Clinical trial NCT02942771
Conditions: Healthy Adult Volunteers
Sponsor: Linda Van Eldik
Start date: 2017-03-20; Completion date: 2018-06-04
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this Study is to find out whether an investigational drug is safe and well tolerated. MW189 is being studied as a possible short-term treatment for people with different types of brain injury. MW189 has previously been given to healthy human volunteers as a single dose, and there were no significant problems or bad effects in people who received the Study drug. However, before it can be tested in people with brain injury, it is important to test MW189 in healthy volunteers when given multiple doses.

Detailed description:
This is a phase 1b study. Written informed consent will be obtained from each study participant before any study-specific procedures or assessments are done.

At various time points noted below, pharmacokinetic (PK) blood sampling will be performed on study participants.

Throughout the study the investigator will be assessing adverse events and concomitant medication.

On-Study/On-Interventions Evaluations/procedures: Participants will arrive at the Phase 1 unit after fasting a minimum of 10 hours, for admission into the unit and will undergo procedures:

* Medical and medication histories
* Infection screen
* Body temperature
* Vital signs (blood pressure and heart rate)
* Physical examination and weight
* Neurological exam
* Safety laboratory tests (blood and urine)
* Urine pregnancy test (females only)
* Alcohol screening (Breathalyzer)
* Urine drug screen
* Hepatitis B, C and HIV screening
* Randomize: Only participants who meet eligibility requirements will be randomized into the study.

Day 1 - Dosing: A light breakfast will be given prior to dosing. Participants will have the following tests/procedures performed at various time points during the day following confirmation of eligibility.

* 8 electrocardiograms (ECG)
* 8 vital signs (blood pressure and heart rate)
* 1 body temperature
* 12 PK Blood draws
* 2 study drug administrations

Day 2: A light breakfast will be given prior to dosing.

* 8 ECGs
* 8 vital signs (blood pressure and heart rate)
* 1 body temperature
* 1 PK blood draw
* 2 study Drug administration

Day 3: Participants will fast for a minimum of 10 hours. Water is allowed. A Light breakfast will be given before dosing

* 1 safety laboratory tests (blood and urine)
* 1 ECG
* 2 vital signs (blood pressure and heart rate)
* 1 body temperature
* 1 PK blood draw
* 1 neurological examination
* 2 study drug administrations

Day 4: A Light breakfast will be given before dosing

* 2 vital signs (blood Pressure and heart rate)
* 1 body temperature
* 1 PK blood draw
* 2 study drug administrations

Day 5: A Light breakfast will be given before dosing

* 1 ECG
* 2 vital signs (Blood Pressure and heart rate)
* 1 body temperature
* 12 PK blood draw
* 2 study drug administration

Day 6: Participants will fast for a minimum of 10 hours. Water is allowed. A Light breakfast will be given

* 1 safety laboratory test (blood and urine)
* 1 vital sign (Blood pressure and heart rate)
* 1 body temperature
* 1 neurological examination
* 2 PK blood draw

Day 7: A light breakfast will be provided

* 1 vital sign
* 1 body temperature
* 1 PK blood draw

Day 8 (Discharge): Participants will fast for a minimum of 10 hours. Water is allowed. A light breakfast will be offered

* 1 safety laboratory test (blood and urine)
* 1 ECG
* 1 vital sign (blood pressure and heart rate)
* 1 body temperature
* 1 physical examination including weight
* 1 neurological examination

  2 Week Follow-up Visit: Participants will fast for a minimum of 10 hours. Water is allowed.

during this visit participants will have the following tests and procedures performed:

* 1 safety laboratory test (blood and urine)
* 1 ECG
* 1 vital sign (blood pressure and heart rate)
* 1 body temperature

6-8 Week Follow-up Phone Call: Participants will be asked about any adverse events and any medications they may be taking.

Arms: arm 1: TT301/MW189 0.075 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive arm 2: TT301/MW189 0.15 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive arm 3: TT301/MW189 0.25 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive arm 4: TT301/MW189 0.30 mg/kg IV (or matched placebo). Each subject will receive 1 dose level of study drug twice daily (bid) on Days 1 through 5, inclusive arm 5: No drug intervention.
Interventions: intervention 1: 0.075mg/kg TT301/MW189 intervention 2: 0.15mg/kg TT301MW189 intervention 3: 0.25mg/kg TT301/MW189 intervention 4: 0.30mg/kg TT301/MW189 intervention 5: Placebo
Intervention descriptions: intervention 1: 0.075 mg/kg IV twice daily on Days 1 through 5 intervention 2: 0.15 mg/kg IV twice daily on Days 1 through 5 intervention 3: 0.25 mg/kg IV twice daily on Days 1 through 5 intervention 4: 0.30 mg/kg IV twice daily on Days 1 through 5 intervention 5: 0.9% sodium chloride

Protocol documents:
Prot_SAP_000.pdf: 
A MAD Study of TT301/MW189 in Healthy Volunteers 
 Study Title: A MAD Study of TT301/MW189 in Healthy Volunteers 
Institution/Site:  
University of Kentucky 
Document (Approval/Update) Date: 
04/22/19 
NCT Number: 
NCT02942771 
IRB Number 
77200 
Coversheet created: 
05/12/20 
 
 


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Statistical Analysis Plan 
 
TT301/MW189 
IND #124357 
Duke IRB Protocol #77200 
Clinical Trials.gov #NCT02942771 
 
 
A Phase 1b, Double-Blind, Randomized, Placebo-Controlled Multiple Ascending Dose 
Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of TT301/MW189 
Administered Intravenously to Healthy Volunteers 
 
 
Version 2.1 
22 April 2019 
 
Sponsor: University of Kentucky 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE AND APPROVALS 
 
Linda J. Van Eldik, PhD 
Principal Investigator 
Director, Sanders-Brown Center on Aging  
University of Kentucky 
Jeffrey Guptill, MD 
Duke Site Principal Investigator  
Duke Early Phase Research Unit 
Tracy Spears, MS 
Biostatistician III 
 Duke Clinical Research Institute  
Christoph Hornik, MD 
Associate Director 
Pharmacometrics 
Duke Clinical Research Institute 
 
 
 
 
 
 
 
 
 


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History of Changes to this Document 
Date 
Version 
Changes 
1 November 2018 
1.0 
Original document 
11 March 2019 
2.0 
Addition of Neurological 
Exam section (10.6) 
Statistical analyses will be 
performed with a Linux 
server-based SAS 
installation, rather than with 
PC SAS 
Removed plan for list of 
protocol deviations 
Addition of DCRI names to 
signature page 
22 April 2019 
2.1 
Study Populations:  
 Added explanation of 
population 
assignment of 
replaced and 
replacement subjects 
 PK analyses and 
populations not 
described in this SAP 
Vital Signs 
 Temperature added 
to tables, lists 
ECG 
 Determination of 
baseline value from 
triplicate results  
 Figures removed 
Physical Exam 


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MW189 SAP Version 2.1 
 
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 Table added for 
weight 
 List will include 
abnormal findings 
only 
Neurological Exam 
 List will include 
abnormal findings 
only 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS .........................................................................................................6 
2.0 
INTRODUCTION ............................................................................................................................7 
3.0 
OBJECTIVES................................................................................................................................ 12 
Primary Objectives ....................................................................................................................... 12 
Secondary Objectives .................................................................................................................. 12 
4.0 
SUBJECT POPULATIONS ........................................................................................................ 13 
4.1 
RANDOMIZED POPULATION .................................................................................... 13 
4.2 
SAFETY POPULATION ................................................................................................ 13 
4.3 
PK POPULATION .......................................................................................................... 13 
5.0 
STUDY DISPOSITION................................................................................................................. 14 
6.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................... 15 
7.0 
STATISTICAL ISSUES ............................................................................................................... 16 
7.1 
GENERAL ANALYSIS CONVENTIONS .................................................................................. 16 
8.0 
EXTENT OF EXPOSURE ........................................................................................................... 17 
8.1 
STUDY MEDICATION ................................................................................................... 17 
9.0 
PHARMACOKINETIC ANALYSIS ............................................................................................ 18 
10.0 
SAFETY ANALYSES .................................................................................................................. 19 
10.1 
ADVERSE EVENT ASSESSMENTS .......................................................................... 19 
10.2 
CLINICAL LABORATORY TESTING ........................................................................ 19 
10.3 
VITAL SIGNS ................................................................................................................. 19 
10.4 
ELECTROCARDIOGRAM MONITORING ................................................................. 20 
10.5 
PHYSICAL EXAMINATIONS ....................................................................................... 20 
10.6 
NEUROLOGICAL EXAMINATIONS ........................................................................... 20 
11.0 
DETERMINATION OF SAMPLE SIZE ..................................................................................... 22 
 
 
 


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1.0 
LIST OF ABBREVIATIONS 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
DEPRU 
Duke Early Phase Research Unit 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
IV 
Intravenous 
MAD 
Multiple Ascending Dose 
PK 
Pharmacokinetic 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment Emergent Adverse Event 
 
 
 


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2.0 
INTRODUCTION 
 
TT301/MW189 (hereafter called MW189) is a small molecule drug candidate developed as a 
selective suppressor of disease and injury-induced glia proinflammatory cytokine 
overproduction associated with destructive glia inflammation/neuron dysfunction cycles, and 
their long-term neurotoxic effects. MW189 treatment attenuates the stressor-induced rise in 
brain proinflammatory cytokine levels with a downstream improvement in behavior dysfunction 
and synaptic dysfunction markers in multiple animal models of CNS disorders where up-
regulation of proinflammatory molecules is implicated in disease progression. MW189 is being 
developed for the treatment of acute brain injuries such as traumatic brain injury or 
intracerebral hemorrhage. The development program is based on nonclinical evidence that 
MW189 reduces the recruitment of activated microglia, reduces cerebral edema, and improves 
motor skills and neurocognitive outcomes in animal models of neuroinflammatory disorders.  
 
The present study will provide safety and pharmacokinetic (PK) information on multiple 
ascending doses (MAD) of MW189 to support decisions for continued clinical development. This 
study will assess the safety, tolerability, and PK profile of escalating repeated doses of MW189 
in healthy adult participants. The trial design will be a double-blind, placebo-controlled, MAD 
study of MW189 in healthy volunteers. Three dosing cohorts are initially planned. All subjects 
and the study personnel responsible for assessing adverse events (AEs) will be blinded.  
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of safety and tolerability data as outlined and/or specified in the most recent 
amendment of the protocol.  
 
In the study design, 32 healthy male and female volunteers, ages 18-50 years, will be dosed in 
1 of 4 dosing cohorts of 8 subjects each (6 MW189, 2 matched placebo). Subjects will be 
admitted to the Phase 1 unit on the day prior to dosing (Day -1) and will remain in the clinical 
research unit until discharge on Day 8.  Follow-up will be done through a clinic visit at 2 weeks 
and a phone call 4 weeks from end of dosing. 
 
Subjects will receive 2 doses per day for 5 consecutive days. Doses will be given 12 hours 
apart. 
Cohort 1: 0.075 mg/kg MW189 iv bid over 20 minutes (or matched placebo) 
Cohort 2: 0.15 mg/kg MW189 iv bid over 20 minutes (or matched placebo) 
Cohort 3: 0.30 mg/kg MW189 iv bid over 20 minutes (or matched placebo) 
Cohort 4: 0.25 mg/kg MW189 iv bid over 20 minutes (or matched placebo) (added after protocol 
amendment) 
 
Dose levels selected for the MAD study at 0.075 mg/kg, 0.15 mg/kg, 0.25 mg/kg, and 0.30 
mg/kg twice daily for 5 days are based on the safety, PK separation and steady-state PK 
simulations derived from the phase 1a SAD study of MW189. 
For this phase 1b MAD study, dosing will start at the lowest dose in the 1st cohort, then escalate 
in the 2nd cohort, then escalate in the 3rd cohort. Each subject will receive 1 iv dose level of 
MW189 twice daily (bid) on Days 1 through 5, inclusive.  After all subjects in Cohort 1 have 
completed the study through the clinic visit at 2 weeks, data will be collected for the safety 
review. Dosing of Cohort 2 will proceed upon joint recommendation by the Safety and Medical 
Monitors, after reviewing Cohort 1’s safety data including AEs, SAEs, vital signs, safety 
laboratory tests and ECGs. Dosing of Cohort 3 will proceed upon joint recommendation by the 
Safety and Medical Monitors, after reviewing Cohort 2’s safety data including AEs, SAEs, vital 


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signs, safety laboratory tests and ECGs. Should the safety data warrant, the 2nd or 3rd dose 
levels may be reduced or additional cohorts added in order to generate a comprehensive 
understanding of the clinical dose range, if deemed necessary by the sponsor and 
recommended by the Data Safety Monitoring Board (DSMB). The maximum dose in this study 
will not exceed 0.30 mg/kg bid. Any changes to dosing will be made during the safety review. 
 
Screening will be conducted within 28 days of first dose. After giving written informed consent, 
each subject will undergo a medical screen consisting of the following procedures: 
demographics; medical history; concomitant medication review; body temperature; 12-lead 
ECG; vital signs; physical exam; alcohol and drug screen; Hepatitis B, Hepatitis C, HIV, and TB 
screens; and safety laboratory work and pregnancy testing.  
 
One day prior to dosing (Day -1), subjects will be admitted to the Duke Early Phase Research 
Unit (DEPRU) Phase 1 unit for final qualification assessments. These assessments will include 
inclusion/exclusion review, medical history, physical exam, infection screen, body temperature, 
alcohol and drug screen, vital signs, pregnancy test, neurological exam, and safety laboratory 
tests.  
 
Dosing will be twice daily, starting on Day 1 and ending on Day 5 for a total of 5 days with 10 
doses. The second dose of the day will be approximately 12 hours after the morning dose. The 
morning dose each day will be anchored to the initial dose on Day 1 so that the Day 2 morning 
dose will be 24 hours after the Day 1 morning dose and the Day 3 morning dose will be 48 
hours after the Day 1 morning dose, etc. During dosing, subjects will be continuously monitored 
with 12-lead ECG, blood pressure, and heart rate.  Plasma samples will be drawn at sequential 
time points for PK analysis. 
 
Subjects will remain in the clinical research unit until discharge on Day 8. Follow-up will be done 
through a clinic visit at 2 weeks and a phone call 4 weeks from end of dosing. The follow-up visit 
will consist of safety lab work, body temperature, ECG, vital signs, concomitant medication review, 
and assessment of adverse events (AEs). The follow-up phone call will include a concomitant 
medication review, and assessment of any safety issues.  
 
 
 


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Table 1. Schedule of Activities 
 
Footnotes to Schedule of Activities 
(1)  Screening will occur within 28 days of 1st dose 
PROCEDURES 
  
SCRN(1) 
 
D-1 
D1 
D2 
D3 
D4 
D52 D6 
 
D7 
  D8 
(ET)(
2) 
    
W2 
 
W4 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination(3) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Infection Screen(4) 
 
X 
 
 
 
 
 
 
 
 
 
 
Body Temperature(5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurological Examination(6)  
X 
 
 
X 
 
 
X 
 
X 
 
 
Safety Laboratory Tests(7) 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Drug Screen (urine) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol Screen 
(breathalyzer) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis B & C /HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
TB Test (blood test) 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG(8) 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Vital Signs (BP/HR)(9) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK Blood Sampling(10) 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Admit to Unit 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization(11) 
 
X 
 
 
 
 
 
 
 
 
 
 
Dosing(12) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse Event 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge From Unit 
 
 
 
 
 
 
 
 
 
X 
 
 


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(2)  Subjects who discontinue from the study should undergo all Early Termination assessments as per 
the Day 8 visit. 
(3)  Weight will be measured during all physical examinations and height will be measured at Screening 
only. 
(4)  On Day -1, subjects will be screened for the presence of infection as part of physical examination, 
body temperature, recent/current antibiotic use, recent surgery, evidence of dental abscess, unhealed 
skin lesions etc. On Day 1 before dosing, subjects will be screened for emergence of acute illness. 
(5)  Body temperature will be measured at the following time-points: 
 
Screening 
 
Day -1 
 
Day 1 – Day 5 before the morning dose   
 
Day 6 – Day 7 approximately 24h and 48h, respectively, after the Day 5 morning dose 
 
Day 8 approximately 72h after the Day 5 morning dose 
 
Day 14 
 (6)  Neurological Examination will include mental status evaluation, cranial nerves 2-12 testing, motor 
system and coordination testing, reflex evaluation and sensory system evaluation. 
(7)  All Safety laboratory samples (Hematology/Coagulation/Biochemistry/Urinalysis) will be taken after 
the subject has fasted for a minimum of 10 hours and before the morning dose (on dosing days) as 
follows: 
 
Screening (all except creatine kinase, amylase, lipase, cholesterol, HDL/LDL/ triglycerides) 
 
Day -1 
 
Day 3 
 
Day 6 
 
Day 8 
 
Day 14 
(8)  A 12-lead ECG will be performed (after lying quietly for 5 minutes). Triplicate tracings (3x) will be 
taken at Day 1 pre-dose only: 
 
Screening 
 
Day 1: Pre-dose (3x) and at approximately 1h, 2h, 4h after the start of the morning dose and pre-
dose and 1h, 2h, 4h after the start of the second dose 
 
Day 2: Pre-dose and at approximately 1h, 2h, 4h after the start of the morning dose and pre-dose 
and 1h, 2h, 4h after the start of the second dose   
 
Days 3, 5 and 6 before the morning dose   
 
Day 8 approximately 72h after the Day 5 morning dose  
 
Day 14 
 (9)  Vital signs will include BP and HR.  Vitals will be performed at the following time-points: 
 
Screening 
 
Day -1 
 
Day 1: Pre-dose and at 1h, 2h, 4h after the start of the morning dose and pre-dose and 1h, 2h, 4h 
after the start of the second dose 


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 
Day 2: Pre-dose and at 1h, 2h, 4h after the start of the morning dose and pre-dose and 1h, 2h, 4h 
after the start of the second dose   
 
Day 3 – Day 5 before the morning dose and before the second dose   
 
Day 6 – Day 8 approximately 24h, 48h and 72h, respectively, after the Day 5 morning dose  
 
Day 14 
 (10)  PK samples will be taken at the following time-points, anchored to the start of each injection.  
 
Day 1 Morning Dose: Pre-dose, 20min (at the end of injection; sample should be collected prior to 
completion of the injection), 1h, 2h, 4h, 7.5h and 12 hours (immediately before the Day 1 Second 
Dose) post-dose 
 
Day 1 Second Dose: 20min (at the end of injection; sample should be collected prior to 
completion of the injection) 1h, 2h, 4h, 7.5h post-dose  
 
Day 2 Morning Dose: Pre-dose (approximately 24h after Day 1 morning dose) 
 
Day 3 Morning Dose: Pre-dose (approximately 48h after Day 1 morning dose) 
 
Day 4 Morning Dose: Pre-dose (approximately 72h after Day 1 morning dose) 
 
Day 5 Morning Dose: Pre-dose (approximately 96h after Day 1 morning dose), 20min (at the end 
of injection; sample should be collected prior to completion of the injection), 1h, 2h, 4h, 7.5h and 
12 hours (immediately before the Day 5 Second Dose) post-dose 
 
Day 5 Second Dose: 20min (at the end of injection; sample should be collected prior to 
completion of the injection), 1h, 2h, 4h, 7.5h post-dose 
 
Day 6: approximately 16h after Day 5 second dose, approximately 24h after Day 5 second dose 
 
Day 7: approximately 48h after Day 5 second dose  
(11)  Randomization is expected to occur on D-1, but if there are delays in receiving prequalification 
safety labs randomization may occur on D1 prior to dosing. 
(12)  Dosing will be twice daily, starting on Day 1 and ending on Day 5 for a total of 5 days with 10 doses. 
The second dose of the day will be approximately 12 hours after the morning dose. The morning dose 
each day will be anchored to the initial dose on Day 1 so that the Day 2 morning dose will be 24 hours 
after the Day 1 morning dose and the Day 3 morning dose will be 48 hours after the Day 1 morning dose, 
etc.


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3.0 
OBJECTIVES 
 
Primary Objectives 
To assess the safety and tolerability of multiple ascending doses of MW189 when administered 
iv to healthy volunteers. 
The hypothesis is that MW189 will be safe in humans when administered in a MAD paradigm, 
similar to its already documented safety in a SAD study, with no severe or serious adverse 
events. 
Secondary Objectives 
To assess the PK profile of multiple ascending doses of MW189 when administered iv to 
healthy volunteers. 
 
 


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4.0 
SUBJECT POPULATIONS 
 
Any subject who discontinues the study prior to dose administration or prior to receiving all 
doses for reasons other than AEs may be replaced by a different subject. The replacement 
subject will receive the same treatment assignment as the original subject.  
 
 
4.1 
RANDOMIZED POPULATION 
 
The Randomized Population will consist of all subjects who sign informed consent and who are 
randomized to a treatment group in the study. Both the original and replacement subject will be 
included. 
 
 
4.2 
SAFETY POPULATION 
 
The Safety Population will consist of all subjects in the Randomized Population who receive any 
double-blind study medication (MW189 or placebo). Both the original and replacement subject 
will be included. 
 
 
4.3 
PK POPULATION 
 
PK Population and analyses will be defined in the PK Analysis Plan.  
 
The Randomized and Safety Populations will be summarized by study dose cohort. 
 
 
 


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5.0 
STUDY DISPOSITION 
 
The number of subjects included in each study population (i.e., Randomized, Safety) will be 
summarized by cohort, and active drug vs. placebo.  
The number and percentage of subjects who completed and prematurely discontinued the study 
during the double-blind periods will be presented for each treatment group and overall for the 
Randomized Population. Reasons for premature discontinuation from the double-blind periods 
as recorded on the completion page of the CRF will be summarized, as applicable. 
 
 
 
 
 


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6.0 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
 
Demographic parameters (e.g. age, race, sex, weight, height, BMI) and other baseline 
characteristics, such as medical history, will be summarized by treatment group for the Safety 
Population. In addition, data listings will be generated. 
 
 
 
 


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7.0 
STATISTICAL ISSUES 
 
7.1 
GENERAL ANALYSIS CONVENTIONS 
 
Detailed statistical analysis plans will be created for the study and signed off in advance of 
database lock. One plan will be created for the analysis of PK data and a separate plan will be 
created for the analysis and presentation of all other study data. General statistical approaches 
are presented below.   
All subjects who receive any study treatment will be included in the safety analysis grouped by 
treatment received. Statistical analysis of safety data will be descriptive.  
Baseline is defined as the last assessment prior to first dose of study medication.   
For continuous variables, summaries will include sample size, mean, standard deviation, 
minimum, and maximum.  For categorical variables, the summaries will include frequencies and 
corresponding percentages. No inferential hypothesis testing will be performed on the safety 
variables. Repeat or unscheduled results will not be included in the summaries, but will be 
listed. Data from placebo subjects will be pooled for final presentations.  
Statistical analyses will be performed on Linux sever installation of-SAS, Version 9.4. 
 
 
 


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8.0 
EXTENT OF EXPOSURE 
 
8.1 
STUDY MEDICATION 
 
Exposure to study medication for the Safety Population will be summarized in terms of the 
amount of dose administered (in mg/kg) for each dose cohort and treatment group. Concomitant 
medications will be summarized. Any instance of a subject receiving a dose other than the 
assigned dose will be listed. Descriptive statistics will be presented by treatment group.  
 
 
 
 


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9.0 
PHARMACOKINETIC ANALYSIS 
 
The plasma concentrations of MW189 will be determined, and used to estimate appropriate 
pharmacokinetic (PK) parameters. The PK analysis is outside the scope of this SAP and is 
described in a separate PK statistical analysis plan.  
 
 


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10.0 
SAFETY ANALYSES 
 
The safety analysis will be performed using the Safety Population. Safety and tolerability will be 
assessed on the basis of physical examination, neurological examination, vital signs, clinical 
laboratory values, ECG readings, and adverse event (AE) reports. The frequencies of AEs and 
SAE (serious adverse events) will be tabulated by dose as will all other safety measurements.  
For each safety parameter, baseline is defined as the last evaluation before dosing. 
All subjects who receive any study treatment will be included in the safety analysis grouped by 
treatment received. Statistical analysis of safety data will be descriptive.   
 
10.1 
ADVERSE EVENT ASSESSMENTS 
 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) v21.0 – 5 Level. AEs will be listed and summarized by treatment group and dose 
level. Where applicable, AEs may also be summarized by severity, seriousness, relationship to 
study treatment and by system organ class and preferred term. The number and percentage of 
subjects who experience events will be shown in the summaries. Listings for all AEs will be 
presented. 
A treatment-emergent AE (TEAE) is an AE, regardless of relationship to study drug, which 
occurs during or after the first dose of study treatment. TEAEs will be summarized by MedDRA 
System Organ Class and Preferred Term.  
 
All AEs will be listed. 
 
 
10.2 
CLINICAL LABORATORY TESTING 
 
Summary statistics of observed and change from baseline data will be presented for each 
treatment group and dose level where applicable. Summary statistics will include number of 
subjects, mean, median, standard deviation, minimum, and maximum. Shift tables summarizing 
the numbers of subjects shifting from normal pre-dose values to abnormal post-dose values will 
also be presented where applicable. Listings for all laboratory assessments will be presented. 
 
 
10.3 
VITAL SIGNS 
 
Vital signs (systolic and diastolic blood pressure, heart rate/pulse, body temperature) and 
changes from baseline at each time point will be presented by cohort and treatment group. 
Summary statistics for systolic blood pressure, diastolic blood pressure, temperature, and 
change from baseline (pre-dose) summaries will be presented for each treatment group and 
dose level where applicable. Summary statistics will include number of subjects, mean, median, 
standard deviation, minimum, and maximum. Listings for all vital signs will be presented.  
 
Post-dose clinically notable vital signs will be listed and summarized by treatment and dose. 
Criteria for Clinically Notable Vital Sign abnormalities are indicated in Table 2 below. 
 
 


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Table 2: Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic BP (supine) 
> 30 mmHg increase from baseline 
> 30 mmHg decrease from baseline 
Diastolic BP (supine) 
> 20 mmHg increase from baseline 
> 30 mmHg decrease from baseline 
Heart Rate 
> 120 bpm and an increase in HR of 
 15 bpm from baseline 
< 40 bpm and a decrease in HR of  15 
bpm from baseline 
Body Temperature 
> 39.0oC (> 102.2oF) 
< 35.0oC (< 95.0oF) 
 
 
10.4 
ELECTROCARDIOGRAM MONITORING 
 
Descriptive statistics for ECG parameters (e.g. Ventricular Heart Rate, PR interval, QRS 
interval, QTc interval, QTcB, and QTcF interval, RR interval) at baseline and changes from 
baseline at each assessment time point will be presented by cohort and treatment group. 
Baseline will be the median of each subject’s available Day 1 pre-dose results for each 
parameter.  
 
Shift tables summarizing the numbers of subjects shifting from normal pre-dose values to 
abnormal post-dose values will also be presented.  Numeric ECG data will be summarized by 
treatment group and dose level and mean summary tables, including change from baseline will 
be presented. The ECG results will be listed by treatment group and dose level. Post-dose 
clinically notable ECGs will be listed and summarized by treatment and dose. Notable 
abnormalities are indicated in Table 3 below: 
 
Table 3: Criteria for Clinically Notable ECG Abnormalities 
Parameter 
High Threshold 
Low Threshold 
PR interval 
PR  220 ms 
PR ≤ 120 ms 
QRS duration 
QRS duration  120 ms and an increase of  20 ms 
from baseline 
- 
QT interval 
QT interval > 500 ms 
- 
QTcF interval 
Men: QTcF interval  450 ms and an increase of 60 
ms from baseline OR QTcF interval >500 ms 
Women: QTcF interval  470 ms and an increase of 
60 ms from baseline OR QTcF interval >500 ms 
- 
 
10.5 
PHYSICAL EXAMINATIONS 
 
Weight will be measured during all physical examinations (Screening, Day -1, Day 8) and height 
will be measured at Screening only. Descriptive statistics for weight at baseline and changes from 
baseline at each assessment time point will be presented by cohort and treatment group. A listing 
of abnormal physical examination data for all subjects will be provided. 
 
10.6 
NEUROLOGICAL EXAMINATIONS 


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Neurological examinations include mental status, cranial nerves 2-12, motor system and 
coordination, reflexes, and sensory system. Shift tables summarizing the numbers of subjects 
shifting from normal pre-dose values to abnormal post-dose values will be created. A listing of 
abnormal neurological examination data for all subjects will be provided.  
 
 
 


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11.0 
DETERMINATION OF SAMPLE SIZE 
 
This trial is designed to investigate the safety, tolerability, and PK properties of the drug MW189 
in a dose escalation Phase Ib study. The number of subjects is based upon the need to gain 
this knowledge in healthy individuals using as few subjects as possible. Since this is the first 
MAD study of MW189 in humans, there is no prior experience upon which to base estimates of 
variability for the PK responses to MAD treatment with MW189. No power analysis is conducted 
but the cohort size is based on accepted standards in similar Phase I studies: 8 subjects per 
dose with 6 randomly assigned to active drug while the remaining 2 subjects receive placebo. 
Eight subjects per cohort was deemed sufficient for obtaining an adequate preliminary 
description of the responses of interest.