The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition
Phase: PHASE2
Conditions: Type1 Diabetes Mellitus, Hypoglycemia Unawareness
Sponsor: University of Utah

 
 
The Use of Amitriptyline for Improving Hypoglycemia 
Course and Recognition 
 
 
NCT03591458 
 
Document Date: 04/24/2019 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
Page 1 of 33 
 
 
 
Study: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
 
IRB # 00110853 
 
 
Principal Investigator 
Yu Kuei Lin, MD 
yu.lin@hsc.utah.edu 
 
Sub-investigator(s) 
Simon J. Fisher, MD, PhD 
simon.fisher@u2m2.utah.edu 
 
Michael Varner, MD 
michael.varner@hsc.utah.edu 
 
Funding Organization 
NIDDK/Washington University-University of Utah 
Diabetes Research Center 
Contact: Karen Muehlhauser 
kmuehlha@wustl.edu 
 
Investigational Agent 
Amitriptyline 
 
IND Number 
Pending – applying for IND exemption  
 
 
 
 
 
 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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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 .......................................................................................................................... 12 
4 
STUDY DESIGN..................................................................................................................................... 15 
4.1 
Description................................................................................................................................. 15 
4.2 
Number of Subjects ................................................................................................................... 15 
4.3 
Number of Study Centers .......................................................................................................... 16 
4.4 
Study Duration ........................................................................................................................... 16 
5 
ELIGIBILITY CRITERIA ........................................................................................................................... 16 
5.1 
Inclusion Criteria ........................................................................................................................ 16 
5.2 
Exclusion Criteria ....................................................................................................................... 16 
6 
TREATMENT PLAN ............................................................................................................................... 18 
6.1 
Administration Schedule ........................................................................................................... 18 
6.1.1 
Treatment Arm 1 ................................................................................................................... 18 
6.1.2 
Treatment Arm 2 ................................................................................................................... 18 
6.2 
Treatment (include name of each treatment as section header) ............................................. 19 
6.2.1 
How Supplied, Stored, Packaged and Labeled ...................................................................... 19 
6.2.2 
Preparation and Administration ........................................................................................... 19 
6.2.3 
Accountability and Compliance ............................................................................................. 19 
6.3 
Duration of Therapy .................................................................................................................. 19 
7 
TOXICITIES AND DOSE MODIFICATION ............................................................................................... 20 
7.1 
Dose Modification ..................................................................................................................... 20 
7.2 
Supportive Care ......................................................................................................................... 20 
8 
STUDY CALENDAR ............................................................................................................................... 21 
9 
STUDY PROCEDURES ........................................................................................................................... 22 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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9.1 
Participant Identification/Recruitment Process ........................................................................ 22 
9.2 
Informed Consent ...................................................................................................................... 23 
9.3 
Study Entrance Criteria .............................................................................................................. 24 
9.4 
Demographics and Medical History........................................................................................... 24 
9.5 
Laboratory Variables ................................................................................................................. 24 
9.5.1 
Comprehensive Metabolic Panel .......................................................................................... 24 
9.5.2 
HbA1c .................................................................................................................................... 24 
9.5.3 
Pregnancy Testing ................................................................................................................. 25 
Urine collection will be conducted for Qualitative Beta-human chorionic gonadotropin assessment.
 ............................................................................................................................................................ 25 
9.5.4 
Specimen Collection, Preparation, Storage and Shipping ..................................................... 25 
9.6 
Physical Examination ................................................................................................................. 25 
9.7 
Vital Signs................................................................................................................................... 25 
9.8 
Electrocardiogram ..................................................................................................................... 25 
9.9 
Concurrent Medications ............................................................................................................ 25 
9.9.1 
Prohibited Concurrent Medications ...................................................................................... 25 
9.9.2 
Prohibited Procedure/Device ................................................................................................ 25 
9.10 
Efficacy Measurements ............................................................................................................. 25 
9.10.1 
Primary Objective Assessment ......................................................................................... 26 
9.10.2 
Secondary Objective Assessment ..................................................................................... 26 
9.11 
Safety Measurements ................................................................................................................ 26 
9.11.1 
Adverse Events .................................................................................................................. 26 
9.11.2 
Serious Adverse Events ..................................................................................................... 27 
9.11.3 
Serious Adverse Event Reporting Requirements .............................................................. 28 
9.11.4 
Reporting of Pregnancy .................................................................................................... 28 
9.12 
Study Protocol Modification or Study Termination .................................................................. 29 
10 
STATISTICAL CONSIDERATIONS ...................................................................................................... 29 
11 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 29 
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 .............................................................................................. 30 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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12.3 
Protocol Deviations ................................................................................................................... 31 
12.4 
FDA Annual Reporting ............................................................................................................... 31 
12.5 
Clinical Trials Database .............................................................................................................. 31 
13 
REFERENCES ................................................................................................................................... 31 
 
 
 
 
 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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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 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitoring 
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 
HbA1c 
Hemoglobin A1C 
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 
MTD 
Maximum Tolerated Dose 
NIH 
National Institutes of Health 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
PI 
Principal Investigator 
rtCGM 
Real-time continuous glucose monitoring 
SAE 
Serious Adverse Event 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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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 Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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STUDY SUMMARY 
Title 
The Use of Amitriptyline for Improving 
Hypoglycemia Recognition and Course 
Short Title 
Amitriptyline as an anti-hypoglycemic agent 
Protocol Number 
IRB # 00110853 
IND 
Pending – applying for IND exemption 
Phase 
Pilot, clinical phase II 
Design 
Double blind, randomized, placebo control, cross-
over design 
Study Duration 
38 weeks 
Study Center(s) 
University of Utah Hospital and Clinics 
Objectives 
To evaluate whether amitriptyline improves the 
hypoglycemia course and the ability to recognize 
hypoglycemia in type 1 diabetes patients who are 
using real-time continuous glucose monitoring 
devices 
Number of Subjects 
Approximately 80 participants for Run-in Period, 
with a goal of randomizing 24 patients for drug 
intervention phase 
Main Eligibility Criteria 
Inclusion Criteria 
• Subjects with T1DM for one years or more 
• Age between 21 to 60 years old 
• HbA1c less or equal to 9% with the last 
measurement in the last three months 
• Ongoing use of real-time CGM for at least 3 
months 
Exclusion Criteria 
• Ongoing or recent history of major depressive 
disorder, or other ongoing major psychiatric 
disorders 
• History of anti-depressant use within the last 
three months 
• History of advanced cardiac, liver, kidney and 
neurological disease 
• Active malignant or HIV diseases 
• Advanced diabetic retinopathy, neuropathy or 
nephropathy 
• Female in pregnancy or not able to practice 
effective contraception during the study period 
• Contraindication to amitriptyline use 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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• < 70% of CGM readings available over the last 
2-week period 
• Time spent in hypoglycemia (i.e., < 70 mg/dL) 
for < 5% over a 2-week period on based on 
CGM reading 
Study Product, Dose, Route, Regimen 
Amitriptyline 25 mg and 50 mg oral daily at bedtime 
Duration of Administration 
Up to 12 weeks 
Reference Therapy 
Placebo 
Statistical Methodology 
The Wilcoxon rank sums test as adapted 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: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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STUDY SCHEMA 
 
 
 
 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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1. OBJECTIVES 
The overall goal of the current study is to evaluate whether amitriptyline improves the 
hypoglycemia course and the ability to recognize hypoglycemia in type 1 diabetes patients 
who are using real-time continuous glucose monitoring (rtCGM) devices. 
1.1 
Primary Objectives and Endpoints 
• The area-under-curve (AUC) of glucose <70 and 54 mg/dL on continuous 
glucose monitoring (CGM). 
• The ratio of recognized-to-total hypoglycemic episodes. 
1.2 
Secondary Objectives and Endpoints 
 Count of severe hypoglycemic episodes. 
 Hypoglycemic course, including episode count, total time, average 
time/episode, and percentage of glucose < 70, 54 and 40 mg/dL; AUC of 
glucose < 40 mg/dL; average nadir glucose. 
 Nocturnal hypoglycemic course, including episode count, total time, average 
time/episode, percentage and AUC of glucose < 70, 54 and 40 mg/dL; average 
nadir glucose. 
 Hypoglycemia awareness score (Gold [1], Clarke [2] and Pedersen-Bjergaard 
[3]). 
 Other glucose regulation: Average glucose, glycemic variability, time in 
hyperglycemia with level above 180, 250 and 300 mg/dL, percentage of time in 
normal glucose, HbA1c. 
• Hypoglycemia Fear Survey score [4]. 
2 
BACKGROUND 
Poorly controlled 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 by intensive insulin therapy and strict blood glucose control aiming for 
hemoglobin A1C (HbA1c) less or equal to 7%. [5, 6] However, a tighter glycemic control 
correlates with a higher incidence of hypoglycemia. [7] Recurrent episodes of hypoglycemia 
induce an attenuation or loss of catecholamine counter-regulatory responses (a condition 
termed hypoglycemia-associated autonomic failure) and the ability to recognize 
hypoglycemic episodes (impaired awareness of hypoglycemia). [8, 9] Hypoglycemia-
associated autonomic failure and impaired awareness of hypoglycemia are associated with a 
25 and six-fold increased risk of severe hypoglycemia, respectively. [9-11]  Severe 
hypoglycemia leads to seizures, emergency room visits/hospitalization, fear of 
hypoglycemia, compromised quality of life and potentially death. [12] Thus, hypoglycemia-

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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associated autonomic failure and impaired awareness of hypoglycemia are major barriers to 
optimal glycemic control. [8] 
Real-time continuous glucose monitoring (rtCGM) is a technique which measures interstitial 
glucose levels every five minutes to estimate coincidental blood glucose levels. [13] A 
rtCGM will alert patients of hyper/hypoglycemic events at set glucose thresholds and when 
the blood glucose levels are rapidly rising/declining. While rtCGM has demonstrated to 
significantly decrease the daily time spent in hypoglycemia, patients wearing rtCGM still 
spend approximately 3-7% of time in hypoglycemia in average, equivalent to 43-101 
minutes in a day.[14-16] While the prevalence of T1DM using CGM is rapidly increasing, 
there has been no adjuvant therapy demonstrating its ability to further decrease the 
hypoglycemic burden for this patient population.   
In the current study, we propose to test amitriptyline, a tricyclic antidepressant, as an 
adjuvant treatment of rtCGM to further improve hypoglycemia course and T1DM 
patients’ ability to recognize hypoglycemic episode. Our lab has constructed a 2-Deoxy-
D-glucose (2DG)-mediated impaired awareness model in rats, in order to identify therapies 
for rapid translational testing and clinical use. 2DG blocks normal glucose metabolism and 
causes cellular glucose deprivation. Repeated 2DG infusions thus assimilate repetitive 
“cellular hypoglycemia”. [17] Based on this concept, our lab has developed a rodent model 
of repetitive 2DG infusion-mediated impaired hypoglycemia awareness. We use the amount 
of food intake in response to subsequent insulin-induced hypoglycemia as an objective 
measurement of impaired awareness in this model, as food intake is an important behavioral 
defensive mechanism and can reflect hunger (a hypoglycemic symptom). 
In our model, rats decreased food intake during a subsequent insulin-mediated 
hypoglycemic episode after repetitive 2DG infusion (figure 1), evident for the development 
of impaired hypoglycemia awareness. After testing 50+ drugs, we observed that 
amitriptyline both prevented and restored the attenuated food intake response (figure 2). 
[18] These findings suggest that amitriptyline has a potential role in clinically improving 
hypoglycemic course. In addition, amitriptyline is a common and safe therapy for diabetic 
neuropathy. [19-21] We therefore propose that amitriptyline is a strong testing candidate for 
mitigating hypoglycemia burden in T1DM patients.  
 
Figure 1. Model of repetitive 2DG-induced 
impaired hypoglycemia awareness 
Figure 2. Tricyclic antidepressants in 
restoring hypoglycemia awareness 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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3 
DRUG INFORMATION 
Amitriptyline (investigational drug) has been approved by the FDA for indications unrelated 
to the current study. [22] In the current study, we will use amitriptyline as our 
investigational drug. A summary of the FDA label for amitriptyline has been provided in the 
following: 
DESCRIPTION  
Amitriptyline HCl, a dibenzocycloheptadiene derivative, is a white, or practically white, 
odorless, crystalline compound which is freely soluble in water and alcohol.  
It is designated chemically as 10,11-Dihydro-N,N-dimethyl- 5H-dibenzo[a,d] cycloheptene-
Δ5, γ-propylamine hydrochloride. It has the following structural formula:  
 
Each tablet for oral administration contains 10, 25, 50, 75, 100, or 150 mg amitriptyline 
hydrochloride.  
CLINICAL PHARMACOLOGY  
Amitriptyline HCl is an antidepressant with sedative effects. Its mechanism of action in man 
is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by 
stimulation of the central nervous system.  
Amitriptyline inhibits the membrane pump mechanism responsible for uptake of 
norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically, 
this action may potentiate or prolong neuronal activity since reuptake of these biogenic 
amines is important physiologically in terminating transmitting activity. This interference 
with reuptake of norepinephrine and/or serotonin is believed by some to underlie the 
antidepressant activity of amitriptyline.  
DOSAGE AND ADMINISTRATION  
Oral Dosage  
Dosage should be initiated at a low level and increased gradually, noting carefully the 
clinical response and any evidence of intolerance.   
Initial Dosage for Adults  
For outpatients, 75 mg of amitriptyline HCl a day in divided doses is usually satisfactory. If 
necessary, this may be increased to a total of 150 mg per day. Increases are made preferably 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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in the late afternoon and/or bedtime doses. A sedative effect may be apparent before the 
antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days 
to develop.  
An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg 
amitriptyline HCl at bedtime. This may be increased by 25 or 50 mg as necessary in the 
bedtime dose to a total of 150 mg per day.  
Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 
200 mg a day if necessary. A small number of hospitalized patients may need as much as 
300 mg a day.   
Maintenance  
The usual maintenance dosage of amitriptyline HCl is 50 to 100 mg per day. In some 
patients, 40 mg per day is sufficient. For maintenance therapy, the total daily dosage may be 
given in a single dose, preferably at bedtime. When satisfactory improvement has been 
reached, dosage should be reduced to the lowest amount that will maintain relief of 
symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen 
the possibility of relapse.   
Plasma Levels  
Because of the wide variation in the absorption and distribution of tricyclic antidepressants 
in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. 
However, determination of plasma levels may be useful in identifying patients who appear 
to have toxic effects and may have excessively high levels, or those in whom lack of 
absorption or noncompliance is suspected. Because of increased intestinal transit time and 
decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a 
given oral dose of amitriptyline hydrochloride than in younger patients. Elderly patients 
should be monitored carefully and quantitative serum levels obtained as clinically 
appropriate. Adjustments in dosage should be made according to the patient’s clinical 
response and not on the basis of plasma levels. For this study, as we are using low 
amitriptyline dose, we will not conduct plasma level monitoring. 
METABOLISM  
Studies in man following oral administration of 14C-labeled drug indicated that 
amitriptyline is rapidly absorbed and metabolized. Radioactivity of the plasma was 
practically negligible, although significant amounts of radioactivity appeared in the urine by 
4 to 6 hours and one-half to one-third of the drug was excreted within 24 hours.  
Amitriptyline is metabolized by N-demethylation and bridge hydroxylation in man, rabbit, 
and rat. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of 
metabolites, with little unchanged drug appearing in the urine. Other metabolic pathways 
may be involved.   
INDICATION, CLINICAL USE, ADVERSE EVENT, CONTRAINDICATIONS AND 
PREGNANCY IMPLICATION 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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Amitriptyline is indicated for depression/major depressive disorder. Prior studies also 
supported its effectiveness in treating diabetic neuropathy [23], chronic pain management 
[24], fibromyalgia [25], insomnia [26], interstitial cystitis [27], irritable bowel syndrome 
[28], postherpetic neuralgia [29], post-traumatic stress disorder [30] and sialorrhea 
(excessive production of saliva) [31], and preventing migraine [32]. 
The following adverse events were observed and have been reported in patients using 
amitriptyline: 
• Cardiovascular: Atrioventricular conduction disturbance, cardiac arrhythmia, 
cardiomyopathy (rare), cerebrovascular accident, ECG changes (nonspecific), edema, 
facial edema, heart block, hypertension, myocardial infarction, orthostatic hypotension, 
palpitations, syncope, tachycardia 
• Central nervous system: Anxiety, ataxia, cognitive dysfunction, coma, confusion, 
delusions, disorientation, dizziness, drowsiness, drug withdrawal (nausea, headache, 
malaise, irritability, restlessness, dream and sleep disturbance, mania [rare], and 
hypomania [rare]), dysarthria, EEG pattern changes, excitement, extrapyramidal reaction 
(including abnormal involuntary movements and tardive dyskinesia), fatigue, 
hallucination, headache, hyperpyrexia, insomnia, lack of concentration, nightmares, 
numbness, paresthesia, peripheral neuropathy, restlessness, sedation, seizure, tingling of 
extremities 
• Dermatologic: Allergic skin rash, alopecia, diaphoresis, skin photosensitivity, urticarial 
• Endocrine & metabolic: Altered serum glucose, decreased libido, galactorrhea, 
gynecomastia, increased libido, SIADH, weight gain, weight loss 
• Gastrointestinal: Ageusia, anorexia, constipation, diarrhea, melanoglossia, nausea, 
paralytic ileus, parotid gland enlargement, stomatitis, unpleasant taste, vomiting, 
xerostomia 
• Genitourinary: Breast hypertrophy, impotence, testicular swelling, urinary frequency, 
urinary retention, urinary tract dilation 
• Hematologic & oncologic: Bone marrow depression (including agranulocytosis, 
leukopenia, and thrombocytopenia), eosinophilia, purpura 
• Hepatic: Hepatic failure, hepatitis (rare; including altered liver function and jaundice) 
• Hypersensitivity: Tongue edema 
• Neuromuscular & skeletal: Lupus-like syndrome, tremor, weakness 
• Ophthalmic: Accommodation disturbance, blurred vision, increased intraocular pressure, 
mydriasis 
• Otic: Tinnitus 
• Postmarketing and/or case reports: Angle-closure glaucoma, neuroleptic malignant 
syndrome (rare), serotonin syndrome (rare) 
The contraindications of amitriptyline are hypersensitivity to amitriptyline or any 
component of the formulation; coadministration with or within 14 days of MAOIs; 
coadministration with cisapride; acute recovery phase following myocardial infarction. 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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Amitriptyline can be used as an antidepressant. Antidepressants increase the risk of suicidal 
thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with 
major depressive disorder and other psychiatric disorders. For the current study, patients 
with ongoing and recent history of depression or other major psychiatric disorders will be 
excluded from recruitment. Furthermore, short-term studies did not show an increased risk 
in patients >24 years of age and showed a decreased risk in patients ≥65 years.  
Amitriptyline is Pregnancy Category C. Adverse events have been observed in some animal 
reproduction studies. Amitriptyline crosses the human placenta; CNS effects, limb 
deformities, and developmental delay have been noted in case reports (causal relationship 
not established). Tricyclic antidepressants may be associated with irritability, jitteriness and 
convulsions (rare) in the neonate. Crying, constipation, problems with urinating, and nausea 
may also occur in neonate exposed during pregnancy. For the current study, pregnancy will 
be ruled out before initial recruitment and before study drug intervention. Consultation for 
contraception will also be provided.  
4 
STUDY DESIGN 
4.1 
Description 
The current investigation is a pilot phase II clinical trial with placebo control, 
randomization and double-blinding design.  
After the initial recruitment (Visit 1), the study participants will enter a two-week “Run-
in Period”, during which the participants will be asked to continue their CGM use and 
record their symptom(s) on Hypoglycemic Event Reports for all their hypoglycemic 
events. For the participants who meet the criteria to be initiated on study drug (see 
recruitment criteria), they will then be randomized to be initiated either on daily 
amitriptyline or a matching placebo (Visit 2). All participants will undergo a two-week 
drug “Titration Period”, and at the end of this period (i.e., the end of Week 4), the 
amitriptyline dose will be titrated up with a matching placebo and continued until Visit 4. 
During this “Intervention Period”, the patient will receive telephone follow-ups at Week 
5 and Week 7, and undergo a return visit (Visit 3). After Visit 3, the participants will 
again start to record their hypoglycemic symptoms, and then return to Visit 4 at the end 
of the Intervention Period. The participants will then undergo a two-week study drug 
“Tapering Period” to complete the study drug intervention. At week 27 and 39 of the 
study, the participants will be assessed with follow-up questionnaires. 
4.2 
Number of Subjects 
Up to 80 participants are expected to be enrolled into the study for the Run-in Period 
assessment. For the study drug testing phase, 24 participants will be randomized and 
equally divided into two arms (i.e., 12 participants in the amitriptyline arm and 12 
participants in the matching placebo arm). 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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4.3 
Number of Study Centers 
This study will be a single-center study conducted at the University of Utah. 
4.4 
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 39 
weeks, with 15 weeks of active assessment/intervention and 24 weeks of distant follow-
up. 
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 T1DM for ≥ five year or more 
2.  
 Age between 21 to 60 years old 
3.  
 HbA1c less or equal to 9% with the last measurement in the last three 
months 
4. ______ Use of rtCGM providing continuous glucose data points for at least 3 
months with ≥ 80% of CGM readings over the last 2-week period 
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.  
 Ongoing or recent history of major depressive disorder, or other 
ongoing major psychiatric disorders 
2. ______ History of anti-depressant use within the last three months 
3. ______ Insulin pump linked to a CGM with programmed automatic insulin 
adjustment/suspension 

Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
Page 17 of 33 
4.  
 History of advanced cardiac, liver, kidney and neurological disease 
5. ______ Active malignant  
6. ______ Uncontrolled HIV diseases 
7.  
 Advanced diabetic retinopathy, neuropathy or nephropathy 
8. ______ Frequent acetaminophen use which can disrupt CGM accuracy 
9.  
 Pregnancy or female of child-bearing potential unable to practice 
effective contraception during the study period 
10. ______ Breastfeeding female or female with prospective plan to initiate 
breastfeeding 
11. ______ Ongoing history of alcohol abuse 
12.  
Contraindication to amitriptyline use, including hypersensitivity to 
amitriptyline or any component of the formulation, coadministration with or 
within 14 days of MAOIs and coadministration with cisapride 
13.  
 Inability to understand or cooperate with study procedure, including 
taking study drugs and record hypoglycemic symptoms 
The participants meeting the above criteria will enter “Run-in Period”. At the Visit 2, the 
following additional exclusion criteria will be applied before study drug randomization: 
14. ______ < 80% of CGM readings available over the last 2-week period 
15. ______ Time spent in hypoglycemia (i.e., < 70 mg/dL) for < 5% over a 2-
week period on based on CGM reading. 
I verify that this subject meets all eligibility criteria for enrollment onto this study 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
Date 
 

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6 
TREATMENT PLAN 
6.1 
Administration Schedule 
6.1.1 Treatment Arm 1 
After randomization at Visit 2, participants of the Treatment Arm 1 will be 
initiated on Amitriptyline 25 mg daily (to be taken at bedtime) for two weeks 
during the “Titration Period”. Starting at Study Week 5, the amitriptyline dose 
will be titrated up to 50 mg (two capsules of amitriptyline 25 mg) when entering 
the “Intervention Period”. For those participants who report intolerance to the 50 
mg dose due to the adverse effect, the dose will be tapered down to 25 mg dose 
for three to five days, before another trial for the 50 mg dose. For those who still 
do not tolerate amitriptyline 50 mg, they will be asked to continue the 25 mg dose 
for the rest of the Intervention Period.  
At the end of the Intervention Period, the participants who take amitriptyline 50 
mg will be reduced to amitriptyline 25 mg daily for another one to two weeks 
(“Taper Period”), and discontinue the 25 mg daily dose as tolerated. For the 
participants who are taking amitriptyline 25 mg at the end of the Intervention 
Period, they will discontinue treatment with the study drug at that time. 
6.1.2 Treatment Arm 2 
After randomization at Visit 2, participants of the Treatment Arm 2 will be 
initiated on the matching placebo of Amitriptyline 25 mg daily (to be taken at 
bedtime) for two weeks during the “Titration Period”. Starting at Study Week 5, 
the matching placebo of amitriptyline 50 mg (two capsules of matching placebo 
of amitriptyline 25 mg) will be initiated when entering the “Intervention Period”. 
For those participants who report intolerance to the matching placebo of 
amitriptyline 50 mg dose due to the adverse effect, the matching placebo will be 
switched back to that of the amitriptyline 25 mg for three to five days, before 
another trial for the matching placebo for amitriptyline 50 mg. For those who still 
do not tolerate the matching placebo for amitriptyline 50 mg, they will be asked to 
continue the matching placebo of amitriptyline 25 mg dose for the rest of the 
Intervention Period.  
At the end of the Intervention Period, the participants who take the matching 
placebo of amitriptyline 50 mg will be asked to take the matching placebo of 
amitriptyline 25 mg for another one to two weeks (“Taper Period”), and 
discontinue the matching placebo as tolerated. For the participants who are taking 
matching placebo of amitriptyline 25 mg at the end of the Intervention Period, 
they will discontinue treatment with the study drug at that time. 

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6.2 
Treatment (include name of each treatment as section header) 
6.2.1 How Supplied, Stored, Packaged and Labeled 
Amitriptyline 25 mg: Over-encapsulated for blinding. 
Matching placebo capsules: Capsules identical to the ones used to encapsulate 
amitriptyline 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). Dispense in a tight, light-
resistant container. 
6.2.2 Preparation and Administration 
At Visit 2, participants will be given a 10-week supply of amitriptyline sufficient 
for 2 weeks of 25 mg daily and 8 weeks of 50 mg (i.e., two capsules of 25 mg) 
daily. At Visit 3, the participants will then be given a 2-week supply of 
amitriptyline 25 mg, if needed. 
The matching placebo will be provided in a similar fashion. 
6.2.3 Accountability and Compliance 
Participants will be asked to return medication bottles and any unused study drugs 
at the end of the Interventional Periods (i.e., Visit 3) for reconciliation. For 
participants who will require amitriptyline 25 mg or matching placebo for the 
Taper Periods, Guide of Safe Medicine Disposal following the FDA and Utah 
State regulations, including returning the unused study drugs to the study team, 
will be provided. 
6.3 
Duration of Therapy 
The total duration of the treatment period will last about 12 weeks.   
 
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 or at the request of their 
legally authorized representative.  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: 

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• 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. 
 
Discontinued or withdrawn subjects may be replaced for each treatment arm. 
7 
TOXICITIES AND DOSE MODIFICATION 
Toxicities will be monitored in each study subject according to the study calendar and 
Section 9.11, 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. Treatment may be reduced and 
resumed if adverse events resolve to a tolerable level as determined by the investigator. 
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 
For those participants who report intolerance to the 25 mg dose due to the adverse effect, 
the amitriptyline will be stopped for three to five days before another trial. Similarly, for 
those participants who report intolerance to the 50 mg dose after up-titration from 25 mg, 
the dose will be tapered down to 25 mg dose for three to five days, before another trial 
for the 50 mg dose. For those who still do not tolerate amitriptyline 50 mg, they will be 
asked to continue the 25 mg dose for the rest of the Intervention Period.  
7.2 
Supportive Care 
All supportive measures consistent with optimal subject care will be given throughout the 
study.  

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8 
STUDY CALENDAR 
 
1. All screening procedures should be completed within 4 weeks of study enrollment, except that an ECG and 
laboratory evaluation completed within 3 months will be considered as valid.  
2. Telephone call follow-up to assess participants’ adverse events, and to remind study drug 
titration/adherence. 
3. Telephone call follow-up to assess participants’ general well-being, and to complete questionnaire surveys 
for Secondary Objective Assessment. 
4. All visits/telephone calls can occur within +/- 3 days of the anticipated dates based on the schedule calendar 
5. Follow-up physical exam to be conducted at the discretion of PI/Sub-investigator based on reported adverse 
events. 
6. Comprehensive Metabolic penal include Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, 
Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, Chloride, Glucose, 
Potassium, Protein, Sodium and Urea Nitrogen. 
7. Including instructions about Hypoglycemic Event Reports and conducting questionnaires surveys to assess 
baseline status. Will only be provided only after obtaining the consent. 
Period 
Screening1
/Run-in 
Treatment 
Follow-up 
Visit No. 
1 
2 
-2 
-2 
3 
4 
-3 
-3 
Week4 
-4 to 1 
3 
5 
7 
11 
13 
27 
39 
Assessments 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
X 
X 
 
 
Physical Examination 
X 
X5 
 
 
X5 
X5 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
ECG 
 
X1 
 
 
 
 
 
 
Comprehensive Metabolic 
Panel6 
X 
 
 
 
 
 
 
 
HbA1c 
 
X 
 
 
 
X 
 
 
AE Assessment 
 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
X 
X 
 
 
X 
X 
 
 
Investigational Drug 
Treatment 
 
X 
X 
X 
X 
X 
 
 
Primary Objective 
Assessment 
X7 
X 
 
 
X 
X 
 
 
Secondary Objective 
Assessment 
X7 
X 
 
 
X 
X 
X 
X 

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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 
Participant Identification/Recruitment Process 
 
Describe the recruitment/participant identification process in detail 
(e.g. who will review charts or records, who can refer participants 
to the study, where will flyers be posted, how often will recruitment 
letters be sent, when will follow-up phone calls be made, etc.):  
 
2) Study flyers which include the study survey web link/address will be printed. These 
printed study flyers will be placed in patient encounter rooms of the University of Utah 
Endocrinology clinics. The study flyers will also be placed/distributed at the front desk 
for interested patients. Information about the current study will be distributed to clinical 
providers, including University of Utah Endocrinologists and diabetes educators. 
3) The study investigator(s) and coordinator(s) may approach the potential candidates 
after visits for clinical and research purposes and to discuss with potential candidates 
about the current research opportunity. 
For each recruitment route, the candidates may "optout" for no further contact to be 
made for this study. On the myChart message/email/mail/flyer/study survey, contact 
information will be provided for candidates' inquiries. 
The PI will work with the University of Utah Enterprise Data Warehouse (EDW) for 
initial candidate screening with based on the elements of inclusion/exclusion criteria (e.g. 
type 1 diabetes, age, recent HbA1c, etc) on the Human Subject Recruitment tool. The 
Human Subject Recruitment tool is a computer software managed by the EDW for 
subject recruitment with a constantly updating database, and this tool is commonly 
utilized for clinical investigations at the University of Utah. The study team will then 
review of these candidates' medical charts for further candidate selection. The study team 
will also review the medical charts of the patients with recent/upcoming visits scheduled 
with University of Utah Endocrinology Clinics for potential candidates screening. A list 

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of potential candidates will be generated and used to recruit subjects in the following 
routes: 
1) Care providers (including primary care physicians, Endocrinologists or Diabetes 
Educators) with established clinical relationships 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 sent via mail or email or myChart message to the potential 
candidates. If no response is received in at least 7 days after the mail/message being sent, 
a phone call may be generated to discuss the study. 
3) A research assistant/coordinator may present at the University of Utah Clinics to 
discuss with the potential candidates. Communication with the care providers will be 
done before the research assistant/coordinator approaches the potential candidates. 
Other recruitment methods include the following: 
1) Study flyers will be placed in patient encounter rooms, phlebotomy site and the front 
desk at the Endocrinology Clinics. 
2) 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 each recruitment route, the candidate may opt-out request for no further contact to be 
made for this study. 
For interested candidates, we will proceed with further eligibility screening through 
telephone discussions and mailing/emailing surveillance of Personal Medical History and 
other questionnaires. A copy of the consent form will also be mailed/emailed to the 
candidates to look over for at least 1 day before obtaining consent. 
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. 

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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 financial participant support/study compensation being an undue influence, 
we will not share the financial participant support information during 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 
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. Further recruitment criteria is to be applied prior to the 
randomization and study drug intervention. 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 type 
1 diabetes, and other relevant past medical history will be collected during the screening 
period and recorded in the appropriate CRF. 
9.5 
Laboratory Variables 
Comprehensive Metabolic Panel, HbA1c and pregnancy test will be performed as 
indicated on the Study Calendar. Comprehensive Metabolic Panel and HbA1c Analyses 
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 Comprehensive Metabolic Panel 
Phlebotomy will be conducted for the Comprehensive Metabolic Panel analysis, 
including Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium and Urea Nitrogen. 
9.5.2 HbA1c 
Phlebotomy will be conducted for the HbA1c assessment. 

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9.5.3 Pregnancy Testing 
Urine collection will be conducted for Qualitative Beta-human chorionic 
gonadotropin assessment. 
9.5.4 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, heart 
rate are to be measured. 
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 amitriptyline 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: 
• Antidepressants, including monoamine oxidase inhibitors, selective 
serotonin reuptake inhibitors, and tricyclic antidepressant other than the 
study drug. 
9.9.2 Prohibited Procedure/Device 
• Anticipation of changing CGM device or modifying CGM settings should 
be discussed with the study team to determine whether these changes will 
potentially interfere with the study. 
9.10 Efficacy Measurements 
On all Treatment visit days, dosing will occur after all safety and efficacy assessments 
scheduled for that visit are complete. 

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9.10.1 Primary Objective Assessment 
The primary objective assessment will be done through the determining area-
under-curve for CGM glucose level < 70/54 mg/dL and the total and recognized 
hypoglycemic episodes based on CGM data and hypoglycemic event reports, 
respectively.  
A single CGM hypoglycemic episode will be defined by any CGM readings < 70 
mg/dL lasting equal to or more than 20 minutes on the CGM data.   
A participant will complete a hypoglycemic event report for all hypoglycemic 
events during the surveillance periods. A hypoglycemic event report will include 
information about whether the participants perceive symptom(s) for 
hypoglycemic episodes recorded based on CGM. 
At each visits, CGM data will be downloaded into a secure system and exported 
into an Excel format, and the hypoglycemic event reports will be prepared for 
analysis. 
9.10.2 Secondary Objective Assessment 
In brief, the count of severe hypoglycemic episodes will be generated by 
participant surveillance at each Visit/telephone call. The hypoglycemic/nocturnal 
hypoglycemic courses, and other glucose regulation will be assessed with CGM 
data download and venous blood HbA1c assessment. A nocturnal hypoglycemia 
will be defined for all hypoglycemic episodes occur during 00:00-06:00 on CGM 
clock. Hypoglycemia awareness status and fear of hypoglycemia status will be 
assessed through hypoglycemia awareness questionnaires (Gold, Clark and 
Pedersen-Bjergaard) and Hypoglycemia Fear Survey Questionnaire. CGM data 
will be collected at Visit 1-4, and the questionnaires will be completed by study 
subjects at the first, second and the last Visit, and with the follow-up phone calls. 
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 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 

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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 
amitriptyline and continue through the last follow-up 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 or phone contact 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.  [For multi-drug regimens, relationship will be assessed 
for each drug]. 
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. 
9.11.2 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 

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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. 
9.11.3 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. 
9.11.4 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 

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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. 
9.12 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 trial of 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 as adapted to compare the primary 
outcome defined by the ratio of recognized-to-total (i.e. CGM) hypoglycemic events 
between the amitriptyline and placebo treatments under the assumption of no-carry over 
effects. Hodges-Lehman estimates 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 and period. 
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. 

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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. 
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 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 
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 

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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 FDA Annual Reporting 
If this study requires IND approval, 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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Protocol Title: The Use of Amitriptyline for Improving Hypoglycemia Course and Recognition 
Version Date: 
March 24, 2018 
Principal Investigator: Yu Kuei Lin 
 
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Principal Investigator: Yu Kuei Lin 
 
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