7 is 
available and with no major protocol violations.   
8.3 Data Analysis 
AEs will be presented in listings and Treatment Emergent Adverse Events (TEAEs) will 
be summarized. Individual results of laboratory tests (hematology, chemistry, and 
urinalysis) will be listed and change from baseline will be summarized using shift tables. 
Individual results of vital signs will be listed and observed values and changes from 
baseline will be summarized.  
Individual results of quantitative ECG parameters from the 12-lead safety ECGs will be 
listed and observed values and changes from baseline will be summarized and analyzed 
consistent with the ICH E14 (3).  
All summaries will be performed by placebo and each EXT608 dose level. Placebo data 
will be pooled across cohorts. Physical exam findings will be presented in data listings.  
Concentrations of EXT608 will be summarized by dose over each scheduled sampling 
time using descriptive statistics. Individual plasma concentration data versus time will be 
presented in a data listing. PK parameters will be summarized by dose using descriptive 


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statistics. Dose proportionality will be assessed graphically and using a power model. PD 
will be presented in listings and summarized by dose and time point.  
Detection of ADA and NAbs will be presented in listings and summarized by dose and 
time point.  
No formal hypothesis testing will be conducted as part of this study.  
DMB data packages will be based on the FAS for safety and PP for PK/PD. 
Further details are described in the Statistical Analysis Plan. 
 
9 Direct Access to Source Data/Documents 
Extend Biosciences, Inc. or agents thereof, the reviewing IRB/EC, and health authorities 
from the US or other countries will have access to source documents at the 
investigational site for monitoring, auditing or inspection purposes.  
 
10   Quality Control and Quality Assurance 
10.1   Monitoring 
The study will be monitored by qualified site monitors approved by the Sponsor.  
Monitoring will be done via on-site visits by the site monitor, who will review the eCRFs 
and source documents, and via remote review of eCRF entries.  The site monitor will 
make sure that the investigation is conducted according to protocol design, GCP, and 
regulatory requirements. 
Alternatively, due to the ongoing SARS-CoV-2 pandemic, all monitoring may be remote 
using a combination of source documents uploaded to the EDC and other tools for 
viewing site documents, e.g., for signed ICFs, for SDV. Further details will be described 
in a Clinical Monitoring Plan. 
10.2   Data Management 
Data will be entered in the electronic data capture (EDC) system at the investigational 
site.   
The data management plan will describe the methods used to collect, check, validate, and 
process clinical data in detail.  It will also clarify the roles and responsibilities for the 
different functions and personnel involved in the data management process.   
AEs and medical/surgical history will be classified according to the terminology of the 
Medical Dictionary for Regulatory Activities (MedDRA; version specified in the Data 
Management Plan).  Medications will be classified according to the latest World Health 
Organization (WHO) Drug Dictionary. 
Quality control procedures will be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  When all data have been coded, 
validated, and locked, clean file will be declared.  Any treatment-revealing data may 
thereafter be added and the final database will be locked. 


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10.2.1 Audits 
In addition to monitoring, the Sponsor, Sponsor’s representative, US or foreign 
regulatory authorities, and/or the reviewing IRB/ethics committee, may audit the conduct 
of the study.  The auditors must have access to all study documents, the facilities where 
the study was conducted, and the study staff for interviews. The investigator will contact 
the Sponsor immediately if contacted by a regulatory agency about an inspection at the 
center. 
 
11   Ethics 
The study will be performed in accordance with applicable regulatory requirements, the 
International Council for Harmonisation (ICH) guideline for Good Clinical Practice 
(GCP), and the ethical principles that have their origins in the Declaration of Helsinki. 
An IRB will approve the final study protocol, including the final version of the informed 
consent form and any other written information and/or materials to be provided to the 
subjects, before any subjects are enrolled.  The investigator will ensure the distribution of 
these documents to the applicable IRB/EC and to the staff of the study site. 
11.1   Informed Consent 
Prior to performing any study procedures, written informed consent will be obtained from 
the subject.  The method of obtaining and documenting the informed consent and the 
contents of the informed consent will comply with ICH-GCP and all applicable 
regulatory requirements. 
 
12   Data Handling and Recordkeeping 
The investigator must keep the study documentation for 15 years after the completion of 
the study. 
 
13   Publication Policy 
The Sponsor intends to publish the findings of the study and in general follows the 
guidelines set forth by the Internal Committee of Medical Journal Editors (ICMJE) (6). 
The investigator may publish the data from the site one year after the last participant 
finished the study.  
 
 


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14   References 
1. EXT608 Investigator’s Brochure 
2. NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_8.5x11.pdf Accessed 23-Sep-2020. 
3. ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. October 2005. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-
clinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic-potential-non-
antiarrhythmic-0 . Accessed 26-Sep-2020 
4. American Association for Clinical Chemistry https://labtestsonline.org/tests-index  
5. Mayo Clinic Laboratories https://www.mayocliniclabs.com/test-catalog/ 
6. ICMJE. Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals: Writing and Editing for Biomedical Publication. www icmje org 2020 
October 10; Available from: URL: www.icmje.org 
 
 


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15   Appendix 1 
 CLINICAL LABORATORY TESTS  
 
See Sections 7.1 and 7.1.1 for timing of tests 
 
Laboratory 
Assessments 
Parameters 
Hematology 
Complete blood count (CBC) including RBCs, hemoglobin, hematocrit, 
WBC, and platelets, at all scheduled time points.  
At screening and end of study, the CBC will also include a differential 
count. 
Clinical 
Chemistry 
Serum glucose, calcium, albumin, total protein, sodium, potassium, 
bicarbonate, chloride, blood urea nitrogen (BUN), creatinine, alkaline 
phosphatase, alanine amino transferase (ALT), aspartate 
aminotransferase (AST), total bilirubin 
Serology 
Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV), Human 
immunodeficiency virus (HIV) 
Urinalysis 
Color and clarity, chemical testing for specific gravity, pH, bilirubin, 
urobilinogen, protein, glucose, ketones, blood, leukocytes, nitrite, and 
creatinine 
Serum PD 
assessments 
Serum PTH, Total calcium, Phosphate, Magnesium, Serum creatinine, 
25-hydroxy-vitamin D (25-OH-D), 1,25-dihydroxy-vitamin D (1,25-
OH-D) 
Urine PD 
u-calcium, u-phosphate, u-magnesium, u-bicarbonate, u-sodium, and u-
chloride and u-creatinine. 
Other Tests 
Urine drug screen  
Urine cotinine 
Serum or urine pregnancy test 
 
 
 


Extend Biosciences, Inc.  
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                 Clinical Study Protocol EXT608-101, V3, 24 October 2022 
 
16     Appendix 2 
 
Visual Analog Scale 
 
Please draw a single vertical line through the scale below that corresponds to the 
intensity (severity) of any pain you are feeling right now.  
 
To indicate “no pain” or “worst possible pain” please circle the words instead of marking 
on the line. 
 
 
 
 
 
 
 
 
 
Worst possible pain 
No pain 

SAP_001.pdf: 
EXTBIO EXT608-101 Statistical Analysis Plan, V2, 2023-JULY-04 
 
IMD SOP ST-002 Appendix 1, V3 
Confidential 
Page 1 of 27 pages 
 
STATISTICAL ANALYSIS PLAN 
Trial ID: EXT608-101 
EXT608 in Human Healthy Adults; A First-in-Human, 
Randomized, Double-blind, Placebo-controlled, 
Single Dose Escalation Study 
(Version 2.0) 
 
 
 
Approval:  _____________________ _________________ ____________ 
 
Statistician/Name     
Signature 
          Date 
Approval:  _____________________ _________________ ___________ 
 
 Medical Monitor/Name  
Signature   
           Date 
Approval:  _____________________ _________________ ___________ 
 
 Role/Name  
Signature   
           Date 
This confidential document is the property of IMD and Extend Biosciences. No 
unpublished information contained herein may be disclosed without prior written 
approval from IMD or Extend Biosciences. Access to this document must be restricted 
to relevant parties. 
LEI SHI
Digitally signed by LEI SHI 
Date: 2023.07.20 13:59:34 
-04'00'
Poul Strange
Digitally signed by Poul Strange 
Date: 2023.07.20 14:09:34 -04'00'
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      
   
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Table of Contents 
1 
OVERVIEW ...................................................................................................................................... 4 
1.1 
INTRODUCTION ............................................................................................................................. 4 
1.2 
OBJECTIVES ................................................................................................................................... 4 
1.2.1 
Primary Objective ................................................................................................................. 4 
1.2.2 
Secondary Objectives............................................................................................................ 4 
1.2.3 
Exploratory Objectives .......................................................................................................... 4 
1.3 
ANALYSIS SOFTWARE .................................................................................................................... 4 
1.4 
MODIFICATIONS FROM THE STATISTICAL SECTION IN THE PROTOCOL ......................................... 5 
2 
INVESTIGATIONAL PLAN ................................................................................................................. 6 
2.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................... 6 
2.1.1 
Study Design ......................................................................................................................... 6 
2.1.2 
Randomization ..................................................................................................................... 7 
2.1.3 
Sample Size Justification ....................................................................................................... 7 
3 
STATISTICAL AND ANALYTICAL PROCEDURES.................................................................................. 8 
3.1 
ANALYSIS POPULATIONS ............................................................................................................... 8 
3.1.1 
Safety or Full Analysis Set population (FAS) ......................................................................... 8 
3.1.2 
Per-protocol (PP) Population ................................................................................................ 8 
3.2 
DATA HANDLING CONVENTIONS ........................................................................................................... 9 
3.2.1 
Missing Data ........................................................................................................................ 9 
3.2.2 
Per Protocol Time Points Vs Actual Time Points ................................................................... 9 
3.2.3 
Repeated and Unscheduled Visit .......................................................................................... 9 
3.2.4 
Major Protocol Violations and Minor Protocol Deviations ................................................... 9 
3.2.5 
Visit Window ...................................................................................................................... 10 
3.3 
ANALYSIS VARIABLES ................................................................................................................... 11 
3.3.1 
Demographic Characteristics Variables.............................................................................. 11 
3.3.2 
Trial conduct variables ....................................................................................................... 12 
3.3.3 
Efficacy Variables ............................................................................................................... 12 
3.3.4 
Safety Variables .................................................................................................................. 17 
3.4 
STATISTICAL METHODS ............................................................................................................... 19 
3.4.1 
General Considerations for all analyses ............................................................................. 19 
3.4.2 
Disposition of Participants .................................................................................................. 19 
3.4.3 
Demographic Characteristics analyses ............................................................................... 19 
3.4.4 
Efficacy Analysis ................................................................................................................. 20 
3.4.5 
Safety Analyses ................................................................................................................... 21 
3.5 
INTERIM ANALYSES FOR SAFETY REVIEW .................................................................................... 23 
4 
LIST OF PLANNED LISTINGS, TABLE AND FIGURES ......................................................................... 24 
5 
SOFTWARE DOCUMENTATION ...................................................................................................... 25 
6 
REFERENCE ................................................................................................................................... 26 
7 
REVISION HISTORY ........................................................................................................................ 27 
 
 
 
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ABBREVIATION AND DEFINITIONS 
 
λz: Terminal rate constant  
 
ADA: Anti-drug Antibodies 
 
AE: Adverse Event 
 
ANOVA: Analysis of Variance 
 
AUC: Area under the curve 
 
AVG: Average 
 
CMax: Maximum Concentration 
 
CL/F: Clearance 
 
DIABP: Diastolic Blood Pressure 
 
ECG: Electrocardiogram 
 
EDC: Electronic Data Capture systems 
 
EXT608: Name of the study medication 
 
FAS: Faull Analyses Set 
 
FIH: First-in-human 
 
LLOQ: Lower limit of quantification 
 
MedDRA: Medical Dictionary for Regulatory Activities 
 
Nab: Neutralizing subset 
 
PD: Pharmacodynamics 
 
PK: Pharmacology 
 
PP: Per Protocol 
 
PT: Preferred Term 
 
SAD: Single Ascending Dose 
 
SAE: Serious Adverse Event 
 
SAS: Analyses Software by SAS institute 
 
SOC: System Organ Class 
 
SYSBP: Systolic Blood Pressure 
 
TMax: Time corresponding to the Maximum Concentration 
 
tHalf,early: Half-life Early  
 
tHalf,late: Half-life Late 
 
VAS: Visual Analogue Scale 
 
Vz/F: Volume Distribution 
 
V: Volume 
 
 
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1 OVERVIEW  
1.1 INTRODUCTION  
This documentation describes the planed data analyses for Extend Biosciences EXT608-
101 clinical trial. 
1.2 OBJECTIVES 
1.2.1 Primary Objective 
The primary objective is to characterize the safety and tolerability profile of escalating 
dose levels of EXT608 when administered to healthy adult participants as a single 
injection as assessed by: 
 Incidence, nature, and severity of adverse events (AEs) and withdrawals due to 
treatment emergent AEs (TEAEs) [Time Frame: Day 0 up to Day 28] 
 Frequency and severity of post-dose change from baseline in hematology, serum 
chemistries, urinalysis, electrocardiogram (ECG), vital signs, and physical 
examination (Exam) findings [Time Frame: Day 0 up to Day 28] 
 Percentage of participants with injection or infusion site reactions [Time Frame: 
Day 0 to Day 7]  
1.2.2 Secondary Objectives 
The secondary objectives are to assess: 
 Single dose PK including AUC0-24h, AUC0-48h, AUC0-28d, AUC0-≈, Cmax, Tmax, 
T½, ƛz, Cl/F and Vz/F. 
 Single dose PD by post-dose change from baseline in serum chemistries with 
particular attention to Se-Ca, phosphate, magnesium, and creatinine. Urinalysis 
will also be performed. 
1.2.3 Exploratory Objectives 
Furthermore, the exploratory objectives are to assess: 
 Single dose Immunogenicity by anti-drug antibodies (ADA) and any neutralizing 
subset (NAb), 
 Single dose effect on vitamin D metabolism by serum 25-hydroxy-vitamin D and 
1,25-dihydroxy-vitamin D concentrations. 
1.3 ANALYSIS SOFTWARE 
SAS 9.4 Windows 
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1.4 MODIFICATIONS FROM THE STATISTICAL SECTION IN THE 
PROTOCOL  
None 
 
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2 INVESTIGATIONAL PLAN 
2.1 STUDY DESIGN AND RANDOMIZATION 
2.1.1 Study Design  
This is a randomized, double-blind, first-in-human (FIH), placebo-controlled single 
ascending dose (SAD) study to study the safety, tolerability, PK, and PD of EXT608 in 
healthy adult participants.  
This is a multiple cohort study. Participants will be enrolled into 1 of up to 6 planned 
single dose cohorts (designated as S1 through S6, respectively) in ascending fashion. 
 Each cohort will consist of 4 participants randomized to receive either EXT608 or 
placebo, whereby 3 will receive a single injection of EXT608 and 1 will receive 
matching placebo.  
 Up to approximately 30 participants may be enrolled to the study intervention 
such that approximately 24 evaluable participants complete the study. 
 Participants who discontinue prematurely may be replaced at the discretion of 
the Sponsor.  
 Additional participants and cohorts may be enrolled pending review of study 
data and recommendation by a Data Monitoring Board (DMB) and ratification by 
the Sponsor. 
Figure 1 Study Design 
 
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2.1.2 Randomization  
Treatment allocation is performed in the EDC in a manner that ensures only the 
unblinded pharmacist or unblinded monitoring person know the treatment code. The 
treatment assignment is computer generated by the EDC at the point of randomization.  
 Participants are randomized 3:1 EXT608:Placebo in blocks of 4.  
 A Pocock-Simon (Pocock and Simon 1975) allocation minimization procedure is 
implemented into the randomization process to ensure the balance between 
each treatment arm.  
 The balance procedure is based on the serum calcium (mg/dL) obtained at visit 
Day -1 of each participant. 
 Participants who discontinue prematurely may be replaced at the discretion of 
the Sponsor. 
2.1.3 Sample Size Justification 
The sample size is not determined for inferential testing purposes. The sample size of 4 
participants per cohort (3 EXT608: 1 Placebo) is considered sufficient for evaluation of 
safety, tolerability, and PD of EXT608 prior to making a decision about dose escalation as 
Se-Ca is very tightly regulated and determination of effect based on simulations can 
therefore reliably be made with the small sample.  
 
 
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3 Statistical and analytical procedures  
3.1 ANALYSIS POPULATIONS 
Two participant populations are defined. 
3.1.1 Safety or Full Analysis Set population (FAS) 
The Safety or Full Analysis Set population (FAS) will be defined as all participants who 
are randomized.  
 In the event of subjects having received treatments that different from those 
assigned according to the randomized schedule, then the safety analyses will be 
conducted according to the treatment received rather than according to the 
randomization groups. 
 Participate who is replaced and received at least one study medication will also 
be included in this population. 
3.1.2 Per-protocol (PP) Population 
The Per-Protocol (PP) population will be a subset of the Safety/FAS population and only 
include participants for whom evaluable data to and including Day 7 is available and 
with no major protocol violations. 
 
 
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3.2 Data Handling Conventions 
3.2.1 Missing Data 
 
Any blank value will be treated as missing (unknown) 
 
Blank value will be left as blank in the data listings. 
 
Missing data will not be estimated unless specified 
3.2.2 Per Protocol Time Points Vs Actual Time Points  
Unless specified in the analyses section, actual blood sampling times, if available, will be used 
for individual figures while protocol times will be used for grouping summary.  
3.2.3 Repeated and Unscheduled Visit 
A repeated visit is a visit planned, by the site, to replace a scheduled visit. Usually same data 
measurements as the scheduled visit will be collected. 
Unscheduled visit is an unplanned visit which includes unexpected data collection. 
 
Whether a visit is repeated or unscheduled is determined by site and reported in the 
EDC. 
3.2.3.1 
Repeated Visit 
The principle of last observation priority will be used to handle the situation of repeated visit. 
Some general recommendations are listed below: 
 
If a variable (except dates and all lab transferred data) is measured/collected at the 
repeated visit, the value from the repeated visit will be used for analyses. 
 
Dates and Lab transferred data will be determined case by case based on its 
scientifically meaningful and the date/time relative to the treatment date/time. 
 
If a variable is not measured / collected at the repeated visit, then the value from the 
original visit will be used for analyses. 
3.2.3.2 
Unscheduled Visit 
Unscheduled visit usually includes data not scheduled to be collected or not required by 
protocol.  
 
Data from unscheduled visit will be listed but not used for analyses, except: 
o The data be used to substitute a missing data in the scheduled visit if it clinically 
meaningful and within a suitable visit window. This is usually determined by the 
Medical Monitor. 
3.2.4 Major Protocol Violations and Minor Protocol Deviations 
Towards the end of trial, the scientifically responsible contact (medical monitor) and the 
statistician will review all protocol deviations and decide if any fit the criteria of a Major Protocol 
Violation, for the purpose of determining if the participants satisfy the requirement of per 
protocol population. 
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 
The decision should be documented  
 
For a blinded trial, the decision should be made before unblinding 
3.2.5 Visit Window  
The following visit window is defined based on protocol. 
Table 1 Protocol Defined Visit Schedule 
 
Table 2 Protocol Defined Sequestered Schedule for Day 0-3 
 
Based on the above tables (Table 1 and Table 2), for convenience, the following visit name will 
be used for all analyses. 
Table 3 Visit name used in the analyses 
Screening Day -1 Day 0-3 Day 5 Day 7 Day 14 Day 22 Day 28 Early Termination 
 
 
 
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3.3 ANALYSIS VARIABLES 
This section describes any reformatting, calculation or transformation that might be 
applied to any variable before analyses. 
 Unless specified, Unit will be kept as originally reported regardless if it is Metric 
or American system 
 If a variable is reformatted, the new format will be displayed in the data listing. 
 If a variable is calculated, both the original value and the calculated value will be 
displayed in the data listing. 
o This usually refers to the substitution of any missing value 
 If a variable is transformed for analyses, only the original value will be will be 
displayed in the data listing, as the transformation is usually an intermediate 
step in analyses. 
3.3.1 Demographic Characteristics Variables 
Common Demographic variables include: 
 Demographics 
 Height weight 
 Medical history 
 Physical Exam 
Reformatting maybe applied for display purpose but no additional calculation (except 
BMI) or transformation will be done before analyses. 
 For Physical Exam and Medical history, if the Body system is “Other”, it will not 
be coded unless the “Other” category becomes the largest or 2nd to the largest 
category. 
 Weight: Change from baseline will be calculated 
o Baseline is the weight at the beginning of visit Day -1. 
 Physical Exam: Change from baseline will be evaluated 
o Baseline is Physical Exam status at screening 
o Change from baseline will be the status changes from screening to Day 28 
or end of study. The following categorization will be used: 
 Normal -> Normal 
 Normal -> Abnormal 
 Abnormal -> Abnormal 
 Abnormal -> Normal 
 Unknown (if the status is missing as either of the time point) 
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3.3.1.1 Age 
Since only the month and year of birth are collected in the EDC, we will use number 15 
to substitute the day of birth. 
Then the Age will be calculated by: 
Age = Floor((Day 0 −(The approximated Date of Birth)
365.25
) 
 Function floor means age will take the largest integer (e.g., age 50.8 will become 
age 50). 
 For participant who is not advanced to Day 0, i.e. screening failure or 
randomized but not dosed, there will be no Age calculated. 
3.3.1.2 Medical History 
Reformatting maybe applied for display purpose but no additional calculation or 
transformation will be done before analyses. 
3.3.2 Trial conduct variables 
These include the visit dates and the study completion data of each participant. These variables 
are usually used for disposition or drug exposure summaries. 
Reformatting maybe applied for display purpose but no additional calculation or transformation 
will be done before analyses unless specified in the analyses.  
3.3.2.1 Day 0  
Day 0 is anchor day used to define timeline. Based on the visit windows (section 3.2.5): 
Day 0 = date of Dose (or IP administration in EDC) 
3.3.2.2 Last date in study 
Last date in study is determined by site and directly reported in EDC. However, in rare case 
when a participant lost to follow-up and site report unknown for “last date in study”, the last 
known day that the participant is in clinic will be used.  
3.3.3 Efficacy Variables 
3.3.3.1 Handling of (Possible) Multiple Peaks of PK Curve 
We expect the PK curve to have a single peak. However, it is possible that multiple peaks or no 
peak will be observed. The following are ways to handle PK curves: 
1. Determination of single peak/no peak/Multi-peak will be based on the plot of the PK 
curve 
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a. The statistician will make the judgement based the visual observation of each 
plot of the PK curve 
2. No peak. (i.e. the variables keep rising until the last PK measurement) 
a. The Maximum (CMax), Time to Maximum (TMax), Time to Half-Maximum (T-
Half) will be set as missing. We will consider these variables as undefined. 
b. The AUC0-t will be calculated but the AUC0-∞ will be set as missing. 
3. Multi-peak. 
a. If the same Maximum value appears at two or more time point, the CMax, Time 
to T-Half (early) will be estimated based on the first occurrence and Time to T-
Half (late) 
3.3.3.2 PK values at baseline, infinity, and  under Lower Limitation of Qualification 
(LLOQ) 
PK is assumed to be 0 at baseline (i.e. prior to time 0) and at infinity.  
Additionally, any PK value that is LLOQ between time 0 and infinity will be assumed to be: 
 
1/2 of the value of LLOQ specification (specified in the comment for PK results by Lab), 
or 
 
100pg/mL, if no LLOQ specification is given (default is 200 pg/mL) 
3.3.3.3 Handling of missing PK time  
If PK collection time is missing but PK result is available (include LLOQ), the collection time 
stamp will be estimated using the scheduled time and the time 0. 
For example, if the value of PK at 24 hour post dose is not missing, but the collection Time of 24 
hour post dose PK is unknown. Then the collection time 24 hour post dose PK will be estimated 
as:  T0 + 24 hour. 
3.3.3.4 PK Parameters 
The following PK parameters will be developed directly from the PK data. 
 PK parameters will only be calculated or evaluated for participants who receives 
EXT608 dose. PK parameters will not be calculated for placebo participants. 
3.3.3.4.1 Time 0 
Time 0 is defined as the date and time of IP Administration. 
3.3.3.4.2 The Maximum (CMax) 
CMax is the maximum PK readings from time 0 to the last PK measurement. 
 
In a “No Peak” case, this will be set as missing. 
3.3.3.4.3 Time to Maximum (TMax) 
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Tmax is the minutes, from time 0, to the time when CMax is reached the first time. 
 
In a “No Peak” case, this will be set as missing. 
3.3.3.4.4 Terminal rate constant λz 
Terminal rate constant λz is needed before we estimate AUC0-t. Since we are expecting the 
terminal PK will have an exponential decline, λz is estimated by: 
a. Find the PK after TMax  
i. If there only 1 or 0 available PK readings after PK Tmax, then λz will be 
set as missing. 
b. Do a regression of log-transformed PK vs Time 
c. λz is -1 * (slope from this regression) 
d. In a “No Peak” case, λz will be set as missing 
3.3.3.4.5 AUC0-t 
The AUC0-t of PK over time will be calculated using trapezoid rule and the actual time points. 
Missing data for the calculation of the AUC will be handled as followed: 
1. If the reading for Time 0 is missing, it will be the assumed as 0.  
2. If any reading between Time 0 and TMax is missing: 
a. It will be imputed with linear interpolation. 
3. If any reading after CMax is missing: 
a. If λz is available, it will be imputed using the regression line obtained when 
estimate λz 
b. If λz is missing, AUC0-t will be set as missing. 
We will calculate the following AUC0-t 
Table 4 AUC0-t 
AUC  0-24 Hour 
AUC  0-48 Hour 
AUC  0-7 Day 
AUC  0-14 Day 
AUC  0-21 Day 
AUC  0-28 Day 
 
3.3.3.4.6 AUC0-∞ 
AUC0-∞ is estimated as:  
AUC0-∞ = AUC0-last + AUClast,  where  AUClast  = PKlast/λz , and PKlast is the last available PK reading 
 
If λz is missing, then AUC0-∞ is set as missing. 
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3.3.3.4.7 Time to Half-Maximal PK, Both Early and Late (tHalf,early & tHalf,late) 
Thalf,early is the time in minutes, from time 0,  to the time when PK rises to half way to the 
maximum. It is calculated as followed: 
 
Thalf,early =  Time corresponding to 
CMax
2
  - t0, linear interpolation may be used if needed. 
 
If CMax is missing, Thalf,early will also be set as missing. 
Thalf,late is the # of days, from TMax, to the time when PK reduced to half way to the maximum. 
Since we assume the PK is exponential decline, Thalf,late is calculated as followed 
 
𝑇ℎ𝑎𝑙𝑓,𝑙𝑎𝑡𝑒 = 
𝐿𝑛(2)
𝜆𝑧   
 
If λz is missing, Thalf,late will also be set as missing. 
3.3.3.4.8 Clearance (CL/F) 
Clearance is calculated as the dose divided by the AUC0-∞ : 
 
𝐶𝐿/𝐹  =
𝐷𝑜𝑠𝑒
𝐴𝑈𝐶0−∞ 
 
 
If is missing, then CL/F is set as missing. 
3.3.3.4.9 Volume Distribution (Vz/F) 
Volume Distribution is calculated as: 
 
𝑉𝑧/𝐹  =
𝐷𝑜𝑠𝑒
λz ∗ 𝐴𝑈𝐶0−∞ 
 
 
If λz is missing, then Vz/F is set as missing. 
3.3.3.5 PD Parameters 
The PD variables include:  
 
Serum total calcium (corrected for albumin)(Se-Ca) 
 
Phosphate 
 
Magnesium 
 
Creatinine 
 
Serum PTH  
 
Creatinine with estimated GFR  
 
25-hydroxy-vitamin D (25-OH-D)   
 
1,25-dihydroxy-vitamin D (1,25-OH-D)  
3.3.3.5.1 Change from baseline 
Change from baseline will be calculated for all numeric variables where baseline is the 
measurement at Day -1. 
 
Baseline will be the measurements collected on Day 0 Pre-Dose. 
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 
If the measurements on Day 0 Pre-dose is not available, the measurements collected on 
day -1 will be used. 
3.3.3.5.2 Change of severity status along time 
Additionally, the change of severity (normal/abnormal) status along time will also be 
categorized. The severity is determined by lab and reported to IMD directly. 
In the EDC, the abnormal status is defined as: 
 
L = Low 
 
H = High 
 
A = Abnormal 
 
If the abnormal status variable is blank, then it is considered as Normal. 
The change between two consecutive time points will be categorized based on the reported 
severity starting from baseline. The following category will be evaluated: 
 
Normal -> Normal 
 
Normal -> High 
 
Normal -> Low 
 
Normal -> Abnormal 
 
High -> High 
 
High -> Normal 
 
High -> Low 
 
Low -> Low 
 
Low -> Normal 
 
Low -> High 
 
Abnormal -> Abnormal 
 
Abnormal -> Normal 
 
Unknown (if lab test results at any of the consecutive time points is missing) 
3.3.3.6 Urine PD Volume 
The Urine Volume is reported in the EDC along with starting and ending date/time. The volume 
will be normalized for the volume per hour (Vupd): 
𝑉𝑢𝑝𝑑=
𝑅𝑒𝑝𝑜𝑟𝑡𝑒𝑑 𝑉𝑜𝑙𝑢𝑚𝑒
𝐸𝑛𝑑𝑖𝑛𝑔 𝐷𝑎𝑡𝑒𝑡𝑖𝑚𝑒−𝑆𝑡𝑎𝑟𝑡𝑖𝑛𝑔 𝐷𝑎𝑡𝑒𝑡𝑖𝑚𝑒 
60 × 60
 
The 4-hour Urine PD volume on Day 0 will then be estimated as 𝑉𝑢𝑝𝑑 𝑥 4 
The 12-hour Urine PD volume on Day 1-3 will then be estimated as 𝑉𝑢𝑝𝑑 𝑥 12 
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Note: Assuming the value of datetime variable is in seconds. If either the date, time or volume is 
missing, this variable will also be set as missing. No imputation will be done. 
3.3.4 Safety Variables 
3.3.4.1 Adverse Events (AE) 
All observed or volunteered adverse events regardless in the treatment group or suspected 
causal relationship to the investigational device are captured in the EDC.   
For all AEs, reformatting maybe applied and necessary transformation/Substitution may be 
needed as specified below: 
 
If an AE has known onset date but unknown onset time, then 12:00 will be used to 
substitute the onset time 
o The purpose of this substitution is for the determination of the TEAE 
 
If an AE has unknown onset date, no substitution will be done. 
Treatment‐emergent adverse event (TEAE) is defined as a post‐baseline adverse event with 
onset date and time after the initiation of study treatment.  
 
Baseline is the IP administration date and time 
 
In this study, TEAE are the AEs that occur after the first successful IP administration. 
o If the AE has an unknown onset date, it will be assumed to be non-TEAE unless 
the investigational site confirms it is an TEAE 
AE Coding: 
 
AE will be coded with latest available, at the time of coding, MedDRA code.  
3.3.4.2 Vital Signs 
Change from baseline will be calculated for vital sign from Day 0 to Day 28. 
 
Baseline will be the vital signs collected at Day 0 -90 pre-dose 
 
If Day 0 -90min vital signs are missing, then the vital signs on Day -1 will be considered 
as baseline. If the vital sign on Day -1 is also missing, then the change from baseline will 
be set as missing. 
3.3.4.3 ECG 
Change from baseline will be calculated for ECG from Day 1 to Day 3. 
 
Baseline will be the ECG collected at Day -1 
 
If Day -1 ECG is missing, then the ECG on Screening will be used as baseline.  
3.3.4.4 Lab evaluations 
Handling of the safety lab variables will be the same as the PD variables (section 3.3.3.5) 
3.3.4.5 Injection site reaction  
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Injection site Assessment includes Tenderness, VAS pain score, Edema and Erythema. 
 
If Tenderness is “None” and VAS pain score is missing, then VAS pain score will be set as 
0 
 
No substitution will be done for any missing VAS if Tenderness is not None. 
Although the standard VAS line is 100mm, the actual VAS line printed on paper could be deviate 
from 100mm due to printer settings. Thus, all reported VAS will be normalized to 100mm scale 
for analyses.  
The normalized VAS (VASnom) score is calculated as below: 
VAS𝑛𝑜𝑚 = 𝑀𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑉𝐴𝑆(𝑚𝑚) ×  100
𝑇𝑜𝑡𝑎𝑙 𝑉𝐴𝑆(𝑚𝑚)
 
The following describes the handling of Edema and Erythema related variables. 
 
If “none” reported for edema or Erythema, then the following variables will be 
substitute as 0 for analyses only 
o Shortest length (Edema or Erythema) 
o Longest length (Edema or Erythema) 
o Tallest height (Edema)  
o Grade (Erythema)  
 
If “not done” reported, there is no substitution 
Edema and Erythema is assumed to be Ellipse, and the area will be calculated as: 
𝐴𝑟𝑒𝑎 𝑜𝑓 𝐸𝑑𝑒𝑚𝑎 𝑜𝑟 𝐸𝑟𝑦𝑡ℎ𝑒𝑚𝑎= (3.14159 × 𝑠ℎ𝑜𝑟𝑡𝑒𝑠𝑡 𝑙𝑒𝑛𝑔𝑡ℎ × 𝑙𝑜𝑛𝑔𝑒𝑠𝑡 𝑙𝑒𝑛𝑔𝑡ℎ )
4
 
The Grade of Erythema is expected to be the following: 
 
1: very faint, 2: faint, 3: bright, 4: very bright 
 
If a non-integer number is reported, it will be rounded to the nearest integer. 
The tallest height of Edema will be used directly. 
3.3.4.6 Immunogenicity variables 
Immunogenicity variables include anti-drug antibodies (ADA) and any neutralizing subset (NAb). 
These are variables for exploratory analysis. Handling of these variables will not be pre-defined 
in this analyses plan. 
 
 
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3.4 STATISTICAL METHODS 
3.4.1 General Considerations for all analyses 
Unless specified, the following will apply to all summary tables: 
 
Continuous variable descriptive summary will include N, Mean, median, standard 
deviation, maximum and minimum.  
 
Categorical variable descriptive summary will include Total, count, and percentage.  
3.4.2 Disposition of Participants  
Descriptive summaries of participants’ disposition will be provided. It will show the count and 
percentage. 
The following will be presented for all screened participants: 
 
Screen failed  
 
Enrolled (qualified)  
 
Randomized  
The following will be presented for all randomized participants: 
 
Cohorts 
 
Fully completed  
 
Early terminated 
 
Safety/FAS Population 
 
PP Population  
 
Treatment Randomized 
 
Treatment Received 
3.4.3 Demographic Characteristics analyses 
The demographic characteristics analyses will be done for Safety/FAS population. 
3.4.3.1 Demographics 
Descriptive summaries of the following will be provided: 
 
Age 
 
Race 
 
Ethnicity 
 
BMI 
3.4.3.2 Medical History  
Descriptive summaries of Body System will be provided. 
3.4.3.3 Physical Exam 
Descriptive summaries of Body System will be provided. 
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Additionally, change from baseline of the status of each Physical Exam will be summarized for 
each treatment arm. 
3.4.3.4 Height, Weight and BMI 
Height, weight and BMI will be summarized descriptively for each treatment arm at screen visit. 
Additionally, weight will be summarized at each time point for each treatment arm from 
baseline. 
3.4.3.5 Medication 
Only a listing of the medication used by each participant will be provided. 
It will be done for safety population only. 
3.4.3.6 Protocol Compliance 
The protocol compliance summary can be inferred from the disposition summary in section 
3.4.2. Thus, there is no separated analysis. 
3.4.4 Efficacy Analysis 
All Efficacy analyses will be done for Safety/FAS population unless specified. 
3.4.4.1 PK Analyses 
All PK parameters (section 3.3.3.2) will be presented descriptively for each treatment arm.  
A simple ANOVA model with treatment arm as the factor will be applied to each PK parameter 
to compare the active treatment arms to the pooled placebo group. The estimated mean 
difference and 95% Confidence Interval between each treatment arm and the placebo group will 
be presented. The corresponding p-value will also be reported although we do not expect it to 
be significant given the small sample size. 
Additionally, a statistical model will be attempted to model the dose response of each PK 
parameters. The mode will not be pre-defined. We will plot the mean of each PK parameter 
against the dose and find an appropriate model if any. 
 
In additional to the Safety/FAS population, it will also be done with the PP population 
3.4.4.2 PD Analyses 
All PD parameters (section 3.3.3.5) including the change from baseline will be presented 
descriptively for each treatment arm. 
Additionally, the change of severity (normal/abnormal) status along time will also be 
summarized for each treatment arm. 
 
In additional to the Safety/FAS population, it will also be done with the PP population 
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3.4.4.3 Urine PD Volume 
The Urine PD volume will be summarized descriptively for each treatment arm. 
3.4.5 Safety Analyses 
All Safety analyses will be done for Safety/FAS population. 
3.4.5.1 Adverse Event 
All AE (including TEAE and non-TEAE) will be listed. 
Unless there are less than or equal to 5 TEAE in the whole study period, TEAE will be 
summarized as followed: 
All TEAE will be presented with the number and percentage of participants and events (counts 
only), by System organ class (SOC) and by Preferred Term (PT).  
The same summary will also be presented for the following group: 
 
All TEAE that may have a relationship to the study medication (i.e., site categorize the 
relationship in EDC as either Related, Probable, Possible, or Unlikely) 
 
Intensity Categorization Groups: Mild, Moderate and Severe 
 
Serious TEAE (SAE) 
An overview of the above summary with count and percentage of participants will also be 
provided. 
Any non-TEAE will be provided as listing only. 
3.4.5.2 Laboratory tests Results 
This section will describe the summary of safety lab test results. Summary of PK and PD results 
are described in previous section (3.4.4.1 and 3.4.4.2). 
All safety lab test results will be listed.  Additionally, each Lab Test results of each subject at 
different time points will be plot against the time points to show the trend. 
The change of baseline of any numeric safety lab results will be for each treatment arm. 
The change of severity (normal/abnormal) status of each safety lab results along time will also 
be summarized for each treatment arm. 
3.4.5.3 Vital Sign 
Vital sign at each time point and the corresponding Change from (section 3.3.4.2) baseline will 
be presented descriptively by treatment arm. 
3.4.5.4 ECG 
ECG at each time point and the corresponding Change from (section 3.3.4.3) baseline will be 
presented descriptively by treatment arm. 
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3.4.5.5 Injection site reaction  
Injection site reactions include VAS, tenderness, Edema and Erythema. The parameters defined 
in section 3.3.4.5 will be summarized descriptively by each treatment arm. 
 
 
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3.5 INTERIM ANALYSES FOR SAFETY REVIEW 
Interim analyses are planned for the safety review after each cohort. Blinded Interim summaries 
of selected variables are generated for the safety review committee. Details of those analyses 
are specified in the safety monitoring plan.  
 
 
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4 List of planned listings, table and figures 
Please see the attached Table of Contents Excel file.  
Note that this is the planned Table of Contents, based on the actual data, table numbers, table 
names and structures may change. 
 
 
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5 Software documentation 
PC SAS – Windows version 9.4 or higher. 
[PC R - Windows version 12.0 or higher.] 
[WinNonlin - Professional Version 5.2 or higher.] 
Excel - Microsoft Excel 2007 or higher. 
 
 
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6 Reference 
Pocock S J, Simon R, Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial, Biometrics. 1975 Mar; 31(1):103-15. 
 
 
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7 Revision History 
Version 
Summary 
1.0 
Initial Document 
2.0 
1.Add sections dealing with different LLOQ used by the PK Lab 
2.Clarified how to handle missing values in PK 
3.Corrected few typos 
 
 
 
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