Clinical trial NCT04026750
Conditions: Type 1 Diabetes Hypoglycemia
Sponsor: High Point Clinical Trials Center
Start date: 2019-09-15; Completion date: 2020-02-16
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine the safety, tolerability and pharmacodynamics of pitolisant in patients with Type 1 Diabetes

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pitolisant
Intervention descriptions: intervention 1: Pitolisant will be administered orally for 7 days. Patients may have their study drug dose adjusted downward if the starting dose is not tolerated.

Protocol documents:
Prot_SAP_000.pdf: 
Version: FPITO-T1D-01.01 SAP FINAL v1.0
 
This document is confidential and proprietary to Ferox Therapeutics. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Ferox Therapeutics, 
except that this document may be disclosed to appropriate Institutional Review Boards under the condition 
that they keep the information confidential. 
 
STUDY PROTOCOL AND STATISTICAL ANALYSIS 
PLAN 
13 December 2019 FINAL 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED INSULIN 
TOLERANCE TEST STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND 
PHARMACODYNAMICS OF PITOLISANT IN PATIENTS WITH TYPE 1 
DIABETES 
 
 
 
 
PROTOCOL NUMBER FPITO-T1D-01.01 
 
 
 
 
 
SPONSORED BY 
 
Ferox Therapeutics LLC 
197 Midland Avenue 
Montclair, NJ 07042 
919-423-2300 
 
 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 East NC 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax: (919) 408-0999 
 
 
 


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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
1.0 
13 December 2019 
Original 


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APPROVALS 
 
 
Approved: 
 
Date: 
Joyce Harp 
Chief Executive Officer 
Ferox Therapeutics 
 
 
 
 
Date: 
Marcus Herman-Giddens 
Biostatistician 
Rho, Inc. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 6 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 7 
2. 
PROTOCOL SUMMARY .......................................................................................... 8 
2.1 
Study Objectives ........................................................................................... 8 
2.1.1 
Primary Objectives ............................................................................... 8 
2.1.2 
Secondary Objectives .......................................................................... 8 
2.2 
Overall Study Design and Plan ...................................................................... 8 
2.3 
Study Population ........................................................................................... 9 
2.4 
Treatment Regimens ..................................................................................... 9 
2.5 
Treatment Group Assignments or Randomization ....................................... 10 
2.6 
Sample Size Determination ......................................................................... 10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................. 11 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
4.1 
Safety Analysis Population .......................................................................... 12 
4.2 
Modified Intent to Treat (MITT) Analysis Population .................................... 12 
5. 
STUDY SUBJECTS ............................................................................................... 13 
5.1 
Disposition of Subjects ................................................................................ 13 
5.2 
Protocol Deviations ..................................................................................... 13 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 14 
6.1 
Demographic Characteristics ...................................................................... 14 
6.2 
Medical History ........................................................................................... 14 
6.3 
Prior and Concomitant Medications ............................................................. 14 
6.3.1 
Prior Medications ............................................................................... 15 
6.3.2 
Concomitant Medications ................................................................... 15 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE AND DRUG 
ADMINISTRATION ................................................................................................ 16 
8. 
SAFETY EVALUATION ......................................................................................... 17 
8.1 
Overview of Safety Analysis Methods ......................................................... 17 
8.1.1 
Primary Endpoint ............................................................................... 17 
8.2 
Adverse Events ........................................................................................... 17 
8.3 
Patient Record Hypoglycemia ..................................................................... 19 
8.4 
Clinical Laboratory Evaluation ..................................................................... 19 
8.4.1 
Pregnancy Tests ................................................................................ 19 
8.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 19 
8.5.1 
Vital Signs .......................................................................................... 19 
8.5.2 
Physical Examinations ....................................................................... 20 
8.5.3 
12-Lead ECGs ................................................................................... 20 
8.5.4 
Other Safety Measures ...................................................................... 20 
9. 
EFFICACY EVALUATION ..................................................................................... 21 
9.1 
Handling of Dropouts or Missing Data ......................................................... 21 
9.2 
Analysis Methods ........................................................................................ 21 
9.2.1 
Primary Endpoint ............................................................................... 21 
9.2.2 
Secondary Endpoints ......................................................................... 22 


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9.2.3 
Exploratory Endpoints ........................................................................ 22 
10. OTHER ANALYSES .............................................................................................. 24 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 25 
12. REFERENCES ....................................................................................................... 26 
13. APPENDICES ........................................................................................................ 27 
13.1 
Study Flow Chart ........................................................................................ 27 
13.2 
Schedule of Events ..................................................................................... 28 
14. ATTACHMENTS .................................................................................................... 31 


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LIST OF ABBREVIATIONS 
 
AE
adverse event
ARS 
abbreviated study report 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGM 
continuous glucose monitor(ing) 
CRU 
clinical research unit 
DKA 
diabetic ketoacidosis 
ECG 
electrocardiogram 
GAD 
generalized anxiety disorder 
HbA1c 
glycosylated hemoglobin 
HIV 
human immunodeficiency virus 
HYPO Log 
hypoglycemia log 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ITT 
insulin tolerance test 
MedDRA 
Medical Dictionary for Regulatory Activities
MITT 
Modified Intent to Treat 
PCSV 
potentially clinically significant value 
PHQ 
Patient Health Questionnaire 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
T1D 
type 1 diabetes 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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1. PURPOSE OF THE ANALYSES 
 
The statistical analysis plan (SAP) has been developed based on the Ferox Therapeutics, 
LLC (Ferox) protocol FPITO-T1D-01.01 (April 29, 2019). The SAP contains detailed 
information to aid in the implementation of the statistical analyses and reporting of the 
study results for use in the abbreviated study report (ASR). This SAP is being written 
with due consideration of the recommendations outlined in the most recent International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled 
Guidance for Industry: Structure and Content of Clinical Study Reports. 
This SAP describes the analysis sets that will be analyzed and the patient characteristics 
and parameters that will be evaluated. The details of the specific statistical methods that 
will be used are provided in this SAP. 


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2. PROTOCOL SUMMARY 
 
 
2.1 Study Objectives 
 
2.1.1 Primary Objectives 
 
In subjects with type 1 diabetes (T1D) and on insulin for ≥ 4 years. 
 
 
To determine the effect of 7 days of pitolisant treatment on peak glucagon 
response to hypoglycemia during an insulin tolerance test (ITT) 
 
To assess the safety and tolerability of pitolisant administered orally for 7 
days 
 
2.1.2 Secondary Objectives 
 
 
To determine the effect of pitolisant on time to return to euglycemia during 
the ITT 
 
To determine the effect of pitolisant on the plasma glucose nadir during the 
ITT 
 
To determine the effect of pitolisant on plasma glucose area under the  
curve during the ITT 
 
 
2.2 Overall Study Design and Plan 
 
This is a randomized, double-blind, placebo-controlled parallel study design to be 
conducted in patients with T1D to determine the effect of pitolisant on glucagon secretion 
during insulin-induced hypoglycemia. 
Pitolisant 36 mg per day or placebo will be administered daily orally for 7 days. Patients 
may have their study drug dose adjusted downward at Visit 4 to 18 mg if the 36 mg dose 
is not tolerated. 
Patients will undergo screening and baseline evaluation for study eligibility from day -21 
(Visit 1) to day -1 (Visit 3). Eligible patients will have CGM (Dexcom G6) instruction 
and sensor placement on day -9 (Visit 2) and will continue to wear the study CGM until 
day -1 (Visit 3). Glucose values will be masked to patients and select study staff 
evaluating patient adverse events (AEs). Study staff will assess CGM data sufficiency at 
Visit 3 and patients with data sufficiency greater than 70% will be admitted to the clinical 
study unit for randomization and the baseline ITT the following morning. 
Eligible patients will be admitted the night before the baseline ITT study, where they will 
receive an overnight continuous intravenous (IV) infusion of regular insulin to maintain 
glucose levels at target range (100–120 mg/dL) on the morning of the ITT. The ITT will 
not begin if three consecutive glucose determinations made every 5 minutes are outside 


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the 100-120 mg/dL range. The continuous IV insulin infusion also must not have been 
adjusted by more than approximately 10% during the final hour before beginning the 
ITT. 
All patients will be studied after an overnight fast and in the supine position. In the 
morning of the baseline ITT, two baseline blood samples 10 minutes apart will be 
obtained for plasma glucose and glucagon. Plasma and serum samples will be archived. 
Site personnel having direct contact with patients will be blinded to patient treatment 
assignments. Only the study site pharmacist and Ferox study personnel will be unblinded 
to treatment assignments. At least one study nurse, Principal Investigator (PI), and one 
study physician will be unblinded to bedside glucose monitoring to manage insulin 
dosing during the inpatient periods. The study PI who is conducting the ITT and the 
physician assessing AEs will remain blinded to treatment assignment. Plasma glucose 
and glucagon will be masked to all site personnel until the end of the study. Safety and 
tolerability will be assessed by treatment-emergent adverse events (TEAEs), physical 
exam, vital signs, electrocardiogram (ECG), and laboratory and clinical evaluation. 
Patients will be asked to report all AEs experienced from the time of informed consent 
until their end of study visit. Hypoglycemia will be further assessed using the 
Hypoglycemia Log (HYPO Log). 
Serum and plasma samples will be aliquoted and archived for additional research studies. 
Up to 14 patients will be enrolled to obtain 12 evaluable patients. Two additional patients 
may be randomized to replace patients who drop out prior to the first ITT. 
The study duration is up to 37 days. 
 
 
2.3 Study Population 
 
Men and women, ages 18-65 years inclusive, with a history of T1D and on insulin for 4 
or more years with glycosylated hemoglobin (HbA1c) ≤ 10.0%. Patients with a history of 
hypoglycemia unawareness, cardiovascular disease, or recent (7 days) antihistamine 
intake will be excluded. Women of childbearing potential must use effective methods of 
pregnancy prevention. 
Additional inclusion and exclusion criteria for the study are enumerated in Section 4.2 of 
the protocol. 
 
2.4 Treatment Regimens 
 
Pitolisant 36 mg per day or placebo will be administered daily orally for 7 days. Patients 
may have their study drug dose adjusted downward at Visit 4 to 18 mg if the 36 mg dose 
is not tolerated. 


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2.5 Treatment Group Assignments or Randomization 
 
Up to 14 patients will be randomized in a 2:1 ratio to receive either pitolisant or placebo 
according to a randomization scheme provided by the unblinded pharmacist (or qualified 
designee). All site personnel will be blinded to subject treatment assignment, except for 
the designated study pharmacist(s). Ferox study personnel will be unblinded to subject 
treatment assignment. Unblinding of treatment assignment for a subject may be necessary 
due to a medical emergency or any other significant medical event (e.g., pregnancy). 
 
 
2.6 Sample Size Determination 
 
A sample size of 8 pitolisant and 4 placebo subjects is sufficient to evaluate the efficacy 
of pitolisant. Patients who drop out of the study without completing the initial ITT may 
be replaced but the number of replacements will not exceed 2. The study is 80% powered 
at a two-sided 0.05 alpha level and is predicted to detect a peak glucagon of 208 pg/mL in 
the pitolisant group, assuming the placebo group has a peak of 123 pg/mL, with placebo 
having a mean change of 65 and a SD of change of 49 pg/mL, and both have a baseline 
glucagon of 58±41 pg/mL 
 
See protocol Section 9.2 for justification of sample size. 


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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
 
The following is a list of general analysis and reporting conventions to be applied for this 
study. 
 
Tabular summaries will include a column for each treatment group and a total column 
combining patients across all treatment groups. 
 
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (xx.x).” All percentages will be rounded to one decimal 
place. If a count is 0, no percentage will be shown. If a percentage is 100%, 100.0% will 
be shown. To ensure completeness, summaries for categorical and discrete variables will 
include all categories, even if no subjects had a value in a particular category. 
 
All continuous variables will be summarized using number of patients with non-missing 
data, mean, SD, minimum, maximum, and median. The mean and median will be 
reported to 1 more level of precision than the original observations, and the SD will be 
reported to 2 more levels of precision than the original observations. The minimum and 
maximum will be the same precision as the original data. 
 
All analysis will be performed using SAS® System version 9.4 or later. 
Dates in listings will be displayed as yyyy-mm-dd (e.g., 2015-01-24). 
Age will be calculated in years using the date of birth and the date of first dose as [(date 
of first dose – date of birth+1)]/365.25, rounded down to the nearest integer using the 
floor function. 
Unless otherwise specified, the baseline assessment for all measurements will be the 
latest available valid measurement taken prior to the administration of the investigational 
product. 
Laboratory values with “<” or “>” signs will be analyzed without the signs in tabular 
summaries. 


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4. ANALYSIS POPULATIONS 
 
4.1 Safety Analysis Population 
 
The safety analysis population includes all randomized subjects who receive at least one 
dose of randomized drug and will be based on the treatment received (as treated). 
Treatment compliance/administration and all clinical safety variables will be analyzed 
using the safety analysis set. 
 
4.2 Modified Intent to Treat (MITT) Analysis Population 
 
The MITT primary efficacy analysis population includes all randomized subjects who 
completed the baseline and day 7 ITT. 


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5. STUDY SUBJECTS 
 
5.1 Disposition of Subjects 
 
Summaries will be provided based on all screened subjects regardless of the treatment 
group. 
 The number of screened subjects who signed the informed consent form (ICF) 
 The number (n) and percentage (%) of subjects randomized 
 The number (n) and percentage (%) of subjects not randomized 
 The number (n) and percentage (%) of subjects who were not randomized by 
the reasons 
Summaries will be provided based on all randomized subjects. 
 The number of subjects randomized and randomized but not receiving study 
treatments. 
 The number (n) and percentage (%) of subjects randomized and receiving 
study treatments 
 The number (n) and percentage (%) of subjects who completed treatment and 
discontinued treatment, respectively, and the reasons for discontinuation 
 The number (n) and percentage (%) of subjects who completed the study and 
discontinued the study, respectively, and the reasons for discontinuation 
A single listing will be provided for subjects who failed during the screening period, who 
were randomized, and who were not randomized but received study treatments 
separately. 
 
5.2 Protocol Deviations 
 
Protocol deviations will be categorized into major or minor protocol deviations. A single 
listing of subjects with protocol deviations will be provided. 
 
See Section 9.5 of the protocol for additional information on protocol deviations. 


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6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
 
Summaries of demographic and baseline characteristics and randomized subject 
disposition will be presented for pitolisant and placebo. 
Unless otherwise specified, the baseline assessment for all measurements will be the 
latest available valid measurement taken prior to administration of the investigational 
product. 
 
6.1 Demographic Characteristics 
 
Demographic characteristics will include age, sex, race, weight, height, body mass index 
(BMI), age of onset of T1D, years on insulin, history of diabetic ketoacidosis (DKA), 
hypoglycemia frequency and severity, and diabetes complications. Age (years) will be 
calculated using the date of first dose and the date of birth. Race will have potential 
values of White, Black or African American, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Asian, or Other. 
 
Demographic characteristics will be summarized in a table. 
 
6.2 Medical History 
 
Medical history will be collected at the Screening Visit. Medical history data will be 
coded using MedDRA version 22.0. 
A listing for medical history will be provided by treatment group. 
 
6.3 Prior and Concomitant Medications 
 
Medication use will be collected at all visits. 
Prior and concomitant medications will be coded using the WHODRUG Global Version 
B3 March 2019 World Health Organization (WHO) Drug Dictionary. 
All prior and concomitant medications will be listed by subject. A flag will be added to 
the listing to denote a concomitant medication administered to treat an AE and a separate 
flag denoted if a concomitant medication was a prohibited medication. 
The daily insulin dose taken by patients will be captured on their HYPO Log and 
recorded in an insulin-specific eCRF. 
If the start date of a prior or concomitant medication is incomplete or missing, it will be 
assumed to have occurred on or after the first dose of investigational product, except if an 
incomplete date (e.g., month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed. 


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6.3.1 Prior Medications 
 
Prior medications are defined as any medications with a start date prior to 
the first day of dosing. 
 
6.3.2 Concomitant Medications 
 
Concomitant medications are defined as any medications that are taken on 
or after the day of first dose of study drug. This includes medications that 
were started before the study and are ongoing during the study. In general, 
if it is not clear whether a medication is concomitant due to missing or 
incomplete medication start and/or end dates, the medication will be 
considered to be concomitant unless the non-missing portions of the start 
and end dates indicate otherwise. 


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7. MEASUREMENTS OF TREATMENT COMPLIANCE AND DRUG 
ADMINISTRATION 
 
At Days 1, 3, and 7 subjects are to be dosed at the study site under the supervision of 
appropriate study personnel. At Days 2, 4, 5 and 6 patients will self-administer the study 
drug in the AM. Study drug adherence will be assessed at Day 3 and Day 6. All drug 
compliance records will be kept current and will be made available for inspection by the 
Collaborator and regulatory agency inspectors. 


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8. SAFETY EVALUATION 
 
8.1 Overview of Safety Analysis Methods 
 
The safety analyses will be performed using the safety analysis set for safety measures, 
which include adverse events (AEs), vital signs, clinical laboratory data, 
electrocardiograms (ECG), body weight, and physical exam. 
 
Thresholds for treatment-emergent PCSV are defined in Appendix 4 of the protocol for 
laboratory variables, hematology variables, urinalysis, vital sign variables, and ECG 
variables. 
 
No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be performed. 
 
8.1.1 Primary Endpoint 
 
1. Incidence and severity of treatment-emergent adverse events (TEAEs) through 
end of study (day 37) 
Incidence and severity of treatment-emergent adverse events will be descriptively 
summarized by treatment group. Incidence tables will reflect a count and 
percentage of subjects experiencing at least 1 AE in each SOC, PT and grouping or 
severity. Evaluation will be performed on the safety analysis set. 
 
 
8.2 Adverse Events 
 
For safety variables, 2 observation periods are defined: 
 The pre-treatment period is defined as the time from signing the ICF to before 
the first dose of investigational product. 
 The on-treatment period is defined as the time from first dose of 
investigational product to the last study visit or early termination. 
Treatment-emergent AEs (TEAEs) are AEs that develop or worsen in severity on or after 
the dosing of study treatment through the end of study. Non-treatment AEs are those that 
occur from signing the ICF up to the first dose of study drug. The half-life of the 
investigational product is 12 hours. AEs occurring between Day 10 and Day 16 are 
considered at or below detectable drug levels. 
All AEs reported in this study will be coded using the currently available version of the 
Medical Dictionary for Regulatory Activities (MedDRA) version 22.0. Coding will be to 
the lowest level terms. 
Primary SOCs will be sorted according to the order described in the Guideline on 
summary of product characteristics (December 1999, European Commission), with the 


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total overall classes coming first and labeled “Any class”. Within each primary SOC, PTs 
will be sorted by decreasing frequency of investigational product. 
If the start date of an AE is incomplete or missing, it will be assumed to have occurred on 
or after the first dose of investigational product, except if an incomplete date (e.g., month 
and year) clearly indicates that the event started prior to treatment. If the partial date 
indicates the same month or year of the intake of study medication date, then the start 
date by the study medication intake date will be imputed; otherwise, the missing day or 
month by the first day or the first month will be imputed. 
By-subject listings of AEs will include all events regardless of treatment emergence. 
Rules for Severity and Relationship of Adverse Events 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency 
tables by intensity of TEAEs. If the assessment of relationship of a TEAE to the 
investigational product is missing, it will be classified as related to the investigational 
product. 
 
If a subject experiences the same adverse event multiple times, the event with the 
strongest severity or relationship to study drug will be counted. 
 
Planned Summaries of Adverse Events 
 
 Total number of TEAEs 
 Total number of serious TEAEs 
 Total number of study drug-related TEAEs 
 The number (n) and percentage (%) of subjects with at least 1 TEAE 
 The number (n) and percentage (%) of subjects with serious TEAEs 
 The number (n) and percentage (%) of subjects with study drug-related 
TEAEs 
 The number (n) and percentage (%) of subjects with TEAEs leading to 
discontinuation 
 The number (n) and percentage (%) of subjects with TEAEs leading to death 
 The number (n) and percentage (%) of subjects with TEAEs of special interest 
 
 
An overall summary showing the number and percentage of subjects with a TEAE, a 
serious TEAE, a treatment- related TEAE, a TEAE leading to treatment discontinuation, 
a TEAE resulting in death, and a TEAE of special interest. This summary will be 
presented on an overall basis. 


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All percentages will use the number of safety analysis set subjects as the denominator. 
No statistical tests will be performed on adverse events. 
 
8.3 Patient Record Hypoglycemia 
 
Subject recorded hypoglycemia in the HYPO Log will be defined as outlined below. 
Severe hypoglycemia events recorded in the Hypo Log by the subject that were not 
spontaneously reported may be used to report these AEs in the Hypo eCRF, if deemed a 
severe hypoglycemia event by the blinded investigator. 
 Level 1: Glucose < 70 mg/dL and glucose ≥ 54 mg/dL 
 Level 2: Glucose < 54 mg/dL 
 Level 3: A severe event characterized by altered mental and/or physical status 
requiring assistance 
 
8.4 Clinical Laboratory Evaluation 
 
For continuous clinical laboratory test measurements, results will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive 
statistics; for categorical or ordinal data, frequencies and percentages will be provided for 
each category. 
The number and percentage of patients with at least 1 post-baseline value outside the 
normal range will be summarized for each clinical laboratory test with a normal range 
supplied by the central lab. 
The number and percentage of patients meeting the predefined criteria for potentially 
clinically significant value (PCSV) at any post-baseline time point, including 
unscheduled visits, will be summarized for each clinical laboratory test. 
 
 
8.4.1 Pregnancy Tests 
 
A serum pregnancy test will be administered at the Screening Visit. A urine pregnancy 
test will be administered at Day -1, Day 6, and Day 16. 
 
 
8.5 Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
 
8.5.1 Vital Signs 
 
Vital signs will be measured at all visits and will be summarized by baseline and change 
from baseline to each scheduled assessment time with descriptive statistics. Change from 


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baseline summaries will only include subjects with a baseline value and at least one post- 
baseline value. In addition, the number and percentage of subjects with at least 1 
treatment-emergent PCSV at any post-baseline time point will be summarized and a 
listing for subjects with at least 1 treatment-emergent PCSV provided. 
 
The following vital signs will be recorded during this study: 
 
 Pulse rate 
 Respiratory rate 
 Blood pressure (systolic and diastolic in mmHg) 
 Temperature 
 
 
8.5.2 Physical Examinations 
 
A complete physical examination will be conducted at the Screening Visit, Day 7, and 
Day 16. 
 
 
8.5.3 12-Lead ECGs 
 
12-lead ECGs will be obtained in triplicate at the Screening Visit, Day 1, Day 7, and at 
Day 16. 
Electrocardiogram variables including ventricular heart rate (bpm), RR interval (msec), 
PR interval (msec), QRS interval (msec), QT interval (msec), and QTcF interval (msec) 
and will be listed by subject. 
 
 
8.5.4 Other Safety Measures 
 
Other safety measures include body weight. 


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9. EFFICACY EVALUATION 
 
9.1 Handling of Dropouts or Missing Data 
 
There will be no imputation for missing data. 
 
 
9.2 Analysis Methods 
 
The MITT analysis population will be used in all ITT related primary, secondary, and 
exploratory endpoints. The safety analysis population will be used for the safety and 
hypoglycemia endpoints. The primary hypothesis that in patients with T1D, treatment 
with pitolisant 36 mg once daily orally for 7 days will increase peak glucagon response to 
insulin-induced hypoglycemia will be analyzed using a t-test. 
 
9.2.1 Primary Endpoint 
 
1. Change in peak plasma glucagon during the ITT 
The ITT will occur at baseline (Day 1) and at Day 7. Glucagon will be measured at 
timepoints -10, 0, 15,30, 45, 60, 90, 120, and 180 minutes and peak plasma glucagon will 
be identified for each subject at both baseline and Day 7. Change from baseline will be 
calculated for each subject. 
 
Difference in mean change from baseline of peak plasma glucagon between treatment 
groups will be analyzed by the two-tailed t-test for independent samples of equal variance 
(pooled variance). Treatment difference results (p-value, 95% confidence interval) will be 
presented. 
 
Mean change from baseline of peak plasma glucagon within treatment groups will be 
analyzed for each group by the two-tailed t-test for paired samples. Treatment difference 
results (p-value, 95% confidence interval) will be presented for each group. 
 
Sample data distributions will be visually inspected for skewness and/or outliers. Non- 
parametric tests will be used if the sample data suggests that the t-test normality 
assumption cannot be defended. 
 
No adjustments for multiple comparisons will be made. Both analyses will use PROC 
TTEST, SAS, version 9.4 or greater, SAS Institute, Inc., Cary, North Carolina. 
 
A figure illustrating the time course of mean plasma glucagon by group will be presented 
for Day 1 and Day 7. 


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Protocol No. FPITO-T1D-01.01
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Statistical Analysis Plan 
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9.2.2 Secondary Endpoints 
 
1. 
Time to return to plasma glucose ≥ 70 mg/dL during the ITT on Day 1 and 
Day 7 
2. 
Plasma glucose nadir during the ITT on Day 1 and Day 7 
3. 
Glucose  area  under  the  curve,  calculated  from  time  0   minutes   to  
180 minutes for the ITT period on Day 1 and Day 7 
The ITT will occur at baseline (Day 1) and at Day 7. Glucose will be measured at 
timepoints -10, 0, 15,30, 45, 60, 90, 120, and 180 minutes. 
 
Summary statistics using n, mean, standard deviation, minimum, median, and maximum 
by treatment group will be provided for all secondary endpoints 
 
Glucose area under the curve (AUC) is defined as the area under the glucose curve for the 
ITT period. It is calculated from time 0 to 180 minutes using the trapezoidal rule. A 
figure illustrating the time course of mean glucose plasma by group will be presented for 
Day 1 and Day 7. 
 
 
 
 
9.2.3 Exploratory Endpoints 
 
1. Glucagon area under the curve, calculated from time 0 minutes to 180 minutes for the 
ITT period on Day 1 and Day 7 
2. Hypoglycemia counts < 54 mg/dL and ≥ 54 and < 70 mg/dL by Dexcom G6 CGM in 
each study period 
Additional CGM exploratory endpoints: 
a. Data sufficiency (% time CGM active) 
b. Mean glucose 
c. Standard deviation 
d. Coefficient of variation 
e. Time in ranges (< 54 mg/dL, < 70 mg/dL, 70-180 mg/dL, > 180 mg/dL, 
> 250 mg/dL) 
 For values < 54 mg/dL 
 average minutes/day 
 mean number of episodes/day/period 
 mean duration of each episode in minutes/day 
 
Hypoglycemia will also be assessed using the Hypoglycemia Log (HYPO Log) which 
includes patient self-report of hypoglycemic events using their usual method of self- 
monitoring as well as their daily insulin dose. Summary statistics will be performed on 


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Protocol No. FPITO-T1D-01.01
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masked Dexcom G6 CGM data according to study period: baseline, on active treatment, 
and off treatment using the standard data reporting endpoints. However, this analysis may 
not by conducted if the primary endpoints are not met. 
 
Glucagon area under the curve (AUC) is defined as the area under the glucagon curve for 
the ITT period. It is calculated from time 0 to 180 minutes using the trapezoidal rule. 


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Statistical Analysis Plan 
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10. OTHER ANALYSES 
 
Not applicable. 


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Statistical Analysis Plan 
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11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
 
Not applicable. 


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12. REFERENCES 
 
Not applicable. 


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13. APPENDICES 
 
13.1 Study Flow Chart 
 


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13.2 Schedule of Events 
 
Activity 
Screening 
CGM 
Inpatient 
Baseline ITT 
Out- 
patient 
Resupply 
Out- 
patient 
Inpatient 
Treatment ITT 
Out- 
patient 
End of 
study 
 
Visit 1 
Visit 2 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Day 
-21 to -10 
Day 
-9 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4, 5 
Day 
6 
Day 
7 
Day 
8-15 
Day 
16 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Height, Weight, BMI a 
X 
 
 
X 
 
 
 
 
Xa
 
X 
Physical Examination a 
X 
 
 
 
 
 
 
 
X 
 
X 
12-lead 
Electrocardiogram 
X 
 
 
X 
 
 
 
 
X 
 
X 
Adverse Events 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
PHQ-9 and GAD-7 
X 
 
 
 
 
 
 
 
 
 
 
Admission to CRU 
 
 
X 
 
 
 
 
X 
 
 
 
Intravenous catheter 
placement 
 
 
X 
 
 
 
 
X 
 
 
 
Overnight Intravenous 
Insulin Infusion 
 
 
X 
 
 
 
 
X 
 
 
 
ITT b 
 
 
 
X 
 
 
 
 
X 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Dispensing of Study 
Drug 
 
 
 
X 
 
X 
 
 
 
 
 
Administration of 
Study Drug 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Study Drug Adherence  
 
 
 
 
X 
 
X 
 
 
 


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Protocol No. FPITO-T1D-01.01
CONFIDENTIAL
Statistical Analysis Plan 
13 December 2019
Version: FPITO-T1D-01.01 SAP FINAL v1.0
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Activity 
Screening 
CGM 
Inpatient 
Baseline ITT 
Out- 
patient 
Resupply 
Out- 
patient 
Inpatient 
Treatment ITT 
Out- 
patient 
End of 
study 
 
Visit 1 
Visit 2 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Day 
-21 to -10 
Day 
-9 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4, 5 
Day 
6 
Day 
7 
Day 
8-15 
Day 
16 
HbA1c c 
X 
 
 
 
 
 
 
 
 
 
 
C-peptide c 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV
Screeningc 
X 
 
 
 
 
 
 
 
 
 
 
Hematology (complete
blood count)c 
X 
 
 
X 
 
 
 
 
X 
 
X 
Fasting Plasma
Glucose c,d 
X 
 
 
X 
 
 
 
 
X 
 
X 
Blood Chemistry
Panelc 
X 
 
 
X 
 
 
 
 
X 
 
X 
Fasting lipid Panel c,d 
X 
 
 
 
 
 
 
 
 
 
X 
Urinalysis (dip stick
and microscopy)c 
X 
 
 
X 
 
 
 
 
X 
 
X 
Serum Pregnancy Testc 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
X 
 
 
 
 
X 
 
 
X 
Glucagonc 
X 
 
 
X 
 
 
 
 
X 
 
X 
Histaminec 
X 
 
 
 
 
 
 
 
 
 
 
Archived Research
Samplec 
X 
 
 
X 
 
 
 
 
X 
 
X 
Masked CGM 
training/education 
 
X 
X 
 
 
X 
 
X 
 
 
 
Masked CGM sensor 
insertione-g 
 
X 
X 
 
 
 
 
X 
 
 
 
Masked CGM 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Masked CGM upload 
 
 
X 
 
 
 
 
X 
 
 
X 
Provide HYPO Log 
with instruction 
X 
X 
 
X 
 
X 
 
 
X 
 
 


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Protocol No. FPITO-T1D-01.01
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Statistical Analysis Plan 
13 December 2019
Version: FPITO-T1D-01.01 SAP FINAL v1.0
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Activity 
Screening 
CGM 
Inpatient 
Baseline ITT 
Out- 
patient 
Resupply 
Out- 
patient 
Inpatient 
Treatment ITT 
Out- 
patient 
End of 
study 
 
Visit 1 
Visit 2 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Day 
-21 to -10 
Day 
-9 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4, 5 
Day 
6 
Day 
7 
Day 
8-15 
Day 
16 
Patient to Record in 
HYPO Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Turn in HYPO Log 
completed record 
 
X 
X 
 
 
X 
 
X 
 
 
X 
Discharge from CRU 
 
 
 
X 
 
 
 
 
X 
 
 
BMI = body mass index; CGM = continuous glucose monitoring; CRU = clinical research unit; HbA1c = glycosylated 
hemoglobin; HIV = human immunodeficiency virus; HYPO Log = Hypoglycemia Log; ITT = insulin tolerance test 
a Height and BMI captured at screening only, all other time points only weight is collected. Full physical exam at baseline and 
Day 16 or End of Study; Abbreviated physical exam at day 7. 
b ITT Glucose must be 100-120 mg/dL; insulin dose during last hour of intravenous insulin must be stable (not >10% change); 
ITT sampling timepoints -10, 0, 15, 30, 45, 60, 90, 120, 180 for plasma glucose and glucagon. Study drug administered after ITT 
completed on day 1. Study drug administered 1 hour before ITT -10-minute blood draw on day 7. 
c Laboratory samples will be sent to and analyzed at LabCorp with the exception of glucagon sample that will be sent to Mercodia. 
Histamine samples and archive research samples will be stored at the local laboratory until end of study. 
d Laboratory samples to be obtained after an 8 hour fast. 
e Day -9 to -1 baseline CGM period 
f Day 1 to +6 on-drug CGM period 
g Day 7 to +16 off-drug CGM period 


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14. 
ATTACHMENTS 
 
Not applicable.