Clinical trial NCT04416737
Conditions: Type 1 Diabetes
Sponsor: Stanford University
Start date: 2021-11-01; Completion date: 2023-06-02
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
In normal physiology insulin is secreted by beta cells into the portal vein. There have been a number of purported benefits among long-term intraperitoneal insulin users. In the present study we will inject ultra-rapid acting insulin into the upper and lower peritoneum under ultrasound guidance and compare it to subcutaneous injection. We will measure glucose, insulin and glucagon following these injections, to assess for benefits in counter-regulatory hormone production and insulin pharmacokinetics.

Detailed description:
The eventual goal of this line of work is an implanted insulin pump that delivers insulin automatically into the peritoneum based on continuous glucose data. All prior intraperitoneal pharmacokinetic studies used only concentrated regular insulin, which may be too slow to provide full closed-loop insulin delivery without meal announcement. A description of intraperitoneal ultra-rapid insulin kinetics, as well as counter-regulatory hormonal factors that may counter hypoglycemia is needed. Upper versus lower peritoneal delivery may also affect insulin kinetics. A possible benefit of intraperitoneal insulin is restoration of glucagon response in longstanding diabetes and clearance of insulin by the liver, both of which could provide hypoglycemic rescue in automated insulin delivery systems.

Arms: arm 1: Ultra-fast acting insulin will be injected into the upper peritoneum then lower peritoneum then subcutaneous space. arm 2: Ultra-fast acting insulin will be injected into the lower peritoneum then upper peritoneum then subcutaneous space.
Interventions: intervention 1: Ultra-rapid insulin
Intervention descriptions: intervention 1: Following 0.5-3 hours of insulin suspension from insulin pump, participants will receive insulin injection in respective locations (separated by at least 1 week) and then have serial lab measurements (YSI glucose, insulin and glucagon) taken during induced hypoglycemia.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
Evaluating the Benefits of Physiologic Insulin Delivery   
Study Protocol and Statistical Analysis Plan 
NCT04416737 
June 14, 2022 
 
 


 
SPECIFIC AIMS 
As of 2015, 30 million Americans (9.4% of the US population) had diabetes and it was the seventh 
leading cause of death based on 79,535 death certificate [131]. In addition to the American Diabetes 
Association (ADA) reported 1.25 million people in the United States with type 1 diabetes, about 29% of the 29 
million individuals with type 2 diabetes use insulin [132]. Long-term complications of hyperglycemia include 
retinopathy, nephropathy, neuropathy, and cardiovascular disease [133, 134]. The latest position statement by 
the ADA recommends a hemoglobin A1c goal of <7% in adults and <7.5% in pediatric age-groups [55, 135]. 
This goal challenges even the most motivated, knowledgeable and socioeconomically privileged patient. 
Despite a $327 billion investment in diabetes healthcare in 2017, nearly half of those with diabetes have a 
hemoglobin A1c above goal [136] and 31% have a hemoglobin A1c >9% [131]. 
Insulin replacement treatment is a significant burden with a narrow therapeutic margin, too much insulin 
results in acutely debilitating hypoglycemia and too little causes hyperglycemia that, over years, results in 
microvascular and coronary artery disease. In 2016, following years of clinical trials performed at Stanford and 
other centers, the FDA approved the Medtronic 670G "hybrid" closed-loop system which automatically controls 
insulin delivery based on continuous glucose monitor (CGM) data [137]. Unfortunately, current subcutaneous 
insulin pharmacokinetics are too slow to provide meal coverage without announcement and the kinetics make 
it necessary to choose between hypoglycemia and hyperglycemia prevention, inevitably generating alarms 
when the user hits the opposite extreme [138]. Additionally, there are many who stop using CGM or insulin 
pumps; there reasons for discontinuation include: alarms, trust in the technology and dislike of wearing devices 
[102]. An implanted "invisible" pump could deliver intraperitoneal insulin with more rapid pharmacokinetics 
providing full closed-loop glucose control and thereby reduce the burden and morbidity of diabetes. 
Prior investigation of intravenous and intraperitoneal automated insulin delivery technology were limited 
by the absence of practical, accurate CGM technology. Consequently, these approaches were erroneously 
discarded. CGM, catheter and insulin pump technology continue to evolve rapidly, but the optimal location of 
insulin delivery for full closed-loop control remains unknown. We posit that long-term intraperitoneal insulin 
delivery will be more physiologic with multiple benefits including improved body composition and BMI 
(important additional cardiovascular risk factors), bone health and user experience while at the same time 
providing the necessary kinetics and glucagon response for fully automated insulin delivery. Intraperitoneal 
insulin delivery will be simulated from available data with assessment of multiple control strategies. 
AIM 1: To identify unique benefits of long-term intraperitoneal insulin use. Utilizing data being collected 
from Dr. Eric Renard's (co-mentor) cohort of intraperitoneal users with type 1 diabetes, we will evaluate body 
composition, bone health and human factors compared to matched controls using subcutaneous insulin. 
Hypothesis 1: Long-term intraperitoneal use is associated with decreased BMI, body fat percentage and 
visceral adiposity with improved markers of bone health, and more positive opinions of diabetes technology. 
 
AIM 2: To describe the pharmacokinetics and compare glucagon response to hypoglycemia of novel 
insulin formulations delivered via upper peritoneal, lower peritoneal and subcutaneous routes. 
Hypothesis 2: Pharmacokinetics of intraperitoneal insulin will be faster and lead to greater counter-regulatory 
glucagon response than subcutaneous insulin. Upper peritoneal delivery will be faster than lower peritoneum. 
 
AIM 3: To use available intraperitoneal pharmacokinetic and counter-regulatory data to perform in 
silico modeling and test performance with various control strategies. The optimal algorithm will be the 
least computationally demanding that provides glycemic control in range (70-180mg/dL) over a variety of 
physiologic conditions. 
Hypothesis 3: With more rapid pharmacokinetics we can utilize more 
straightforward control strategies to achieve >90% time in range. 
This work will deliver a greatly needed control strategy for 
intraperitoneal insulin delivery that allows for full closed-loop glucose 
control. Our results will help guide the development of an implanted 
insulin pump being developed by PhysioLogic Devices (Figure 1). An 
efficient control algorithm will be needed to run on an embedded 
microcontroller with limited power. The goal of our combined efforts will 
be multi-center human clinical trials to achieve full closed-loop, reducing 
the burden of diabetes, and achieving optimum glycemic control. 
 
 
 
Figure 1. ThinPump vs Prior 
MiniMed 2007 (inches) 


e. 
e
AIM 2: To describe the pharmacokinetics and compare glucagon response to hypoglycemia of novel 
insulin formulations delivered via upper peritoneal, lower peritoneal and subcutaneous routes. 
Hypothesis 2: Pharmacokinetics of intraperitoneal insulin will be faster and lead to greater counter-regulatory 
glucagon response than subcutaneous insulin. Upper peritoneal delivery will be faster than lower peritoneum. 
Rationale/Preliminary Data: All prior intraperitoneal pharmacokinetic studies used only concentrated regular 
insulin [2, 149, 150], which may be too slow to provide full closed-loop insulin delivery without meal 
announcement [117, 119, 124]. Dr. Appel, an R01-funded Stanford collaborator, has developed excipients that 
stabilize insulin analogs [234] for implanted delivery. Novo Nordisk received FDA approval for fast-acting 
insulin aspart (Fiasp) in 2017. It is the fastest subcutaneous insulin and contains the excipients niacinamide 
and L-arginine hydrochloride thought to increase the formation of biologically active Aspart monomers, 
accelerate insulin absorption and add stability [235]. A description of intraperitoneal Fiasp kinetics, as well as 
counter-regulatory hormonal factors that may counter hypoglycemia is needed. Upper versus lower peritoneal 
delivery may also affect insulin kinetics [2]. Another important benefit of intraperitoneal insulin is restoration of 
glucagon response in longstanding diabetes, which has been studied in a small number of intraperitoneal 
users [21-25]. We conducted a preliminary proof-of-concept study on intravenous, intraperitoneal and 
subcutaneous Fiasp administration in one subject to compare kinetics in each compartment (Figure 2). 
Glucose data was collected by raising blood 
sugar to ~300mg/dL for 30 minutes with only basal 
insulin running (no recent boluses) then 
administering a fixed dose of Fiasp in each 
compartment. The experiment concluded when 
glucose stabilized for 15 minutes. In each 
compartment Fiasp had a shorter duration of action 
than prior studies with regular insulin (IV: 50mins vs 
90 mins [236], IP: 85mins vs 180mins [237] and 
SubQ: 4hrs vs 8.4hrs [238]). Intravenous and 
intraperitoneal insulin provide substantially more 
rapid glucose reduction than subcutaneous. 
Ultrasound-guided intraperitoneal insulin 
administration was painless. 
 
Research Design: This will be a descriptive 
pharmacokinetic study of upper and lower versus 
subcutaneous Fiasp, with assessment of glucagon 
response to insulin-induced hypoglycemia. 15 healthy 
adult participants with type 1 diabetes on insulin pump and 
continuous glucose monitor will be consented and asked 
to come in for three visits separated by at least one week. 
Before any other invasive procedure the abdominal area 
will be assessed by an experienced interventional 
radiologist with gray-scale and color Doppler ultrasound to 
determine the safest puncture site (Figure 3). Gray-scale 
sonography will be used to find the area that provides the 
most separation between the anterior abdominal wall and 
the bowel loops. If the experienced interventional 
radiologist feels no safe area exists, the subject will be 
excluded. 
Participants will fast overnight and suspend subcutaneous 
insulin delivery approximately 1 hour prior to each procedur 
For the first two visits, participants will be randomized to eith 
upper or lower peritoneal injection. An IV will be inserted 
for blood draws for YSI glucose, insulin, and glucagon levels. Another IV will be placed for dextrose 
administration. Color Doppler sonography of the puncture site will be performed to visualize the epigastric 
vessels and verify they are at least 1 cm away from the determined puncture site. Under sonographic 
guidance, a 22-gauge needle is inserted at the selected site with the needle angled 45° caudally. Real-time 
Figure 2. Glucose Response to IV, IP and 
Subcutaneous Fiasp 
350 
250 
150 
50 
0 
50 
100 
150 
200 
250 
Time (Minutes) 
IV Fiasp 
IP Fiasp (Normalized) 
SubQ Fiasp (Normalized) 
Figure 3. Anterior Abdominal Ultrasound with 
Needle Placement (Red Line) 
Blood Glucose (mg/dl) 


visualization of the needle insertion through the subcutaneous tissue, rectus abdominis muscle, and 
peritoneum will be performed. The peritoneum is seen as an echogenic line just deep in relation to the rectus 
abdominis muscle fibers. The needle will be taken to the edge of this echogenic line which may be 
associated with minimal momentary discomfort [239]. Approximately 0.25 units/kg Fiasp will be administered 
through the needle and the needle removed. Following injection, blood collection and measures will occur 
every 5 minutes for either 150 minutes or until glucose concentration has a stable trend. A 10% dextrose 
bolus of 2.5mL/kg will be provided following a blood sugar reading ≤50mg/dL. After 150 minutes have 
elapsed or glucose remains stable within 10mg/dL for 2 time points, the patient will resume their home insulin 
regimen. Data from the patient’s CGM will be downloaded. 
At least one week from the last peritoneal injection a similar subcutaneous procedure will take place. 
An IV will be inserted for blood draws for YSI glucose, insulin, and glucagon levels. Another IV will be placed 
for dextrose administration. Approximately 0.2 units/kg Fiasp will be administered by subcutaneous injection. 
Following injection, blood collection and measures will occur every 15 minutes for 6 hours or until glucose is 
stable. A 10% dextrose bolus of 2.5mL/kg will be provided following a blood sugar reading ≤50mg/dL. After 
6 hours have elapsed or glucose remains stable within 10mg/dL for 2 time points, the patient will resume their 
home insulin regimen. Data from the patient’s CGM will be downloaded. See Figure 4 for study diagram. 
Statistical Considerations 
and Power Analysis: 
Using analyses 
appropriate for paired 
measures, we will employ 
paired t-tests or the 
analogous non- 
parametric test (e.g., 
Wilcoxon signed-rank) to 
assess differences in 
pharmacokinetic features 
between delivery 
mechanisms. In the prior 
2000 study by Oskarsson 
and colleagues, 7 
subjects with longstanding type 1 diabetes receiving subcutaneous and intraperitoneal insulin underwent 
induced hypoglycemia with IV insulin and had glucagon measured at baseline and during hypoglycemia [1]. 
The maximal glucagon response subtracted from baseline was 7.5 ± 3.0 pg/mL on subcutaneous insulin and 
17.0 ± 3.1 pg/mL on intraperitoneal insulin. Assuming a type I error rate of 0.05, 15 individuals will provide 
>90% power to detect an effect size of 1.0 (maximal change in glucagon of 3.0). 
Expected Outcomes: We will test if there is a significant difference in glucagon response during hypoglycemia 
between intraperitoneal and subcutaneous administration. A mean pharmacokinetic curve will be generated 
from the above data for upper/lower intraperitoneal and subcutaneous insulin administration. We anticipate 
that intraperitoneal Fiasp will have faster pharmacokinetics than subcutaneous delivery, and that 
intraperitoneal delivery will result in a more significant counter-regulatory glucagon response. The upper 
peritoneal pharmacokinetic profile may be more rapid than lower peritoneal delivery. 
 
Potential Pitfalls & Alternative Strategies: There has been only 1 reported case of inadvertent bowel puncture 
with ultrasound guidance, occurring after the probe was removed and the needle unintentionally advanced. 
The patient received antibiotics and had no clinical sequelae [240]. We are deeply vested in the safety of our 
human subjects. All invasive procedures will be performed by an experienced interventional radiologist. To 
avoid this specific complication we will only take the needle tip to the edge of the visceral peritoneum, use a 
smaller needle and continue ultrasound recording until the needle is removed. The procedure to access the 
intraperitoneal space is derived from that used to place intraperitoneal catheters for peritoneal dialysis. An 
alternative procedure would be to perform the study in those with existing peritoneal catheters. Subjects with 
peritoneal dialysis catheters likely have impaired renal clearance or have recently received kidney transplant, 
which would alter pharmacokinetics. We have chosen not to use existing intraperitoneal pump users since 
prolonged suspension of insulin delivery may increase the risk of occlusions. We use Fiasp as it is the 
fastest subcutaneous insulin available. 1-hour suspension reduces plasma insulin with low risk of ketosis 
[241]. 
Figure 4. SA2 Study Diagram 


Contact PD/PI: Lal, Rayhan 
 
 
 
 
Section 2 - Study Population Characteristics (Study 1) 
 
2.1. Conditions or Focus of Study 
❍ Type 1 Diabetes Mellitus 
2.2. Eligibility Criteria 
Eligibility Criteria 
To be eligible for the study, a subject must meet the following criteria: 
1. 
18-60 years of age 
2. 
Clinical diagnosis of type 1 diabetes 
3. 
On insulin pump therapy and continuous glucose monitor (CGM) for at least 3 months 
4. 
Ability to safely receive intraperitoneal injection 
5. 
For females, not currently known to be pregnant 
6. 
Understanding and willingness to follow the protocol and sign informed consent 
7. 
Ability to speak, read and write in the language of the investigators 
 
Exclusion Criteria 
The presence of any of the following is an exclusion for the study: 
1. 
Diabetic ketoacidosis in the past 3 months 
2. 
Severe hypoglycemia resulting in seizure or loss of consciousness within 3 months prior to enrollment 
3. 
Pregnant or lactating 
4. 
Active infection 
5. 
A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol 
6. 
Known cardiovascular events in the last 6 months 
7. 
Known seizure disorder 
8. 
Inpatient psychiatric treatment in the past 6 months 
9. 
Lack of stability on medication 1 month prior to enrollment including antihypertensive, thyroid, anti-depressant or lipid 
lowering medication. 
10. 
Suspected drug or alcohol abuse 
11. 
Chronic kidney disease (GFR < 60 mL/min/1.73mA2) 
2.3. Age Limits 
Min Age: 
18 Years 
Max Age:  60 Years 
 
INCLUSION OF WOMEN, MINORITIES, AND CHILDREN 
We will attempt to recruit an equal gender distribution and minority population representative of the 
surrounding demographic of people with type 1 diabetes. We are excluding children in these initial studies of 
intraperitoneal insulin injections. We hope to eventually be able perform studies on this more vulnerable 
population to improve modeling. 
 
RECRUITMENT AND RETENTION PLAN 
We will contact adult with type 1 diabetes using our existing database of patients who have consented to be 
contacted about future diabetes research studies. A short description of the present study will be given to 
them via e-mail, phone or in-person. We will also recruit subjects at the time of their scheduled appointments. 
A one-page brochure will be prepared and sent to providers who have referred patients to us in the past. 
Information on the study will also be posted on our website, and the information provided on the brochure will 
also be made available to diabetes support groups in our area and at local events hosted by JDRF and 
CarbDM. If a person expresses interest, then the study will be presented in detail. The study will be eligible to 
adults with type 1 diabetes, in good health, who are not currently enrolled in other intervention studies. 
Subjects participating in a registry study (no interventions) may participate. 
 
Participants will be informed that the study will require 3 visits, at least 1 week apart. We will obtain and verify 
contact information. The intraperitoneal experiments will be conducted first, as this is the more invasive 
intervention. To reduce unnecessary exposure, we will only perform the subcutaneous intervention once we 
are certain that we can safely perform intraperitoneal injections. Patients completing the intraperitoneal visits 
are likely to return for subcutaneous testing since this represents standard of care for insulin delivery. 


Contact PD/PI: Lal, Rayhan 
 
 
 
STUDY TIMELINE 
We intend to perform specific aim 2 during the second and third years (1/2022-6/2023) of funding. See Figure 
1 for study diagram. 
 
Figure 1. SA2 Study Diagram 
 
We plan to recruit 15 subjects, and each individual will need to be consented and come in for three visits 1 
week apart. Given the amount of testing and monitoring needed for each subject, we will perform testing on 1 
subject at a time. Allocating 3 weeks for each participant gives a total study duration of around 1 year. See 
Table 1 for study timeline. 
 
Table 1. Study Timeline 
Task 
Estimated Completion Date 
(Month / Year) 
Finalization of protocol, informed consent 
1/2022 
IRB Approval 
2/2022 
Major equipment, materials procured 
6/2022 
DSMB committee planning 
6/2022 
Study staff recruitment and training complete 
6/2022 
25% subjects complete study 
9/2022 
50% subjects complete study 
12/2022 
75% subjects complete study 
3/2023 
Final Report 
6/2023 


Contact PD/PI: Lal, Rayhan 
 
 
 
 
PROTECTION OF HUMAN SUBJECTS 
1. 
Risks to Human Subjects 
Human Subjects Involvement, Characteristics, and Design 
In Aim 2 we will require human subjects to collect real-world pharmacokinetic data and compare glucagon 
response to hypoglycemia for insulin Fiasp delivered via upper peritoneal, lower peritoneal and subcutaneous 
routes. 15 healthy adult participants (age 18-60 years) with type 1 diabetes on insulin pump and continuous 
glucose monitor will be recruited. Patients with other chronic health conditions must demonstrate stability on 
current treatment regimens for at least 3 months. Subjects will be excluded if they have had recent severe 
hypoglycemia or diabetic ketoacidosis. Pregnant or breastfeeding individuals and those with medical 
conditions that alter insulin resistance, insulin clearance, mentation, seizure threshold or increase the risk of 
major adverse cardiac events will also be excluded. 
 
The diabetes clinic at Stanford Hospital and Clinics serves a large, diverse population with over 400 adults with 
type 1 diabetes. This population represents a diverse mix of urban, suburban, and rural patients from a variety 
of racial and ethnic backgrounds. 
 
Sources of Materials 
Any individually identifiable private information about human subjects will be 
obtained at enrollment in a private room. Health information related to this study will include name, age, 
gender, race/ethnicity, diabetes duration, height/weight, pregnancy test results if female, date of study visits, 
insulin doses, hemoglobin A1c, continuous glucose monitoring results, measures of YSI glucose and 
insulin/glucagon ELISA. During the procedure, venous blood will be collected and appropriately disposed of 
when lab processing is complete. For security and confidentiality purposes, subjects will be assigned an 
identifier that will be used instead of their name. Study doctors and study coordinators are responsible for de- 
identifying the data. Dr. Lal and the research staff involved with this study will have access to the data and 
specimens. Staff will be current in HIPAA and CITI training, and will be reminded during training for this specific 
study to maintain privacy of participants and confidentiality of the data and specimens. 
Potential Risks 
Participation includes travel to Stanford and possible missed work that may pose a financial hardship. Injection 
and catheter placement carry common risks of discomfort, bleeding, bruising and infection. For more invasive 
intraperitoneal catheter insertion procedures (rather than injection utilizing our technique), there has been one 
reported case of bowel puncture, treated with antibiotics, without clinical sequelae. All procedures will be 
carried out by experienced providers, further decreasing the risk of complications. Time-limited hyperglycemia 
may occur prior to insulin injection, when the insulin pump is suspended, this relatively short period is not 
associated with diabetic ketoacidosis or long-term sequelae. During the trial subjects will undergo insulin- 
induced hypoglycemia which may be associated with temporary sweating, jitteriness, and not feeling well. The 
blood volume needed for each visit will be approximately 100 mL. The alternative is not to participate. 
 
 
2. 
Adequacy of Protection against Risks 
Recruitment and Informed Consent 
We will contact adult with type 1 diabetes using our existing database of patients who have consented to be 
contacted about future diabetes research studies. A short description of the present study will be given to 
them via e-mail, phone or in-person. We will also recruit subjects at the time of their scheduled appointments. 
A one-page brochure will be prepared and sent to providers who have referred patients to us in the past. 
Information on the study will also be posted on our website, and the information provided on the brochure will 
also be made available to diabetes support groups in our area and at local events hosted by JDRF and 
CarbDM. 


Contact PD/PI: Lal, Rayhan 
 
 
 
If a person expresses interest, then the study will be presented in detail. Informed consent will be obtained 
from adult participants by Dr. Lal or trained research staff under the supervision of Dr. Lal. Consent 
documents will discuss the potential risks of the study (time to complete study procedures, potential breach of 
confidentiality of data, intravenous catheter placement, intraperitoneal/subcutaneous injection, hyperglycemia, 
hypoglycemia and blood draws). Benefits of participating in the research (improved therapy for others with type 
1 diabetes), and the alternative of not participating in the study will be discussed. The potential participant will 
be given time to review the consent and ask any questions in a private room. Dr. Lal will be available to 
discuss the consent process with participants. 
 
Protections against Risk 
Subjects will be instructed on the signs and symptoms of hypoglycemia and hyperglycemia, and the 
interventions we will take to correct these states during the study procedure. They will be wearing a continuous 
glucose sensor which will aid in the early detection of hypoglycemia between YSI measurements. Patients will 
be offered topical anesthetic prior to any of these procedures to reduce discomfort. Following injection and 
removal of intravenous catheter pressure will be applied to reduce and stop bleeding. All areas will be 
cleansed prior to invasive procedures and intraperitoneal injections will be carried out under sterile conditions 
to reduce risk of infection. For safety, intraperitoneal injections will be performed under continuous ultrasound 
guidance until the needle is removed and needles will be advanced only to the visceral peritoneal membrane to 
eliminate concern of bowel puncture. Where needed, intravenous catheter placement can be performed under 
ultrasound guidance as well. In addition, all subjects will be provided with the study doctor's contact 
information should they request any medical guidance following procedures. 
 
A Data and Safety Monitoring Board (DSMB) will be formed consisting of 2 adult endocrinologists and an 
interventional radiologist working at institutions other than Stanford. The DSMB will review the protocol and 
procedures before the study is started, and will review the results after 5 patients have completed the three 
CTRU admissions. The PI will be responsible for reporting unexpected problematic events involving any 
aspect of the study to the DSMB, NIH and local IRB per institutional guidelines. Unanticipated problems to be 
assessed include adverse events, deviations from the study protocol, problems with informed consent, and 
confidentiality violations. The PI will report unanticipated problems to the DSMB, NIH and IRB within 3 
business days of their occurrence. A significant study related adverse event (such as seizure, diabetic 
ketoacidosis, bowel puncture, severe bleeding or infection) would result in the study being put on hold until the 
DSMB has reviewed the event. The DSMB will review such cases and determine what actions must be taken 
to address or resolve the situation and if it is safe to continue the study. 
 
 
3. 
Potential Benefits of the Proposed Research to Human Subjects and Others 
Use of Continuous Glucose Monitor data will provide each subject individualized information about their 
glucose response to intraperitoneal and subcutaneous insulin. The data on subcutaneous insulin may allow 
optimization of active insulin time for pump therapy. Additionally, participants with long-standing diabetes will 
acquire data about his or her glucagon secretory capacity when insulin is delivered in a more physiologic 
manner. The precautions taken greatly reduce any risk to the subjects and optimize the benefits. 
 
 
4. 
Importance of the Knowledge to be gained 
Insulin replacement treatment is a significant burden with a narrow therapeutic margin, too much insulin results 
in acutely debilitating hypoglycemia and too little causes hyperglycemia that, over years, results in 
microvascular and coronary artery disease. Unfortunately, current subcutaneous insulin pharmacokinetics are 
too slow to provide automated meal coverage and the kinetics make it necessary to choose between 
hypoglycemia and hyperglycemia prevention, inevitably generating alarms when the user hits the opposite 
extreme. Additionally, there are many who stop using CGM or insulin pumps; there reasons for discontinuation 
include: alarms, trust in the technology and dislike of wearing devices. An implanted "invisible" pump could 
deliver intraperitoneal insulin with more rapid pharmacokinetics providing full closed-loop glucose control and 
thereby reduce the burden and morbidity of diabetes. 


Contact PD/PI: Lal, Rayhan 
 
 
 
In order to test control algorithms for full closed-loop control we will need a description of insulin kinetics in the 
intraperitoneal space, as well as counter-regulatory hormonal factors that could counter hypoglycemia. All 
prior studies have used only concentrated regular insulin, which may be too slow to provide full closed-loop 
insulin delivery without meal announcement. Further, Dr. Eric Appel at Stanford University has recently 
developed excipients that stabilize newer concentrated insulin analogs. The pharmacokinetics of fast-acting 
insulin aspart (Fiasp) is untested in the intraperitoneal space. Another important benefit of intraperitoneal 
insulin is restoration of glucagon response, which has been reported in a small number of intraperitoneal 
insulin users. 
 
The risks of the current study are minimal, with multiple safeguards in place. Data from the current study will 
directly inform a model that can be abstracted to a wide array of simulated patients. Findings from the current 
study will be important for the future study and development of intraperitoneal closed-loop technology. Such 
technology may be useful for a large number of patients utilizing insulin. 
 
DATA AND SAFETY MONITORING PLAN 
This is a single-site descriptive pharmacokinetic study comparing glucagon response to hypoglycemia for 
insulin Fiasp delivered via upper peritoneal, lower peritoneal and subcutaneous routes on three separate visits 
separated by at least one week. Demographic data and venous blood samples will be collected including 
glucose determined by YSI, and insulin/glucagon measured by ELISA. Following hypoglycemia :550mg/dL, 
patients will receive intravenous dextrose. See Figure 1 for study diagram. The primary outcome will be 
glucagon response to induced hypoglycemia and a secondary outcome will be descriptive pharmacokinetics. 
15 healthy adults with type 1 diabetes on insulin pump and continuous glucose monitor will be consented and 
patient demographic data collected. Dr. Lal or a research assistant will consent subjects in a private room with 
sufficient time allocated to answer any questions. 
Figure 1. SA2 Study Diagram 
 
Before any other invasive procedure the abdominal area will be assessed by an experienced interventional 
radiologist with gray-scale and color Doppler ultrasound to determine the safest puncture site. If the 
experienced interventional radiologist feels no safe area exists, the subject will be excluded prior to any 
invasive procedures. Subjects will perform the more difficult intraperitoneal interventions first, in random order, 
to avoid unnecessary procedures. If intraperitoneal access is unsuccessful, the subject will be excluded. To 
avoid the possibility of even minor bowel puncture, we will only take the needle tip to the edge of the visceral 
peritoneum, use a smaller needle and continue ultrasound recording until the needle is removed. The 
procedure to access the intraperitoneal space is derived from that used to place intraperitoneal catheters for 
peritoneal dialysis. These widespread techniques are performed safely at many health centers. 
 
A Data and Safety Monitoring Board (DSMB) will be formed consisting of 2 adult endocrinologists and an 
interventional radiologist working at institutions other than Stanford. The DSMB will review the protocol and 
procedures before the study is started, and will review the results after 5 patients have completed the three 
CTRU admissions. Dr. Lal, affiliated research staff and DSMB, will periodically perform data and safety 


Contact PD/PI: Lal, Rayhan 
 
 
monitoring on an ongoing basis. During the course of the trial, data will be reviewed weekly for completeness 
and accuracy. Frequent reviews will be performed to examine the occurrence of adverse events and whether 
participants are satisfied with their participation. The DSMB will be responsible for evaluating each 
unanticipated problem and determining whether it affects the risk/benefit ratio of the study and whether 
modifications to the protocol and consent forms are required. The PI will be responsible for reporting 
unexpected problematic events involving any aspect of the study to the NIH, DSMB and local IRB per 
institutional guidelines. Unanticipated problems to be assessed include adverse events, deviations from the 
study protocol, problems with informed consent, and confidentiality violations. Secure communication between 
the study team and participants will occur by telephone. All study samples will be de-identified, data will be 
password protected and encrypted. The PI will report unanticipated problems to the NIH, DSMB and IRB 
within 3 business days of their occurrence. A significant study related adverse event (such as seizure, diabetic 
ketoacidosis, bowel puncture, severe bleeding or infection) would result in the study being put on hold until the 
DSMB has reviewed the event. The DSMB will review such cases and determine what actions must be taken 
to address or resolve the situation and if it is safe to continue the study. 
 
OVERALL STRUCTURE OF STUDY TEAM 
The principal investigator for the study will be Dr. Rayhan Lal. Dr. Avnesh Thakor, an experienced 
interventional radiologist and Dr. Victoria Young (diagnostic radiologist) 
will be performing intraperitoneal injection under ultrasound guidance. The study will 
take place in Stanford's Clinical and Translational Research Unit, staffed by specialized research nurses 
familiar with diabetes study protocols, who will place IVs and perform blood draws. A research assistant will be 
in charge of enrolling, contacting and scheduling subjects. YSI glucose measures and insulin/glucagon 
ELISAs will be performed either by Dr. Lal or qualified study personnel. 
 
Section 4 - Protocol Synopsis (Study 1) 
 
4.1. Brief Summary 
This will be a descriptive pharmacokinetic study of intraperitoneal versus subcutaneous Fiasp, with assessment of glucagon 
response to insulin-induced hypoglycemia. 
4.2. Study Design 
4.2.a. Narrative Study Description 
15 healthy adult participants with type 1 diabetes on insulin pump and continuous glucose monitor will be consented and 
asked to come in for three visits separated by at least one week. Before any other invasive procedure, the abdominal 
area will be assessed by an experienced radiologist with gray-scale and color Doppler ultrasound 
to determine the safest puncture site. Gray-scale sonography will be used to find the area that provides the most 
separation between the anterior abdominal wall and the bowel loops. If the radiologist feels 
no safe area exists, the subject will be excluded. 
 
Participants will fast overnight and suspend subcutaneous insulin delivery 3 hours prior to each procedure. For the 
first two visits, participants will be randomized to either upper or lower peritoneal injection. An IV will be inserted for 
blood draws for YSI glucose, insulin, and glucagon levels. Another IV will be placed for dextrose administration. 
Color Doppler sonography of the puncture site will be performed to visualize epigastric vessels and verify that they are 
at least 1cm away from the determined puncture site. Under sonographic guidance, a 22-gauge needle is inserted 
at the selected site with the needle angled 45° caudally. Real-time visualization of the needle insertion through the 
subcutaneous tissue, rectus abdominis muscle, and peritoneum will be performed. The peritoneum is seen as an 
echogenic line just deep in relation to the rectus abdominis muscle fibers. The needle will be taken to the edge of this 
echogenic line which may be associated with minimal momentary discomfort. Approximately 0.25u/kg Fiasp 
will be administered through the needle and the needle removed. Following injection, blood collection and measures will 
occur every 5 minutes for 150 minutes or until glucose 
stabilizes. A 10% dextrose bolus of 2.5ml/kg will be provided following a blood sugar reading ೦50mg/dl. After 150 
minutes have elapsed or glucose remains stable within 10mg/dl for 2 time points, the patient will resume 
their home insulin regimen. Data from the patient's CGM will be downloaded. 
 
At least one week from the last peritoneal injection a similar subcutaneous procedure will take place. An IV will 
be inserted for blood draws for YSI glucose, insulin, and glucagon levels. Another IV will be placed for dextrose 
administration. Approximately 0.25 units/kg 
Fiasp will be administered by subcutaneous injection. Following injection, blood collection 
and measures will occur every 15 minutes for 6 hours or until glucose stabalizes. A 10% 
dextrose bolus of 2.5ml/kg will be provided following a blood sugar reading ≤ 50mg/dl. After  


Contact PD/PI: Lal, Rayhan 
 
 
 
 4 hours have elapsed and glucose remains stable within 10mg/dl for 2 time points, the patient 
will resume their home insulin regiment. Data from the patient's CGM will be downloaded. 
 
 
4.3. Outcome Measures 
 
Type 
Name 
Time Frame 
Brief Description 
Primary 
Glucagon Response to 
Induced Hypoglycemia 
Determined during upper 
peritoneal, lower peritoneal 
and subcutaneous infusion of 
insulin 
Patient's will be given insulin via upper peritoneal, 
lower peritoneal and subcutaneous routes 
sufficient to induce hypoglycemia. We will 
measure change in glucagon response for venous 
glucose ೦50mg/dl 
Secondary 
Descriptive pharmacokinetics 
Determined during upper 
peritoneal, lower peritoneal 
and subcutaneous infusion of 
insulin 
Insulin levels will be measured following upper 
peritoneal, lower peritoneal and subcutaneous 
insulin administration to better characterize the 
kinetics of intraperitoneal insulin administration. 
 
 
STATISTICAL DESIGN AND POWER 
Using analyses appropriate for paired measures, we will employ paired t-tests or the analogous non-parametric 
test (e.g., Wilcoxon signed-rank) to assess differences in pharmacokinetic features between delivery 
mechanisms. In the prior 2000 study by Oskarsson and colleagues, 7 subjects with longstanding type 1 
diabetes receiving subcutaneous and intraperitoneal insulin underwent induced hypoglycemia with IV insulin 
and had glucagon measured at baseline and during hypoglycemia. The maximal glucagon response 
subtracted from baseline was 7.5 ± 3.0 pg/ml on subcutaneous insulin and 17.0 ± 3.1 pg/ml on intraperitoneal 
insulin. Assuming a type I error rate of 0.05, 15 individuals will provide >90% power to detect an effect size of 
1.0 (maximal change in glucagon of 3.0). 

ICF_000.pdf: 
 
 
 
 
 
Evaluating the Benefits of Physiologic Insulin Delivery 
Informed Consent Form 
NCT04416737 
June 14, 2022 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 1 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
Are you participating in any other research studies? _____ Yes _____No 
 
• Your consent is being sought for research participation that is completely 
voluntary 
• The purpose of this research is to understand the effects of intraperitoneal 
insulin administered into the deep upper and lower abdomen compared to 
subcutaneous delivery.  If you are willing and able, we will ask you to come to 
our Clinical and Translational Research Unit (CTRU) for 3 visits, separated by at 
least 1 week.  At each visit you will be injected with insulin in a different body 
location, blood will be collected through an intravenous catheter and dextrose 
infused for low blood sugar. 
• We are asking for your time and there may be financial hardship if you miss 
work.  Injection and catheter placement carry common risks of discomfort, 
bleeding, bruising and infection.  All insulin injections come with the possibility of 
hypoglycemia, allergic reactions, hypersensitivity, injection site reactions, 
lipodystrophy, and weight gain. During the experiment, we will be causing 
hypoglycemia for a brief period to test if your body produces glucagon when 
insulin is injected into the peritoneum.  Symptoms of hypoglycemia can include 
sweating, jitteriness, and not feeling well.  We will be performing the test under 
very controlled conditions and will give you IV dextrose to rapidly increase the 
blood sugar back to normal. 
• Use of continuous glucose data will provide you individualized information 
about glucose response to intraperitoneal and subcutaneous insulin.  The data 
on subcutaneous insulin may allow you optimization the active insulin time for 
pump therapy.  The data we obtain could also suggest if your glucagon 
production could be restored when insulin is delivered in a more physiologic 
manner.  
• You do not have to participate in this research study to be treated for your 
diabetes. The alternative is not to participate.   
• You can decide to participate now, but withdraw your consent later and stop 
being in the study without any loss of benefits or medical care to which you are 
entitled. 
• If you are coming in-person to research visits, you are required to be fully 
vaccinated—2 doses (1 for Johnson and Johnson), 2 weeks out and to 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 2 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
provide proof of your vaccination (e.g., CDC COVID-19 Vaccination Card, e-
Health record, etc.) to the researcher prior to study participation.  Alternately, 
you can provide a negative COVID test within 72 hours of your visit. 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of the effects of intraperitoneal 
insulin administered into the deep upper and lower abdomen compared to 
subcutaneous delivery.  We hope to learn the speed of absorption of 
intraperitoneal insulin Fiasp and whether it can restore glucagon production.  The 
insulin is FDA-approved but has not been extensively tested in the peritoneal 
space.  You were selected as a possible participant in this study because you have 
type 1 diabetes and are using an insulin pump (which can be suspended) and 
continuous glucose monitor (CGM).   
 
If you decide to terminate your participation in this study, you should notify 
Rayhan Lal, MD at 650-725-6549 or inforay@stanford.edu.   
 
This research study is looking for 15 people in good health with type 1 diabetes 
using an insulin pump and CGM.  Enrollment will occur only at Stanford 
University.   
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to 
participate will not have any negative effect on you or your medical care.  You 
can decide to participate now, but withdraw your consent later and stop being in 
the study without any loss of benefits or medical care to which you are entitled. 
 
 
DURATION OF STUDY INVOLVEMENT  
 
This research study is expected to take approximately 12 months; each 
participant will come in for 3 visits separated by at least 1 week.  There is a gap 
of 1 week to allow the body to reset itself after a controlled low blood sugar and 
so that the effects of one injection does not influence the others.  
 
 
PROCEDURES 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 3 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
If you choose to participate, the Protocol Director and his research study staff 
will collect some baseline data including your name, age, gender, race/ethnicity 
and diabetes duration.  A physical exam will be performed including vital signs, 
height, weight and BMI.  We will record the value of the most recent  
hemoglobin A1c if performed in the last 6 months, and will record glucose 
management indictor (GMI) or a calculated equivalent if a recent HbA1c is not 
available. All participants who are female will receive a urine pregnancy test.  
During this initial visit we will perform an ultrasound to make sure it is safe to 
perform the intraperitoneal injection.  If this is normal, you be randomly assigned 
to receiving the injection in the upper peritoneum or lower peritoneum first.   
 
You will be asked to not eat anything after midnight the night prior to the first 
visit so that you have no carbohydrates in your system.  Approximately 1 hour 
prior to the visit we will ask you to suspend insulin delivery so that you have very 
little subcutaneous insulin on board at the time of the procedure.  Two IVs will 
be placed: (1) for blood draws that measure insulin, glucose and glucagon and 
(2) for dextrose administration. Ultrasound of the injection site will be performed 
to pick a safe site in the upper or lower belly.  While we do not expect the 
procedure to be painful, you can choose if you would like a local anesthetic 
injected first.  We will perform the insulin injection under ultrasound guidance.  
Approximately 0.25 units/kg Fiasp will be administered through the needle and 
the needle immediately removed.  Following injection, blood will be collected 
through the IV and measures will occur every 5 minutes for either 150 minutes 
or until blood glucose concentration stabilizes.  If blood sugar drops to 50mg/dL 
or below, dextrose will be administered through the IV.  After 150 minutes or a 
stable glucose trajectory, you will be done with blood tests and can restart your 
pump.  The data from your CGM will also be downloaded. 
 
At least 1 week later, the same study will be performed but using the other area 
of the abdomen. 
 
A final visit will occur at least 1 week later.  At this visit the two IVs will again be 
placed.  This time for the purposes of comparison, standard subcutaneous insulin 
will be administered.  Using a standard insulin syringe approximately 0.25 
units/kg Fiasp will be injected.  Following injection, blood samples will be taken 
every 15 minutes for the lesser of either 6 hours until blood glucose 
concentration stabilizes. If blood sugar drops to 50mg/dL or below, dextrose will 
be administered through the IV.  After 6 hours or a stable glucose trajectory, the 
trial is complete and you can restart your pump.  Once again, your CGM data will 
be downloaded.  You will be contacted by e-mail or telephone within 7 days of 
this final visit. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 4 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
 
The samples of blood needed for each set of tests is minimal (less than half a 
tablespoon).  In total for each visit, we will require less than 7 tablespoons 
blood.  This research will not include whole genome sequencing.   
 
Participants of Childbearing Potential 
If you are a participant who is able to become pregnant, it is expected that you 
will use an effective method of birth control to prevent exposing a fetus to a 
potentially dangerous agent with unknown risk.  If you are pregnant or currently 
breast feeding, you may not participate in this study.  You understand that if you 
are pregnant, if you become pregnant, or if you are breast-feeding during this 
study, you or your child may be exposed to an unknown risk. 
 
To confirm to the extent medically possible that you are not pregnant, you agree 
to have a pregnancy test done before beginning this research study.  You must 
agree to avoid sexual intercourse or use a birth control method judged to be 
effective by the investigator and which will not interfere with the proposed 
investigation.  You must accept the risk that pregnancy could still result despite 
the responsible use of reliable method of birth control.  You agree to notify the 
investigator as soon as possible of any failure of proper use of your birth control 
method, or if you become pregnant, either of which may result in your being 
withdrawn from the study. 
 
Future Use of Private Information and/or Specimens 
We are not storing blood and samples will not be saved for future research.  
Your information and/or specimens will not be used or distributed for future 
research studies even if all identifying information is removed. 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study staff. 
• Keep your study appointments.  If it is necessary to miss an appointment, 
please contact the Protocol Director or research study staff to reschedule 
as soon as you know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, 
doctor visits, or hospitalizations that you may have. 
• Tell the Protocol Director or research staff if you believe you might be 
pregnant or gotten your partner pregnant. 
• Ask questions as you think of them. 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 5 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
• Tell the Protocol Director or research staff if you change your mind about 
staying in the study. 
 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your 
decision will not affect your ability to receive medical care for your disease and 
you will not lose any benefits to which you would otherwise be entitled.  
 
If you decide to withdraw your consent to participate in this study, you should 
notify Rayhan Lal, MD at 650-725-6549. 
 
The Protocol Director may also withdraw you from the study without your 
consent for one or more of the following reasons: 
o Failure to follow the instructions of the Protocol Director and 
study staff. 
o The Protocol Director decides that continuing your 
participation could be harmful to you. 
o Pregnancy  
o You need treatment not allowed in the study. 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research 
study.  These deserve careful thought.  You should talk with the Protocol 
Director if you have any questions. 
 
Study Participation 
Participation includes travel to Stanford and possible missed work which may 
pose a hardship.  Any clinical research may involve risks to the subject, which 
are currently unforeseeable. 
 
Invasive Testing 
Injection and catheter placement carry common risks of discomfort, bleeding, 
bruising and infection.  All such procedures will be carried out by experienced 
providers, to decrease the risk of these complications.   


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 6 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
 
Insulin 
As with all insulin adverse reactions include: hypoglycemia, allergic reactions, 
hypersensitivity, injection site reactions, lipodystrophy, and weight gain. 
 
Hypoglycemia 
During the experiment, we will be causing hypoglycemia for a brief period to test 
if your body produces glucagon when insulin is injected into the peritoneum.  
Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling 
well.  We will be performing the test under very controlled conditions and will 
give you IV dextrose to rapidly increase the blood sugar back to normal.   
 
Hyperglycemia 
Since we are asking you to suspend insulin delivery before each study visit, there 
is a chance of time limited high blood sugar.  This relatively short period is not 
associated with diabetic ketoacidosis or long-term complications. 
 
 
POTENTIAL BENEFITS                              
 
Use of CGM data will provide you individualized information about glucose 
response to intraperitoneal and subcutaneous insulin.  The data on 
subcutaneous insulin may allow you optimization the active insulin time for 
pump therapy.  Additionally, it is believed that those with long-standing type 
1 diabetes do not produce much glucagon in response to low blood sugar.  
The data we obtain could suggest if glucagon could be restored when insulin 
is delivered in a more physiologic manner.  
 
We cannot and do not guarantee or promise that you will receive any 
benefits from this study. 
 
 
ALTERNATIVES 
 
You do not have to participate in this research study to be treated for your 
diabetes. The alternative is not to participate.  Your decision not to participate in 
this research study will have no effect on your current treatment or any other 
future treatment you require. 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 7 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell 
the Protocol Director.   
 
You will be told of any important new information that is learned during the 
course of this research study, which might affect your condition or your 
willingness to continue participation in this study. 
 
 
ClinicalTrials.gov 
 
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. 
 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as 
required by law.  However, there is always some risk that even de-identified 
information might be re-identified.  
 
The purpose of this research study is to obtain information on the safety and 
effectiveness of intraperitoneal injection of ultra-rapid acting insulin; the results 
will be provided to the sponsor (the National Institute of Health), the Food and 
Drug Administration (FDA) and other federal and regulatory agencies as 
required.  The FDA, for example, may inspect research records and learn your 
identity if this study falls within its jurisdiction. 
 
CERTIFICATE OF CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. The researchers with this Certificate may not disclose or use 
information, documents, or specimens that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other action, suit, or 
proceeding, or be used as evidence, for example, if there is a court subpoena, 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 8 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
unless you have consented for this use. Information, documents, or specimens 
protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that 
requires disclosure (such as to report child abuse or communicable diseases but 
not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, see below); if you have consented to the disclosure, including for 
your medical treatment; or if it is used for other scientific research, as allowed by 
federal regulations protecting research subjects 
The Certificate cannot be used to refuse a request for information from 
personnel of the United States federal or state government agency sponsoring 
the project that is needed for auditing or program evaluation by the National 
Institutes of Health which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA).  You should understand that a Certificate of Confidentiality 
does not prevent you from voluntarily releasing information about yourself or 
your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected 
with the research, you must provide consent to allow the researchers to release 
it. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as 
required by federal, state, or local law of child abuse and neglect, or harm to self 
or others. 
 
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 9 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
Authorization To Use Your Health Information 
For Research Purposes  
 
Because information about you and your health is personal and 
private, it generally cannot be used in this research study without 
your written authorization.  If you sign this form, it will provide that 
authorization.  The form is intended to inform you about how your 
health information will be used or disclosed in the study.  Your 
information will only be used in accordance with this authorization 
form and the informed consent form and as required or allowed by 
law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my 
health information be utilized in the study? 
The purpose of this study is to evaluate the effects of intraperitoneal 
insulin administered into the deep upper and lower abdomen 
compared to subcutaneous delivery.  We hope to learn the speed of 
absorption of intraperitoneal insulin Fiasp and whether it can restore 
glucagon production.  Because the results of these studies may be 
altered by other health conditions, we request access to your health 
records to screen for these health problems. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, 
you will not be able to participate in this research study.  Signing the 
form is not a condition for receiving any medical care outside the 
study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your 
authorization regarding the use and disclosure of your health 
information (and to discontinue any other participation in the study) 
at any time.  After any revocation, your health information will no 
longer be used or disclosed in the study, except to the extent that 
the law allows us to continue using your information (e.g., necessary 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 10 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
to maintain integrity of research).  If you wish to revoke your 
authorization for the research use or disclosure of your health 
information in this study, you must write to:  
 
Rayhan Lal, MD 
Stanford University, Department of Endocrinology 
453 Quarry Road, 
Palo Alto, CA 94304 
 
What Personal Information Will Be Obtained, Used or 
Disclosed? 
Your health information related to this study, may be used or 
disclosed in connection with this research study, including, but not 
limited to, health information relevant to the study, past medical 
history and laboratory results. Personal information such as your 
name, date of birth, gender, race/ethnicity, date of diagnosis, weight 
and height may be used. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your 
health information in connection with this research study: 
• The Protocol Director: Rayhan Lal, MD 
• The Stanford University Administrative Panel on Human 
Subjects in Medical Research and any other unit of Stanford 
University as necessary 
• Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your 
health information to the following persons and organizations for 
their use in connection with this research study:  
 
• The Office for Human Research Protections in the U.S. 
Department of Health and Human Services 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 11 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
Your information may be re-disclosed by the recipients described 
above, if they are not required by law to protect the privacy of the 
information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health 
information will end on January 1, 2050 or when the research project 
ends, whichever is earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have 
access to any health information developed as part of this study until 
it is completed.  At that point, you would have access to such health 
information if it was used to make a medical or billing decision about 
you (e.g., if included in your official medical record).  
 
 
________________________________             
  ______________ 
Signature of Adult Participant                                        Date 
 
 
________________________________             
 
Print Name of Adult Participant                                         
 
 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 12 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
FINANCIAL CONSIDERATIONS 
 
Payment/Reimbursement 
You will not be paid to participate in this research study. 
 
 
Costs 
If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with the study that are not a part of your 
routine medical care.  However, there may be additional costs to you.  These 
include basic expenses like transportation and the personal time it will take to 
come to the study visits.  You and/or your health insurance must pay for 
services, supplies, procedures, and care that are required during this study for 
routine medical care.  You will also be responsible for any co-payments 
and/or deductibles as required by your insurance.  Participation in this 
study is not a substitute for health insurance.   
 
Sponsor 
The NIH is providing financial support and/or material for this study.  
 
Consultative or Financial Relationships 
Dr. Bruce Buckingham is a paid advisor to Novo Nordisk, the company whose 
products may be used in this study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental 
– involve some risk of injury.  In spite of all precautions, you might develop 
medical complications from participating in this study.  If such complications 
arise, the Protocol Director and the research study staff will assist you in 
obtaining appropriate medical treatment.  In the event that you have an injury or 
illness that is directly caused by your participation in this study, reimbursement 
for all related costs of care first will be sought from your insurer, managed care 
plan, or other benefits program.  You will be responsible for any associated 
co-payments or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, 
managed care plan or other benefits program, you may be responsible for these 
costs.  If you are unable to pay for such costs, the Protocol Director will assist 
you in applying for supplemental benefits and explain how to apply for patient 
financial assistance from the hospital. 
 


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 13 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
Approval Date:   June 14, 2022 
Expiration Date: June 14, 2023  
Participant ID: 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or 
complaints about this research study, its procedures, risks and benefits, or 
alternative courses of treatment, you should ask the Protocol Director, Rayhan 
Lal, MD at 650-725-6549.  You should also contact him at any time if you feel 
you have been hurt by being a part of this study.  
 
Independent Contact:  If you are not satisfied with how this study is being 
conducted, or if you have any concerns, complaints, or general questions about 
the research or your rights as a participant, please contact the Stanford 
Institutional Review Board (IRB) to speak to someone independent of the 
research team at (650)-723-5244 or toll free at 1-866-680-2906.  You can also 
write to the Stanford IRB, Stanford University, 1705 El Camino Real, Palo Alto, 
CA 94306. 
 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but 
are not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably 
to be expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices 
that might be advantageous to the subject, their relative risks and 
benefits; 
• 
be informed of the avenues of medical treatment, if any available to the 
subject after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or 
the procedures involved;  
• 
be instructed that consent to participate in the medical experiment may 
be withdrawn at any time and the subject may discontinue participation 
without prejudice;  
• 
be given a copy of the signed and dated consent form; and  


 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
Rayhan Lal, MD 
Protocol Title:   Evaluating the benefits of physiologic insulin delivery 
 
 
Page 14 of 14 
 
SU_MainICF_HIPAA rev 052519                                                                                 ICF v1.3 
IRB Use Only 
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Expiration Date: June 14, 2023  
Participant ID: 
• 
be given the opportunity to decide to consent or not to consent to a 
medical experiment without the intervention of any element of force, 
fraud, deceit, duress, coercion or undue influence on the subject's 
decision. 
 
May we contact you about future studies that may be of interest to you?    
____ Yes  ____ No 
 
Signing your name means you agree to be in this study and that you will receive 
a copy of this signed and dated consent form.  
 
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Signature of Adult Participant 
 
 
 
   
   Date 
 
 
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Print Name of Adult Participant                                         
 
 
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Signature of Person Obtaining Consent  
 
   
  Date 
 
 
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Print Name of Person Obtaining Consent