The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients With Type 1 Diabetes Mellitus
Phase: PHASE2
Conditions: Hypoglycemia Unawareness
Sponsor: Owen Chan, PhD

The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients 
with T1DM 
 
 
NCT03538015 
 
Document Date: 10/10/2019 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 1 of 36 
  
 
 
The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
 
IRB #00108879 
 
 
Principal Investigator 
Owen Chan, Ph.D. 
Associate Professor 
 
15 North 2030 East 
EIHG Building 533, Rm 2420B 
Salt Lake City, UT 84112 
 
Tel: (801) 585-0444 
Fax: (801) 585-0956 
Email: ochan@u2m2.utah.edu 
 
Sub-investigator(s) 
Matthew Wahl, M.D. 
Simon J. Fisher, MD, PhD 
 
 
 
Funding Organization 
Juvenile Diabetes Research Foundation 
 
Investigational Agent 
Carvedilol 
 
IND Number 
[IND number issued by FDA, if applicable] 
 
 
 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 2 of 36 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................................... 5 
STATEMENT OF COMPLIANCE ...................................................................................................................... 6 
STUDY SUMMARY ......................................................................................................................................... 7 
STUDY SCHEMA ............................................................................................................................................. 9 
1. 
OBJECTIVES ......................................................................................................................................... 10 
1.1 
Primary Objectives and Endpoints .............................................................................................. 10 
1.2 
Secondary Objectives and Endpoints .......................................................................................... 10 
2 
BACKGROUND ..................................................................................................................................... 10 
3 
DRUG INFORMATION .......................................................................................................................... 14 
4 
STUDY DESIGN..................................................................................................................................... 16 
4.1 
Description .................................................................................................................................. 16 
4.2 
Dose Limiting Toxicity ................................................................................................................. 16 
4.3 
Number of Subjects ..................................................................................................................... 16 
4.4 
Number of Study Centers............................................................................................................ 16 
4.5 
Study Duration ............................................................................................................................ 16 
5 
ELIGIBILITY CRITERIA ......................................................................................................................... 167 
5.1 
Inclusion Criteria ....................................................................................................................... 177 
5.2 
Exclusion Criteria ......................................................................................................................... 17 
6 
TREATMENT PLAN ............................................................................................................................. 188 
6.1 
Administration Schedule ............................................................................................................. 18 
6.2 
Treatment (include name of each treatment as section header) ............................................. 188 
6.2.1 
How Supplied, Stored, Packaged and Labeled .................................................................. 188 
6.2.2 
Preparation and Administration ......................................................................................... 18 
6.2.3 
Accountability and Compliance ........................................................................................ 188 
6.3 
Duration of Therapy .................................................................................................................. 188 
7 
TOXICITIES AND DOSE MODIFICATION ............................................................................................. ..20 
7.1 
Dose Modification ....................................................................................................................... 20 
7.2 
Supportive Care ........................................................................................................................... 20 
8 
STUDY CALENDAR ............................................................................................................................. 211 
9 
STUDY PROCEDURES ........................................................................................................................... 22 
9.1 
Informed Consent ....................................................................................................................... 22 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 3 of 36 
9.2 
Study Entrance Criteria ............................................................................................................... 22 
9.3 
Demographics and Medical History ............................................................................................ 22 
9.4 
Laboratory Variables ................................................................................................................... 22 
9.4.1 
Hematology and Clinical Chemistries.................................................................................. 22 
9.4.2 
Urinalysis ............................................................................................................................. 23 
9.4.3 
Pregnancy Testing ............................................................................................................... 23 
9.4.4 
Specimen Collection, Preparation, Storage and Shipping .................................................. 23 
9.5 
Physical Examination ................................................................................................................... 23 
9.6 
Vital Signs .................................................................................................................................... 23 
9.7 
Electrocardiogram ....................................................................................................................... 23 
9.8 
Continuous Glucose Monitor (CGM) ........................................................................................... 23 
9.9 
Concurrent Medications ............................................................................................................. 23 
9.9.1 
Prohibited Concurrent Medications ................................................................................... 23 
    9.10     The Clamp Procedure…………………………………………………………………………………………………………….24 
9.11 
Efficacy Measurements ............................................................................................................... 25 
9.11.1 
Primary Objective Assessment ............................................................................................ 26 
9.11.2 
Secondary Objective Assessment ....................................................................................... 26 
9.12 
Safety Measurements ................................................................................................................. 27 
9.12.1 
Adverse Events .................................................................................................................... 27 
9.12.2 
Serious Adverse Events ....................................................................................................... 28 
9.12.3 
Serious Adverse Event Reporting Requirements ................................................................ 28 
9.12.4 
Reporting of Pregnancy ....................................................................................................... 29 
9.13 
Study Halting Rules ..................................................................................................................... 29 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................... 29 
11 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 30 
11.1 
Records Retention ....................................................................................................................... 30 
11.2 
Disclosure and Publication Policy ............................................................................................... 30 
12 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................. 30 
12.1 
Institutional Review .................................................................................................................... 30 
12.2 
Data and Safety Monitoring Plan ................................................................................................ 31 
12.3 
Protocol Deviations ..................................................................................................................... 31 
12.4 
FDA Annual Reporting ................................................................................................................. 31 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 4 of 36 
12.5 
Clinical Trials Database ............................................................................................................... 31 
13 
REFERENCES .................................................................................................................................... 32 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 5 of 36 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring  
CIOMS 
Council for International Organizations of Medical Science 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ERICA 
Electronic Research Integrity and Compliance Administration System 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
VMH 
Ventromedial Hypothalamus 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 6 of 36 
 
STATEMENT OF COMPLIANCE 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and according to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the U.S. code of federal 
regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 
CFR Part 312 and/or 21 CFR Part 812), and the applicable ICH guidelines for Good Clinical Practice 
(GCP).   
I will promptly submit the protocol to the IRB for review and approval.  Once the protocol has been 
approved by the IRB, I understand that any modifications made during the course of the study must first 
be approved by the IRB prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study.  I will discuss this material with them to ensure that they are fully 
informed regarding the study treatment, the conduct of the study, and the obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the Principal 
Investigator in the University of Utah IRB Electronic Research Integrity and Compliance Administration 
(ERICA) system. 
 
 
 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 7 of 36 
STUDY SUMMARY 
Title 
The Use of Low-Dose Carvedilol to Improve 
Hypoglycemia Awareness in Patients with T1DM 
Short Title 
Carvedilol for Hypoglycemia Unawareness 
Protocol Number 
IRB #: 00108879 
IND 
Exemption Approved 
Phase 
Phase II   
Design 
Double-blinded, 
randomized, 
placebo-controlled 
study. 
Study Duration 
From Fall 2018 to Spring 2020 
Study Center(s) 
University of Utah Health  
Objectives 
The aim of the study is to investigate whether low-
dose carvedilol treatment can improve hypoglycemia 
awareness and the counterregulatory hormone 
responses to hypoglycemia in Type 1 diabetic 
patients with impaired awareness of hypoglycemia.  
Number of Subjects 
A total of 21 Type 1 diabetic patients with impaired 
awareness of hypoglycemia will be recruited for the 
study – 7 subjects will be treated with placebo and 7 
subjects will be treated with one of two different 
doses of carvedilol (2.5 or 3.125mg). 
Diagnosis and Main Eligibility Criteria 
Patients with Type 1 diabetes and hypoglycemia 
unawareness will be included in this study. 
Inclusion criteria: 
• Type 1 diabetes of >5yrs duration 
• >18yrs of age 
• Impaired hypoglycemia awareness/ 
unawareness assessed by validated 
questionnaires.  
• Intensive insulin treatment as defined by 
multiple daily insulin injections (3 or more) 
or insulin pump therapy. 
• Negative pregnancy test. 
• Signed informed consent. 
Exclusion Criteria:   
• Major medical disorders (including liver 
disease, 
cardiovascular 
disease, 
kidney 
disease, COPD, asthma, active malignancy 
and HIV). 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 8 of 36 
• Overt diabetic complications (neuropathy, 
nephropathy, retinopathy). 
• Anemia. 
• Current or recent use of beta-blocker therapy. 
• Use of diuretics. 
• Allergies or contraindications to beta-
blockers or heparin. 
• Pregnant. 
• Use of benzodiazepines. 
• 
Alcohol, drug or medication abuse. 
• 
Frequent use of acetaminophen. 
Study Product, Dose, Route, Regimen 
Hypoglycemia unaware T1DM subjects will be 
randomly segregated into one of two therapeutic 
treatment groups: Placebo or Carvedilol. Carvedilol 
will be administered orally at either 2.5mg or 
3.125mg twice daily. Likewise, the placebo drug will 
also be administered orally twice daily.  
Duration of Administration 
4 weeks 
Reference Therapy 
Placebo 
Statistical Methodology 
Treatment effects will be analyzed using one- or two-
way analysis of variance (ANOVA) for independent 
or repeated measures as appropriate, followed by 
suitable post-hoc analysis. Analyses will be 
performed using the GraphPad Prism® or SAS® suite 
of software. 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 9 of 36 
STUDY SCHEMA 
 
Figure 1: Schematic of the study design. 
  
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 10 of 36 
1. OBJECTIVES 
1.1 
Primary Objectives and Endpoints 
• To investigate whether T1DM patients with impaired awareness of hypoglycemia 
receiving carvedilol treatment will show marked improvements in hypoglycemia 
symptomatic awareness scores, as well as improvements in their counterregulatory 
hormone responses to hypoglycemia. 
1.2 
Secondary Objectives and Endpoints 
• To investigate whether carvedilol treatment reduces the amount of time T1DM patients 
with hypoglycemia unawareness spend in the hypoglycemic range as assessed by 
blinded CGM.  
• To investigate whether carvedilol reduces the fear of hypoglycemia. 
 
2 
BACKGROUND 
Hypoglycemia elicits a multifaceted hormonal response that helps restore glycemic levels to normal. 
As blood glucose levels start to fall, insulin secretion ceases. At the top of this hierarchy of 
counterregulatory responses are glucagon and epinephrine which are the two principal hormones that act 
rapidly to increase glucose production and inhibit glucose utilization to raise plasma glucose levels back 
to normal1. In cases of prolonged and/or more severe hypoglycemia, growth hormone and cortisol are 
mobilized to stimulate the synthesis of gluconeogenic enzymes and inhibit glucose utilization2. In non-
diabetic individuals, glucagon and epinephrine are usually very effective and the latter responses are 
rarely required in the acute situation. In contrast, impaired glucose counterregulation presents itself in 
longstanding diabetes and with antecedent hypoglycemia3. Within the first five years after the onset of 
Type 1 diabetes (T1DM), the primary defense against hypoglycemia, the release of glucagon, either 
becomes significantly attenuated or is completely absent in diabetic patients and this impairment appears 
to be specific for the stimulus of hypoglycemia4,5. Hence, patients with diabetes primarily depend on the 
release of epinephrine as their main defense against hypoglycemia. Unfortunately, with longer duration 
of diabetes and especially with poor glycemic control, epinephrine secretion is also compromised, 
making these patients even more vulnerable to the threat of hypoglycemia5-7. In patients with diabetes, 
hypoglycemia arises from the interplay of a relative excess of exogenous insulin and defective glucose 
counterregulation and it remains a limiting factor in attaining proper glycemic management. Both the 
Diabetes Control and Complications Trial (DCCT) conducted in Type 1 patients8 and the United 
Kingdom Prospective Diabetes Study (UKPDS) conducted in Type 2 patients9, have established the 
importance of maintaining good glucose control over a lifetime of diabetes to avoid cardiovascular, renal 
and neurological complications. However, lowering glycemic goals for diabetic patients increases their 
risk for hypoglycemia exposure. According to the DCCT, T1DM patients put on intensive insulin 
therapy, though having improved outcomes for diabetic complications, are at a 3-fold higher risk of 
experiencing severe hypoglycemia compared to those on conventional insulin therapy10. Moreover, 
recent antecedent hypoglycemia reduces autonomic (epinephrine) and symptomatic (which normally 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 11 of 36 
prompts behavioral defenses such as eating) responses to subsequent bouts of hypoglycemia11-14. Thus 
begins the vicious cycle of recurrent hypoglycemia (RH) where hypoglycemia leads to further 
impairment of counterregulatory responses which in turn, begets more hypoglycemia and so forth. 
Because of the imperfections of current insulin therapies, those patients attempting to achieve glycemic 
control suffer an untold number of asymptomatic hypoglycemic episodes. Current estimates of 
symptomatic hypoglycemic episodes range from 2-3 incidences per week on average and severe, 
debilitating episodes occur once or twice each year. Therefore, developing therapies to prevent or 
eliminate hypoglycemia is of great importance.  
Sensors that detect changes in blood glucose levels and initiate glucose counterregulatory responses 
have been identified in both the periphery15-20 and within the brain21-29. These sensors have been localized 
to the hepatic portal vein17,18, the carotid body30 and the brain21,22,24,31. In the brain, the dominant sensors 
are located in the hypothalamus. While peripheral glucose sensors may play a role in mediating the 
immediate counterregulatory responses to hypoglycemia, it is thought that glucosensors located within 
the brain may have a redundant regulatory and/or modulatory role in regulating glucose counterregulatory 
responses. It is well established that brain glucose sensors are crucial for detecting falling blood glucose 
levels and for initiating counterregulatory responses22,31. These sensors are located in the hindbrain, the 
lateral hypothalamus, the paraventricular nucleus, the dorsal hypothalamus and the ventromedial 
hypothalamus (VMH)22,27,32-34. The neurons within the VMH contain much of the same glucose sensing 
machinery as the pancreatic β-cells29. To date, two main types of glucose sensing neurons have been 
identified in the brain – those that increase their firing rate in response to increases in glucose levels, the 
“glucose-excited” or GE neurons and those that decrease their firing rate in response to increasing glucose 
levels, the “glucose-inhibited” or GI neurons35-38. The mechanism by which GE neurons sense changes 
in blood glucose concentrations is believed to be similar to that used by pancreatic β-cells39 whereas GI 
neurons respond to decreases in ambient glucose levels through activation of the metabolic fuel sensor, 
AMP kinase (AMPK), and closure of chloride channels that result in increased activity of GI neurons28,40. 
Although many of these sensing components have been identified, it is still not entirely clear how glucose 
sensing neurons regulate counterregulatory hormone release. It has been proposed that alterations in the 
firing rates of VMH glucose sensing neurons in response to glucose or fuel deficits can inhibit (as is the 
case for GE neurons) or stimulate (as is the case for GI neurons) the exocytosis of vesicles containing 
neurotransmitters that can modulate the counterregulatory hormone response39,41,42. 
The inhibitory neurotransmitter, GABA, and the stimulatory neurotransmitters, glutamate and 
norepinephrine, act within the VMH to suppress or stimulate the counterregulatory responses to 
hypoglycemia, respectively. In response to an initial bout of hypoglycemia, VMH GABA levels decrease 
while glutamate and norepinephrine levels increase, allowing for activation of the counterregulatory 
hormone responses43-47. While these studies underscore the importance of VMH neurotransmitter 
signaling in regulating glucose homeostatic mechanisms, to date, the mechanisms that lead to their 
dysregulation in models of counterregulatory failure are not entirely clear. Recent evidence suggests that 
lactate, which serves as an alternate fuel substrate in the brain, plays an important role in precipitating 
the defects noted above48,49. Lactate produced from neighboring astrocytes can supplement higher energy 
requirements during periods of increased neuronal activity or when glucose supply is limited50. If this is 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 12 of 36 
the case, then lactate can be used in place of glucose as a fuel for VMH glucose sensing neurons, 
preventing them from detecting a fall in glucose levels, causing (inhibitory) GABA tone to be enhanced 
and (stimulatory) glutamate output to be reduced. Together, these actions ultimately suppress the release 
of counterregulatory hormones. In recent years, it has been shown that lactate levels are sensed by the 
brain and more specifically, can act in the hypothalamus to regulate glucose homeostasis, appetite and 
body weight51-56. Lactate prevents the activation of hypothalamic neurons during glucose deprivation51,57 
and more pertinent to this application, attenuates glucose counterregulatory responses to hypoglycemia 
when locally administered into the VMH58. Data from our research group revealed VMH extracellular 
lactate concentrations are elevated in RH and diabetic animals and in particular, these conditions also 
increase expression of the lactate transporter, MCT2, in the VMH48. When VMH lactate uptake is 
pharmacologically inhibited using 4CIN, we can improve neurotransmitter and counterregulatory 
responses in both RH and diabetic animals, suggesting lactate plays an important role in dysregulating 
neurotransmitter systems in the VMH, which in turn, impairs counterregulatory responses. Our 
preliminary data suggests that therapeutic strategies that can reduce brain lactate levels, may help 
restore hypothalamic glucose sensing mechanisms and the counterregulatory response to hypoglycemia. 
Hence, identifying the mechanisms that increase VMH lactate levels may lead to suitable therapeutic 
strategies to prevent hypoglycemia.  
To this end, we investigated one mechanism that can enhance lactate production and/or utilization in 
the brain - activation of norepinephrine (NE) receptors. Norepinephrine can enhance lactate production 
from astrocytes and it can also increase the uptake of lactate into neurons through the activation of β2-
adrenergic receptors (β2AR), potentially helping to co-ordinate both the supply and uptake of lactate into 
neurons 59-61. Normally, in response to an acute bout of hypoglycemia, VMH norepinephrine levels rise 
and act through β2ARs to enhance the sympathoadrenal response46,62,63. Although activation of VMH 
β2ARs augments the counterregulatory response during acute bouts of hypoglycemia, less is known 
about the effects of RH on this neurotransmitter system. It has been reported that VMH NE levels are not 
altered by successive bouts of hypoglycemia, suggesting activation of the VMH NE system is not 
dampened by RH and that its suppressive effects on counterregulatory hormone release may lie 
downstream of NE release 64. In support of this finding, adrenergic blockade during antecedent bouts of 
hypoglycemia was shown to prevent counterregulatory failure in healthy human subjects65. Therefore, 
while acute activation of VMH adrenergic receptors may be beneficial in its capacity to enhance the 
counterregulatory response, repeated activation of this neurotransmitter system may contribute to 
counterregulatory failure, but the mechanism(s) by which this occurs have not been fully identified.  
 To evaluate whether repeated activation of the VMH NE system contributes to counterregulatory 
failure, we locally microinjected NE into the VMH of non-diabetic, hypoglycemia-naïve rats for 3hrs/d 
for 3 consecutive days before subjecting the animals to a hypoglycemic glucose clamp on day 4 (Figure 
1). Repeated activation of the VMH NE system in the absence of hypoglycemia, increased VMH lactate 
levels and more importantly, blunted the counterregulatory hormone responses to hypoglycemia. This 
phenomenon was recapitulated with microinjection of salbutamol, a short-acting β2AR agonist, into the 
VMH using the same protocol as for NE, suggesting the suppressive effects of NE are mediated through 
VMH β2ARs. In a subgroup of animals treated with NE, we administered 4CIN into the VMH to block 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 13 of 36 
the uptake of lactate into neurons immediately prior to the hypoglycemic clamp. In this group, we saw 
the suppressive effects of NE treatment on glucose counterregulation were completely abolished. Hence, 
our preliminary data suggests that repeated activation of the VMH NE system plays a role in the 
development of counterregulatory failure, in part by enhancing central lactate production and therefore, 
the use of β-adrenergic blockers may be a promising treatment to preserve the responses to 
hypoglycemia. As proof-of-concept, our preliminary data shows that RH rats treated with low doses of 
the non-specific β-blocker, carvedilol (3mg/kg, intraperitoneally), during the induction of RH, required 
less exogenous glucose during the hypoglycemic clamp compared to RH animals treated with vehicle 
(Figure 2). More importantly, we also saw reductions in VMH lactate levels and significant 
improvements in the counterregulatory hormone responses to hypoglycemia in the carvedilol-treated RH 
animals.  
 It is important to note, however, that treatment of diabetic patients with β-blockers has been somewhat 
controversial due to its perceived potential to attenuate the responses to hypoglycemia. However, 
compelling clinical evidence to support this possibility is lacking. In the recent GEMINI study which 
evaluated the use of two different β-blockers in T2DM patients with hypertension, carvedilol, was shown 
to effectively reduce overall hypoglycemia 
burden scores66. Likewise, the vast majority 
of clinical studies show that treatment of 
non-diabetic and T1DM patients with β-
blockers 
improved 
counterregulatory 
hormone responses without increasing the 
frequency 
of 
hypoglycemia 
or 
hypoglycemia unawareness67-72, although 
loss 
of 
tremulousness 
and 
reduced 
tachycardia were reported in some studies. 
One study found that treatment of T1DM 
hypoglycemia 
aware 
patients 
with 
propanolol reduced glycemic thresholds for 
adrenergic symptoms, but this deficit was 
offset by higher hypoglycemia symptom 
scores 
stemming 
from 
augmented 
diaphoresis73. 
Other 
neuroglycopenic 
symptoms were not affected. Moreover, in a prospective study of 150 diabetic patients, 50 of whom were 
on β-blockers, no difference in the incidence of hypoglycemic unconsciousness was noted between those 
patients who were on β-blockers compared to those who were not, suggesting the use of β-blockers in 
T1DM patients does not increase the incidence of severe hypoglycemia 68 and may be a safe therapeutic 
option that can be used in conjunction with insulin. Therefore, the current application will evaluate the 
effectiveness of low-dose carvedilol as a treatment for restoring the counterregulatory hormone responses 
to hypoglycemia and improving hypoglycemia awareness in patients with Type 1 diabetes. 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 14 of 36 
    Carvedilol is a third generation non-selective, vasodilating β-blocker, which is FDA-approved for the 
treatment of congestive heart failure and hypertension. Carvedilol mainly blocks β2- and β1-adrenergic 
receptors and some α1-adrenergic receptors. Due to its lipophilic nature, carvedilol readily crosses the 
blood-brain-barrier. As the brain is our primary target, this beneficial pharmacokinetic property of 
carvedilol improves CNS bioavailability, allowing lower doses to be used to deliver treatment to the 
brain. With lower doses, we can reduce the potential for side effects stemming from unnecessary 
exposure of peripheral tissues to high levels of β-adrenergic blockade Based on data gathered by the Food 
and Drug Administration (FDA), in a population study of 36,044 patients who reported having side 
effects while taking carvedilol, only ~1% of these patients experienced hypoglycemia. As carvedilol is 
currently FDA-approved for clinical use, it can potentially be repurposed for use as a preventive treatment 
for hypoglycemia. Therefore, we are proposing to evaluate the effectiveness of low-dose carvedilol 
treatment for 4 weeks as a treatment for restoring the counterregulatory hormone responses to 
hypoglycemia and improving hypoglycemia awareness in patients with Type 1 diabetes. 
 
3 
DRUG INFORMATION 
In this study, carvedilol will be administered twice daily to the intervention group. Carvedilol is currently 
approved by the FDA for indications that are unrelated to the current study. The following is a summary 
of 
the 
FDA 
label 
for 
carvedilol 
which 
can 
be 
found 
in 
the 
following 
link: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/ 020297 s013lbl.pdf. 
 
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of 
C24H26N2O4. Carvedilol is rapidly and extensively absorbed following oral administration, with absolute 
bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism.  
 
Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally 
ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. 
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein 
binding is independent of concentration over the therapeutic range. Carvedilol is extensively metabolized. 
Less than 2% of the dose is excreted unchanged in the urine. The oxidative metabolites are further 
metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted 
primarily via the bile into the feces. Plasma concentrations of the active metabolites are about one-tenth 
of those observed for carvedilol and have pharmacokinetics similar to the parent. The primary P450 
enzymes responsible for the metabolism of carvedilol in human liver microsomes are CYP2D6 and 
CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. Since carvedilol undergoes substantial 
oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction 
or inhibition of cytochrome P450 enzymes such as Rifampin, Cimetidine and Digoxin.  
 
Indications for use of carvedilol are congestive heart failure, left ventricular dysfunction following 
myocardial infarction and hypertension. It is contraindicated in patients with bronchial asthma or related 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 15 of 36 
bronchospastic conditions, in patients with hypersensitivity to any component of the product second- or 
third-degree AV block, sick sinus syndrome or severe bradycardia (unless a permanent pacemaker is in 
place), or in patients with cardiogenic shock or who have decompensated heart failure requiring the use 
of intravenous inotropic therapy. It is also not recommended in patients with clinically manifest hepatic 
impairment.   
 
In terms of pregnancy and teratogenic effects, carvedilol is categorized in Pregnancy Category C. Studies 
performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats 
at doses of 300 mg/kg/day (50 times the MRHD as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 
times the MRHD as mg/m2). In rats the no-observed-effect level for developmental toxicity was 60 
mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as 
mg/m2). There are no adequate and well-controlled studies in pregnant women.  
 
The most common side effects are:  
 
Body as a Whole: allergy, malaise, hypovolemia, fever, leg edema.  
Cardiovascular: fluid overload, postural hypotension, aggravated angina pectoris, AV block, 
palpitation, hypertension.  
Central and Peripheral Nervous System: hypesthesia, vertigo, paresthesia.  
Gastrointestinal: melena, periodontitis.  
Liver and Biliary System: SGPT increased, SGOT increased.  
Metabolic and Nutritional: hyperuricemia, hypoglycemia, hyponatremia, increased alkaline 
phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, 
creatinine increased.  
Musculoskeletal: muscle cramps.  
Platelet, Bleeding and Clotting: prothrombin decreased, purpura, thrombocytopenia.  
Psychiatric: somnolence.  
Reproductive, male: impotence.  
Special Senses: blurred vision.  
Urinary System: renal insufficiency, albuminuria, hematuria.  
 
In clinical trials, carvedilol has been shown to cause bradycardia in about 2-9% of hypertensive patients. 
In clinical practice, if the pulse rate drops below 55 beats/minute, the dosage is typically reduced. 
 
In the United States, the FDA recommend the starting dose of carvedilol to be 3.125 mg, twice daily for 
2 weeks. Patients who tolerate a dose of 3.125 mg twice daily may have their dose increased to 6.25, 
12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. In clinical practice, patients 
should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated 
with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after 
dosing. Thus, during these periods they should avoid situations such as driving or hazardous tasks, where 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 16 of 36 
symptoms could result in injury. In addition, carvedilol should be taken with food to slow the rate of 
absorption. In Japan, a lower dose of carvedilol (2.5 mg twice daily) has been used and tested for clinical 
efficacy74. 
 
4 
STUDY DESIGN 
4.1 
Description 
The current study will be a double-blinded, placebo-controlled study in which Type 1 diabetic 
patients with hypoglycemia unawareness are randomized to either 1) placebo treatment, 2) 2.5mg 
carvedilol twice daily or 3) 3.125mg carvedilol twice daily. After enrollment, the participants will 
be placed on (blinded) CGM monitoring which will be continued until the end of the study. 
Additionally, participants will be provided with a glucometer to measure their blood glucose and 
for calibrating the CGMs during the study. One week after CGM placement, the participants will 
undergo the first hypoglycemic clamp study to obtain baseline measures of hypoglycemia 
frequency (from downloaded CGM data), hypoglycemia awareness scores and hormone 
responses. Following the initial clamp procedure, the patients will be randomized to either 4 
weeks use of carvedilol or placebo. After the 4 weeks of treatment, the participants will undergo 
a second hypoglycemic clamp session. Patients will be hospitalized the night before each clamp 
study to ensure stable glucose levels.   
4.2 
Dose Limiting Toxicity 
Patients allocated to the drug treatment groups will receive a dose of either 2.5mg or 3.125mg of 
carvedilol twice daily. The goal is to use the lowest efficacious dose for improving hypoglycemia 
awareness in T1DM patients with little to no side effects. Our preclinical data suggests that at 
higher doses, β-blockers provide no benefits in terms of improving hypoglycemia awareness. 
4.3 
Number of Subjects 
21 Type 1 diabetic patients with hypoglycemia unawareness will be recruited for the study. The 
21 T1DM patients will be randomly allocated to one of the following treatments: 1) placebo 
(N=7), 2) 2.5mg carvedilol twice daily (N=7) or 3) 3.125mg carvedilol twice daily (N=7). Placebo 
will be taken twice daily. 
4.4 
Number of Study Centers 
This is a single-center study being conducted at the University of Utah.   
4.5 
Study Duration 
The enrollment of patients will begin in the late fall of 2018. We anticipate that the study 
procedures will begin in the fall of 2018 and continue until spring 2020. Data analysis and 
publication of the results are expected to be completed in the late spring or summer of 2020.  
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 17 of 36 
5 
ELIGIBILITY CRITERIA 
This checklist is used to determine subject eligibility; it should be completed for each subject, 
including review and signature by the enrolling investigator and filed in the subject research chart. 
 
Subject ID:  
 
 
 
 
 Subject Initials:  
 
 
 
 
5.1 
Inclusion Criteria 
Yes/No (a response of ‘No’ indicates the subject is ineligible) 
1.  
 Type 1 diabetes for more than 5 years 
2.  
 Age > 18 years 
3.  
 Presence of impaired hypoglycemia awareness/unawareness  
4.  
 Intensive insulin treatment as defined by multiple daily insulin injections (3 
or more) or insulin pump therapy 
5. ______ Negative pregnancy test 
6.  
 Able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 
 
5.2 
Exclusion Criteria 
Yes/No (a response of “Yes” indicates the subject is ineligible) 
1.  
  Major medical disorders (including liver disease, cardiovascular disease, 
kidney disease, COPD, asthma, active malignancy or HIV) 
2.  
 Overt diabetes complications (neuropathy, nephropathy, retinopathy) 
3.  
 Anemia   
4.  
 Current or recent use of beta-blocker therapy 
5. ______ Use of diuretics 
6. ______ Allergies or contraindications to beta-blockers or heparin 
7. ______ Use of benzodiazepines 
8. ______ Alcohol, drug or medication abuse 
9. ______ Frequent use of acetaminophen 
 
I verify that this subject meets all eligibility criteria for enrollment onto this study 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
Date 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 18 of 36 
6 
TREATMENT PLAN 
6.1 
Administration Schedule 
The treatment group will receive an oral dose of either 2.5mg or 3.125mg carvedilol twice 
daily for 4 weeks. The placebo group will receive a placebo pill twice daily for 4 weeks.  
6.2 
Treatment (Carvedilol) 
6.2.1.1 How Supplied, Stored, Packaged and Labeled  
Carvedilol will be supplied by Investigational Drug Services (IDS) at the University of 
Utah Hospital. The carvedilol capsules will be over-encapsulated for blinding. Likewise, 
matching placebo capsules will be produced. 
The capsules will be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 
30°C (59° to 86°F). They will be protected from light, moisture, freezing and excessive 
heat. They will be dispensed in a tight, light-resistant container as defined in the USP in a 
locked cabinet where only staff associated with the study has access to.  
6.2.2 Preparation and Administration 
Investigation Drug Services (IDS) will prepare the capsules with either carvedilol or 
placebo in a blinded fashion. Each container will have a number and will match the 
number the patient receives at randomization. Both the investigational staff and the 
patients will be blinded to the treatment that the patient is receiving. Randomization will 
be conducted by the Study Design and Biostatics Center (SDBC) who will provide a 
randomization code to IDS. The randomization code will be stored in a central database 
and the file will not be opened until the study is complete or if patient safety requires it.  
 
At randomization, the patients will each receive their own container matching the 
randomization number. The container will have enough capsules for the 4-week treatment 
period. On the day of the second hypoglycemic clamp study, the subjects will be asked to 
return the container including any unused capsules. 
6.2.3 Accountability and Compliance 
The study investigators will keep a record of the container that each patient receives. This 
information will be noted in the participant’s clinical research file. When the patients 
return for the second hypoglycemic clamp study, they will bring their container and the 
remaining pills will be counted and noted in the clinical research file as well. The patient 
will also be asked to assess how often, if at all, he or she forgot to take the medication.   
 
6.3 
Duration of Therapy 
The period of treatment is 4 weeks (28 days). 
 
Subjects will be withdrawn or discontinued from the study if any of the following occurs:  

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 19 of 36 
• The subject withdraws consent for further participation in the clinical trial. At any time 
during the trial and without the need to provide a reason or rationale, a subject may 
choose to decline to participate further in the study. The subject will not suffer any 
consequences as a result. 
• Subject is lost to follow-up despite efforts to contact them. 
• Episodes of severe bradycardia and hypotension requiring hospitalization.  
• Episodes of severe hypoglycemia develop which involve seizure development or 
which require hospitalization. The patient population that we are studying are Type 1 
diabetic individuals with impaired awareness of hypoglycemia. Thus, these patients 
are at a higher risk of experiencing hypoglycemia, and it is expected that these patients 
will have episodes of hypoglycemia (whether treated with investigational drug or 
placebo).   Patients are required to report all episodes of hypoglycemia. Hypoglycemic 
episodes can range from mild-moderate to severe. Severe hypoglycemia is defined as 
“hypoglycemic episodes with severe cognitive impairment requiring external 
assistance for recovery”.  In the event the study participant experiences an episode of 
severe hypoglycemia, the circumstances regarding the patient's episode of 
hypoglycemia will be evaluated by our medical staff who have expertise in treating 
patients with Type 1 diabetes.  Decisions will be made on a case-by-case basis as to 
whether it is safe for the participant to continue in the study. Obviously the severity of 
hypoglycemia will impact this clinical decision. Specifically, in the event the 
participant experiences an unexplained episode of severe hypoglycemia that involves 
loss of consciousness, seizures or hospitalization, the participant will be immediately 
removed from the study, the study drug treatment condition will be unblinded, and the 
IRB notified. For other cases, we will evaluate the circumstances regarding the 
patient's episode of hypoglycemia individually, and determine whether it is medially 
safe for the participant to continue in the study. If the participant is withdrawn from 
the study, the study drug treatment condition will be unblinded, and the IRB notified. 
As a part of the usual standard of medical care, any participant who experiences severe 
hypoglycemia will also receive education on how to avoid hypoglycemia. 
 
Subjects may be withdrawn or discontinued from the clinical trial for the following reasons: 
• The subject is non-compliant with study treatment requirements and/or protocol 
procedures, including the use of prohibited concomitant medications. 
• The occurrence of an AE, laboratory abnormality or other medical condition or situation 
such that in the investigator’s opinion, continued participation in the study would not be 
in the best interest of the subject. 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 20 of 36 
7 
TOXICITIES AND DOSE MODIFICATION 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) version 
4.0 for adverse event and serious adverse event reporting. 
7.1 
Dose Modification 
In this study, participants will receive either a 2.5mg or 3.125mg of carvedilol twice daily. 
Patients will not have the dose increased. However, if patients experience profound side effects 
due to the medication such as hypotension and syncope, the PI can reduce the dose by one-half 
(i.e. one dose per day vs twice daily) or consider withdrawing the participant (see section 6.3). If 
treatment is delayed, the subject’s participation in the study will be discontinued.    
 
7.2 
Supportive Care 
All supportive measures consistent with optimal subject care will be given throughout the study 
and all participants will be given a telephone number which they can call if they have any 
questions or concerns regarding the study and/or their participation in the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
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8 
STUDY CALENDAR 
 
Period 
Screening 
Treatment Period 
 
Intervention Phase (4 weeks) 
 
 
Baseline 
CGM 
1st Hypoglycemic 
Clamp Study 
Follow-Up 
2nd Hypoglycemic 
Clamp Study 
Visit No. 
1 
2 
3 
4 
5 
Week1 
-5 to -2 
-2 
0 
1-2 
4 
Assessments 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
Pregnancy Test 
X 
X 
X 
 
X 
ECG 
X 
 
X 
 
X 
Hematology/Chemistry/ 
Urinalysis2 
X 
 
 
 
 
AE Assessment 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
CGM and Glucometer 
 
X3 
X 
X 
X3 
Fear Survey 
 
 
X 
X 
X 
Hypoglycemia Awareness 
Survey 
X 
 
 
X 
X 
Overnight Hospital 
Admission 
 
 
X 
 
X 
Investigational Drug 
Treatment 
 
 
X4 
X 
X4 
Primary Objective 
Assessment 
 
 
X 
 
X 
Secondary Objective 
Assessment 
 
 
X 
 
X 
1. All screening procedures should be completed within 4 weeks of study enrollment (Visit 1), with the exception of 
laboratory tests which must be completed within 2 weeks, and pregnancy test which must be completed within 48 hours 
of screening (Visit 1).  All visits within the “Treatment Period”, except the 2nd hypoglycemic clamp study, should occur 
within ± 3 days of target date. The 2nd hypoglycemia clamp may be postponed up to 7 days due to hypoglycemia prior 
to the clamp study.   
2. Hematology labs include CGC with differential and platelets; Chemistry labs include c-peptide, HbA1c, Hemoglobin, 
Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Creatinine, 
Glucose, Potassium, TSH, Sodium and Urea Nitrogen; Urinalysis is a dipstick urinalysis including Protein, Hemoglobin 
and Glucose 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 22 of 36 
3. The CGM is placed after enrollment and until the completion of the second hypoglycemic clamp study. Bayer Contour 
Next EZ® glucometer will be provided to participant and they will be required to use it to monitor their blood glucose 
and to calibrate the blinded CGMs. 
4. The investigational drug treatment is to be started after the first hypoglycemic clamp study and completed on the day 
prior to the second hypoglycemic clamp study. 
 
9 
STUDY PROCEDURES 
Detailed descriptions of subject evaluations required for this protocol are described in this section.  
These evaluations will be performed during the indicated visits/weeks of the study as described in the 
Study Calendar and in this section. 
All data collected are to be recorded on source documents and entered into the appropriate CRF page. 
The PI is responsible for maintaining a record of all subjects pre-screened, screened, and enrolled 
into the study.  All subjects must provide written informed consent before the performance of any 
study procedures. 
9.1 
Informed Consent 
Prior to conducting any study-related procedures, written informed consent will be obtained from 
the subject. The nature, scope and possible consequences, including risks and benefits, of the 
study will be explained to the subject by the PI or designee in accordance with the regulations 
and guidelines in the Statement of Compliance. 
9.2 
Study Entrance Criteria 
At screening, each subject will be assessed for eligibility against the inclusion/exclusion criteria.  
Subjects who do not meet the study entrance criteria will not be allowed to enroll and participate 
in the study. The reason(s) for ineligibility will be documented in the subject research chart. 
9.3 
Demographics, Medical History and Hypoglycemia Awareness Survey 
Subject information including gender, age, date of birth, race, ethnicity, diagnosis of (condition), 
and other relevant past medical history will be collected during the screening period and recorded 
in the appropriate CRF. Subjects will also be administered a questionnaire to evaluate 
hypoglycemia awareness. 
9.4 
Laboratory Variables 
A 30mL blood draw will be conducted to obtain blood samples for routine and safety clinical 
laboratory tests (hematology, clinical chemistry) as indicated below. In addition, participants will 
be asked to leave a 100-120mL sample of urine for urinalysis and pregnancy testing as indicated 
below. Analysis of laboratory samples will be performed by ARUP Laboratories: 500 Chipeta 
Way Salt Lake City, UT.  
9.4.1 Hematology and Clinical Chemistries 
Hematology: hematocrit, platelet count, white blood cell count, hemoglobin 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 23 of 36 
Serum Chemistries and Liver Function Tests: potassium, sodium, blood urea nitrogen, 
albumin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, creatinine,  
Additional tests: TSH, glucose levels, C-peptide, HbA1c 
 
9.4.2 Urinalysis 
Urinalysis will be performed to evaluate urine microalbumin levels. 
9.4.3 Pregnancy Testing 
A urinary pregnancy test evaluating human chorionic gonadotropin (hCG) levels will be 
performed during the initial screening visit, at the time CGM is placed, as well as the night 
before each of the hypoglycemic clamp studies.  
9.4.4 Specimen Collection, Preparation, Storage and Shipping 
The collection, preparation, storage and shipping of specimens will be conducted in 
accordance with procedures outlined by ARUP Laboratories. Blood samples collected for 
assessment of plasma glucose during the clamping procedure will be collected into 
heparin coated tubes to prevent coagulation. 
 
9.5 
Physical Examination 
A complete physical examination including assessment of the respiratory system, cardiovascular 
system, abdomen as well as specific tests for neuropathy will be conducted at the screening visit.  
9.6 
Vital Signs 
Vital signs, including measurement of systolic and diastolic blood pressure, pulse, heart rate, 
respiration rate and O2 saturation will be measured at the screening visit, as well as during the 
hypoglycemic clamp sessions.  
9.7 
Electrocardiogram 
An ECG will be completed during the screening period to assess for cardiac conduction 
abnormalities. 
9.8 
Continuous Glucose Monitor (CGM) and Glucometer 
A blinded continuous glucose monitor (CGM) will be placed after enrollment and continue until 
the end of the second hypoglycemic clamp study. At this time, the participants will also be 
issued a Bayer Contour Next EZ® glucometer which they will use to monitor their blood 
glucose for the duration of the study and also to calibrate the CGMs. Instructions on how to use 
the glucometer will be provided at this time. 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 24 of 36 
9.9 
Concurrent Medications 
All prescription and non-prescription medications including pharmacologic doses of vitamins, 
herbal medicines, or other non-traditional medicines, taken from 5 weeks prior to the first dose 
of carvedilol through the last study visit must be documented and recorded in the CRF. 
9.9.1 Prohibited Concurrent Medications 
The following medications are prohibited during the study: 
• Use of any other beta blocker 
• Use of diuretics 
• Use of benzodiazepines 
• Use of acetaminophen 
• Use of SSRIs, naltrexone and other medications that have been proposed to have 
the potential to improve hypoglycemia awareness or prevent the development of 
impaired awareness of hypoglycemia. 
9.10 The Clamp Procedure 
Patients will be asked to reduce the dose of long-acting insulin 24 hours prior to the clamp 
study if applicable. The night before the clamp study, the subjects will be admitted into the 
CSC and the CGMs will be checked for hypoglycemia (reading <75-80mg/dl). We are 
setting this cut-off a little higher than the clinical definition of hypoglycemia (<70mg/dL) 
to ensure central mechanisms that are normally triggered by mild hypoglycemia are not are 
not activated75. If hypoglycemia (<75-80mg/dL) is noted within 24 hours of beginning the 
clamp study, then the study will be delayed for one week. Qualifying subjects will be 
provided with a standardized low glycemic index meal to avoid fluctuations in blood 
glucose levels during the overnight fast. The CSC nursing staff will introduce an 
intravenous (antecubital vein) insulin drip in the subject and blood glucose levels will be 
maintained between 90-120mg/dl during the overnight fasting period. Blood glucose 
concentrations will be determined from a fingerstick using a point-of-care glucometer in 
order to titrate the insulin drip. 
 
 
First Hypoglycemic Clamp: The next day, the patient will be asked to void their bladder 
prior to the start of the clamping procedure. The participant will then remain in bed in a 
supine position for the procedure. The participant will be asked to refrain from watching 
television during the procedure. A second catheter will be inserted into the contralateral 
hand vein for blood sampling and the sampling hand placed into a heated (~55֯C) box to 
arterialize the blood. An ECG will also be connected to the subject to monitor heart 
electrical activity. Heart rate, blood pressure and ECG will be monitored every 15 minutes 
throughout the study. Prior to the drawing of each blood sample, the deadspace volume 
(~5-6ml) will be withdrawn into a syringe. A new syringe will be replaced onto the luer 
lock and the required blood volume drawn into new syringe. Following blood collection, 
the collected deadspace volume will be reinfused, followed by a saline infusion through 
the intravenous line to clear it of residual blood. Baseline blood samples (30mL) will be 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 25 of 36 
collected to measure glucose, HbA1c, hematocrit and hormones (glucagon, 
catecholamines, insulin, cortisol, growth hormone, pancreatic polypeptide). Blood samples 
collected for assessment of plasma glucose (1mL) during the clamping procedure will be 
aliquoted into heparin coated 1ml Eppendorf tubes to prevent coagulation and processed 
immediately in the YSI and/or Analox Instruments glucose analyzer. In addition, the 
participants will be asked to fill in questionnaires to assess their perception of 
hypoglycemic symptoms (Edinburgh Hypoglycemia Symptom Scale) and their fear of 
hypoglycemia. Subsequently, the subjects will be given KCl tablets (20-40mEq) to help 
maintain potassium levels during the clamping procedure. Once assessment of baseline 
parameters has been completed, constant insulin (2mU/kg/min) and variable 20% dextrose 
infusions will be started at -60 minutes to establish stable glucose levels of ~90mg/dl before 
gradually lowering plasma glucose levels in three steps from 90-65-55-45 mg/dl by 
gradually reducing the glucose infusion rate. Plasma glucose levels will be monitored from 
a 1ml blood sample every 5min using a YSI and/or Analox glucose analyzer. A second 
Analox Instruments glucose analyzer and glucometer will be kept on hand as a backup. It 
is important that the glucose levels NOT be communicated verbally during the clamping 
procedure as notification of declining glucose concentrations to the participant might 
trigger confounding (i.e. artificially higher) awareness scores or stress hormone responses. 
Each glycemic step will be held for 30 minutes, allowing enough time for blood collection 
(~30mL at each glycemic plateau) and completion of the Edinburgh questionnaire at each 
glycemic plateau. At each glycemic step, plasma hormones (glucagon, catecholamines, 
insulin, cortisol, growth hormone, pancreatic polypeptide) will be evaluated. The frequent 
assessment of hypoglycemia symptom scores allows us to identify the threshold at which 
hypoglycemic symptoms are first noticed by the subject. We chose glycemic targets of 55 
and 45mg/dl as hypoglycemic symptoms generally first appear between 55-65mg/dl in 
hypoglycemia aware individuals. In contrast, symptoms may not manifest in hypoglycemia 
unaware patients until glucose levels reach 45mg/dl. Targets of 55 and 45mg/dl allow us 
to safely determine whether carvedilol treatment raises the glucose threshold at which 
symptoms are first detected (i.e. improving hypoglycemia awareness). No more than 
500mL of blood will be collected throughout the entire clamping procedure which is 
equivalent to the volume of a single blood donation. After the clamp, the participant’s 
glucose levels will be recovered to normal by stopping the insulin infusion and raising the 
glucose infusion rate. In addition, a meal will be provided to aid recovery. This first set of 
clamps will establish a baseline response in the participant prior to the start of the 
intervention phase of the study. Dispersal of Intervention Drug: At the end of the clamp 
procedure, the subjects will be supplied with either placebo or one of two different doses 
of carvedilol, 2.5mg or 3.125mg, along with instructions on how to take the medication. 
The research staff and participant will be blinded to the treatment being received. The 
initial dose will be taken on the day following the clamp. In addition, the participant will 
also receive a hypoglycemia log book along with instructions on how to document 
hypoglycemia incidences and whom to contact in case of medical concerns. Once the 
participant’s blood glucose levels are stable and he/she is ready to be discharged, we will 
provide them with glucose tablets and we will cover the cost of transportation home as a 
precautionary measure. 
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 26 of 36 
Follow-Up Visit: About 7-14 days after the start of the intervention phase, the subjects will 
be asked to come into the clinic for a follow-up visit where vital signs, AE and CGM data 
will be monitored or evaluated. Subjects will also be asked to complete a hypoglycemia 
awareness and fear survey at this time. 
Second Hypoglycemic Clamp: At the end of the four-week intervention phase, the subjects 
will return to the CSC for the overnight stay and second hypoglycemic clamp procedure. 
The second hypoglycemic clamp procedure will be identical to the first described above.  
 
9.11 Efficacy Measurements 
On all treatment visit days, dosing will occur after all of the safety and efficacy assessments that 
are scheduled for that particular visit have been completed. 
9.11.1 Primary Objective Assessment 
The primary objective assessments are 1) improvements in the hypoglycemia symptom 
scores at each of the (hypoglycemic) glycemic plateaus, 2) shift in the threshold for the 
detection of hypoglycemia and 3) whether counterregulatory hormone responses improve 
during the second hypoglycemic clamp in T1DM patients with impaired awareness of 
hypoglycemia after 4 weeks of carvedilol treatment compared to their baseline and/or 
compared to the placebo-treated control group.  
 
The symptom scores will be assessed by the Edinburgh Hypoglycemia Symptom Score. 
Results will be kept in the patients CRF. After the study is complete, the results will be 
loaded into a secure electronic database and analysis will begin. When reporting the results 
of the hypoglycemia symptom scores, we will evaluate individual as well as overall or 
total symptom scores.  In addition, symptoms will be grouped into autonomous, 
neuroglycopenic and other symptoms for evaluation.  
 
The counterregulatory hormone responses (glucagon, epinephrine, norepinephrine, 
cortisol and growth hormone) will be analyzed from the drawn blood samples. Whole 
blood samples will be collected and aliquoted into vacutainers containing the appropriate 
preservatives and anticoagulants, spun down and the plasma portion will be stored in a -
80֯C freezer until the samples are analyzed.  
 
9.11.2 Secondary Objective Assessment 
The secondary objective assessment will establish whether the frequency of CGM-
determined hypoglycemic episodes differs during 4 weeks of carvedilol treatment 
compared to baseline and compared to the placebo-treated control group.   
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 27 of 36 
Patients will wear a blinded CGM that is installed 14 days prior the first clamp study and 
the device will continue to be worn throughout the entire study. These CGMs will be 
calibrated using the provided Bayer Contour Next EZ® glucometer. During the first clamp 
study, the follow-up visit and the second clamp study, data from the CGM will be 
downloaded and saved onto a secure server and exported into an Excel format for analysis. 
We will identify the number hypoglycemic excursions during the intervention period and 
compare this to the number of hypoglycemic episodes encountered during the 7-day 
period before the first clamp study, the “baseline” period. Comparisons between treatment 
groups at baseline and following the intervention period, as well as differences from 
baseline within each treatment group will be made.  
 
Analysis of the CGM data will emphasize the number of hypoglycemic episodes as well 
as the duration and depth of the hypoglycemic episodes. A single hypoglycemic episode 
is defined as a glucose reading <70 mg/dL, followed by a reading ≥70mg/dL, lasting at 
least 15 minutes or at least two readings below 70mg/dL over 15 minutes. If there is less 
than 30 minutes between two registered episodes of hypoglycemia these are considered 
as one episode. 
 
We will also evaluate the answers to the fear surveys to determine whether those patients 
who are treated with carvedilol have a reduction in their fear of hypoglycemia compared 
to those on placebo. 
 
 
9.12 Safety Measurements 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
version 4.0 for AE and SAE reporting.  An electronic copy of the CTCAE v.4 can be found at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
9.12.1 Adverse Events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug treatment, even if the event is 
not considered to be related to the study drug. For the purposes of this study, the terms 
toxicity and adverse event are used interchangeably. Medical conditions/diseases present 
before starting on the study drug are only considered adverse events if they worsen after 
starting study drug. Abnormal laboratory values or test results constitute adverse events 
only if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy 
Collection of adverse events will begin following the initial treatment with carvedilol and 
continue through to the last visit (the second clamp study).  Adverse events will be 
documented in the study source record and recorded in the CRF. 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
Version Date: October 10, 2019 
 
Principal Investigator: Owen Chan 
 
Page 28 of 36 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or 
other means, will be collected and recorded and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit or phone contact during the study. Adverse events may also be 
detected when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test or other assessments. As much as possible, each 
adverse event should be evaluated to determine: 
1. The severity grade based on CTCAE v.4 
2. The relationship of the event to the study drug(s): definite, probable, possible, 
unlikely, not related.   
3. The duration: start and end dates, or continuing at final follow-up visit 
4. Action taken: (e.g. study drug interrupted or dosage modified, concomitant medication 
taken, non-drug therapy, hospitalization, or no action taken) 
5. Whether the event constitutes a Serious Adverse Event (SAE) 
All adverse events will be treated appropriately. Such treatment may include changes in 
study drug treatment as listed in the dose modification section of this protocol (see section 
7 for guidance). Once an adverse event is detected, it should be followed until its 
resolution and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
9.12.2 Serious Adverse Events 
Information about all serious adverse events will be documented in the study source record 
and recorded in the CRF. A serious adverse event is an undesirable sign, symptom or 
medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability or incapacity 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(unless the hospitalization is for routine treatment or monitoring of the studied 
indication, or elective or pre-planned treatment of a pre-existing condition 
unrelated to the indication under study) 
• Causes a congenital anomaly or birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the subject or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
Toxicities which fall within the definitions listed above must be documented as an SAE 
regardless if they are felt to be treatment related or not. 

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9.12.3 Serious Adverse Event Reporting Requirements 
An event determined to be an SAE must be reported to the IRB and the FDA according to 
the requirements described below: 
 
IRB Notification: 
The PI is responsible to report SAEs that meet the definition of an Unanticipated Problem 
through the ERICA system within 10 working days from the time the investigator learns 
of the event.  An Unanticipated Problem is an event that is: 
• Unexpected – unforeseen by the investigator in terms of nature, severity, or 
frequency, given the research procedures and the subject population being studied 
• Related or Probably Related – determined by the investigator to be related or 
probably related to participation in the clinical trial 
• Greater Risk – the severity or scope of the event suggests that the research places 
subjects or others at greater risk of harm than was previously known or recognized 
 
FDA Notification: 
FDA regulations require the PI to report any serious and unexpected adverse event for 
which there is a reasonable possibility that the drug caused the event.  Fatal or life-
threatening events that meet these criteria must be reported within 7 calendar days from 
the time the investigator learns of the event.  All other reportable events must be reported 
within 15 calendar days.  The SAE should be reported on a MedWatch form and submitted 
as an amendment to the IND.  For studies without an IND, the MedWatch report should 
be submitted to the FDA through the voluntary reporting method. 
9.12.4 Reporting of Pregnancy 
Although pregnancy is not considered an adverse event, it is the responsibility of the PI 
or their designee to report any pregnancy or lactation in a subject, including the pregnancy 
of a male subjects’ female partner as an SAE.  Pregnancies or lactation that occurs during 
the course of the trial or within 30 days of completing the trial or starting another new 
therapy, whichever is earlier, must be reported to the IRB, FDA, and the funding sponsor 
as applicable.  All subjects and female partners who become pregnant must be followed 
to the completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous 
abortion, missed abortion, fetal death, intrauterine death, miscarriage and stillbirth must 
be reported as serious events. 
9.13 Study Halting Rules 
There are no study halting rules for this study.  
 

Protocol Title: The Use of Low-Dose Carvedilol to Improve Hypoglycemia Awareness in Patients with T1DM 
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10 STATISTICAL CONSIDERATIONS 
A total of 21 T1DM patients with impaired awareness of hypoglycemia will be sought for this study. 
For the dose response study, we plan to enroll 21 of these patients who will be randomized to either 
placebo (N=7) or carvedilol (2.5mg or 3.125mg twice daily; N=7 each).  
 
In estimating the appropriate sample sizes required to yield adequate statistical power, assuming a 
Type II error rate (β) of no more than 20% for a given test and a Type I error rate of α=5%, we used 
the following: Power ≥ 1-β = 1-0.2 = 0.8 
 
Treatment effects will be analyzed using one- or two-way analysis of variance (ANOVA) for 
independent or repeated measures as appropriate, followed by suitable post-hoc analysis. Analyses 
will be performed using the GraphPad Prism® or SAS® suite of software. We will use a significance 
level of α<0.05. 
 
Primary variables:  
a) Symptom Scores (autonomous, neuroglycopenic and other symptoms of hypoglycemia) 
b) Counterregulatory Hormone Responses (glucagon, epinephrine, norepinephrine, growth  
    
hormone and cortisol levels) 
 
Secondary variables: 
a) Frequency of hypoglycemia assessed by CGM. 
 
The primary and secondary variables will be analyzed by the statistical approaches mentioned above.  
 
11 DATA HANDLING AND RECORD KEEPING 
Data collection is the responsibility of the clinical trial staff under the supervision of the PI.  The 
investigator is ultimately responsible for ensuring the integrity, accuracy, completeness, legibility, 
and timeliness of the data being reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.  When making changes or corrections, cross out the original entry with a single line, and 
initial and date the change.  Do not erase, overwrite, or use correction fluid or tape on the original 
source data. 
Case Report Forms (CRFs) will be utilized to capture data in the clinical study.  Data collection 
processes and procedures will be reviewed and validated to ensure completeness, accuracy, reliability 
and consistency.   
The PI and study team will conduct periodic reviews of the source data records and CRF database for 
completeness, consistency and accuracy.  Study data will be collected and reported to the DSMB as 
required by the data and safety monitoring plan. 

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11.1 Records Retention 
FDA investigational drug and device regulations, and GCP guidelines state that clinical trial 
records and essential documents should be retained for a minimum of 2 years after the last 
approval of a marketing application, or if no application is to be filed or if the application is not 
approved, at least 2 years have elapsed since the formal discontinuation or conclusion of the 
clinical trial.  Refer to SOP #CTO-04 for maintenance and archiving of clinical trial records. 
11.2 Disclosure and Publication Policy 
This study will comply with the FDAAA regulations and NIH policy for registration and results 
reporting in the ClinicalTrials.gov database, as applicable.  The International Committee of 
Medical Journal Editors (ICMJE) member journals have adopted a clinical trials registration 
policy as a condition for publication.  Registration of the study in the ClinicalTrials.gov database 
prior to study initiation will comply with this policy. 
The results from the study will be summarized in an article, with the intention of publication in a 
peer-reviewed scientific journal. Positive, negative and inconclusive results will be published. Dr. 
Chan will decide the order of the authors and the author disclosure will follow the Vancouver 
declaration. 
 
12 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Institutional Review 
The Institutional Review Board will review the application, protocol and all appropriate 
documentation in order to safeguard the rights, safety, and well-being of study subjects.  The 
study will only be conducted at study centers where IRB approval has been obtained.  The final 
study protocol, including the final version of the Informed Consent Form, must be approved or 
given a favorable opinion in writing by the IRB.  If the protocol is amended, changes will not be 
implemented without prior review and approval from the IRB, except where necessary to 
eliminate an immediate hazard to study subjects. 
12.2 Data and Safety Monitoring Plan 
The clinical trial may be selected for audit within the scope of the Internal Audit Program.  The 
purpose of an audit is to determine and evaluate adherence to applicable federal regulations, to 
the study protocol and to GCP principles.  The PI is responsible for working with the auditor in 
providing all needed study records and for developing corrective actions where necessary and 
ensuring complete and adequate responses to internal audit findings. 
If the study is selected for an FDA or other federal agency inspection, the PI will make requested 
study records and study personnel records available for review (refer to SOP REG-01: FDA 
Inspections). 

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12.3 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and treatment 
plans as outlined in the protocol version submitted and previously approved by the IRB.  Protocol 
deviations have the potential to place participants at risk and can also undermine the scientific 
integrity of the study thus jeopardizing the justification for the research.  Protocol deviations are 
unplanned and unintentional events. 
 
Because some protocol deviations pose no plausible threat to participant safety or scientific 
integrity, reporting is left to the discretion of the PI within the context of the guidelines below.  
The IRB requires the prompt reporting (within 10 working days) of protocol deviations which 
are: 
• Exceptions to eligibility criteria 
• Intended to eliminate apparent immediate hazard to a research participant 
• Harmful – caused harm to participants or others, or placed them at increased risk of harm, 
including physical, psychological, economic, or social harm 
• Possible serious or continued noncompliance 
12.4 FDA Annual Reporting 
Within 60 days of the anniversary date that the IND went into effect, a brief report of the progress 
of the investigation will be submitted to the FDA following the requirements set out in 21 CFR 
Part 312.33. 
12.5 Clinical Trials Database 
The clinical trial will be registered at initiation and study results will be reported on the 
ClinicalTrials.gov database as required per 42 CFR Part 11. 
 
 
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Principal Investigator: Owen Chan 
 
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