Conditions: CKD Diabetic Kidney Disease Type 2 Diabetes Mellitus in Obese Obesity Severe Obesity
Keywords: ckd obesity kidney transplant transplant wait list diabetic kidney disease glp-1 semaglutide
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
This randomized study evaluates the effect of subcutaneous semaglutide /in combination with lifestyle counseling in patients with type 2 diabetes mellitus (T2DM), overweight/obesity, and stage 4-5 chronic kidney disease (CKD) or dialysis-dependent end-stage kidney disease (ESKD) on patients' eligibility for kidney transplantation at the end of 9 months.

Detailed description:
Transplant policies regarding listing consider uncontrolled diabetes and severe obesity to be contraindications though there is great variability for exact BMI (35-45 kg/m2) and A1c (9-10%) thresholds for listing by center. Glucagon-lowering peptide-1 receptor agonists (GLP-1 RAs) offer great promise in this population as they have been shown to reduce weight, central adiposity, A1c, and risk of cardiovascular outcomes with similar effects in patients with and without CKD.

In this double-blind, placebo-controlled randomized controlled trial, the investigators will evaluate the effect of subcutaneous semaglutide 1.34 mg/ml (up to 1.0 mg per week) in combination with lifestyle counseling in patients with T2DM, overweight/obesity, and stage 4-5 CKD or dialysis-dependent ESKD on patients' eligibility for kidney transplantation in terms of diabetes control (A1c \<9%) and obesity (BMI \<35 kg/m2 or 35-40 kg/m2 with waist circumference \<120 cm) at the end of 9 months.

Arms:
arm 1: This arm will receive semaglutide. arm 2: This arm will receive placebo.

Interventions: intervention 1: Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection solution intervention 2: Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution
Intervention descriptions: intervention 1: Dose will be started at 0.25 mg per week. Dose escalation will occur every 4 weeks to mitigate risk of gastrointestinal side effects to a maximum dose of 1.0 mg per week. intervention 2: Matched placebo solution for injection will be provided by Novo Nordisk in a 1.5 ml pre-filled pen-injector for subcutaneous injection with the same instructions on dose escalation.

Protocol document:
Prot_SAP_000.pdf: 
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Protocol Title 
A Randomized Trial Examining the Effect of Subcutaneous Semaglutide (Ozempic) on Kidney 
Transplant Candidacy for Patients with Stage 4-5 CKD or dialysis-dependent ESKD
INVESTIGATOR-SPONSORED STUDY PROPOSAL
UNIVERSAL TRIAL NUMBER (UTN)
U1111-1249-8833
 
Department Name - Kidney Health Research Institute
Institution Name - Geisinger
Institution Address – 100 N Academy Ave, Danville, PA 17822  USA
Correspondence to:
Principal Investigator’s Name – Alexander Chang, MD, MS
Principal Investigator’s Title – Assistant Professor, Clinical Research
Principal Investigator’s Address – 100 N Academy Ave, Danville, PA 17822
Phone 570-271-8026
Fax 570-271-5623
Email achang@geisinger.edu
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BACKGROUND AND SIGNIFICANCE:
Prevalence of obesity continues to rise globally(1), accompanied by increases in type 2 diabetes 
and chronic kidney disease (CKD). In the U.S., approximately 24% of CKD is attributable to 
diabetes(2). Among persons with type 2 diabetes mellitus (T2DM), 10-year mortality is 
exceptionally higher for those with CKD than those without CKD (31.1% vs. 11.5%), accounting 
for the majority of excess mortality risk in T2DM(3). Patients with diabetes who progress to end-
stage kidney disease (ESKD) requiring dialysis are at particularly high risk for death (~20 deaths 
per 100 person-years); transplant is associated with ~11 more years of life among patients with 
diabetes and ESKD(4). Unfortunately, patients with T2DM and CKD are frequently unable to be 
waitlisted for kidney transplant. While there are many reasons why patients are excluded for 
transplant (e.g. active malignancy, severe heart and lung disease), one of the most common 
reasons for exclusion is severe obesity, which increases risk for adverse transplant outcomes(5-
8); a staggering 22% of U.S. patients with CKD have BMI ≥ 35 kg/m2 (1). 
Transplant policies regarding listing consider uncontrolled diabetes and severe obesity to be 
contraindications though there is great variability for exact BMI (35-45 kg/m2) and A1c (9-10%) 
thresholds for listing by center(9). At Geisinger, exclusion criteria includes uncontrolled diabetes 
(A1c ≥9%) and severe obesity (BMI ≥ 40 kg/m2; or BMI ≥ 35 kg/m2 with waist circumference 
≥120 cm). Pre-transplantation hemoglobin A1c increases risk of cardiovascular death with those 
with A1c ≥ 10% having a 4-fold higher risk of cardiovascular death(10). Currently, medical 
management to help potential transplant candidates achieve waitlisting is suboptimal. In a study 
of 170 patients with ESKD and severe obesity (majority with diabetes; A1c not reported) being 
evaluated for kidney transplantation at University of Cincinnati, no patient made the BMI 
cutpoint for transplant eligibility after 6 months of lifestyle management(11, 12)(11, 12)(11, 12). 
Sleeve gastrectomy was performed on 52 patients with many being waitlisted and transplanted 
with excellent outcomes in long-term follow-up(11,12). Unfortunately, the suboptimal medical 
management outcomes and increasing reliance on bariatric surgery in such patients reflects the 
experience at Geisinger and other institutions(13-15). 
Glucagon-lowering peptide-1 receptor agonists (GLP-1 RAs) offer great promise, even in patients 
with GFR <30, and their preferred use along with sodium-glucose co-transporter-2 inhibitors, 
which are restricted to eGFR >45-60, have been endorsed in patients with T2DM and CKD by the 
European Renal Association-European Dialysis and Transplantation Association (16-19). In the 
SUSTAIN-6 trial that included 939 (28.5%) patients with eGFR < 60 ml/min/1.73m2, and 107 
(3.2%) with eGFR < 30 ml/min/1.73m2, risk of the primary cardiovascular outcome was lower in 
the semaglutide group than the placebo group (6.6% vs. 8.9%), with similar effects in those with 
CKD(18). A1c was significantly lower at week 104 for semaglutide 0.5 mg qwk (-0.7%, 95% CI: -
0.80, -0.52) and 1.0 mg qwk (-1.1%, 95% CI: -1.2%, -0.9%), compared to placebo. Dosing in renal 
insufficiency does not need to be adjusted as semaglutide exposure was similar across the 
spectrum of renal function after a single 0.5 mg subcutaneous semaglutide dose was given in a 
pharmacokinetic study(20). Other GLP-1 RA trials that have included individuals with T2DM and 
CKD have shown that GLP-1 RAs have reasonable safety and beneficial effects on cardiovascular 
disease and renal outcomes, driven mainly by new-onset macroalbuminuria outcomes(21-28). 
A systematic review and meta-analysis found that subcutaneous semaglutide at the maximum 
diabetes dose (1.0 mg qweek) reduced weight by a mean of 3.5 kg and waist circumference by 
2.6 cm(29). In a weight loss trial using subcutaneous semaglutide combined with lifestyle 
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intervention, the 0.1 mg per day dose resulted in greater reductions in weight (-8.6% vs. -2.3% 
for placebo) and waist circumference (-8.8 cm vs. -3.5 cm for placebo)(30).
The impact of GLP-1 RAs on reducing central obesity is particularly important as central obesity 
is a stronger predictor for mortality than BMI in dialysis and transplant populations(31, 32), 
partly because BMI does not distinguish between fat and muscle or between visceral and 
subcutaneous fat distribution. Thus, many transplant centers informally use central obesity to 
determine whether patients between BMI 35-40 kg/m2 should be transplanted; median (25-75th 
percentile) waist circumference of CKD patients with BMI 35-40 kg/m2 using NHANES data is 120 
cm (114-126 cm)(33).
Geisinger preliminary data
Current transplant exclusion includes 
uncontrolled diabetes (A1c ≥ 9%) and 
severe obesity (BMI ≥ 40 kg/m2; or BMI 
35-40 kg/m2 with elevated waist 
circumference ≥120 cm). Among 4,200 
adults with T2DM and stage 4-5 CKD or 
ESKD who had an outpatient visit at 
Geisinger over the past 15 months, 30% 
had BMI ≥ 35 kg/m2, 13% had BMI ≥ 40 
kg/m2, and 10.7% had A1c ≥ 9% (Table 
1). Use of GLP-1 RAs is quite low with 
only 6% taking GLP1-RAs, similar to the 
rest of the country (34) whereas 15% 
are on sulfonylureas, despite their 
increased risk of hypoglycemia, weight 
gain, and lack of evidence for 
cardiovascular benefit (35, 36). Based 
on data from Geisinger, the proportion 
of patients with BMI ≥ 40 kg/m2 are 
more than 4 times less likely to be 
transplanted. In short, there is a 
significant patient population that 
cannot be transplanted due to issues 
with obesity and/or uncontrolled 
diabetes. With better control of 
diabetes and weight loss, these patients can potentially be transplanted and lead a healthier 
and longer life.
These numbers are just the tip of the iceberg as many more patients from other nephrology 
practices and dialysis centres are never even referred for transplant evaluation. The transplant 
centers send a list of contraindications (including BMI cut offs) to referring physicians and 
dialysis units. Due to this reason a significant number of patients are never referred for 
transplant. Access to transplant offers significant benefits in terms of mortality risk. Patients 
who are transplanted have 5-fold lower mortality (even at BMI ≥ 35 kg/m2), compared to 
those who remain on the waitlist (37, 38). Being on the transplant waitlist (without receiving 
transplant yet) is associated with nearly 7-fold lower mortality compared to patients on 
dialysis not on the waitlist (38).
Table 1. Characteristics of Stage 4-5 CKD/ESKD patients with T2DM who had an outpatient 
Geisinger visit in last 15 months
Variable
eGFR <15
No Dialysis
n = 676
eGFR 15-30
No Dialysis
n = 2,543
Dialysis
n = 981
Total
n = 4,200
Age
71.1 ± 12.8
75.3 ± 11.7
67 ± 12.4
72.7 ± 12.5
Female
53%
57.1%
42.4%
53%
Black
6.4%
2.7%
8.5%
4.6%
Last BMI
32.4 ± 8.8
32.3 ± 8.1
31.3 ± 7.9
32.1 ± 8.2
Last A1c
6.9 ± 1.6
7.2 ± 1.5
6.9 ± 1.7
7.1 ± 1.6
BMI ≥ 35
29.8%
31.2%
28.0%
30.2%
BMI ≥ 40
15.4%
15.5%
11.4%
12.6%
BMI ≥ 40 and A1c ≥9%
2.2%
1.7%
2.0%
1.8%
A1c ≥ 9
9.7%
11.4%
12.1%
10.7%
Meglitinides 
3.3%
3.6%
1.6%
3.1%
Biguanides 
7.5%
9.1%
0.5%
6.9%
Thiazolidinediones 
1.3%
2%
0.3%
1.5%
Sulfonylurea 
12.1%
18.8%
7%
15%
DPP inhibitor 
11%
14.1%
5.1%
11.5%
GLP1-4A inhibitor 
3%
8.3%
3.1%
6.2%
SGLT inhibitor 
0.3%
0.6%
0.2%
0.5%
Alpha-glucosidase 
inhibitor 
0.3%
0.2%
0.1%
0.2%
Short-acting short-
acting insulin
44.7%
38.9%
52.6%
43%
Intermediate or long-
acting insulin
51.8%
44.9%
53.8%
48.1%
Any antidiabetic class 
medication
79.9%
78.1%
74.3%
77.5%
Prior history of visit 
with dietitian
25.9%
27.8%
33.4%
28.8%
Prior weight loss clinic 
i i
6.5%
6.9%
9.2%
7.4%
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A combined lifestyle modification program with optimal medical management for T2DM 
patients with overweight/obesity and stage 4-5 CKD/ESKD could be very valuable in helping 
patients get listed for transplant and improving survival. To our knowledge, the only published 
medical management to increase transplant listing of obese CKD patients was a non-randomized 
study with orlistat, which showed some success compared to non-participants in the program 
(35% vs 6%)(39). Use of GLP-1 RAs for patients with T2DM, overweight/obesity, and advanced 
CKD, in combination with lifestyle counseling, could be particularly helpful in helping control 
A1c, reduce weight, and waist circumference. 
In this study, we aim to evaluate the effect of subcutaneous semaglutide 1.34 mg/ml (up to 1.0 
mg per week) in combination with lifestyle counseling in patients with T2DM, 
overweight/obesity, and advanced CKD or dialysis-dependent ESKD on patients’ eligibility for 
kidney transplantation in terms of diabetes control (A1c <9%) and obesity (BMI <35 kg/m2 or 35-
40 kg/m2 with waist circumference <120 cm) at the end of 9 months. 
Study rationale: Despite demonstrated CVD benefits of GLP-1 agonists, these agents are greatly 
underutilized, particularly among patients with advanced kidney disease, for which there is 
limited data. Clearly, this is a huge unmet need and a great opportunity to improve outcomes in 
patients with T2DM, overweight/obesity, and advanced CKD who are unable to be listed for 
transplant. The purpose of this study is to determine the effect of subcutaneous semaglutide 
1.34 mg/ml (up to 1.0 mg per week) on patients’ eligibility for kidney transplantation.
SPECIFIC OBJECTIVES:
Primary objective.
The primary objective of this study is to determine the effect of using subcutaneous semaglutide 
1.34 mg/ml (up to 1.0 mg per week), on top of standard of care (SoC), on patients’ eligibility for 
kidney transplantation. 
Secondary objectives.
1 – Evaluate the efficacy of subcutaneous semaglutide 1.34 mg/ml, on top of SoC) on lowering 
A1c, weight, and waist circumference, and % body fat.
2 - Provide additional data on the safety profile of subcutaneous semaglutide 1.34 mg/ml in 
patients with advanced CKD or dialysis-dependent ESKD.
RESEARCH DESIGN AND METHODS
Study Hypothesis (hypotheses):
We hypothesize that use of subcutaneous semaglutide 1.34 mg/ml (up to 1.0 mg per week) will 
increase the proportion of patients achieving Geisinger Medical Center transplant requirements 
for glycemic control (A1c <9%) and obesity (BMI <35 kg/m2 or BMI 35-40 kg/m2 with waist 
circumference <120 cm), compared to placebo in patients with advanced CKD or dialysis-
dependent ESKD. 
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Endpoints:
Primary endpoint is kidney transplant candidacy, defined as alive at 9 months and meeting 
glycemic control criteria (A1c <9%) and obesity criteria (BMI < 35 kg/m2 or BMI 35-40 kg/m2 with 
waist circumference < 120 cm); or alive at 9 months and had referral/listing for kidney 
transplant during the 9-month follow-up period. If patients have A1C better controlled, they can 
be referred for transplant, and depending on the time to achieve A1C/weight goal, patients can 
be listed as well. 
Secondary endpoints: change in A1c, change in BMI, change in waist circumference, change in 
body fat percentage (at 9 months compared to baseline), and kidney transplant
Note: In patients with ESKD, there are some limitations with A1c. While other glycemia markers 
such as glycated albumin and fructosamine have been proposed, A1c remains the gold standard 
used clinically(40).  Continuous glucose monitoring is another option considered for this trial but 
will not be performed due to budget constraints. It is recognized that transplant listing and 
kidney transplantation may be dependent on many other factors and longer-term follow-up is 
needed to examine these outcomes. 
Other endpoints: changes in automated office blood pressure (AOBP)-measured systolic blood 
pressure (SBP) and diastolic blood pressure (DBP), fasting triglycerides, and fasting low-density 
lipoprotein (LDL) cholesterol
Safety outcomes: gastrointestinal disorders, gallbladder disorders, hepatic events, injection-site 
reactions, allergic reactions, neoplasms, hypoglycemia events, and acute pancreatitis events, all-
cause hospitalizations, CVD events, doubling of creatinine or ESKD, death, change in urine 
albumin/creatinine ratio (only among non-dialysis patients), change in estimated glomerular 
filtration rate (eGFR) using CKD-EPIcr equation (only among non-dialysis patients).
Study type: This will be a multi-site, two-arm, parallel, double-blind, placebo-controlled 
randomized trial conducted at 3 sites at Geisinger (Geisinger Medical Center in Danville, PA; 
Geisinger Wyoming Valley Medical Center in Wilkes-Barre, PA; Geisinger Lewistown Hospital in 
Lewistown, PA).
The intervention will last 9 months with final study outcomes measured at 9 months follow-up.
Rationale for study Design
Limited data exists on use of GLP1-Ras in advanced CKD/ESKD, particularly in the context of an 
intensive lifestyle intervention to help patients’ eligibility for kidney transplantation. There could 
be great benefits to this strategy in relation to lowering future risks of cardiovascular events and 
mortality in this patient population. 
Study population:
Planned number of subjects to be electronically screened: 300-1000 patients (200 patients 
referred or being seen in Geisinger’s transplant weight loss clinics; the remainder recruited using 
EHR data pulls, followed by mailings/phone calls)
Number of subjects to be studied: 200
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Planned number of subjects to be treated in run-in period: 200
Planned number of subjects to be randomized/started on study medication(s): 150
Inclusion Criteria
1 - Age ≥ 18 years
2 - BMI 25-45 kg/m2
3 - T2DM
4 - Advanced CKD* (last eGFR <30 ml/min/1.73m2 in EHR or ESKD on dialysis prior to screening) 
or Stage G3B/A2-3 CKD (eGFR 30 to <45 ml/min/1.73m2 with albumin/creatinine ratio >30 
mg/g).
5 - Fulfill kidney transplant listing criteria except for one or more of the following reasons (1: 
uncontrolled diabetes [A1c ≥9%); 2: severe obesity (BMI ≥ 40 kg/m2 or BMI 35-40 kg/m2 with 
waist circumference >120 cm).  See exclusion criteria for general contraindications used for 
transplant listing used by majority of U.S. transplant centers]. 
6 – Ability to provide informed consent before any trial-related activities
7 – Access to a telephone
*The cause of the CKD does not need to be due specifically to diabetes
Exclusion Criteria
General contraindications used for transplant listing used by majority of U.S. transplant centers
1 - Active malignancy
2 - History of pancreatitis
3 - Active substance abuse
4 - Severe COPD
5 – Pulmonary fibrosis
6 - Symptomatic angina or recent myocardial infarction within 6 months
7 - Severe peripheral vascular disease
8 – Cirrhosis
9 – New York Health Association (NYHA) Class III-IV congestive heart failure
10 - Severe cognitive impairment
11 - Drug addiction
12 - History of non-adherence to therapy
13 - Active infection
14 - Expected life expectancy < 5 years
Additional exclusion criteria
15 - Type 1 diabetes mellitus
16 - History of diabetic ketoacidosis within the last 12 months
17 - Planning on undergoing bariatric surgery in next 9 months.
18 – Pregnant, breast-feeding, or planned pregnancy prior to the end of participation or not 
using adequate contraceptive measures
19 – Self-reported average consumption of > 21 alcoholic beverages per week or binge drinking
20 – Psychiatric hospitalization in past year
21 – Principal investigator discretion (i.e. concerns about safety, compliance)
22 – Known or suspected allergy to trial medication
23 – Previous participation (i.e. randomized) in this trial
24 – Use of GLP1-RA or pramlintide within 90 days prior to screening
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25 – For patients with eGFR < 30 ml/min/1.73m2: Use of metformin
26 – Use of DPP-4 inhibitors within 30 days prior to screening
27 – Personal or family history of medullary thyroid cancer, multiple endocrine neoplasia types 
2A and 2B syndrome
28 – Last hemoglobin A1c ≥ 12% 
29-For patients on anti-diabetic medications: last hemoglobin A1C ≤5.7% (likely to be more 
indicative of risk of hypoglycemia). 
Withdrawal Criteria
1 - Subjects may withdraw at will at any time.
2 - Pregnancy or intention of becoming pregnant.
Rationale for Study Population
These are patients who are either in need of listing for kidney transplant or will likely need to be 
listed for a kidney transplant, but who currently do not meet requirements for eligibility at 
Geisinger Medical Center. The exclusion criteria at Geisinger for uncontrolled diabetes is A1c 
≥9% and for severe obesity is BMI ≥ 40 kg/m2 or BMI 35-40 kg/m2 with waist circumference ≥120 
cm.  Listing requirements vary from center-to-center though the inclusion/exclusion criteria 
listed match the practice of the majority of U.S. centers. Additional eligibility criteria are in place 
to ensure adequate patient safety and compliance. Every effort will be made to recruit patients 
who could qualify for this study. For instance, for patients on DPP-4 inhibitors interested in the 
study, we will discuss with their primary care provider whether they can be changed to a 
different medication prior to screening visits.
The study will evaluate the effect of initiation of GLP1-RA, and patients will be encouraged to 
continue participation in the trial, even if they decide to stop taking the intervention 
medication. In the event of kidney transplantation, participants will be encouraged to continue 
the study drug as GLP1-RAs are acceptable post-kidney transplant (41, 42).
Subject Replacement
We will not replace study participants who withdraw from the study. However, statistical 
analyses have accounted for estimated drop-out. 
VISIT PROCEDURES
Recruitment
Participants will be recruited from transplant clinic, nephrology clinics, and transplant weight 
loss clinic. A number of patients, who are referred for transplant but do not meet for listing due 
to BMI and A1C issues will also be enrolled. 
Colleagues within the nephrology, endocrinology, and family medicine/internal medicine will be 
contacted and asked to refer potentially qualifying patients to participate in this study. Targeted 
recruitment using existing data analytics, combined with use of telehealth to ease patient 
burden for frequent visits with clinicians, and dietitians will enable us to easily recruit patients 
for this trial. In a pilot study completed, we demonstrated that use of remote delivery (e.g. 
telephone) to provide intensive lifestyle coaching can be used to reduce weight and 
cardiometabolic risk in patients with CKD (43). In addition to these sources of recruitment, other 
potentially qualifying patients identified via electronic health record (EHR) data pulls will be 
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contacted by study team members by recruitment letters, MyGeisinger messages, or 
recruitment emails followed by recruitment telephone calls.
Patient providers will be made aware of their potential eligible patients through an electronic 
message or letter. 
Screening/baseline visit and informed consent (V1)
Potential participants who meet inclusion criteria will be invited to a screening/baseline visit in 
which trained research staff will obtain informed consent, including consent to access their EHR 
data and receive communication via text messaging and/or MyGeisinger. We will obtain physical 
measurements (weight, height, waist circumference, waist-to-hip ratio, AOBP), fasting morning 
labs (HgbA1c, LDL, triglycerides, serum creatinine, serum potassium, serum albumin, urine ACR 
for non-ESKD patients). Females of childbearing potential will have a pregnancy test performed. 
At this visit, patients will meet with the study physician. They will also either meet with a 
research dietitian, or schedule a time to meet with them after the visit. 
Run-in period (RI)/Randomization
Participants will be required to complete baseline specimen collection as above and have at 
least 1 contact with the RDN via telephone to confirm their willingness to participate in their 
trial and comply with study procedures. Participants will be expected to complete these tasks in 
2 weeks although the run-in period will be up to 4 weeks if there are explanations for delay (e.g. 
travel, vacation, scheduling issues). Assessment of successful completion of the run-in period 
will be done remotely. Following successful completion of the run-in period, participants will be 
contacted and invited to come to an in-person randomization/training visit. They will then be 
randomized 1:1 to the semaglutide 1.34 mg/ml or placebo arm. Randomization assignments will 
be generated using a permuted block design by a computer program, stratified by ESKD status.
Training Visit (V2)
Participants will receive patient education and training on injecting the study drug, in 
accordance with the Directions for Use (DFU) that is provided global clinical supply (CS). Patients 
will have their body fat percentage and weight taken. 
Treatment of subjects: Patients with T2DM, overweight/obesity, and CKD stage 4-5 or ESKD on 
dialysis will be randomized 1:1 to SQ semaglutide 1.34 mg/ml vs placebo for 9 months, on top of 
SoC, which includes intensive lifestyle counseling.
Table 2. Study Drug Titration Schedule
Trial periods
Screening
Treatment 
period 1
Treatment 
period 2
Treatment 
period 3
Visits
V1
V2
V3
V4-V10
Duration of each period
2-4 weeks 
prior to 
randomization
Weeks 1-4
Weeks 5-8
Weeks 9-36
Treatment arm
Subcutaneous 
semaglutide 1.34 mg/ml 
(n=75)
Screening
0.25 mg 
qweek
0.5 mg 
placebo 
qweek
1.0 mg 
placebo 
qweek
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Subcutaneous Placebo 
(n=75)
Screening
0.25 mg 
placebo 
qweek
0.5 mg 
placebo 
qweek
1.0 mg 
placebo 
qweek
Dose escalation will occur every 4 weeks to mitigate risk of gastrointestinal side effects. If 
patients are experiencing GI side effects (nausea and/or vomiting) or unable to tolerate dose at 
a study visit, dose will not be escalated. If the patient is later tolerating the dosage well, the 
dose will escalated the following monthly study visit. If the patient is unable to tolerate the 1.0 
mg or 0.5 mg qweek dose, dose de-escalation is permitted and will administered doses and 
reasons for changes will be carefully tracked.
In the case of missed doses, participants will be advised to take it as soon as possible, provided 
the time to the next scheduled dose is at least 48 hours away. If the dose is missed and the next 
scheduled dose is <48 hours away, the subject should not administer a dose until the next 
scheduled dose. If multiple doses are missed due to unforeseen circumstances unrelated to 
safety of trial product as determined by the investigator (e.g. hospitalization without access to 
trial product), dosing should be continued as early as is possible. If more than one dose is 
missed, a protocol deviation will be reported.
Injection site: Injections can be administered in thigh, abdomen, or upper arm, at any time of 
day irrespective of meals. Participants should administer injections the same day of the week 
during the trial.
Background diabetes medication: We will take a pragmatic approach allowing for other 
treatments for glucose-lowering, blood pressure, or other cardiovascular or kidney risk-
reduction agents at the discretion of the investigators based on individuals’ needs. All 
adjustments, including any needed changes to basal or prandial insulin dosing, will be 
coordinated with the subject’s primary care provider or endocrinologist.
For patients on insulin: Subjects on insulin will be advised to self-monitor plasma glucose 
regularly and inform study team in case of hypoglycemia. During the first 12 weeks after 
randomization, subjects will have insulin doses adjusted based on 3 fasting pre-breakfast self-
measured plasma glucose values, preferably 3 consecutive days before a phone contact or clinic 
visit by a study nurse or physician. These touchpoints are considered standard of care to ensure 
safety with diabetes medication changes. They will occur as needed at the discretion of the 
study physician. Increasing insulin dose will be avoided during the first 12 weeks as semaglutide 
1.34 mg/ml reaches steady dose, unless there is a need to control acute hyperglycemia or 
prevent diabetic complications acutely. Adjustment of insulin dosing, frequency, and timing will 
be at the investigators’ discretion in coordination with the subject’s primary care provider or 
endocrinologist.
Diabetes medication adjustments to optimize safety prior to starting the study drug: 
1 – If patients are taking sulfonylureas, these will be stopped since they are not considered to be 
guideline-recommended if eGFR < 30 ml/min/1.73m2 and because of potential increased risk of 
hypoglycemia with intensive lifestyle intervention and weight loss. If A1c is severely 
uncontrolled at baseline (>9%), additional adjustments to other diabetes medications will be 
made at the investigators’ discretion in coordination with patient’s primary care physician or 
endocrinologist.
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2 – If A1c <8% and on basal insulin, dose of basal insulin will be adjusted according to physician’s 
medical judgement to ensure risks of hypoglycemia are minimized with weight loss and the 
added use of semaglutide 1.34 mg/ml for some subjects.
Suggested actions for any non-study diabetes medication changes that are needed during the 
trial:
1 – Avoid use of other GLP-1 RAs as well as DPP-4 inhibitor and pramlinitide (also an exclusion 
criteria during screening) since they also affect the incretin pathway
2 – Avoid use of sulfonylureas, metformin in stage 4-5 CKD/ESKD due to higher risk of 
hypoglycemia and lactic acidosis
3 – Avoid new prescription of SGLT2 inhibitors for those with eGFR <30 ml/min/1.73m2 as not 
currently approved to start at lower eGFR level for diabetes
Hypoglycemia episodes will be defined as per the ADA. If a patient experiences hypoglycemia 
with blood glucose <56 mg/dL or symptomatic hypoglycemia (<70 mg/dL with typical symptoms 
of hypoglycemia), patients are instructed to call their provider and the study team and use 
glucose tablets or food immediately to raise blood sugar, and insulin doses or other medications 
will be decreased as appropriate. For asymptomatic hypoglycemia, insulin dose will be 
decreased. These episodes will be documented in detail.
Table 3. Safety Levels and actions
Timeframe
Safety Level
Action
Hyperglycemia
First 12 weeks
Average 3 pre-breakfast 
glucose ≥ 250 mg/dL
Per investigator discretion in 
coordination with subjects’ PCP or 
endocrinologist
Weeks 13-36
Average 3 pre-breakfast 
glucose ≥ 200 mg/dL
Per investigator discretion in 
coordination with subjects’ PCP or 
endocrinologist
Hypoglycemia
Entire study
Lowest of 3 pre-breakfast 
glucose <56 mg/dl
-4 Units in basal insulin (for doses >45 
U, suggest dose reduction of 10%); 
contact provider and study team, and 
use glucose tablets or food 
immediately to raise blood sugar
Entire study
Lowest of 3 pre-breakfast 
glucose 56-70 with symptoms
-2 Units in basal insulin (for doses >45 
U, suggest dose reduction of 5%); 
contact provider and study team, and 
use glucose tablets or food 
immediately to raise blood sugar
Entire study
Lowest of 3 pre-breakfast 
glucose 56-70 without 
symptoms
-2 Units in basal insulin (for doses >45 
U, suggest dose reduction of 5%)
Subject Diary: Patients will be provided with a diary and instructed to make entries of the 
following data:
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1 – date, time, dose, and injection site of first dose of trial product
2 – date, time, dose of last injection of trial product prior to each visit/phone contact
3 – hypoglycemic episodes
4 – concomitant medication
5 – adverse events
6 – For insulin-treated subjects: total daily insulin dose and date, time, and value of the fasting 
glucose values for 3 consecutive days, preferably on 3 days before each visit/phone contact in 
the initial 12 weeks after randomization. Subsequent glucose measurements will be per patient 
as agreed upon with the investigator.
Background registered dietitian nutritionist (RDN) medical nutrition therapy: As part of routine 
clinical care, RDNs will complete individualized assessment of needs based on patient’s 
comorbidities, needs, and preferences. This will be done initially and throughout the 
intervention. Visits will be done via telephone, depending on patient preference. Participants 
will receive intensive behavioral counseling to reduce weight with a weight loss goal of ≥5% at 6 
months and to maintain weight loss at 12 months, with goal of biweekly sessions x 2 months, 
then monthly sessions to achieve 5% weight loss similar to ADA guidelines (9, 23). In addition, 
RDNs will be instructed to focus on key factors common to healthy dietary patterns, including 
nonstarchy vegetables, minimizing added sugars and refined grains, choosing whole foods over 
highly processed foods, reduced sodium intake (<2300 mg/d), replacing saturated fats with 
unsaturated fats, lean sources of protein. RDNs will also encourage patients to engage in ≥ 150 
minutes per week of moderate-vigorous activity and to increase walking/light activity. 
Participants will be encouraged to use step trackers or devices as they are able to afford, and 
devices will be connected to Geisinger patient portal through an existing link that can be used by 
the RDNs and clinicians to monitor/encourage patients.
Follow-up study visits during 2-8 months (V3-V10).
Monthly in-person study follow-up visits will be scheduled with the research staff (study 
physician or research nurse). When possible, visits will be scheduled in correlation with routine 
clinical visits with providers for convenience of the participant and to enhance adherence. 
Participants will receive the study drug at these visits along with physical measurements 
(weight, , waist circumference, waist-to-hip ratio, ,). Participants will also bring in self-reported 
glucose logs, and research staff will additionally collect data on adverse events. All adverse 
events will be communicated with the study physician immediately and addressed. 
At months 3 and 6 (V5, V8), non-fasting labs will be completed for all patients including HgbA1c 
and serum albumin. Non-fasting labs for non-ESKD patients will also include serum creatinine, 
potassium, and urine ACR. Data will be collected on adverse events and study drug compliance 
by count of remaining semaglutide 1.34 mg/ml doses.
Final outcome visit at 9 months (V11)
At the final outcome visit, participants meet with the research staff (study physician or research 
nurse) and will complete physical measurements (weight, waist circumference, waist-to-hip 
ratio, AOBP, heart rate, body fat percentage), fasting morning labs (HgbA1c, LDL, triglycerides, 
albumin, and for non-ESKD patients serum creatinine, potassium and urine ACR), collect data on 
adverse events, and assess study drug compliance by count of any remaining semaglutide 1.34 
mg/ml doses.
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As participants receiving GLP-1 RAs would be expected to likely require medication changes 
following withdrawal of the study product, participants will be warned about this possibility and 
instructed to monitor their glucose levels and weights after study closeout and notify their 
providers as soon as possible if they notice worsening glycemia. Participants will be asked to 
confirm that they want to be notified of their randomization assignment (when deemed 
appropriate by investigators; see blinding section), whether results can be shared with their care 
providers (primary care/nephrology/ endocrinology), and whether they wish to receive final 
study results. A letter or electronic health record message (electronic preferred) will be sent to 
providers to remind them of their patient’s participation in this trial, along with their pre/post 
A1c, weight, and medication changes during the trial (blinding will be preserved). They will be 
reminded to consider use of GLP-1 RAs in helping patients achieve optimal glycemic control and 
weight for kidney transplant eligibility. Recommendations will be made to follow-up with their 
primary care provider or endocrinologist within 1 month with the research staff helping 
facilitate scheduling if needed.
Study Close-out visit (V12)
This visit will be scheduled in-person with the research staff (study physician or research nurse) 
to ensure participants receive adequate post-trial follow-up as their blood sugars and weight 
may worsen following participation in the trial. At the study close-out visit, participants will be 
provided details about changes in A1c, weight, and cardiometabolic measures during the trial. If 
needed, research staff will help facilitate follow-up with their primary care provider or 
endocrinologist if this has not already been set up. Participants will also be scheduled for follow 
up in Geisinger’s transplant evaluation clinic and continue to receive RDN follow-up to help 
them achieve transplant listing. 
Disclosure of allocation and results of the study will be provided to study participants within a 
month of primary results being released in a journal publication.
Assessments for Efficacy
Efficacy and outcomes will be evaluated using data collected at study visits, blinded transplant 
committee adjudication reviewing their clinical data (independent of investigators), and EHR 
data as shown below. Assessment of outcomes is done in a manner to provide high accuracy 
and efficiency (i.e. without the need for external adjudication). All study labs are performed at a 
Geisinger Laboratory. Listing for kidney transplant is dependent on many factors (e.g. 
psychosocial, insurance, changes in health status, cardiovascular disease). Thus, the primary 
outcome is the proportion listed for kidney transplant or meeting kidney transplant candidacy 
for A1c (<9%) and obesity (BMI <35 kg/m2 or BMI 35-40 kg/m2 with waist circumference < 120 
cm) at the end of the 9-month period. Participants who are referred/listed for kidney transplant 
or received a transplant during the 9-month period will also count as having achieved the 
primary outcome. While all efforts will be made to retain participants in the research study and 
make sure compliance to the study schedule is adhered to, there will inevitably be participants 
who drop-out or are non-adherent to the study. To address this, we also will collect clinical EHR 
weight and A1c data +/- 3 months to impute missing data in sensitivity analysis (see statistical 
methods section). 
If patients withdraw from the study, no further prospective data collection will occur. These 
patients will continue to receive clinical care from our Nephrology department unless instructed 
otherwise. 
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Table 2. Study Outcomes
Data source
Timing of Outcome 
Assessment
Additional notes
Primary Outcome
Proportion either listed for 
kidney transplant at 9 months 
or meeting kidney transplant 
candidacy criteria for A1c 
(<9%) and obesity (BMI <35 
kg/m2 or BMI 35-40 kg/m2 with 
waist circumference < 120 cm)
Study visit data
Assessed at end of 9 
months
Secondary Endpoints
Change in hemoglobin A1c
Study visit data
Assessed every 3 months
HgbA1c will be collected using routine procedures and 
measured on the same day at the central Geisinger 
laboratory by Turbidmetric inhibition immunoassay.
Change in BMI
Study visit data
Assessed at end of 9 
months
Weight will be measured at each study visit in light 
clothing without shoes by trained, certified staff using a 
calibrated, digital scale. Scales will be calibrated 
annually. Height will be measured at the initial study visit 
to the nearest 0.1 cm using a calibrated, wall-mounted 
stadiometer without shoes on a firm, level surface, with 
head in the horizontal plane. 
 
Change in waist circumference
Study visit data
Assessed at end of 9 
months
Waist circumference will be measured at each study visit 
to the nearest 0.1 cm using a Gulick II tape measure.
Change in waist-to-hip ratio
Study visit data
Assessed at end of 9 
months
Hip circumference will also be measured to the nearest 
0.1 cm using a Gulick II tape measure, and waist-to-hip 
ratio will be calculated.
Change in % body fat
Study visit data
Assessed at end of 9 
months
% Body fat will be measured using a bioelectrical 
impedance analysis device
Activation on the transplant 
list
EHR data; transplant 
meeting data
Assessed at end of 9 
months
Assessed by Geisinger kidney transplant committee 
(blinded to randomization assignment, independent of 
investigators)
Receipt of kidney transplant
EHR data
Assessed at end of 9 
months
Other Endpoints
Change in LDL
Study visit data
Assessed at end of 9 
months
Change in triglycerides
Study visit data
Assessed at end of 9 
months
Fasting LDL and fasting triglycerides will be collected at a 
Geisinger lab using routine procedures and measured on 
the same day at the central Geisinger laboratory by 
spectrophotometry.
Change in SBP
Study visit data
Assessed at end of 9 
months
Change in DBP
Study visit data
Assessed at end of 9 
months
Automated office blood pressure (AOBP) will be 
measured (attended) using the OMRON 907-XL machine, 
with a 5-minute rest period in the seated position, 
followed by 3 measurements separated by 1-minute 
time intervals by trained research staff. Mid-arm 
circumference will be measured, and a cuff of 
appropriate size will be identified and the same size cuff 
will used for both visits.
Safety Outcomes
Change in albuminuria (%) 
among participants without 
ESKD (44, 45)
Study visit data
Assessed at end of 9 
months
Testing at the central Geisinger laboratory, using 
immunoturbidity (albumin) and Jaffe/Enzymatic (Urine 
Creatinine) 
Change in eGFR among 
participants without ESKD
Study visit data
Assessed at end of 9 
months
Testing at central Geisinger lab; Creatinine-based CKD-
EPI equation
All-cause hospitalizations  
EHR data
Entire study period
Collected using Geisinger EHR data
CVD events
EHR data
Entire study period
manual EHR review for CVD-related hospitalizations
Doubling of creatinine or ESKD
EHR data
Entire study period
manual EHR review
Death
EHR data
Entire study period
manual EHR review; discussing directly with patients. 
Gastrointestinal disorders
Study visit data
Entire study period
Assessed at each study visit
Gallbladder disorders
Study visit data
Entire study period
Assessed at each study visit
Neoplasms
Study visit data
Entire study period
Assessed at each study visit
Hepatic events
Study visit data
Entire study period
Assessed at each study visit
Allergic reactions
Study visit data
Entire study period
Assessed at each study visit
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Injection-site reactions
Study visit data
Entire study period
Assessed at each study visit
Hypoglycemia events
Study visit data
Entire study period
Assessed at each study visit
Acute pancreatitis events
Study visit data
Entire study period
Assessed at each study visit
Assessments for Safety
Safety outcomes will be assessed at each study visit and RDNs will also be instructed to report 
any patient adverse events to the study team. Lab assessments take place at 3 months, 6 
months, and 9 months. All adverse events will be coded using the Medical Dictionary for 
Regulatory Activities. Adverse events will be defined as any unfavourable and unintended sign, 
including abnormal lab findings, symptoms, or disease temporally associated use of the 
randomization drug, whether or not considered related to the drug. 
Subject Compliance
Compliance will be assessed by count of any remaining study drug at each study visit.
Schedule of Events
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* Training according to DFU can be conducted at every in-person visit upon the discretion of the investigator.
Note – all patient labs are considered to be standard of care. The study team will accept lab 
results that were collected within 30 days pre/post their applicable study visit date. Lipid panel 
and A1C will be accepted if they were within 60 days pre/post the applicable study visit date. 
Trial Periods
Screening
Run-in
Treatment
Visit
V1
RI
V2 
(randomization/training)
V3
V4
V5
V6
V7
V8
V9
V10
V11 (final 
outcome)
V12 
(Close-
out)
Week
Up to -4 
weeks
-2 
weeks
0
4
8
12
16
20
24
28
32
36
40
Visit window 
(days)
+/- 2 
weeks
+/- 5 days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/- 5 
days
+/-5 days
+/- 5 
days
Visit type
In-person
Remote
In-person
In-
person
In-
person
In-
person
In-
person
In-
person
In-
person
In-
person
In-
person
In-person
In-
person
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Demographics
X
Medical history 
review
X
Medication review
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
measurements
X
X
X
X
X
X
X
X
X
X
X
Self-reported 
glucose 
measurements
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy 
Test
X
Blood Pregnancy 
Test 
*If patient is not 
able to provide 
urine test. 
X
A1c, creatinine, 
potassium, 
albumin)
X
X
X
X
Lipid profile
X
X
Urine collections
X
X
X
X
Randomization
X
Dispense study 
drug 
X
X
X
X
X
X
X
X
X
Training*
X
Research Dietitian 
Calls
X
X
X
X
X
X
X
X
X
X
X
Consideration of 
dose escalation (if 
not at max dose)
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
Transplant 
committee 
outcome 
assessment
X
EHR-based 
outcome 
assessment
X
Facilitate post-trial 
follow-up with 
providers
X
X
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Attend screening-baseline visits
(estimated N=200)
Randomized (N=150)
Excluded (estimated N=50) not
meeting inclusion/exclusion
criteria or fail to complete run-in
procedures
Arm 1 – semaglutide
(n=75)
Arm 2 – placebo (n=75)
9-month visit
Analyzed intention-to-treat (n=60)
Primary outcome (kidney transplant
candidacy)
Secondary outcomes
AE monitoring
Allocation
Follow-up
Lost to follow-up (n=15)
List reasons (n=X)
Analysis
9-month visit
Analyzed intention-to-treat (n=60)
Primary outcome (kidney transplant
candidacy)
Secondary outcomes
AE monitoring
Lost to follow-up (n=15)
List reasons (n=X)
Dose titration
0.25 mg qweek x 4 weeks
0.5 mg qweek x 4 weeks
1.0 mg qweek
(dose escalation as tolerated by patient)
Dietitian counseling (16 sessions 1st 6
months), then monthly
AE monitoring
Dose titration
0.25 mg qweek x 4 weeks
0.5 mg qweek x 4 weeks
1.0 mg qweek
(dose escalation as tolerated by patient)
Dietitian counseling (16 sessions 1st 6
months), then monthly
AE monitoring
STATISTICAL CONSIDERATIONS:
Analysis Plan: All analyses will be done using intention-to-treat principles. Analyses will be 
conducted at conclusion of the 9-month follow-up for all study patients. Blinding will not be 
broken until within a month of primary results being released in a journal publication.
Sample Size Calculation (updated 9/29/22)
Originally,we calculated the effect size that can be detected with 150 subjects. 
Assumptions: Using data from SUSTAIN-6 for the semaglutide 1.0 mg/week diabetes dose, we 
assumed an estimated mean A1c decrease of -1.4% (SD 1.3%) for semaglutide 1.0 mg/d vs. -
0.4% (1.3%) for placebo(18). This does not exactly reflect our study design as there was no 
lifestyle modification program in addition to semaglutide, so weight loss could be expected to 
be greater with our study design. Using data from a dose-ranging, phase 2 trial comparing 
subcutaneous semaglutide, liraglutide, and placebo, in combination with intensive lifestyle 
counseling, (30) BMI decrease for the 0.1 mg/d dose (corresponding roughly to 0.5 to 1.0 
mg/week diabetes dose) was -3.36 (SD 3.3) kg/m2) for the semaglutide arm vs. -0.88 (SD 3.4) 
kg/m2 for the placebo arm, and decreases in waist circumference was -8.8 (SD 9.1) cm for the 
semaglutide arm vs. -3.5 (9.4) cm.
Since drop-out rate was 17% in a trial of dulaglutide in stage 3-4 CKD. We expect patients with 
advanced CKD/ESKD to be a more challenging population although potentially more motivated 
as they are undergoing transplant evaluation; thus, we used a 15% drop-out rate for sample size 
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calculations (27). For the primary outcome of eligibility of kidney transplantation (meeting 
criteria for diabetes A1c < 9% and obesity [BMI <35 kg/m2 or BMI 35-40 kg/m2 with waist 
circumference < 120 cm), we estimate that we would have >80% power to detect an absolute 
difference of 21% (15% in the placebo arm vs. 39% in the semaglutide group), at an alpha of 
0.05(this corresponds to an odds ratio of 3.6). For the secondary outcomes, the effect size was 
calculated using the size of the detectable standard deviation unit (SDU).  The SDU corresponds 
to a beta coefficient in a regression model when we assume the standard normal deviate (i.e. 
N(0,1)).  For an alpha error of 5%, there is 80% power to detect an SDU of 0.50. This corresponds 
to between-arm-differences in A1c change of 0.65%, BMI change of 1.68 kg/m2, and waist 
circumference change 4.65 cm. 
As recruitment has been slower than expected (15 participants in the first 15 months of the 
study with only 1 drop-out), power calculations were re-evaluated 9/29/22 and discussed with 
the Novo Nordisk and also with the Data Safety Monitoring Board 11/14/22, who agreed with 
continuing the study until the end date. Assuming 28/30 participants complete the trial and 
7.14% of the control group meet the primary endpoint, we would have >80% power to detect a 
significant difference at an alpha level of 0.05 if >60% of the control group meets the primary 
outcome. 
Statistical Analysis: 
Descriptive statistics will include evaluation of all data for underlying distribution and summary 
statistics, using means with standard deviations and medians with interquartile range for 
continuous variables, and frequency with percentages for categorical variables. The data will be 
summarized for all patients enrolled and will be stratified by randomization arm. We will assess 
the quality of data, evaluating outliers and patterns of missing data using graphs such as 
histograms and stem-and-leaf plots.  The primary outcome will be examined by comparing groups 
using logistic regression in an intention-to-treat analysis. Analyses will adjust for the stratification 
factors (ESKD status, site) in the randomization scheme. Additional analyses will be employed 
using linear mixed models for continuous variables.  Stopping rules will be outlined in the data 
safety and monitoring plan.
Missing Data Considerations: We will make every possible effort to minimize missing data and to 
capture final assessments for participants opting to discontinue study participation by querying 
the EHR for follow-up visits and sending reminders to each participant to schedule and attend 
appointments. Missing data, however, are inevitable in a longitudinal study due to dropout. We 
anticipate that no more than 15% of randomized subjects will fail to complete the study and 
reasons for dropout will be documented. Before proceeding with primary analyses, we will 
characterize patterns of missingness using exploratory analyses to provide insights into how to 
handle the missing data. Participants with missing data will be compared to participants with 
complete data to ensure there are no differences. Depending on the amount of missing data, we 
will use a non-parametric missing data imputation method based on random forests(46). This 
method has been shown to perform as well as or better than more traditional methods of 
imputation, and it has the advantage of imputing of both continuous and categorical data. By 
using random forests, we can capture non-linear relationships and interactions present in the 
dataset that may otherwise be missed when using a different method. At least 5 complete 
datasets will be created and combined using the multiple imputation methods of Rubin(47).
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DATA HANDLING AND RECORD KEEPING:
Study data will be collected and managed using REDCap (Research Electronic Data Capture) and 
stored on the Geisinger secure network.  All members of the research group will have individual 
computers that are part of the institution network with institutional oversight of security.  Field 
and range checks will be used to minimize data entry errors.  Data distribution will be checked 
periodically, and outliers verified; missing data will be tracked and checked. Only the minimal 
amount of data necessary will be shared with Novo Nordisk, such as a limited data set including 
dates of visits.  All patient information will be identified using a study ID number.  Before 
delivery to Novo Nordisk, a Geisinger Clinic Data Broker will review the data and ensure that it 
does not include unapproved PHI.
ETHICS:
IRB approval will be obtained prior to any study activities begin. Informed consent will be 
obtained for every study participant, who will be informed about the scientific rationale of the 
study, the procedures and potential risks involved, as well as the rights of the participant in the 
study. Before any procedures specified in this protocol are performed, a participant must:

Be informed of all pertinent aspects of the study and all elements of informed 
consent. 

Be given time to ask questions, take time to consider the decision to participate, and 
demonstrate understanding of the study.

Voluntarily agree to participate in the study. 

Sign and date an IRB-approved informed consent form.
The study team will comply with all applicable regulatory and legal requirements, ICH GCP 
guidelines and the Declaration of Helsinki in obtaining and documenting the informed consent.
We have determined that our research trial can be conducted without an IND. Per FDA guidance 
on IND applications, “a clinical investigation of a marketed drug is exempt from the IND 
requirements if all of the criteria for an exemption in § 312.2(b) are met:
1)
The drug product is lawfully marketed in the United States. 
2)
The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other 
significant change in the labeling of the drug. 
3)
In the case of a prescription drug, the investigation is not intended to support a 
significant change in the advertising for the drug. 
4)
The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the 
risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
5)
The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
6)
The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).”
Our trial meets the exemption criteria as follows:
1)
In this trial, the drug product Ozempic® will be used as an adjunct to diet and exercise to 
improve glycemic control for adults with type 2 diabetes as currently approved by the 
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FDA. Per the FDA label, “No dose adjustment of OZEMPIC is recommended for patients 
with renal impairment. In subjects with renal impairment including end-stage renal 
disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics (PK) was 
observed.”
2)
This investigation does not intend to support a change in the labeling of the drug.
3)
This investigation does not intend to support a change in the advertising for the drug.
4)
This investigation does not involve a route of administration, dose, patient population, 
or other factor that significantly increases the risk associated with the use of the drug 
product.
5)
This investigation will be conducted in compliance with the requirements for review by 
an IRB and the requirements for informed consent.
6)
This investigation is not intended to promote or commercialize the drug product. 
All personnel will complete and maintain required education on the protection of human 
research participants. The Geisinger Clinic has a formal program entitled the “Collaborative 
Institutional Training Initiative (CITI)”.  CITI is a web based educational course designed to 
provide formal training in human subjects’ research for all personnel involved in human subject 
research.  
Confidentiality of all medical records is strictly maintained by established procedures.  The 
privacy of study participants is very important to our study team, and it will be protected as 
much as possible.  In compliance with HIPAA requirements, the names, addresses, phone 
numbers, social security numbers, or any other identifying information on our study participants 
will not be released.  If study data are sent outside of the study team for further analysis, these 
data will be sent with a study ID number and/or a limited data set which may include dates of 
visits.  Similarly, any publications generated from the data collected from the proposed studies 
will exclude identifiers.  
STUDY SCHEDULE:
Study Activation (tentative, depending on trial initiation) : January 2021
Recruitment Period: February 2021-June 2023
Start of Study or FPFV: February 2021
Last Patient First Visit: June 2023
End of Study or LPLV: March 2024
Final Report:  June 2024
PUBLICATION PLAN:
Study Design/Rationale paper - September 2021
Abstract Submission/Presentation – November 2024 ASN Kidney Week
Main paper - March 2025
STUDY DRUGS AND MATERIALS:
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Study medication(s) / devices(s)
-
Semaglutide 2 mg/1.5 ml (1.34 mg/ml), prefilled pen-injector for subcutaneous injection 
solution
-
Placebo 1.5 ml, prefilled pen-injector for subcutaneous injection solution
The clinic variant of the cartridge is produced with an army green closure cap compared to a 
dust green closure cap in the marketed Ozempic® product. Ozempic® are marketed in 
different pen variants for different intended dosing regimens. The push button and cartridge 
holder are light grey, and the pen can be found in both a 1.5 ml and 3.0 ml variant, 
dependent on the country. The clinical pen can be found in one variant to support 0.25mg, 
0.5mg and 1mg doses in a 1.5 ml variant. The push button and cartridge holder are light 
brown. Neither closure cap nor the pen is in contact with the product and the differences in 
colours have no impact on the stability of the product.
Packaging and Labelling of Study Medication(s)
Blinded packaging design as per Novo Nordisk. Labelling will be in accordance with local law and 
study requirements.
Storage and Drug Accountability of Study Medication(s)
Geisinger’s Investigational Drug Service is a division of Geisinger Enterprise Pharmacy 
responsible for protecting the safety of patients participating in investigational or clinical 
medication studies by providing a process for the safe and appropriate use of investigational or 
clinical medication drugs within the Geisinger Clinic.  The sponsor-investigator, in collaboration 
with the Geisinger Investigational Drug Service, will ensure the availability of proper storage 
conditions and record and evaluate the temperature.  The Investigational Drug Service will store 
drug within temperature range and storage conditions indicated on package directions.  
Temperature is tracked every 15 minutes via TempTrack with daily summary reports available.  
No trial medication(s) will be dispensed to any person not enrolled in the study.  Unused 
medication(s) will be stored separately from used trial medication(s).  Drug accountability is 
tracked electronically using the Investigational Drug Accountability System (IDAS) (Vestigo). 
Unused trial product(s) are returned to the Investigational Drug Service for return to sponsor-
investigator or destruction as indicated by sponsor-investigator.  
Auxiliary Supply
N/A
Randomization and Blinding
Study investigators and participants will be blinded to treatment allocation. We will use block 
randomization and stratification by ESKD status, generated by a computer program. We will 
request Novo Nordisk global clinical supply to conduct the blinded randomization. Novo Nordisk 
will provide 2 versions of the same randomisation list: one blinded version from which the 
blinded investigator allocates a randomization number to the subject, and one unblinded 
randomization list from which unblinded trial staff reacds which treatment 
(semaglutide/placebo) the randomization number of the subject matches. The unblinded staff 
then allocates the correct trial product according to the randomized treatment.
Breaking of Blinded Codes
The code for a particular subject may be broken in a medical emergency if knowing the identity 
of the treatment allocation would influence the treatment of the subject or if demanded by the 
subject.  Whenever a code is broken, the person breaking the code will record the time, date 
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and reason as well as his/her initials in the source documents.  All codes (whether broken or 
not) will be kept throughout the trial period.   Accountability of all broken or unbroken codes 
(hard copy or electronic) will be performed at or after trial closure.
CONCOMITANT ILLNESSES AND MEDICATIONS:
Definitions:
Concomitant illness: any illness that is present at the start of the trial (i.e. at the first visit).
Concomitant medication: any medication other than the trial product(s) that is taken during the 
trial, including the screening and run-in periods.
A subset of concomitant medications will be collected in the eCRF for this study. Only those 
medications used for the treatment of (a) diabetes or diabetic complications, (b) obesity, (c) 
chronic kidney disease, or (d) medications taken to treat an SEA or AE of interest will be 
captured. These will be recorded at trial entry (i.e. at the first visit). Any changes in these specific 
concomitant medications must be recorded at each visit. If the change influences the subject’s 
eligibility to continue in the trial, the PI must be informed.
The information collected for each concomitant medication includes, at a minimum, trade name 
or generic name, indication, dates of administration, and dose. 
For each concomitant illness, date of onset, date of resolution or continuing, at a minimum, 
should be recorded.
ADVERSE EVENTS:
Definitions
The current version of the FDA approved Prescribing Information or any updates thereof will be 
used for assessment of expectedness adverse events are expected or unexpected. 
Adverse Event (AE):
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered/using a product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
product, whether or not considered related to the product.  This includes events reported from 
the first trial related activity after the subject has signed the informed consent and until 30 days 
after the last study drug treatment the end of the treatment follow-up period as defined in the 
protocol. 
Only the following AEs will be recorded in the eCRF:
• serious adverse events (SAE), suspected unexpected serious adverse reactions (SUSARs), or 
serious adverse drug reactions (SADRs)
• AEs leading to discontinuation of trial product
• The following AEs of clinical interest 

pancreatitis

stage 2-3 acute kidney injury 

gallbladder disease

malignant neoplasms

diabetic retinopathy

medication errors or misuse/abuse of trial product
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The following should not be recorded as AEs:
• Pre-planned procedure, unless the condition for which the procedure was planned has    
worsened from the first trial related activity after the subject has signed the informed consent
• Pre-existing conditions found as a result of screening procedures
• Any AE occurring after 30 days post final dose of study drug
Clinical Laboratory Adverse Event:
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically significant by 
an investigator will be reported in the eCRF (i.e. requiring change of medication dose, 
discontinuation of trial product, more frequent follow-up or diagnostic investigation). Every 
attempt should be made to consolidate symptoms into a comprehensive diagnosis term for 
reporting.
Serious Adverse Event (SAE):
A serious AE is an experience that at any dose results in any of the following:
• Death
• A life-threatening* experience
• In-patient hospitalisation or prolongation of existing hospitalization
• A persistent or significant disability/incapacity
• A congenital anomaly/birth defect
• Important medical events that may not result in death, be life-threatening*, or require
  hospitalisation may be considered an SAE when, based upon appropriate medical judgement, 
they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition
• Suspicion of transmission of infectious agents 
*The term life-threatening in the definition of SAE refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
Serious Adverse Drug Reaction (SADR): 
An adverse drug reaction (ADR) is an adverse event (AE) for which a causal relationship to the 
trial product is at least possible i.e. causal relationship is conceivable and cannot be dismissed. 
Serious adverse reaction (SAR): Adverse event which fulfils both the criteria for a Serious 
Adverse Event and the criteria for an Adverse Reaction.
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
An SAE which is unexpected and regarded as possibly or probably related to the Study Drug by 
the Sponsor-Investigator. 
Medical Events of Special Interest (MESI): A MESI is (1) a medication error (e.g. wrong drug 
administration or wrong route of administration) or (2) a suspected transmission of an infectious 
agent via the product
Non-Serious Adverse Event:
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Severity Assessment Definitions:
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• Mild: Transient symptoms, no interference with the subject’s daily activities
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities
• Severe: Considerable interference with the subject’s daily activities, unacceptable
Relationship to study medication Assessment Definitions:
• Probable: Good reasons and sufficient documentation to assume a causal relationship
• Possible: A causal relationship is conceivable and cannot be dismissed
• Unlikely: The event is most likely related to an etiology other than the trial product. 
FDA-approved prescribing information will be used to evaluate all unexpected events and 
adverse reactions.
Outcome Categories and Definitions:
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to 
the level observed at the first trial related activity after the subject signed the informed 
consent
• Recovering: The condition is improving and the subject is expected to recover from the event. 
This term should only be used when the subject has completed the trial
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with 
sequelae should be rated as an SAE
• Not recovered
• Fatal
• Unknown
Collection, Recording and Reporting of Adverse Events
Adverse events reporting will comply with all local legal, regulatory, and IRB requirements.
The study team will be responsible for reporting serious adverse events (SAE), suspected 
unexpected serious adverse reactions (SUSARs), serious adverse drug reactions (SADRs) and 
adverse events of interest to the competent authority and independent ethics 
committee/institutional review boards based upon federal regulations and local/IRB policies.
The study team will report to Novo Nordisk all SADRs and SAEs related or possibly related to 
study drug use at the same time such events are reported to regulatory authorities or within 15 
days from the sponsor-investigator becoming aware of such adverse events, whichever comes 
first.
The study team will collect the following information at minimum for each of these events:

Study name

Subject identifier

Patient identification (sex, age)
Event term (Preferably diagnosis)

Event description including pertinent medical history, concomitant medications and 
assessments 

Trial drug

Reporter identification (Name and date reported)

Causality
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
Outcome
The investigator will copy Novo Nordisk when expediting SARs to Health Authorities and will 
report all SARs related to Novo Nordisk Product to the local Novo Nordisk affiliate safety 
department. The submission to Novo Nordisk must be within day 15 from the investigator’s first 
knowledge about a valid case. The investigator will also expedite SARs to Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB).
The study physician will report reportable events to MedWatch in accordance with standard of 
care practices. 
Follow-up of Adverse Events
During and following a subject’s participation in a clinical trial, the sponsor-investigator and 
institution will provide adequate medical care to the study subject for any study-related adverse 
events specified above. This medical care for study subjects will be provided regardless of their 
insurance status. 
All adverse events of interest classified as serious or severe or possibly/probably related to the 
trial product must be followed for 30 days post last dose of study drug or until final outcome of 
the event is known or subject lost to further follow-up. 
Pregnancy
Study subjects will be instructed to notify the sponsor-investigator immediately if they become 
pregnant. 
The study team will report to Novo Nordisk any pregnancy occurring during the trial period. 
Reporting of pregnancy by sponsor-investigator should occur within the same timelines 
described above for reporting of Adverse Events. 
 
Pregnancy complications should be recorded as adverse event(s). If the infant has a congenital 
anomaly/birth defect this must be reported and followed up as a serious adverse event.
Precautions/Over-dosage
In the event of study drug overdosage, supportive care and treatment will be provided to 
address clinical signs and symptoms.  Because of the prolonged half-life of the study drug, an 
extended period of observation and treatment will be necessary.  Overdose will be managed by 
the clinicians affiliated with the Geisinger Kidney Health Research Institute.
LIABILITY AND SUBJECT INSURANCE:
During and following a subject’s participation in trial, the sponsor-investigator and his/her 
institution will provide adequate medical care to the study subject for any study-related adverse 
events, including clinically significant laboratory values related to the study. This medical care 
for study subjects will be provided regardless of their insurance status. The patient and/or their 
insurance company will be responsible for the applicable medical care. The study is not 
responsible for those costs.
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The sponsor-investigator will be responsible for the conduct of the study.  Liability language will 
be addressed in the contract.  
EVALUABILITY OF SUBJECTS:
The principal investigator will be responsible for excluding subjects or observations from the 
analysis. The subjects or observations to be excluded, and the reasons for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation will 
be stored together with the remaining trial documentation.
PREMATURE TERMINATION OF STUDY:
If legitimate (e.g. safety) reasons arise prompting consideration of premature termination, a 
decision will be made by the principal investigator. A Data Safety Monitoring Board (DSMB) will 
evaluate adverse event reports and may review individual cases if deemed necessary. The DSMB 
will be compiled of three Geisinger clinicians who are independent of the study – Dr. Gurmukt 
Singh (the lead), Dr. Christopher Still, and Dr. Madiha Alvi. They will meet quarterly as well as on 
an as needed basis. No member of the DSMB will receive reimbursement. 
Any serious adverse events that are definitely or probably related to the protocol and any 
deaths (regardless of relationship to the study) will be reported to the DSMB and corresponding 
IRB within 5 days.  Serious adverse events are defined as: death, life threatening injuries, 
inpatient hospitalization, or persistent or significant disability/incapacity.  For all serious adverse 
events determined by the IRB to be definitely, probably, or possibly related to the study or 
interventions, the IRB will take whatever action(s) it deems appropriate, including but not 
limited to: 
i.
Modification of the protocol
ii.
Modification of the consent form document
iii.
Modification to the timetable for continuing review requirements
iv.
Suspension of new enrollment into the study
v.
Suspension or termination of the study. 
Any unanticipated adverse events that are definitely or probably related to the protocol will be 
reported to the DSMB and corresponding IRB within 5 days.  Other adverse events will be 
reviewed at each DSMB meeting, documented by standard procedures and will be reported at 
the annual IRB protocol review. 
PUBLICATION PLAN:
The study findings will be reviewed in accordance with the final analytic plan.  Important clinical 
findings related to the study aims will be discussed among study personnel and shared with 
Novo Nordisk. A mutually agreeable plan for presentation of the findings at national meetings 
and/or submission to peer-review journals will be carried out.  Preparation of abstracts and 
manuscripts will take place during the final year of the trial.  The study team will register the 
trial with clinicaltrials.gov.
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IRB NUMBER: 2020-1050
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