Propranolol as a Treatment for Impaired Awareness of Hypoglycemia in Type 1 Diabetes
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Sponsor: Anu Sharma

Propranolol as a Treatment for Impaired Awareness of Hypoglycemia in Type 1 
Diabetes Mellitus 
 
NCT03161964 
 
Document Date: August 21, 2018 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 1 of 29 
 
 
 
Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
 
IRB #: 101995 
 
 
Principal Investigator 
Yu Kuei Lin 
yu.lin@hsc.utah.edu 
 
Sub-investigator(s) 
Owen Chan 
ochan@u2m2.utah.edu 
 
Debra Simmons 
debra.simmons@hsc.utah.edu 
 
Vishnu Sundaresh 
vishnu.sundaresh@hsc.utah.edu 
 
Anu Sharma 
Anu.Sharma@hsc.utah.edu 
 
Funding Organization 
University of Utah Diabetes and Metabolism Center 
 
Investigational Agent 
Propranolol 
 
IND Number 
135258 
 
 
 
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 2 of 29 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................................... 5 
STATEMENT OF COMPLIANCE ...................................................................................................................... 7 
STUDY SUMMARY ......................................................................................................................................... 8 
STUDY SCHEMA ........................................................................................................................................... 10 
1. 
OBJECTIVES ......................................................................................................................................... 11 
1.1 
Primary Objective ...................................................................................................................... 11 
1.2 
Secondary Objectives ................................................................................................................ 11 
2 
BACKGROUND ..................................................................................................................................... 11 
3 
DRUG INFORMATION .......................................................................................................................... 12 
4 
STUDY DESIGN..................................................................................................................................... 14 
4.1 
Description................................................................................................................................. 14 
4.2 
Dose Limiting Toxicity ................................................................................................................ 14 
4.3 
Number of Subjects ................................................................................................................... 14 
4.4 
Number of Study Centers .......................................................................................................... 14 
4.5 
Study Duration ........................................................................................................................... 14 
5 
ELIGIBILITY CRITERIA ........................................................................................................................... 14 
5.1 
Inclusion Criteria ........................................................................................................................ 14 
5.2 
Exclusion Criteria ....................................................................................................................... 15 
6 
TREATMENT PLAN ............................................................................................................................... 16 
6.1 
Administration Schedule ........................................................................................................... 16 
6.1.1 
Group 1 .................................................................................................................................. 16 
6.1.2 
Group 2 .................................................................................................................................. 16 
6.2 
Treatment (include name of each treatment as section header) ............................................. 16 
6.2.1 
How Supplied, Stored, Packaged and Labeled ...................................................................... 16 
6.2.2 
Preparation and Administration ........................................................................................... 16 
6.2.3 
Accountability and Compliance ............................................................................................. 16 
6.3 
Duration of Therapy .................................................................................................................. 16 
7 
TOXICITIES AND DOSE MODIFICATION ............................................................................................... 17 
8 
STUDY CALENDAR ............................................................................................................................... 18 
9 
STUDY PROCEDURES ........................................................................................................................... 18 
9.1 
Pre-screening ............................................................................................................................. 19 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 3 of 29 
9.2 
Informed Consent ...................................................................................................................... 20 
9.3 
Screening and Study Entrance Criteria ...................................................................................... 20 
9.4 
Demographics and Medical History........................................................................................... 20 
9.5 
Laboratory Variables ................................................................................................................. 21 
9.5.1 
Hemoglobin A1C .................................................................................................................... 21 
9.5.2 
Pregnancy Testing ................................................................................................................. 21 
9.5.3 
Specimen Collection, Preparation, Storage and Shipping ..................................................... 21 
9.6 
Physical Examination ................................................................................................................. 21 
9.7 
Vital Signs................................................................................................................................... 21 
9.8 
Electrocardiogram ..................................................................................................................... 21 
9.9 
Concurrent Medications ............................................................................................................ 21 
9.9.1 
Prohibited Concurrent Medications ...................................................................................... 21 
9.9.2 
Prohibited Procedure ............................................................................................................ 22 
9.10 
Efficacy Measurements ............................................................................................................. 22 
9.10.1 
Primary Objective Assessment ......................................................................................... 22 
9.10.2 
Secondary Objective Assessment ..................................................................................... 22 
9.11 
Safety Measurements ................................................................................................................ 23 
9.11.1 
Safety Monitoring ............................................................................................................. 23 
9.11.2 
Adverse Events .................................................................................................................. 23 
9.11.3 
Serious Adverse Events ..................................................................................................... 24 
9.11.4 
Serious Adverse Event Reporting Requirements .............................................................. 24 
9.11.5 
Reporting of Pregnancy .................................................................................................... 25 
9.12 
Study Protocol Modification or Study Termination .................................................................. 25 
10 
STATISTICAL CONSIDERATIONS ...................................................................................................... 25 
11 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 26 
11.1 
Records Retention ..................................................................................................................... 26 
11.2 
Disclosure and Publication Policy .............................................................................................. 26 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................. 26 
12.1 
Institutional Review ................................................................................................................... 26 
12.2 
Data and Safety Monitoring Plan .............................................................................................. 27 
12.3 
Protocol Deviations ................................................................................................................... 27 
12.4 
Clinical Trials Database .............................................................................................................. 27 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 4 of 29 
13 
REFERENCES ................................................................................................................................... 28 
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 5 of 29 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CGM 
Continuous Glucose Monitor 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Science 
CRF 
Case Report Form 
CT 
Computed Tomography 
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 
GFR 
Glomerular Filtration Rate 
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 
T1DM 
Type 1 Diabetes Mellitus 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 6 of 29 
VMH 
Ventromedial hypothalamus 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 7 of 29 
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: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 8 of 29 
STUDY SUMMARY 
Title 
Propranolol Use for Treatment of Impaired 
Awareness of Hypoglycemia 
Short Title 
Propranolol in treating hypoglycemia unawareness 
Protocol Number 
IRB #: 00101995 
IND 
Exempted; IND 135258 
Phase 
II Pilot 
Design 
Double-blinded, placebo-controlled 
Study Duration 
Up to 2 years for pilot study 
Study Center(s) 
University of Utah Health 
Objectives 
To evaluate whether propranolol will both improve 
hypoglycemia awareness and also reduce 
hypoglycemia severity and duration in type 1 
diabetes patients with impaired awareness of 
hypoglycemia 
Number of Subjects 
Twelve subjects for pilot study 
Diagnosis and Main Eligibility Criteria 
Type 1 diabetes patients with impaired awareness of 
hypoglycemia 
Inclusion: 
• 
Type 1 diabetes for more than 5 years 
• 
Age between 21 to 59 years old 
• 
Hemoglobin A1C ≤ 9% 
• 
No beta-blocker use in last 6 months 
Exclusion: 
• 
Coronary, cerebral or peripheral vascular disease 
or other major cardiovascular diseases 
• 
Cardiac conduction abnormality or heart failure 
history 
• 
Advanced kidney/liver disease 
• 
Advanced diabetic microvascular complications  
• 
Contraindication, including hypersensitivity to 
beta-blockers 
Study Product, Dose, Route, Regimen 
Propranolol ER 80 mg oral daily 
or matching placebo oral daily 
Duration of Administration 
4 weeks of study drugs (propranolol ER or placebo) 
Reference Therapy 
Reference: Placebo 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 9 of 29 
Statistical Methodology 
The exact Wilcoxon rank sums test to determine 
study outcomes. Hodges-Lehman estimates and 
associated exact 95% confidence intervals will 
provide estimates of the size of the treatment effect.  
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 10 of 29 
STUDY SCHEMA 
 
CGM, continuous glucose monitoring 
 
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 11 of 29 
1. OBJECTIVES 
1.1 
Primary Objective 
• To determine whether propranolol increases the recognition of hypoglycemic 
events 
1.2 
Secondary Objectives 
• To determine whether propranolol improves hypoglycemia awareness 
questionnaire scores; 
• To establish if propranolol reduces hypoglycemia severity and duration; 
• To assess if propranolol decreases in onset-to-diagnosis/treatment and 
diagnosis/treatment-to-recovery duration and total hypoglycemia/severe 
hypoglycemia frequency (total/day/night); 
• To establish whether propranolol decreases fear of hypoglycemia; and  
• To determine if propranolol decreases overall mean blood glucose value. 
2 
BACKGROUND 
Type 1 diabetes mellitus (T1DM) can lead to serious and devastating complications, including 
microvascular (retinopathy, neuropathy and nephropathy) and cardiovascular disease. Both 
diabetic microvascular and cardiovascular complications can be reduced with intensive insulin 
therapy and strict blood glucose control which target hemoglobin A1C to less than 7%. [1] 
However, tighter glycemic control correlates with a higher incidence of hypoglycemia and 
severe hypoglycemia. [2] Recurring exposure to hypoglycemia leads to an attenuated 
sympathoadrenal response to hypoglycemia (which is termed hypoglycemia-associated 
autonomic failure), and thus a loss or decrease in neurogenic hypoglycemic symptoms (i.e. 
impaired awareness of hypoglycemia). [3, 4] Impaired awareness of hypoglycemia is associated 
with a six-fold increased risk of severe hypoglycemia [5] and physician or patient-directed 
higher glycemic goals. Impaired awareness of hypoglycemia is therefore a major barrier in 
diabetes management, by precluding optimal glycemic control and realization of its full benefits. 
[3] 
Several therapeutic strategies have been proposed to improve hypoglycemia awareness in T1DM 
patients. A temporal increase in glycemic goal only sustains hypoglycemia awareness recovery 
for a short-term. [6, 7] Islet transplantation is invasive, extremely expensive and requires life-
long use of immunosuppressants. [8] A widely available and affordable treatment with sustained 
efficacy for improving hypoglycemia awareness is therefore in urgent need. Pharmaceutical 
agents targeting potential mechanisms that contribute to the development of impaired 
hypoglycemia awareness have been proposed, including beta-blockers, opioid receptor 
antagonists and selective serotonin uptake inhibitors (SSRIs). [4] However, none of these agents 
has been approved for the treatment of impaired hypoglycemia awareness.  
In the current study, we will examine the clinical use of beta-blockers, specifically propranolol, 
for the treatment of impaired hypoglycemia awareness. Prior rodent studies suggest that 
norepinephrine levels in the ventromedial hypothalamus (VMH) increase during an acute bout of 
hypoglycemia and that the acute activation of the VMH beta-2 adrenergic receptors enhances the 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 12 of 29 
counterregulatory response to hypoglycemia. [9, 10] However, previous studies investigating the 
effects of repeated VMH noradrenergic system activation suggested that recurring hypoglycemia 
dampened the counterregulatory hormone response to hypoglycemia [11], possibly due to 
repeated activation of VMH beta2-adrenergic receptors [12]. In addition, carvedilol (a non-
specific beta-blocker) prevented the onset of hypoglycemia-associated autonomic failure in rats 
made recurrently hypoglycemic (Chan O, personal communication). Consistent with these 
findings, propranolol, which blocks beta-2 adrenergic receptors, has been shown to prevent 
hypoglycemia-associated autonomic failure in healthy human subjects [13]. These studies 
suggest that the mechanisms which contribute to the development of hypoglycemia-associated 
autonomic failure may lie downstream of β2-adrenergic receptor activation and, as previous 
studies demonstrated, that hypoglycemia avoidance will lead to recovery from impaired 
hypoglycemia awareness [6, 7]. Therefore, an intervention which can block the propagating 
mechanism(s) (i.e. repeated activation of beta2-adrenergic receptors) will likely lead to 
improvements in hypoglycemia awareness. Previous considerations of beta-blocker use in 
diabetes existed; however, both retrospective and prospective studies have proven its safety [14-
22].  In addition, prior insulin clamp study suggested that propranolol increased overall 
hypoglycemia symptom scores by increasing diaphoresis, without compromising other 
neurogenic and neuroglycopenic symptoms. [23] We therefore believe that propranolol is a 
strong testing candidate for potential impaired hypoglycemia awareness treatment.  
3 
DRUG INFORMATION 
Propranolol (investigational drug) has been approved by FDA for indications unrelated to the 
current study. [24] In the current study, we will use Propranolol extended release (ER). A 
summary of the FDA label for propranolol has been provided in the following. 
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water 
and ethanol. Its molecular weight is 295.80. Propranolol hydrochloride extended-release capsules 
are formulated to provide a sustained release of propranolol hydrochloride.  
Propranolol is highly lipophilic and almost completely absorbed after oral administration. 
However, it undergoes high first pass metabolism by the liver and on average, only about 25% of 
propranolol reaches the systemic circulation. 
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha-
1-acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is preferentially 
bound to alpha-1-glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The 
volume of distribution of propranolol is approximately 4 liters/kg. Propranolol crosses the blood-
brain barrier and the placenta, and is distributed into breast milk. Propranolol is extensively 
metabolized with most metabolites appearing in the urine.  
Propranolol is indicated for hypertension, angina pectoris due to coronary atherosclerosis, 
migraine and hypertrophic subaortic stenosis.  
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than 
first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to 
propranolol hydrochloride.  
There have been reports of exacerbation of angina and, in some cases, myocardial infarction, 
following abrupt discontinuance of propranolol therapy. Therefore, when discontinuance of 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 13 of 29 
propranolol is planned, the dosage should be gradually reduced over at least a few weeks, and the 
patient should be cautioned against interruption or cessation of therapy without the physician's 
advice. Since this study will be using the lowest dose of propranolol LA, and the age of the 
tested population imposes a lower risk of significant atherosclerotic disease, the dose will not be 
tapered. 
Propranolol is Pregnancy Category C based on animal studies. There are no adequate and well-
controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and 
congenital abnormalities have been reported in neonates whose mothers received propranolol 
during pregnancy. Neonates whose mothers are receiving propranolol at parturition have 
exhibited bradycardia, hypoglycemia and/or respiratory depression. Adequate facilities for 
monitoring such infants at birth should be available. Propranolol hydrochloride extended-release 
capsules should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus.  
The following adverse events were observed and have been reported in patients using 
propranolol.  
Cardiovascular: Bradycardia; congestive heart failure; intensification of Atrioventricular node 
block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, 
usually of the Raynaud type.  
Central Nervous System: Light-headedness; mental depression manifested by insomnia, 
lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an 
acute reversible syndrome characterized by disorientation for time and place, short-term memory 
loss, emotional lability, slightly clouded sensorium, and decreased performance on 
neuropsychometrics. For immediate release formulations, fatigue, lethargy, and vivid dreams 
appear dose related.  
Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, 
constipation, mesenteric arterial thrombosis, ischemic colitis.  
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis 
and agranulocytosis; erythematous rash; fever combined with aching and sore throat; 
laryngospasm; respiratory distress.  
Respiratory: Bronchospasm.  
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.  
Autoimmune: Systemic lupus erythematosus.  
Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry eyes, 
exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and 
psoriasisiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes, 
and conjunctivae reported for a beta-blocker (practolol) have not been associated with 
propranolol.  
Genitourinary: Male impotence; Peyronie's disease. 
 
 
 
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 14 of 29 
4 
STUDY DESIGN 
4.1 
Description 
The current investigation is a phase II pilot clinical trial with randomization and double-
blinding design. After recruitment, the subjects will be randomized into two arms (Group 
1 or Group 2), and under go a two-week assessment with Hypoglycemia Event Report 
and continuous glucose monitoring (CGM) with a Dexcom Professional CGM system. 
The subjects will then to be placed on either propranolol (Group 1) or placebo (Group 2) 
for a 4-week Intervention. Two weeks after the intervention is initiated, subjects will 
again be asked to undergo Hypoglycemic Event Report and CGM assessments for 
another two weeks.  
4.2 
Dose Limiting Toxicity 
Propranolol ER will be administered at a dose of 80 mg daily during the Interventional 
Phase.  This dose of propranolol is within the range of other indications that have been 
approved by FDA previously. If study subjects experience serious adverse events or 
intolerable toxicities determined by the PI to be related to treatment with propranolol, 
subjects will be discontinued from the trial, or treatment may be held for one week and 
resumed if adverse events resolve to a tolerable level as determined by the investigator. 
4.3 
Number of Subjects 
Twelve patients will be enrolled and treated on this pilot study.  We will use the collected 
information to conduct a power analysis to determine the number of subjects needed for 
the definitive trial. 
4.4 
Number of Study Centers 
This study will be a single-center study conducted at the University of Utah. 
4.5 
Study Duration 
The pilot study is expected to last for two years, and will help provide the estimated time 
for the final study. The duration of each patient’s participation in the study will be three 
months. 
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.  
 Subjects with Type 1 diabetes for more than 5 years 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 15 of 29 
2.  
 Age between 21 to 59 years old 
3.  
 Hemoglobin A1C ≤ 9%; most recent value within 3 months 
4.  
 No beta-blocker use history in the last 6 months 
5.  
 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.  
 History of coronary, cerebral, peripheral vascular or other major 
cardiovascular diseases 
2.  
 History of cardiac conduction abnormality or heart failure 
3.  
 History of advanced kidney disease 
4.  
 History of advanced liver disease 
5. ______ Active malignancy 
6.  
 Major Central or Peripheral Nervous System disease 
7.  
 History of human immunodeficiency virus infection 
8.  
 Contraindication to beta-blockers, including hypersensitivity to beta-
blocker and bronchial asthma 
9.  
 Female in pregnancy or not able to practice effective contraception 
during the study period 
10.  
 Concomitant acetaminophen use 
11.  
 Current use of unblinded real-time continuous glucose monitoring 
12.  
 Advanced diabetic microvascular complications including 
retinopathy, neuropathy and nephropathy 
13.  
 Inability to understand or cooperate with study procedure, including 
performing glucometer glucose assessment a minimum of four times a day, 
carrying glucose tablets and following standardized hypoglycemia treatment, 
completing hypoglycemia diary, wearing continuous glucose monitoring, and 
using a single glucometer 
14.  
 Recent or current use or involvement in clinical studies of other 
therapies (e.g. opioid antagonist, behavioral modification, relaxation of 
glycemic control) that may improve hypoglycemia awareness or prevent 
impaired hypoglycemia awareness development 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 16 of 29 
I verify that this subject meets all eligibility criteria for enrollment onto this study 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
Date 
 
6 
TREATMENT PLAN 
6.1 
Administration Schedule 
6.1.1 Group 1 
After randomization and the initial two-week CGM assessment, subjects 
randomized to Group 1 will be initiated on propranolol ER 80 mg daily (before 
bedtime) for four weeks, and will then stop the intervention. 
6.1.2 Group 2 
After randomization randomization and the initial two-week CGM assessment, 
subjects randomized to Group 2 will be initiated on placebo: one capsule daily 
(before bedtime) for four weeks, and will then stop the intervention. 
6.2 
Treatment (include name of each treatment as section header) 
6.2.1 How Supplied, Stored, Packaged and Labeled 
Propranolol ER 80 mg capsules: Over-encapsulated for blinding. 
Matching placebo capsules: Capsules identical to the ones used to encapsulate 
propranolol ER for blinding.  
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 
86°F). [See USP Controlled Room Temperature] Protect from light, moisture, 
freezing, and excessive heat. Dispense in a tight, light-resistant container as 
defined in the USP.  
6.2.2 Preparation and Administration 
Subjects will be given a 4-week supply of blinded study medication at treatment 
visit 2.  Subjects will be asked to return this supply with any unused capsules at 
the end of the intervention period. 
6.2.3 Accountability and Compliance 
Subjects will be asked to medication bottles and any unused capsules for 
reconciliation at the end of the intervention period. 
6.3 
Duration of Therapy  
The standard treatment period for the interventional period (propranolol or placebo) will 
last 4 weeks (28 days).  
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
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Subjects must be withdrawn or discontinued from the clinical trial for the following 
reasons: 
• Subject withdraws consent from participation in the clinical trial.  A subject 
must be removed from the study at his/her own request.  At any time during the 
trial and without providing reasons, a subject may decline to participate further.  
The subject will not suffer any disadvantage as a result. 
• Subject is lost to follow-up despite efforts to contact 
• Death 
 
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. 
• Development of severe hypoglycemia for which subject was required to visit 
emergency room or to be hospitalized 
 
Discontinued or withdrawn subjects may be replaced on study to ensure completion of 
five study subjects in each treatment arm. 
 
7 
TOXICITIES AND DOSE MODIFICATION 
Toxicities will be monitored in each study subject according to the study calendar and 
Section 9.9, Safety Measurements.  Serious Adverse Events and intolerable toxicities 
determined by the PI to be related to study medication will result in discontinuation of 
treatment and withdrawal of the subject from the trial, or treatment may be held for one 
week and resumed if adverse events resolve to a tolerable level as determined by the 
investigator. 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Title: Propranolol Use for Treatment of Impaired Awareness of Hypoglycemia 
Version Date: 
August 21st, 2018 
Principal Investigator: Lin, Yu Kuei 
 
 
 
Page 18 of 29 
8 
STUDY CALENDAR 
 
Period 
Screening1 
Study2 
 
 
 
Intervention Phase  
Visit No. 
 
1 
2 
3 
4 
Week 
-4 to 1 
1 
3 
5 
7  
Assessments 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Vital signs 
X 
 
X 
 
X 
Physical Examination 
X 
 
X3 
X3 
X3 
Hemoglobin A1C 
X 
 
 
 
 
Pregnancy Test 
X 
 
X 
 
 
ECG 
X 
 
 
 
 
AE Assessment 
 
 
X 
X 
X 
Concomitant Medications 
 
 
X 
 
X 
Investigational Drug Treatment 
 
 
X 
Primary Objective Assessment 
 
X4 
 
X4 
 
Secondary Objective Assessment 
 
X 
X 
 
X 
ECG, electrocardiogram; AE, adverse event 
1. All screening procedures should be completed within 4 weeks of study enrollment, except that an ECG 
completed within 3 months will be considered as valid.  Screening visit and Study Visit 1 may occur on the 
same day. 
2. All visits within the Intervention Phase should occur within ± 3 days of the target dates. Pregnancy test 
which must be completed within 48 hours before investigational drug treatment starts. 
3.  Physical exam to be conducted at the discretion of PI/Sub-investigator based on reported adverse events. 
4. Two-week assessment with Hypoglycemia Event Reports and continuous glucose monitoring. 
 
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. 

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9.1 
Pre-screening 
The principal investigator (PI) will work with the University of Utah Enterprise Data 
Warehouse (EDW) and generate a list of potential candidates with based on the elements 
of inclusion/exclusion criteria (e.g. type 1 diabetes, age, recent hemoglobin A1C, etc) on 
the Human Subject Recruitment tool. Human Subject Recruitment tool is a computer 
software managed by EDW for subject recruitment with a constantly updating database, 
and this tool has been utilized by clinical investigators at the University of Utah. PI will 
review of these candidates' medical charts for further candidate selection. 
The list of potential candidates will then be used to recruit subjects in the following 
routes: 
1) The primary care physicians or Endocrinologists with established clinical relationship 
with the potential candidates may discuss the research opportunity with the candidates, to 
obtain the permission of contact for interested candidates, and/or offer recruitment letters. 
2) A recruitment letter may be offered to the potential candidates by the medical 
assistants of physicians with established clinical relationship with these candidates, with 
permissions of the physicians. 
3) A recruitment letter sent via mail or myChart message to the potential candidates, and 
if no response is received in at least 7 days, a phone call may be generated to discuss the 
study. 
Information about the current study will also be distributed to clinicians, mostly primary 
care physicians and endocrinologists, and referrals for the current study may be made by 
these physicians. 
For interested candidates, we will proceed with further eligibility pre-screening through 
telephone discussions and mailing paper surveillance of Personal Medical History and 
Hypoglycemia Awareness Questionnaires. A copy of the consent form will also be 
mailed to the candidates to look over for at least 1 day before obtaining consent. 
For each recruitment route, the candidate may opt-out request for no further contact to be 
made for this study. 
Social Networking Sites:  We may share recruitment materials on social network sites 
such as Facebook or Instagram that provide a brief announcement and description about 
the study, along with study contact information directing interested individuals to the 
University of Utah study coordinator(s).  Current required IRB disclaimer language will 
be attached to all online recruitment materials utilized.* Recruitment language options 
are being attached as a word document to this study application.  This recruitment 
language may be utilized in any of the above methods at various times throughout the 
recruitment period of the study.  If the study team determines that IRB approved 
recruitment language requires a substantive change, we will submit that language to the 
IRB prior to use. 

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*IRB Disclaimer Language (required for all social media recruitment) 
The information posted on this site is consistent with the research reviewed and approved 
by the University of Utah Institutional Review Board (IRB).  However, the IRB has not 
reviewed all material posted on this site.  Contact the IRB if you have questions regarding 
your rights as a research participant.  Also contact the IRB if you have questions, 
complaints, or concerns which you do not feel you can discuss with the investigator.  The 
University of Utah IRB may be reached by phone at 801-581-3655 or by email at 
irb@hsc.utah.edu. 
9.2 
Informed Consent 
For candidates interested in the study, a copy of the consent form will be mailed to the 
candidates to look over for at least 1 day before obtaining consent. 
 
The informed consent process is to be completed at the screening visit. Prior to 
conducting any study-related procedures, written informed consent must 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. 
 
The recruiting investigators/coordinators will be trained to discuss the study with the 
potential participants only limited to the informed consent document, including that the 
potential participant will continue the receive the same medical care regardless whether 
he/she decide to participate in the study. The potential participant selection process will 
be independent of the potential participants' diabetes care provider. 
 
To avoid the study compensation being an undue influence, we will not share 
compensation information during pre-screening telephone calls unless the subject asks or 
after they have verbally agreed that they would like to participate. We also will not 
disclose details in compensation before completion of consenting process. 
 
As much time as needed will be used to allow adequate time to exchange information and 
questions during the recruitment. The subjects and the investigators should not feel 
rushed for the recruitment process. 
9.3 
Screening and 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. 
9.4 
Demographics and Medical History 
Subject information including gender, age, date of birth, race, ethnicity, diagnosis of 
T1DM, and other relevant past medical history will be collected during the screening 
period and recorded in the appropriate CRF. 

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9.5 
Laboratory Variables 
Hemoglobin A1C and pregnancy test will be performed as indicated on the Study 
Calendar.  Hemoglobin A1C Analysis of laboratory samples will be performed with 
ARUP Laboratories (500 Chipeta Way, Salt Lake City, UT) protocol and supplies or at 
ARUP Laboratories. Pregnancy test will be performed with Immunostics Inc. (1750 
Brielle Avenue, Ocean Township, NJ) protocol and material. 
9.5.1 Hemoglobin A1C 
Hemoglobin A1C: Hemoglobin A1C, blood 
9.5.2 Pregnancy Testing 
Urinary pregnancy test: Qualitative Beta-human chorionic gonadotropin, urine 
9.5.3 Specimen Collection, Preparation, Storage and Shipping 
Specimen collection, preparation, storage and shipping will be conducted as the 
standard based on ARUP laboratory and Immunostics Inc. protocol. 
9.6 
Physical Examination 
Physical examination, including respiratory, cardiovascular, abdominal and others as 
indicated based on medical history, will be conducted at the screening visit. For the 
follow-up visits, focused physical examination will be conducted at discretion of PI/sub-
investigator based on reported adverse events. 
9.7 
Vital Signs 
Vital signs, including measurement of systolic and diastolic blood pressure, pulse, and 
heart rate are to be conducted. 
9.8 
Electrocardiogram 
An ECG will be completed during the screening period to assess for cardiac conduction 
abnormalities. 
9.9 
Concurrent Medications 
All prescription and non-prescription medications including pharmacologic doses of 
vitamins, herbal medicines, or other non-traditional medicines, taken from 4 weeks prior 
to the first dose of the studied medications (propranolol/placebo) through the last study 
visit will be documented and recorded in the CRF. 
9.9.1 Prohibited Concurrent Medications 
The following medications are prohibited during the study: 
• Beta-blockers other than propranolol 
• Naltrexone and other medications that have been proposed to have the 
potential in improving hypoglycemia awareness or preventing the 
development of impaired awareness of hypoglycemia 

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9.9.2 Prohibited Procedure 
The use of un-blinded continuous glucose monitoring is prohibited during the 
study. Behavioral modifications or relaxation of glycemic control aiming to 
improve hypoglycemia awareness are prohibited. 
9.10 Efficacy Measurements 
9.10.1 Primary Objective Assessment 
The primary objective assessment will be done through the determining the total 
and self-reported hypoglycemic events based on CGM data and hypoglycemia 
diary, respectively.  
A single CGM hypoglycemic episode will be defined by any CGM readings < 70 
mg/dL, followed by at least one reading ≥ 70 mg/dL from the Dexcom 
Professional Mobile CGM system.  A subject’s self-reported hypoglycemic 
episode will be defined by a hypoglycemic symptom record on the hypoglycemia 
diary with a confirmatory glucose value (glucometer value < 70 mg/dL, or CGM 
glucose value < 70 mg/dL if glucometer value is not available), or an incidental 
glucometer value < 70 mg/dL if no hypoglycemia symptom develops. 
The Hypoglycemia Event Report includes the initial glucometer value and time 
and treatment time; the first and the most prominent symptom during the 
hypoglycemia episode; whether the episode requires outside help (severe 
hypoglycemia). 
At the end of each hypoglycemia event report/CGM assessment (i.e., visits 2 and 
4), CGM data will be downloaded into a secure system and exported into an Excel 
format, and Hypoglycemic Event Reports will be collected for analysis. 
The primary objective to determine whether propranolol increases the recognition 
of hypoglycemic events will be determined by an increase in the ratio of self-
reported hypoglycemic events over total (i.e. CGM) hypoglycemic events while 
subjects are in the intervention period treated with propranolol compared to 
placebo. 
9.10.2 Secondary Objective Assessment 
Data for the secondary objective assessments will be collected through 
hypoglycemia awareness questionnaires (Gold, Clark and Pedersen-Bjergaard) 
[25-27], CGM data, and Fear of Hypoglycemia Questionnaire [28].  The 
questionnaires will be completed by study subjects at the first, second and the last 
visit of the study. 
The questionnaires and CGM data will be used to determine changes in 
hypoglycemia awareness, severity and duration of hypoglycemia, onset-to-
diagnosis/treatment and diagnosis/treatment-to-recovery durations, fear of 
hypoglycemia, and overall mean blood glucose values in subjects during the 
intervention period treated with propranolol compared to placebo. 
 

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9.11 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 
9.11.1 Safety Monitoring 
Vital signs, including heart rate and blood pressure, and adverse events will be 
assessed during the screening and at the beginning and the end of the 
interventional phase. Physical examination will be conducted and instruction for 
further medical assessment will be provided if needed. A pregnancy test will be 
conducted during the screening and before the study drug intervention. The 
subjects will be provided contact information for questions and needs related to 
the study. 
9.11.2 Adverse Events 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if the 
event is not considered to be related to study drug. For the purposes of this study, 
the terms toxicity and adverse event are used interchangeably. Medical 
conditions/diseases present before starting 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 
propranolol and placebo and continue through the last treatment visit.  Adverse 
events will be documented in the study source record and recorded in the CRF. 
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 during the study. Adverse events also may be detected 
when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. As far 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) 

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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. 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. 
9.11.3 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. 
9.11.4 Serious Adverse Event Reporting Requirements 
An event determined to be an SAE must be reported to the IRB 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 

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9.11.5 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.  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. 
 
9.12 Study Protocol Modification or Study Termination 
The study protocol will be modified if: 
• If the adherence/recruitment is below expectation or not meet grant 
timelines 
The study protocol will be stopped if: 
• The funding is exhausted, or  
• The risk to benefit ratio is higher than expected 
 
10 STATISTICAL CONSIDERATIONS 
The statistical analyses of the pilot study will evaluate feasibility and address questions 
concerning trial conduct and outcomes, as well as power analysis for sample size which must be 
resolved in order to develop a rigorous design for the full scale cross-over trial as the final study. 
These analyses will be primarily descriptive.  
The statistical analyses to evaluate the effects of the intervention on the primary and secondary 
outcomes will be conducted in both the pilot and final studies. For the pilot study, we will apply 
the exact Wilcoxon rank sums test [S1, S2] to compare the primary outcome defined by the ratio 
self-reported hypoglycemic events over total (i.e. CGM) hypoglycemic events between the 
propranolol and placebo treatments under the assumption of no-carry over effects. Hodges-
Lehman estimates [S3] and associated exact 95% confidence intervals will provide estimates of 
the size of the treatment effect. Other outcomes will be analyzed using either a similar 
nonparametric approach or mixed effect models parameterized to estimate the effects of 
treatment, period, and carryover [S4]. 
 
S1. Tudor, G., & Koch, G. G. (1994). Review of nonparametric methods for the analysis of 
crossover studies. Statistical Methods in Medical Research, 3(4), 345-381. 
S2. Putt, M. E., & Chinchilli, V. M. (2004). Nonparametric approaches to the analysis of 
crossover studies. Statistical Science, 19(4), 712-719. 

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S3. Hettmansperger, T. (1991). Statistical Inference Based on Ranks. Krieger, Malabar, FL 
S4. Jones, Byron, and Michael G. Kenward. Design and Analysis of Cross-Over Trials. CRC 
Press, 2014.  
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 accuracy, completeness, legibility, and 
timeliness of the data 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 
as required by the data and safety monitoring plan. 
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 principal investigator will be responsible for developing publication procedures and 
resolving authorship issues. 
12 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Institutional Review 
The University of Utah 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 

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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 
A review will take place of any adverse events that have occurred after every sixth 
subject has completed the study. Meetings/conference calls with members of the research 
team will be used as needed to discuss problems and make recommendations as an 
ongoing process throughout the study. 
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). 
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 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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Cox, D.J., et al., Fear of hypoglycemia: quantification, validation, and utilization. 
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