Conditions: Bariatric Surgery Candidate
Keywords: Roux-en-Y gastric bypass, sleeve gastrectomy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This study evaluates whether zoledronic acid can prevent the high bone turnover that occurs after Roux-en-Y Gastric Bypass (RYGB) and sleeve gastrectomy (SG) surgery.

Detailed description:
The investigators are evaluating the ability of a single dose of zoledronic acid to improve bone outcomes after RYGB or SG surgery. The investigators have previously shown that RYGB and SG have negative effects on bone density, bone microarchitecture, and that bariatric procedures potentially increase the risk of fractures. The purpose of this study is to evaluate the safety and efficacy of zoledronic acid to prevent the high-turnover bone loss that occurs in adults who have chosen to undergo RYGB or SG.

Arms:
arm 1: Subjects will receive a single intravenous infusion of zoledronic acid (5 mg). Supplemental calcium citrate + vitamin D (500mg+500IU) and vitamin D3 (1000 IU) will be dispensed throughout the study to fit individual needs.

Interventions: intervention 1: Zoledronic Acid intervention 2: Calcium citrate + vitamin D intervention 3: Vitamin D3
Intervention descriptions: intervention 1: 5mg zoledronic acid intervention 2: Chewable 500mg calcium citrate with 500 International Units (IU) Vitamin D3 intervention 3: 1000IU Vitamin D3 gummy

Protocol document:
ICF_002.pdf: 
Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
Page 1 of 11 
 
 
Subject Identification
Protocol Title: Zoledronic Acid to Prevent High-Turnover Bone Loss after
Bariatric Surgery 
 
Principal Investigator: Elaine Yu, MD. 
 
Site Principal Investigator: 
 
 
Description of Subject Population: Obese Adults undergoing bariatric surgery 
 
 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
throughout this consent form. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
.  
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
We have previously shown that Roux-en-Y Gastric Bypass (RYGB) and sleeve gastrectomy 
(SG) have negative effects on skeletal health, including bone loss and higher risk of fractures. 
The purpose of this study is to prevent the bone loss that is occurring in adults who have chosen 
to undergo these surgeries. We are evaluating the ability of a single dose of zoledronic acid given 
before gastric bypass or sleeve gastrectomy to improve bone outcomes after the surgery. 
Zoledronic acid is currently FDA-approved for the treatment of osteoporosis (low bone density), 
but this study is the first to test its use in the prevention of bone loss after gastric bypass and 
sleeve gastrectomy.  
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 2 of 11 
 
 
Subject Identification
We are asking you to take part in this research study because you are planning to undergo RYGB 
or SG and might be at higher risk of bone loss.  We hope to enroll 10 subjects in this research 
study at the Massachusetts General Hospital (MGH). 
 
How long will I take part in this research study? 
 
It will take you about 7 months to complete this research study. During this time, we will ask you 
to make 5 study visits to the MGH. You will make two visits to the MGH prior to your surgery. 
After surgery, you will make 3 visits to the MGH over the course of 6 months.  
 
What will happen in this research study? 
 
If you choose to take part in this study, we will ask you to sign this consent form before we 
complete any study procedures. 
 
Baseline Visit 
This visit will take about 5 hours to complete. At this visit, you receive the following laboratory 
tests, nutrition counseling, and bone density measurements: 
 You will have a blood draw. You will need to fast for this visit for 5 hours.  
 You will have measurements taken of your height and weight. 
 You will receive personalized nutritional counseling. A nutritionist will meet with you to 
ensure that you receive enough calcium and vitamin D throughout the study. You may be 
provided with calcium and vitamin D supplements to take at home. 
 You will undergo a dual energy x-ray absorptiometry (DXA) bone density scan of your 
spine, hip, and whole body. During this test, we will ask you to lie on a padded table for a 
few minutes. The arm-like scanning device will pass over your body as x-ray pictures are 
taken. You must hold still during the scanning procedure to reduce the possibility of a 
blurred image.  
 You will undergo a quantitative computed tomography (QCT) bone density test of your 
spine. This test uses x-rays and a computer to determine bone mass (the density of bone 
tissue in your body). During this test, we will ask you to lie on a moveable table that 
slides into a large tunnel shaped machine. This table will move forward and backward as 
the scan is done. You will be asked to lie still during the scan. The test takes about 10 
minutes. 
 You will receive zoledronic acid through an intravenous catheter (IV). An IV will be 
placed in your arm, and then you will receive a single dose of either zoledronic acid. This 
infusion will occur more than one week prior to your bariatric surgery procedure. 
 You may be given acetaminophen (the active ingredient in Tylenol) to reduce the 
possible side effects related to the study drug. 
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 3 of 11 
 
 
Subject Identification
Visits at Weeks 2 and 12  
At 2 and 12 weeks after your gastric bypass or sleeve gastrectomy surgery, you will be asked to 
return to MGH for study visits. You will need to fast for 5 hours for these visits. You will 
undergo a blood draw, as well as height and weight measurements. You will again meet with a 
nutritionist for personalized nutritional counseling. The nutritionist will ensure that you are 
taking enough calcium and vitamin D through supplements and diet. You may be provided with 
calcium and vitamin D supplements to take at home. These visits will take about 1.5 hours. 
 
Week 24 Visit 
At your final visit, you will have another blood draw. You will need to fast for 5 hours for this 
visit. Your height and weight will be measured. You will again receive personalized nutritional 
counseling. We will again perform a number of bone density measurements, including a DXA of 
the spine, hip, and total body, QCT of the spine. This visit should take about 4 hours to complete.  
 
Stopping your Participation without your Permission 
The study doctor may take you out of the study without your permission. This may happen 
because you have a serious unexpected reaction, you have failed to follow the instructions of the 
study doctor or staff, or if the study is being stopped for other reasons. 
 
Study Information Included in Your Electronic Medical Record 
A notation that you are taking part in this research study may be made in your electronic medical 
record. Information from the research that relates to your general medical care may be included 
in the record (for example, list of allergies, results of standard blood tests done at the hospital 
labs). 
 
Partners Alert System 
Partners has an electronic system that lets your study doctors know if you are admitted to a 
Partners Hospital, or if you visit a Partners Hospital Emergency Department. We want to make 
sure the study doctors know about any possible problems or side effects you experience while 
you are taking part in the study. 
 
Storing Samples at MGH for Future Use 
Samples of your blood and urine will be saved and stored to measure factors related to this study 
that may help explain the change in bone mass. We will also store some of your samples for 
future research related to bariatric surgery or bone health. The stored samples will be labeled 
only with the date and time of collection and a code number. No identifying information (name, 
date of birth) will be on the stored samples. The key to the code connects your name to your 
health information and samples. The research doctor will keep the key to the code in a password 
protected computer.  The samples will be kept in locked freezers. Only members of the study 
staff and the laboratory technicians who perform the measurements will have access to your 
stored samples. We may share your anonymous samples with academic groups participating in 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 4 of 11 
 
 
Subject Identification
research regarding obesity, bariatric surgery, and bone health. These scientists will not know 
who you are.  
 
 
What are the risks and possible discomforts from being in this research 
study? 
 
You may have side effects while taking part in this study. We will watch you carefully for any 
side effects. If you have any side effects during the study, you should tell the researchers right 
away. 
 
Zoledronic Acid 
The most common side effects associated with zoledronic acid include flu-like symptoms (e.g., 
fever, chills, muscle/joint aches) occurring after the infusion. Most of these symptoms occur 
within the first 3 days following drug administration and usually resolve within 3 days of onset 
but resolution can take up to 7-14 days. Taking acetaminophen or ibuprofen after the infusion 
can ease these symptoms. Other common side effects include nausea, tiredness, dizziness, 
headache, or pain/redness/swelling at the injection site.   
 
Very rarely, more severe side effects may occur that include: 
 
-Harm to the jaw bone (called osteonecrosis of the jaw) 
 
-Fracture of your femur (upper leg bone) 
 
-Kidney failure 
 
Hypocalcemia 
A small number of patients experience low blood calcium levels within the first two weeks after 
zoledronic acid administration. It is possible that RYGB or sleeve gastrectomy patients are at a 
higher risk for developing hypocalcemia. Symptoms of hypocalcemia include numbness or 
tingling of the hands or feet and muscle spasms or cramps. To reduce this risk, we will give you 
personalized nutrition counseling to ensure you are taking enough calcium and vitamin D 
supplements. We will also monitor your blood calcium levels throughout the study. You may be 
provided with calcium and vitamin D supplements to take at home. 
 
Calcium and vitamin D supplements 
The MGH Weight Center recommends that all bariatric surgery patients take supplemental 
calcium and vitamin D.  These supplements may be provided to you during the trial.  In the doses 
used in this study, calcium and vitamin D have minimal side effects.  Some individuals may note 
constipation or stomach upset with calcium supplements.  Very rarely, if an individual is over-
supplemented with calcium, a kidney stone could result. 
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 5 of 11 
 
 
Subject Identification
Acetaminophen:  Acetaminophen, commonly known by the brand name, Tylenol, is very safe 
when used appropriately.  If appropriate, a single standard dose will be given to you at the time 
of study drug infusion to decrease the likelihood of uncomfortable side effects.  Overdose of 
acetaminophen may harm the liver. The single dose of acetaminophen at the time of study drug 
infusion will be withheld if you have any signs of liver disease, if a doctor has ever advised you 
to avoid acetaminophen, or if you have ever had a bad experience with acetaminophen.  
 
 
Bone Density Tests (DXA, QCT) 
Bone density scans are painless and take 5-15 minutes each. As a result of your taking part in 
this study you will be exposed to radiation from the x-ray procedures that measure your bone 
density. Please note that this radiation is not necessarily for your medical care and is for research 
purposes only.  
 
Over the 6-month study period, you will receive 2 DXA scans of the lumbar spine, hip, and total 
body, and 2 QCT scans of the spine. One set of scans will be performed at the baseline visit, and 
the second set of scans will be performed at the 6-month visit. The total amount of radiation for 
the entire study is ~3.82 milliSieverts (mSv). A mSv is a unit of radiation dose. This amount of 
radiation is less than the background radiation that one is exposed to from the earth and sky over 
15 months. 
 
Scientists disagree on whether radiation doses at these low levels are harmful. A possible effect 
that could occur at doses used in this study is a slight increase in the risk of developing cancer 
later in life.  
 
If we see something else on your scans that looks like a medical problem, we will ask a 
radiologist (a doctor who specializes in x-rays/scans/test results of this sort) to review the results. 
If the radiologist thinks there might be a problem, we will tell you and help you get follow-up 
care. If the radiologist thinks that you might have a medical problem, but it turns out that you 
 
 
Intravenous Catheter Placement and Blood Collection 
Inserting an intravenous catheter and/or taking blood can cause bruising or pain at the insertion 
site. Some people faint or feel lightheaded when blood is taken or an IV is placed. If you faint 
when your blood is collected, you should not take part in this study. There is a small risk of 
infection, which can be treated. 
 
 
What are the possible benefits from being in this research study? 
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 6 of 11 
 
 
Subject Identification
You may experience increases in bone density and/or prevention of bone loss during the course 
of the study. Information from this study will help us understand if zoledronic acid can prevent 
the deterioration of skeletal health that occurs after RYGB or sleeve gastrectomy. This 
knowledge has the potential to reduce the negative skeletal consequences of RYGB and sleeve 
gastrectomy, which are otherwise the most effective treatments for severe obesity. 
 
 
What other treatments or procedures are available for my condition? 
 
Currently, there are no other methods that have been studied to prevent bone loss after RYGB or 
sleeve gastrectomy.
 
 
research study, or if I stop taking part?  
 
ose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
 
Will I be paid to take part in this research study? 
 
We will pay you $200 if you complete the study.  In addition, we will give you a voucher 
(coupon) to pay for your parking in one of the MGH garages at each visit, or up to $20 to cover 
your travel expenses.  
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 7 of 11 
 
 
Subject Identification
 
What will I have to pay for if I take part in this research study? 
 
Study funds will pay for certain study-related items and services, including the bone density 
scans, blood tests, nutrition counseling, ergocalciferol supplements, calcium and vitamin D 
supplements, study drug infusion, and all the other tests and procedures that are done only for 
research. We may bill your health insurer for, among other things, routine items and services you 
would have received even if you did not take part in the research, such as your bariatric surgery. 
You will be responsible for payment of any deductibles and co-payments required by your 
insurer for this routine care or other billed care. If you have any questions about costs to you that 
may result from taking part in the research, please speak with the study doctors and study staff. If 
necessary, we will arrange for you to speak with someone in Patient Financial Services about 
these costs.  
 
 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.  
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 8 of 11 
 
 
Subject Identification
Elaine Yu, MD is the person in charge of this research study.  You can call her at 617-643-6353 
Monday-Friday 9:00 AM-5:00 PM.   
 
If you need to get in touch with the principal investigator on nights and weekends, call the main 
hospital at 617-726-2000 and have the operator page Elaine Yu, MD at pager # 13495. 
 
If you have questions about the scheduling of appointments or study visits, call the study 
coordinator Katherine Lindeman at 617-724-3255.
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
 Your rights as a research subject 
 Your concerns about the research 
 A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
.
In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so.    
 
In this study, we may collect health information about you from: 
 Past, present, and future medical records 
 Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may 
need to do so: 
 Partners research staff involved in this study 
 The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 
 Other researchers and medical centers that are part of this study and their ethics boards 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 9 of 11 
 
 
Subject Identification
 A group that oversees the data (study information) and safety of this research 
 Non-research staff within Partners who need this information to do their jobs (such as for 
treatment, payment (billing), or health care operations) 
 The Partners ethics board that oversees the research and the Partners research quality 
improvement programs. 
 People from organizations that provide independent accreditation and oversight of 
hospitals and research 
 People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
 Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research)  
 Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
 Other:        
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
 
You have the right not to sign this form that allows us to use and share your health information 
for research
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 10 of 11 
 
 
Subject Identification
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished.  
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
 
 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
     
 
 
Subject 
Date 
 
Time
 


Partners HealthCare System
Research Consent Form 
 
 
 
General Template 
Version Date:  August 2016 
 
 
 
 
Page 11 of 11 
 
 
Subject Identification
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
 
Time  
 
 
Consent of Non-
e 
 
Statement of Hospital Medical Interpreter 
 
As someone who understands both English and the language spoken by the subject, I interpreted, 
in the subject's language, the researcher's presentation of the English consent form.  The subject 
was given the opportunity to ask questions. 
 
 
 
 
 
 
 
 
Hospital Medical Interpreter 
Date 
Time  
 
 
Consent Form Version:  10-18-2018 
 

Prot_SAP_000.pdf: 
1 
 
 
Zoledronic Acid to Prevent High-
Turnover Bone Loss after Bariatric 
Surgery 
 
 
 
 
 
ClinicalTrials.gov ID: NCT03424239 
 
Document Version: January 8, 2019 
 


2 
 
Zoledronic Acid to Prevent High-Turnover Bone Loss after Bariatric Surgery 
 
I. Background and significance 
 
Bariatric surgery is a highly effective and sustainable method for weight loss [1]. Roux-en-Y 
Gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most common bariatric procedures 
performed worldwide, encompassing >85% of all bariatric procedures performed worldwide [2]. 
Sleeve gastrectomy was introduced within the past decade and has seen an explosion in 
popularity, now comprising 61% of all bariatric procedures performed at academic medical 
centers [3].  Although both surgeries lead to dramatic benefits in obesity and obesity-related 
comorbidities, they are associated with large magnitude bone loss. We have previously 
documented bone mineral density (BMD) declines on the order of 10% within the first 2 years 
after RYGB [4, 5] and 5% within the first year after SG [6]. Another study has shown similar 
rates of bone loss between RYGB and SG procedures in the first 2 years after surgery [7]. 
Postmenopausal women appear to be at particular risk for a higher rate of bone loss after RYGB 
than younger women [8, 9]. Furthermore, we have documented parallel deterioration in 
peripheral bone microarchitecture, with increases in cortical porosity and endocortical resorption, 
and decreases in trabecular number and density [5, 9]. By 2 years after RYGB, the declines in 
BMD and microarchitecture translated into a 9-10% drop in estimated bone strength at the radius 
and tibia, as assessed by micro-finite element analysis. SG has increased in popularity only in 
recent years and there have not been many studies of changes in skeletal outcomes to date.  
 
We have recently demonstrated that RYGB confers a 43% increased risk of nonvertebral 
fractures [10]. The higher rate of RYGB-associated fractures was specifically observed for hip 
fractures and wrist fractures relative to adjustable gastric banding (AGB), a bariatric procedure 
that is thought to have a relatively neutral effect on bone [11-13]. Another study confirmed that 
RYGB patients have a 3-5 fold higher incidence of hip, spine, and humerus fractures compared 
to community fracture rates [14]. Currently there are insufficient data to determine whether SG 
leads to increased fracture risk [15]. 
 
We have performed several studies demonstrating the timing and pattern of rise in bone turnover 
markers after RYGB. Most notably, C-telopeptide (CTX), a marker of bone resorption, increases 
as early as postoperative day 10 and peaks at 6 months after surgery, at a range that is 220-245% 
above baseline values [5, 12, 16]. This marked elevation in bone resorption far exceeds the 
increases in bone resorption that occur in the settings of non-surgical weight loss, menopausal 
transition, or immobilization due to 90-day bedrest [17-19]. Longitudinal studies have also noted 
persistently increased bone resorption in the initial years after RYGB [13, 20, 21], with one 
recent study reporting CTX elevations of 140% up to 5 years after RYGB [22]. Several studies 
have also shown significant increases in CTX up to 5 years after SG, though possibly to a lesser 
extent than after RYGB [6, 7, 23]. 
 
Currently there are no effective methods to prevent bone loss in bariatric surgery patients, with 
studies-to-date focused on non-pharmacologic treatments. The proposed pilot study would be the 
first to test a pharmacologic agent for the prevention of RYGB- and SG-induced high-turnover 
bone loss. Intravenous zoledronic acid is ideally suited to prevent the clinically relevant high-
turnover bone loss associated with these surgeries. FDA-approved zoledronic acid is a potent 


3 
 
antiresorptive that significantly reduces spine, hip, and nonvertebral fracture risk in osteoporosis 
[24], and leads to normalization of bone resorption in high-turnover bone disorders, such as 
Paget’s disease, primary hyperparathyroidism, and induced hypogonadism [25-29]. A single 
dose of zoledronic acid can achieve persistent suppression of bone turnover markers and 
improvements in bone density for 5 years [30], as well as remissions of Paget’s disease for over 
5 years [31]. There are currently no studies of the efficacy and safety of zoledronic acid to 
prevent bariatric surgery- induced bone loss. This pilot trial is powered to answer the important 
pathophysiologic question of whether a potent anti-resorptive agent can block the powerful 
increases in bone resorption that are otherwise observed after RYGB and SG.  
 
II. Specific Aims 
 
Our overall aim is to inhibit high bone turnover, prevent bone loss, and ultimately reduce 
fracture risk in at-risk adults undergoing RYGB or SG. We hypothesize that zoledronic acid can 
be used safely for this purpose.  
 
Aim 1  
Our aim is to evaluate the safety and efficacy of preoperative zoledronic acid treatment on bone 
turnover in postmenopausal women and older men undergoing RYGB or SG. We will examine 
6-month postoperative changes in serum CTX and P1NP, markers of bone turnover, after a 
preoperative infusion of zoledronic acid in an open-label fashion. We will also employ and refine 
a perioperative protocol of calcium and vitamin D supplementation, with serial monitoring of 
serum calcium levels.  
Hypothesis: Zoledronic acid safely and effectively inhibits the increases in CTX and 
P1NP after RYGB and SG. 
 
Aim 2 
Our aim is to assess early changes in bone density, and estimated bone strength after 
preoperative zoledronic acid in postmenopausal women and older men undergoing RYGB or SG. 
We will utilize dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography 
(QCT) to preliminarily assess skeletal changes 6 months after RYGB and SG.  
Hypothesis: Zoledronic acid attenuates early RYGB- and SG-induced bone loss  
 
 
III. Subject Selection 
 
This open-label, single arm pilot study is designed as a proof-of-concept study to demonstrate 
feasibility, determine efficacy of surrogate endpoints (e.g. suppression of bone turnover 
markers), and to obtain preliminary data about early (6 month) bone density outcomes. 
 
Inclusion criteria: 
1. Women or men planning to receive RYGB or SG surgery 
2. Women must be aged ≥ 25 years AND postmenopausal by either of the following criteria 
> 36 months since last spontaneous menses; or 
> 36 months since hysterectomy, plus serum FSH > 40 units/liter 
3. Men must be aged ≥ 50 years 


4 
 
 
 
Exclusion criteria: 
1. Prior bariatric surgery 
2. Weight ≥ 400 lbs (due to limitations of bone imaging equipment) 
3. Liver disease (AST or ALT > 2 x upper normal limit) 
4. Renal disease (serum creatinine > 2.0 mg/dL or eGFR < 35 ml/min) 
5. Hypercalcemia (Ca > 10.5 mg/dL) or hypocalcemia (Ca < 8.5 mg/dL) 
6. Hypomagnesemia (Mg < 1.7 mg/dL) 
7. Serum 25-OH vitamin D < 20 ng/mL 
8. HCT < 32% 
9. History of malignancy (except basal cell carcinoma) in the past 5 years 
10. History of radiation therapy 
11. Significant cardiopulmonary disease (unstable coronary disease or stage D ACC/AHA 
heart failure) 
12. Major psychiatric disease 
13. Excessive alcohol or substance abuse 
14. Paget’s disease, primary hyperparathyroidism, or any other known congenital or acquired 
bone disease other than osteoporosis 
15. Current hyperthyroidism or use of levothyroxine and TSH < 0.1 uIU/mL 
16. Current use of loop diuretics 
17. Current use or use in the past 12 months of oral bisphosphonates or denosumab 
18. Current use or use within the past 3 months of estrogens, SERMs, or calcitonin 
19. Any current or previous use of teriparatide, strontium, or any parenteral bisphosphonate 
20. Use of oral or parenteral glucocorticoids for more than 14 days within the past 6 months 
21. Known sensitivity to bisphosphonates 
22. Extensive dental work involving extraction or dental implant within the past 2 months or 
planned in the upcoming 6 months 
23. Aspirin sensitivity with bronchoconstriction 
 
Recruitment: 
Study subjects will be recruited from the MGH Weight Center, and if necessary the Brigham and 
Women’s Hospital Program for Weight Management (PWM). Briefly, we will advertise the 
study using IRB approved materials within Massachusetts General Hospital (MGH) and the 
MGH Weight Center. Recruitment flyers will be posted in approved locations throughout the 
MGH (including the MGH Weight Center) and email announcements will be sent through the 
Partners Clinical Research Program Network. Potential subjects may be identified by their 
treating physician at the weight center and through the Weight Center surgical scheduling 
calendar. These subjects will be sent a letter to introduce the study that is co-signed by their 
treating physician and the study PI. A member of the study staff who is not the treating physician 
will also explain the study to potential bariatric surgical subjects at a pre-operative visit. With 
permission from the treating physician at the Weight Center, we may access potential subjects’ 
medical records to confirm contact information and to identify upcoming visits at the Weight 
Center.  Potential subjects will be given a copy of the full consent form to review. They will also 
will be asked permission to be contacted by study staff either during a clinical visit or by phone 
to further discuss the study. 


5 
 
 
IV. Subject Enrollment 
 
We will enroll 10 participants who are planning RYGB or SG surgery. We will enroll men age 
≥50 and postmenopausal women. 
 
To ensure compliance with HIPAA regulations, subjects that will be pre-screened by telephone 
are informed of the nature and sensitivity of all questions at the beginning of the conversation. 
They will be asked whether this is an appropriate time for them to answer these questions and 
told how long the phone call is expected to take. 
 
Subjects will be asked questions about their medical history to determine their eligibility for the 
study. If they are found to be eligible based on the screening questionnaire, written informed 
consent for the screening procedures will be obtained by a licensed physician or nurse 
practitioner. In situations where a nurse practitioner is obtaining consent, subjects will be offered 
the option for further discussion with a physician investigator if they have any remaining 
questions. This offer will be documented in the research record, and any consent problems will 
be reported to the PHRC in real-time. The screening procedure involves a blood draw to assess 
whether subjects meet all remaining eligibility criteria. If labs and medical history show that all 
criteria are met, the individual will be invited to enroll in the full study.  
 
Written informed consent for the full study will be obtained using a consent form before subjects 
undergo any study procedures other than the screening procedure described above. A licensed 
physician or nurse practitioner will obtain informed consent. In situations where a nurse 
practitioner is obtaining consent, subjects will be offered the option for further discussion with a 
physician investigator if they have any remaining questions. This offer will be documented in the 
research record, and any consent problems will be reported to the PHRC in real-time. All 
subjects will be informed regarding the purpose of the research, the details of the study protocol, 
risks and benefits, alternatives to participation, costs, reimbursements, their right to privacy and 
confidentiality, their right to refuse to participate or withdraw from the study at any time, their 
rights in the event of a study-induced injury, and whom to contact for questions about the study. 
A complete medical history will also be taken to ensure the subject is an eligible candidate for 
the study. Hospital interpreters will be available for subjects for whom English is not their 
primary language, and these subjects will sign an additional short-form as well as the primary 
consent form. Subjects will be given a copy of their signed consent form and an additional copy 
will be kept in our research files.  
 
Subjects will receive $200 compensation for participating in the study, as well as a parking 
voucher for each visit or transportation compensation up to $20.  
 
 
V. Study Procedures 
 
 


6 
 
 
 
Study subjects will be scheduled for a baseline study visit within 6 weeks and at least 1 week 
prior to their planned surgery to have laboratory testing, skeletal evaluation (DXA, QCT), and 
study drug infusion. Subjects will also be asked questions about their medical history. All study 
subjects will receive 3 tablets of oral ergocalciferol 50,000 IU to take in the week preceding 
study drug infusion. As the maximal calcium lowering effect occurs within 7 days of zoledronic 
acid administration [32, 33], the study drug will be administered more than 1 week prior to 
surgery. The study drug must be administered as an infusion over no less than 15 minutes. 
Subjects will be advised to ensure proper hydration prior to receiving study drug, and those 
without a contraindication to acetaminophen will be provided with acetaminophen 650 mg PO at 
the time of infusion.   
 
 Participants will receive personalized nutritional (calcium/vitamin D) counseling throughout the 
study to ensure compliance with guidelines for the postoperative management of bariatric 
surgery patients [34]. A nutritionist will ensure pre-operative intake of at least 1500 mg/day of 
calcium through combination of diet and calcium supplements and at least 3000 IU/day of 
vitamin D. Postoperatively, study subjects will be instructed to take supplemental calcium citrate 
1000 mg/day in divided doses as well as vitamin D 3000 IU/day. Subjects will be advised of 
bariatric formulations of calcium citrate and vitamin D that are chewable, liquid, or quick-
dissolve. Furthermore, most RYGB and SG patients at our institution are prescribed a 
standardized postoperative diet plan that includes ~1200mg of dietary calcium for the initial 2 
postoperative weeks. Throughout the remainder of the study, personalized nutritional counseling 
will ensure post-operative intake (through diet and supplements) of at least 1500 mg/day of 
calcium and 3000IU/day of vitamin D, in accordance with guidelines for the postoperative 
management of bariatric surgery patients [34]. Calcium and vitamin D supplements will be 
provided for all subjects who do not meet these optimal intake levels. 
 
Additional study visits will occur at post-operative weeks 2, 12, and 24 and will include 
assessments for safety and skeletal outcomes. A skeletal evaluation (DXA, QCT) will again be 


7 
 
performed at week 24. Serum calcium, creatinine, and 25-hydroxyvitamin D will be monitored in 
real-time throughout the study and if hypocalcemia occurs, we will follow a strict protocol to 
escalate calcium/D supplements (see Monitoring and Quality Assurance below). An independent 
Data Safety Monitoring Board will review study progress and any adverse events. This study has 
been granted IND-exempt status by the FDA. This study is registered on clinicaltrials.gov under 
NCT03424239. 
 
The following data will be collected: 
1. DXA measurements of the lumbar spine, total hip, femoral neck, and total body at 
baseline and 6-month visit 
2. QCT measurements of the lumbar spine at baseline and 6-month visit 
3. Anthropomorphic measurements of height and weight at each visit 
4. Fasting blood samples for measurements of calcium, albumin, 25-hydroxyvitamin D, and 
PTH at each visit 
5. Batched serum samples will be used to assess levels of bone markers CTX and P1NP at 
each visit 
6. Questionnaires  
a. Medical history 
b. Calcium and vitamin D intake 
c. Physical activity 
 
Technical Methods 
 
DXA 
Dual-energy x-ray absorptiometry (DXA) scans of the lumbar spine, total hip, femoral neck, and 
total body will be obtained at baseline and 6-month visits (QDR Discovery, Hologic, Inc, 
Bedford, MA). These scans will be used to assess areal bone mineral density (aBMD). The short-
term precision for this technique is 1-2% at the MGH Bone Density Center. The effective 
absorbed radiation dose for each set of DXA scans is 0.01 mSv. 
 
QCT 
Quantitative computed tomography (QCT) scans of the lumbar spine (L1-L2) will be obtained at 
baseline and 6-month visits (GE LightSpeed Pro CT scanner, GE Healthcare, Waukesha, WI). 
These scans will be used to assess volumetric bone mineral density (vBMD). Scans are 
performed with helical acquisition, 1.25mm slice thickness, QCTPro calibration phantom, and 
the following settings: L1-L2 (120 kvP, 100 mA). 3D reconstructive analysis for volumetric 
bone density for integral, trabecular and cortical compartments will be performed on QCTPro 
software (Mindways Software, Inc., Austin, TX). The short-term precision for this technique is 
1-2% for vertebral BMD measurements.[35-37] The effective absorbed radiation dose for each 
set of scans is 1.9 mSv.  
 
 
Anthropomorphic Measures 
Height and weight measurements will be obtained at each visit without shoes using standard 
protocols. 
 


8 
 
Questionnaires 
A bionutritionist will assess calcium and vitamin D intake using a validated food frequency 
questionnaire[38] and will provide personalized nutritional counseling. Physical activity will be 
assessed via the International Physical Activity Questionnaire (IPAQ) long format.[39] A self-
administered questionnaire will assess medical history, including fracture history and medication 
use. 
 
Bone Turnover Markers 
Fasting morning blood will be collected at each visit. Serum levels of type 1 cross-linked C-
telopeptide (CTX) will be measured by ELISA (Nordic Bioscience, Denmark), with intra- and 
interassay CV of 1.8% and 2.5%. Serum levels of procollagen type 1 N-terminal propeptide 
(P1NP) will be measured by RIA (Orion Diagnostica, Finland), with intra- and interassay CV of 
6.5% and 6.0%. We will also measure serum 25- hydroxyvitamin D (LC/MS) and PTH (Nichols 
Institute Diagnostics, San Clemente, CA). 
 
Safety Measures 
Serum calcium and albumin will be measured at each visit. Study subjects will also be assessed 
for hypocalcemic signs and symptoms. Hypocalcemia, if detected, will be graded according to 
common terminology for adverse event criteria (CTCAE v.4),[40] with particular attention to 
symptomatic hypocalcemia and/or grade 2-4 hypocalcemia (<8.0 mg/dL). Hypocalcemia will be 
addressed with application of an algorithm (see “Data Safety and Monitoring” section below). 
 
 
VI. Biostatistical Analysis 
 
All analyses will assess the distribution variables, and where appropriate, will employ 
transformation to combat skew or other irregularities. In addition to assessing study feasibility, 
the primary outcome of this pilot study is to obtain preliminary data regarding percent change in 
CTX at 6 months after RYGB and SG. Longitudinal linear mixed models will be applied to 
compare changes from baseline in CTX and P1NP over the 6-month period. The model will 
include random individual subject intercepts and fixed time (0, 2, 12, and 24 weeks) effects. 
Exploratory outcomes include changes in bone density over the 6-month period, which will be 
assessed by within group t-tests. As a safety measure, this pilot study will also document rates of 
postoperative hypocalcemia after bariatric surgery. All analyses will be performed using SAS 9.2 
software (SAS Institute Inc., Cary, NC). 
 
The primary purpose of this pilot is to obtain preliminary data to inform the design of a larger, 
statistically powered randomized controlled trial.  As such, this pilot study is not powered to 
detect significant changes in bone turnover markers or bone density. 
 
 
VII. Risks and Discomforts 
 
Zoledronic Acid 
The most common side effects associated with zoledronic acid include flu-like symptoms (e.g., 
fever, chills, muscle/joint aches) occurring after the infusion. The majority of these symptoms 


9 
 
occur within the first 3 days following drug administration and usually resolve within 3 days of 
onset but resolution can take up to 7-14 days. Taking acetaminophen or ibuprofen after the 
infusion can mitigate these symptoms. Other common side effects include nausea, tiredness, 
dizziness, headache, or pain/redness/swelling at the injection site. 
 
Hypocalcemia 
In the pivotal clinical trial of zoledronic acid for postmenopausal osteoporosis (n=7736), 
approximately 0.2% of patients had notable declines of serum calcium levels to values less than 
7.5 mg/dL within 11 days after zoledronic acid administration [41]. No symptomatic cases of 
hypocalcemia were observed. It is possible that RYGB patients may be more susceptible to 
developing hypocalcemia in response to zoledronic acid due to known reductions in calcium 
absorption that have been documented to occur after surgery [16, 42]. The incidence of 
postoperative hypocalcemia (<8.9 mg/dl) after RYGB is 1-2% and is associated with pre-existing 
renal insufficiency and vitamin D deficiency [43, 44]. Study subjects in this trial will be 
excluded for renal insufficiency and vitamin D deficiency, as well as for low serum calcium or 
magnesium, or use of loop diuretics.  All study subjects will receive ergocalciferol 50,000 IU for 
3 days prior to study drug infusion, and will also receive personalized counseling about calcium 
and vitamin D intake throughout the study. We will monitor serum calcium and 25-
hydroxyvitamin D (25OHD) as per our research protocol. 
 
Risk of ergocalciferol 
There is a very small risk that the ergocalciferol supplement could cause vitamin D toxicity. This 
is unlikely to be an issue for the dose used in this study. 
 
Calcium and vitamin D supplements 
The MGH Weight Center recommends that all RYGB and SG patients take supplemental 
calcium and vitamin D.  These supplements will be provided to study subjects during their 
participation in the trial.  In the doses used in this study, calcium and vitamin D have minimal 
side effects.  Some individuals may note constipation or stomach upset with calcium 
supplements. Very rarely, if an individual is over-supplemented with calcium, a kidney stone 
could result. 
 
Acetaminophen:  Acetaminophen is very safe when used appropriately.  A single standard dose 
will be administered at the time of study drug infusion to decrease the likelihood of acute phase 
response. Overdose of acetaminophen may be hepatotoxic. The single dose of acetaminophen at 
the time of study drug infusion will be withheld if a subject has known significant liver disease, 
reports that a clinician has ever advised avoidance of acetaminophen, or otherwise reports a 
sensitivity to acetaminophen.  An exclusion criterion for the pilot trial is liver disease with AST 
or ALT > 2x the upper limit of normal.   
 
Renal toxicity 
Zoledronic acid has been associated with renal impairment and in rare cases, acute renal failure. 
There is a transient increase in serum creatinine within 10 days of dosing in 1.8% of zoledronic-
acid treated patients versus 0.8% of placebo-treated patients. Renal function will be monitored 
closely throughout the study and patients will be required to have an estimated GFR >35 
(mL/min) to receive zoledronic acid. 


10 
 
 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw is an extremely rare side effect of zoledronic acid when given at the 
doses recommended for osteoporosis treatment. Subjects will not be enrolled if they have any 
major dental work planned during the projected course of the study (extractions or implants). 
 
Atypical Femur Fractures 
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in 
bisphosphonate-treated patients. Atypical femur fractures may be unilateral or bilateral and some 
patients report prodromal dull or aching pain in the thigh in the weeks to months before a 
complete fracture occurs. The incidence of atypical femur fractures is not well-defined but 
appears to be extremely rare and at least somewhat dose-dependent. If a study subject presents 
with thigh or groin pain, she/he will be immediately evaluated to rule out an incomplete femur 
fracture. 
 
Imaging studies 
Over the 6-month study period, subjects will receive 2 DXA scans of the lumbar spine, hip, and 
total body, and 2 QCT scans of the spine. One set of scans will be performed at the baseline visit, 
and the second set of scans will be performed at the 6-month visit. The overall total dose for the 
entire study is ~3.82 mSv.  
 
Blood Draws 
There is some discomfort associated with blood draws and injections. Furthermore, there is a 
slight risk of bleeding, bruising or infections at the needle site.  
 
 
VIII. Potential Benefits 
 
Subjects may experience increases in bone density and improvements in bone microarchitecture 
over the course of the study. The information from the study may help in the understanding of 
the role of antiresorptive therapy in preventing the deterioration of skeletal health that occurs 
after RYGB and SG. This knowledge has the potential to mitigate one of the largest negative 
consequences of these surgeries, which are otherwise the most effective treatments for severe 
obesity.  
 
IX. Data and Safety Monitoring Plan 
 
All subjects will be informed of their rights under the Health Insurance and Portability and 
Accountability Act of 1996 per federal law and hospital policy. The consent form describes what 
protected health information from the research study may be used or shared with others. Data 
collected strictly for research purposes are stored in locked files and on computers with 
passwords required for access. Data will be entered into the Partners-approved secure REDCap 
database system. When the data are published, no names or other materials that allow 
identification of an individual will be used. 
 


11 
 
Study physicians and staff will monitor subjects closely. Routine safety measures (e.g. renal 
function, calcium levels) will be assessed as described in the research plan and reviewed by a 
physician in real-time. The study physicians and the study staff will also meet on a weekly basis 
to discuss any issues relating to adverse events, safety data and outcome data. At the discretion 
of the study physician, any laboratory or physical exam abnormalities can be cause for 
discontinuation. If a subject experiences an adverse event, we will ensure necessary medical 
treatment and will provide that treatment, free of cost if necessary, within our institution.  
 
Although rates of hypocalcemia are rare in osteoporosis studies, RYGB and SG patients might 
be at greater risk of developing hypocalcemia in response to zoledronic acid. Nevertheless, we 
expect these risks to be small. All study subjects will be required to have normal serum calcium, 
magnesium, 25-hydroxyvitamin D, and renal function at study entry. Patients taking loop 
diuretics will be excluded due to increased risk of hypocalcemia with zoledronic acid with 
concomitant use. 
 
In addition to the precautions being taken with all study subjects, postoperative serum 
chemistries will be monitored closely at multiple timepoints as described below:  
 
Postoperative serum calcium and 25OHD levels will be monitored closely at 2-week, 12-week, 
and 6-month timepoints, as indicated in the research protocol.   
• Laboratory results obtained during the follow-up visits will be approached according to the 
following algorithm: 
 
• Serum 25OHD < 30 ng/mL with corrected serum calcium within normal range:  
▪ Serum 25OHD 20-30 ng/dL: increase vitamin D intake by 2000 IU 
▪ Serum 25OHD < 20 ng/dL: increase vitamin D intake by 2000 IU daily and add 
ergocalciferol 50,000 IU three times weekly for 3 weeks   
 
• Hypocalcemia: 
▪ Grade 1, corrected calcium 8.0-8.4 mg/dL:  
o if without symptoms and if vitamin D is to be increased in response to 
25OHD level (see above), no additional treatment beyond the increase in 
vitamin D supplement; repeat serum calcium in 1 week and increase total 
daily calcium intake by 500 mg (up to a maximum daily intake of 2500 
mg/day) if still ≤ 8.4 mg/dL 
o if symptomatic or if 25OHD level already at goal of 30 ng/mL, increase 
total daily calcium intake by 500 mg (up to a maximum daily intake of 
2500 mg/day); repeat serum calcium in 1 week 
▪ Grade 2, corrected calcium 7.0-7.9 mg/dL:  
o if without symptoms and if vitamin D is to be increased in response to 
25OHD level (see above), increase total daily calcium intake by 500 mg 
(up to a maximum daily intake of 2500 mg/day) and increase vitamin D 
supplement as above; repeat serum calcium in 1 week 
o if symptomatic or if 25OHD level already at goal of 30 ng/mL or if 
already at maximum daily calcium intake, also add calcitriol 0.25 mcg 


12 
 
once daily (if 7.5-7.9 mg/dL) or twice daily (if 7.0-7.4 mg/dL); repeat 
serum calcium in 1 week 
▪ If corrected calcium still <8.0 mg/dL at 1-week recheck, increase 
calcitriol by 0.25 mcg daily and repeat 
▪ 
Grade 3 (corrected calcium 6.0-6.9 mg/dL) or grade 4 (corrected calcium <6.0 
mg/dl or severe symptoms): refer to physician for IV calcium and other evaluation 
and treatment 
 
Finally, renal function will be monitored closely and patients are required to have an estimated 
GFR >35 (mL/min) to receive study drug. Additionally, no subject will be enrolled if they have 
any major dental work planned during the course of the study, and all subject complaints of thigh 
or groin pain will be immediately evaluated to rule out an incomplete femur fracture. The risks 
of phlebotomy will be minimized by careful attention to proper technique. 
 
In addition, a Data Safety Monitoring Board will be appointed. This DSMB will be comprised of 
2 physicians, neither of whom are involved in the trial. This DSMB will be responsible for 
ensuring scientific integrity and protecting the safety of study subjects. Specifically, the DSMB 
will meet every 6 months to review all the safety data including changes in primary and safety 
endpoints. The DSMB has access to unblinded data and the authority to perform more formal 
interim analyses should there be a suggestion of increased adverse events occurring in either 
treated group. The DSMB has the authority to recommend stopping the study if any safety 
concerns should arise. The DSMB also reviews investigator and study staff performance 
(recruitment, retention, flow of data forms, protocol adherence, and data quality). 
 
Unanticipated problems will be reported to the PHRC IRB within 7 days of the PI receiving 
notification of the event. All Serious Adverse Events (SAEs) (regardless of expectedness, 
relatedness, or if they meet the definition for unanticipated problems) will be reported to the IRB 
within 48 hours of the PI receiving notification of the event. The report will include a description 
of the event, as well as the Investigator’s assessment of expectedness, relatedness and other 
information, as relevant.  Any action taken by the investigative team should be provided in the 
report. The DSMB will be provided with this information but will provide an independent 
assessment on attribution and expectedness, as well as whether further action is recommended 
(e.g. collection of follow up information).  In the event of a discrepancy between the PI and 
DSMB for determining whether an adverse event is “unanticipated”, the determination of the 
DSMB will be considered final. 
 
 
VERSION DATE: 01/08/2019 
  
 
 


13 
 
 
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14 
 
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15 
 
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