Clinical trial NCT03680105
Conditions: Critical Limb Ischemia
Sponsor: Reven Pharmaceuticals, Inc.
Start date: 2018-08-24; Completion date: 2019-01-15
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Designed as a single center, two-part, double-blind, placebo-controlled, randomized study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RJX in healthy participants.

Detailed description:
Part 1 is designed as a Single Ascending Dose (SAD) escalation study with 6 cohorts. Participants will undertake a screening visit between Day -21 and Day -1 to determine eligibility in the study. Those participants that meet the eligibility criteria will be admitted to the study site on the day prior to dosing (Day -1). Participants will receive a single dose of investigational product via IV infusion on Day 1. The first cohort will include the initial dosing of a sentinel group. The remaining participants in Cohort 1 will be dosed if, in the opinion of the investigator or delegate, there are no significant safety concerns identified in the sentinel participants within the first 24 hours after administration of the dose. Participants will be confined to the study site from Day -1 to Day 2 (24 hours post dose) and then required to return to the study site on Day 5 for a final follow up visit. Safety and PK assessments will be performed at selected time points throughout the study.

Part 2 is designed as a Multiple Ascending Dose (MAD) escalation study with 3 cohorts. The MAD arm of the study will commence in parallel with Cohort 6 of Part 1 following completion and review of safety and PK findings for Cohorts 1, 2, 3, 4, and 5 in Part 1. Participants will undertake a screening visit between Day -21 and Day -1 to determine eligibility in the study. Those participants that meet the eligibility criteria will be admitted to the study site on the day prior to dosing (Day -1). Participants will be randomly assigned to receive 1 of 3 proposed doses of investigational product via IV infusion every day for 7 days.Participants will be confined to the study site from Day -1 to Day 8 (24 hours post the final dose on Day 7) and then return to the study site on Day 12 for a final follow up visit. Safety and PK assessments will be performed at selected time points throughout the study.

Arms: arm 1: Participants in Part 1; Cohort 1 will receive a single 0.024 mL/kg dose of RJX or matching placebo on Day 1. arm 2: Participants in Part 1; Cohort 2 will receive a single 0.076 mL/kg dose of RJX or matching placebo on Day 1. arm 3: Participants in Part 1; Cohort 3 will receive a single 0.240 mL/kg dose of RJX or matching placebo on Day 1. arm 4: Participants in Part 1; Cohort 4 will receive a single 0.5 mL/kg dose of RJX or matching placebo on Day 1. arm 5: Participants in Part 1; Cohort 5 will receive a single 0.759 mL/kg dose of RJX or matching placebo on Day 1. arm 6: Participants in Part 1; Cohort 6 will receive a single dose of RJX or matching placebo, to be determined following review of safety and PK data from Cohorts 1 to 5, on Day 1. arm 7: Participants in Part 2; Cohort 1 will receive a dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days.

The Part 2; Cohort 1 dose will be 1 log down from the maximum tolerated dose determined in Part 1 or at a dose determined to be safe and well tolerated in Part 1 with an acceptable PK profile. arm 8: Participants in Part 2; Cohort 2 will receive an escalated dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days. arm 9: Participants in Part 2; Cohort 3 will receive an escalated dose of RJX or matching placebo, determined based on the findings of Part 1, every day for 7 days.
Interventions: intervention 1: RJX intervention 2: Placebo
Intervention descriptions: intervention 1: RJX is an IV infusion formulation. The appropriate RJX dose is calculated based on mL/kg. The administration dose is prepared by adding the appropriate RJX dose to 0.9% sterile saline such that a constant volume of 100 mL per IV infusion is obtained. Infusion time is 100 mL over 45 minutes (+/- 5 minutes). intervention 2: Matching placebo will be normal saline. To maintain the blind, a sleeve will cover the infusion bag and line such that the appearance will be identical to RJX administration.

Protocol documents:
Prot_SAP_000.pdf: 
Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 1 of 27 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
A Phase 1, Double-blind, Placebo-controlled, Randomized, Two-Part, 
Ascending Dose-escalation Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Rejuveinix (RJX) in Healthy 
Participants 
 
SAP FINAL 3.0 
Date: 12 FEB 2020 
 
for 
 
Protocol No. RPI003 
 
 
Submitted to: 
Reven Pharmaceuticals, Inc. 
600 Corporate Circle, Suite D 
Golden, CO 80401 
United States 
 
Prepared by: 
ICON Clinical Research, LLC 
820 West Diamond Avenue, Suite 100 
Gaithersburg, MD 20878 
Telephone: (301) 944-6800 
Fax: (215) 699-6288 
 
 






Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 4 of 27 
TABLE OF CONTENTS 
SIGNATURES................................................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................4 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................6 
2 
INTRODUCTION .........................................................................................................8 
3 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................9 
3.1 
Primary Objective ..................................................................................................9 
3.2 
Secondary Objectives.............................................................................................9 
3.3 
Exploratory Objective ...........................................................................................9 
3.4 
Primary Endpoints.................................................................................................9 
3.5 
Secondary Endpoints ...........................................................................................10 
3.6 
Exploratory Endpoints ........................................................................................10 
4 
STUDY DESIGN .........................................................................................................11 
4.1 
General ..................................................................................................................11 
4.1.1 
Part 1 ......................................................................................................................11 
4.1.2 
Part 2 ......................................................................................................................11 
4.1.3 
Dose Escalation in Parts 1 and 2 ............................................................................12 
4.2 
Study Population ..................................................................................................12 
4.3 
Evaluations at Screening and Check-in .............................................................12 
4.4 
Randomization and Treatment Assignments ....................................................12 
4.4.1 
Investigational Product Administration .................................................................13 
4.4.2 
Concomitant Medications ......................................................................................14 
4.4.3 
Compliance ............................................................................................................14 
4.5 
Evaluation of Treatment Safety ..........................................................................14 
4.5.1 
Adverse Events ......................................................................................................14 
4.5.2 
Clinical Laboratory Assessments ...........................................................................14 
4.5.3 
Vital Signs ..............................................................................................................15 
4.5.4 
Safety Electrocardiograms .....................................................................................15 
4.5.5 
Physical and Neurological Examinations ..............................................................15 
4.5.6 
Weight and Height .................................................................................................15 
4.5.7 
Protocol Deviation Reporting ................................................................................15 
4.6 
Pharmacodynamic Assessments .........................................................................16 
4.6.1 
Blood pH, Bicarbonate, and Biomarkers ...............................................................16 
4.6.2 
Urinary pH .............................................................................................................16 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS ..................................................................................................................17 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 5 of 27 
6 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR 
DATA ANALYSIS ......................................................................................................18 
7 
STATISTICAL METHODS ......................................................................................19 
7.1 
General ..................................................................................................................19 
7.2 
Handling of Dropouts or Missing Data ..............................................................19 
7.3 
Multicenter Studies ..............................................................................................19 
7.4 
Examination of Subgroups ..................................................................................19 
7.5 
Analysis Populations ............................................................................................19 
7.6 
Participant Accountability ..................................................................................20 
7.7 
Protocol Deviation Reporting .............................................................................20 
7.8 
Participant Demographics and Baseline Characteristics .................................20 
7.9 
Dose Proportionality Analysis ............................................................................20 
7.10 
Analysis of Safety Data ........................................................................................21 
7.10.1 
General ...................................................................................................................21 
7.10.2 
Adverse Events ......................................................................................................21 
7.10.3 
Clinical Laboratory Assessments ...........................................................................22 
7.10.4 
Vital Signs ..............................................................................................................22 
7.10.5 
Safety Electrocardiograms .....................................................................................22 
7.10.6 
Physical and Neurological Examinations ..............................................................22 
7.10.7 
Concomitant Medications ......................................................................................22 
7.11 
Pharmacodynamic Analysis ................................................................................23 
7.12 
Sample Size ...........................................................................................................23 
7.13 
Interim Analysis ...................................................................................................23 
7.14 
General Conventions for Tables, Listings and Figures ....................................23 
8 
TABLES, FIGURES, AND LISTINGS .....................................................................24 
 
 
 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 6 of 27 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
adverse event 
BMI 
body mass index 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
HR 
heart rate 
∆HR 
change from baseline heart rate 
∆∆HR 
placebo corrected change from baseline heart rate 
hsCRP 
high-sensitivity C-reactive protein 
ICAM-1 
intercellular adhesion molecule 1 
ICF 
informed consent form 
IL-6 
interleukin 6 
ITT 
intent to treat 
Kg 
kilogram 
IV 
intravenous 
MAD 
multiple ascending dose 
MedDRA 
medical dictionary for regulatory activities  
mg 
milligram 
mL 
milliliter  
n 
number 
PK 
pharmacokinetics 
PD 
pharmacodynamic 
pH 
negative of the base 10 logarithm of the molar concentration, measured in units of 
moles per liter, of hydrogen ions. 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 7 of 27 
Abbreviation or 
Specialist Term 
Explanation 
PR (interval) 
the period, measured in milliseconds, that extends from the beginning of the P 
wave (the onset of atrial depolarization) until the beginning of the QRS complex 
(the onset of ventricular depolarization) 
∆ PR 
change from baseline PR 
∆∆ PR 
placebo corrected change from baseline PR 
PT 
preferred term 
QRS (duration) 
time interval from onset to end of the QRS complex, a reflection of left 
ventricular depolarization in the heart’s electrical cycle as measured by 
electrocardiogram;  
∆ QRS 
change from baseline QRS 
∆∆ QRS 
placebo corrected change from baseline QRS 
QT 
interval between Q and T wave in the heart’s electrical cycle 
QTc 
corrected QT 
QTcF 
Fridericia-corrected QT 
∆ QTcF 
Change from baseline QTcF 
∆∆ QTcF 
Placebo corrected change from baseline QTcF 
RJX 
rejuveinix 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SRC 
safety review committee  
TBC 
to be confirmed 
TEAE 
treatment-emergent adverse event 
VCAM-1 
vascular cell adhesion molecule 1 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 8 of 27 
2 
INTRODUCTION 
This statistical analysis plan (SAP) is consistent with the statistical methods section of the final 
study protocol (Version 2.0, dated 14 Sep 2018) and includes additional detail of the safety 
summaries and the pharmacodynamics analysis to be included in the clinical study report (CSR). 
The details of the dose proportionality analysis of PK parameters are included in this document 
and this analysis will be done at ICON. 
A separate plan describing the QT/QTc analyses will be prepared by ERT and a separate plan 
describing the bioanalytical and pharmacokinetic (PK) analysis will be prepared by 
AltaSciences. 
 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 9 of 27 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
• To assess the safety and tolerability of escalating doses of RJX administered as single and 
multiple intravenous (IV) infusions in healthy volunteers 
3.2 
Secondary Objectives 
• To assess the PK profile of cyanocobalamin, ascorbic acid, thiamine, magnesium, and 
niacinamide after escalating doses of RJX when administered as single and multiple IV 
infusions in healthy volunteers 
• To assess the PD of escalating doses of RJX when administered as single and multiple IV 
infusions in healthy volunteers 
• To assess the effect on electrocardiogram (ECG) parameters, including 
concentration-QTc analysis, of RJX administered as single and multiple IV infusions in 
healthy volunteers 
• To establish the optimal clinical dose to be investigated in patients with critical limb 
ischemia 
3.3 
Exploratory Objective 
• To assess the effect of RJX on intercellular adhesion molecule 1, vascular cell adhesion 
molecule 1, high-sensitivity C-reactive protein (hsCRP), interleukin 6, and other 
exploratory biomarkers when administered as single and multiple IV infusions in healthy 
volunteers 
3.4 
Primary Endpoints 
The safety and tolerability of RJX will be assessed by changes from baseline for the following 
endpoints:  
• adverse events (AEs) 
• ECG parameters 
• neurological assessments (pyramidal functions, limb strength, cerebellar functions, 
sensory functions) 
• vital signs (body temperature, respiratory rate, heart rate, and sitting systolic and diastolic 
blood pressure) 
• clinical safety laboratory samples (hematology, biochemistry, urinalysis) 
• concomitant medications 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 10 of 27 
3.5 
Secondary Endpoints 
The following endpoints will be evaluated to determine the PK of RJX: 
• concentrations and PK parameters of RJX components in plasma/serum; 
cyanocobalamin, ascorbic acid, thiamine, magnesium and niacinamide 
The PD of RJX will be assessed by changes from baseline for the following endpoints:  
• pH from venous blood 
• pH for urine 
• bicarbonate 
To assess the effect of RJX on ECG parameters, the following endpoints will be evaluated:  
• change from baseline in heart rate (HR), QTcF, PR, and QRS intervals (∆HR, ∆QTcF, 
∆PR and ∆QRS) and placebo-corrected ∆HR, ∆QTcF, ∆PR, and ∆QRS (∆∆HR, 
∆∆QTcF, ∆∆PR and ∆∆QRS) 
• categorical outliers for HR, QTcF, PR, QRS 
• frequency of treatment emergent changes of T-wave morphology and U-wave presence 
3.6 
Exploratory Endpoints 
The PD of RJX will be assessed by changes from baseline for exploratory biomarkers, including: 
intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), high 
sensitivity C-reactive protein (hsCRP), and interleukin 6 (IL-6). 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 11 of 27 
4 
STUDY DESIGN 
4.1 
General 
The study is designed as a double-blind, placebo-controlled, randomized study to assess the 
safety, tolerability, PK, and PD of RJX in healthy participants. This study will be conducted as a 
2-part study. 
4.1.1 
Part 1 
Part 1 is designed as single ascending dose (SAD) escalation study in 52 participants in 
6 cohorts. 
• Cohorts 1 to 5 will include 8 participants per cohort (6 RJX: 2 placebo) between 18 and 
50 years of age, inclusive 
• Cohort 6 will investigate an older population of 12 participants 51 to 70 years of age, 
inclusive (9 RJX: 3 placebo) 
The assignment to either RJX or placebo will be blinded to the participants, investigators, and 
study site staff.  
Part 1 will include screening, treatment, and follow-up periods. Screening will be between 
Days -21 and -1 to determine eligibility in the study. Participants who meet the eligibility criteria 
will be admitted to the study site on Day -1, when they will be assessed for continued eligibility.  
Participants will commence a standardized diet the day prior to dosing to control vitamin intake. 
Participants will receive a single dose of investigation product as an IV infusion on Day 1. 
Cohort 1 will include the initial dosing of a sentinel group (1 RJX and 1 placebo). The remaining 
6 participants in Cohort 1 (5 RJX: 1 placebo) will be dosed if, in the opinion of the investigator 
or delegate, there are no significant safety concerns identified in the sentinel participants within 
the first 24 hours after administration of the dose (RJX or placebo). 
Participants will be confined to the study site from Day -1 to Day 2 (24 hours post dose) and then 
required to return to the study site on Day 5 for follow-up. Safety and PK assessments will be 
performed at selected timepoints throughout the study. 
4.1.2 
Part 2 
Part 2 of the study is designed as a multiple ascending dose (MAD) escalation study in 
24 participants as 3 cohorts of 8 participants (6 RJX: 2 placebo). The MAD arm will commence 
in parallel with Part 1, Cohort 6 following completion and review of the safety findings for 
Part 1, Cohorts 1 to 5.  
Participants will be randomly assigned to receive 1 of 3 proposed doses of RJX or placebo 
(6 RJX: 2 placebo) daily for 7 days.  


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 12 of 27 
Part 2 will consist of screening, treatment, and follow-up periods. Screening will occur between 
Days -21 and -1 to determine eligibility in the study. Those participants who meet the eligibility 
criteria will be admitted to the study site on Day -1, when their continued eligibility will be 
assessed. Participants will commence a standardized diet the day prior to dosing to control 
vitamin intake. 
Participants will be confined to the study site from Days -1 to 8 (24 hours post final dose on 
Day 7) and then return to the study site on Day 12 for follow-up. Safety and PK assessments will 
be performed at selected timepoints throughout the study. 
4.1.3 
Dose Escalation in Parts 1 and 2 
Details about dose escalation are described in Section 6.3.2 of the study protocol. 
4.2 
Study Population 
The study population will include 76 healthy male and female participants between 51 to 
70 years of age (Part 1, Cohort 6) or 18 and 50 years of age (all other cohorts), inclusive, with a 
body mass index (BMI) of 18 to 35 kg/m2, weight not exceeding 132 kg, negative serology and 
drug and alcohol testing, and clinical laboratory test results within normal reference range or 
judged to be not clinically significant. 
4.3 
Evaluations at Screening and Check-in 
A detailed schedule of events is provided in Table 6 (for Part 1) and Table 7 (for Part 2) in 
Section 8.1 of the study protocol. 
4.4 
Randomization and Treatment Assignments 
Participants will be randomly assigned to receive either RJX or placebo.  
A computer-generated randomization schedule and kit list will be prepared prior to the start of 
the study. Investigational product will be prepared and dispensed in accordance with the 
randomization schedule and kit list. The master randomization schedule and kit list will be made 
of randomly permuted blocks of appropriate sizes, as determined by the unblinded study team 
member producing the schedules. The schedules will be generated through the Statistical 
Analysis System software, version 9.3. 
After signing the informed consent form (ICF), each participant will be given a unique screening 
number according to the screening order. Then, prior to dosing, each participant will be allocated 
a randomization number according to their chronological order of inclusion in the study. This 
number will correspond to a treatment (RJX or placebo) as specified on the pre-determined 
randomization schedule. 
Confirmation of the randomization number allocated will be documented in the drug 
accountability records and recorded in the eCRF. Both the screening and randomization numbers 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 13 of 27 
will be used to identify the participant throughout the study period and on all study-related 
documentation.  
If a participant is replaced, the replacement should take the same treatment assignment as the 
original participant to ensure that the treatment groups stay balanced. 
4.4.1 
Investigational Product Administration 
Investigational product will be administered as follows:  
Table 1: Investigational Products Administered – Part 1 
 
Investigational
Route of
Dose
Dose
Infusion Time
Product
administration
(mL/kg)
frequency
RJX 
Intravenous 
Cohort 1: 0.024 
Single dose on  
Day 1 
100 mL over  
45 minutes 
(± 5 minutes) 
Cohort 2: 0.076
Cohort 3: 0.240
Cohort 4: 0.5
Cohort 5: 0.759 
Cohort 6: *RJX 
Placebo 
Intravenous 
NA 
Single dose on 
Day 1 
100 mL over  
45 minutes  
(± 5 minutes)
* Dose in elderly participants (Cohort 6) to be determined following review of safety and PK data from 
Cohorts 1 to 5 
 
Table 2: Investigational Products Administered – Part 2 
 
Investigational
Route of
Starting Dose
Dose frequency 
Infusion Time 
Product
administration
(mL/kg)
RJX 
Intravenous 
Cohort 1: 0.240  
Cohort 2: 0.5  
Cohort 3: 0.759 
Cohort 4: TBC* 
Cohort 5: TBC* 
Dosing every day 
for 7 days  
(Day 1 to Day 7) 
100 mL over 
45 minutes 
(± 5 minutes) 
Placebo 
Intravenous 
NA 
Dosing every day 
for 
7 days (Day 1 
100 mL over 
45 minutes 
(± 5 minutes) 
*To Be Confirmed. Following completion and review of the safety and PK findings for Cohorts 1-5 in Part 1, Part 
2 will commence in parallel with Cohort 6 of Part 1. The starting dose for each Part 2 cohort will be determined 
following completion and review of the safety findings from Part 1 (Cohorts 1-5) and preceding Part 2 Cohorts but 
will not exceed 0.759 mL/kg. 
 
Participants in each cohort will be dosed in staggered dosing. All doses will be administered as 
IV infusion by study unit staff. 
Food restrictions in relation to dosing are described in more detail in Section 6.3.1 of the study 
protocol. The rate of administration of RJX as well as details about dose limiting toxicities and 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 14 of 27 
maximum tolerated dose can be found in Sections 6.3.4 and 6.3.5 of the study protocol, 
respectively. 
4.4.2 
Concomitant Medications 
Should any treatment/medication other than the investigational product be used, the investigator 
must note the use of the concomitant medication in the source documentation and the CRF. This 
record should include the drug name (generic name), total daily dose, route of administration, 
start and stop date of administration, and the indication. 
Concomitant medications will be recorded from Day -1 throughout the study for both study 
parts. 
4.4.3 
Compliance 
Investigational product will be administered via IV by study site staff. 
Every attempt will be made to select participants who have the ability to understand and comply 
with instructions. Noncompliant participants may be discontinued from the study. The time and 
day of investigational product administration will be recorded. Drug accountability records will 
be maintained by the study site. 
4.5 
Evaluation of Treatment Safety 
4.5.1 
Adverse Events 
An AE is defined as any untoward medical occurrence, in a clinical study participant 
administered a medicinal product, that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the medicinal 
(investigational) product, whether or not it is related to the medicinal (investigational) product. 
This includes an exacerbation of pre-existing conditions or events, intercurrent illnesses, drug 
interaction, or the significant worsening of the indication under investigation that is not recorded 
elsewhere in the eCRF under specific efficacy assessments. Assessment of AEs starts with 
signing informed consent. 
It is the responsibility of the investigator to document all AEs that occur during the study. The 
AEs will be elicited by asking the participant a nonleading question, for example, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?” The AEs 
should be reported on the appropriate page of the eCRF. 
4.5.2 
Clinical Laboratory Assessments 
The laboratory safety tests to be analyzed are described in more detail in Section 7.1.7 of the 
study protocol. 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
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4.5.3 
Vital Signs 
Daily vital signs (screening, check-in, and follow-up; also refer to Protocol Appendix 1, Tables 6 
and 7Error! Reference source not found.) measurements will include body temperature, 
respiratory rate, heart rate, and systolic and diastolic blood pressure.  
4.5.4 
Safety Electrocardiograms 
A safety 12-lead ECG will be performed after the patient has rested comfortably in the supine or 
semi-supine position for at least 5 minutes.  
The following parameters will be assessed: heart rate, PR, QRS, QT, and QTcF (Fridericia’s 
formula). The investigator (or a qualified observer at the investigational site) will interpret the 
ECG using one of the following categories: within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant. 
In Part 1, a safety 12-lead ECG will be performed at every visit except follow-up. In Part 2, a 
safety 12-lead ECG will be performed at every visit except check-in (refer to Protocol 
Appendix 1, Tables 6 and 7Error! Reference source not found.). 
4.5.5 
Physical and Neurological Examinations 
Full physical examinations will be performed at screening and follow-up by a physician or a 
clinically qualified delegate at the site. The physical examination will include examination of the 
following: general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, 
cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, 
lymph nodes, and nervous system. Any findings made during the physical examination must be 
noted regardless of whether they are part of the patient’s medical history. An abbreviated 
physical examination will be performed at check-in. 
Daily neurological assessments per standard of care will include pyramidal functions, limb 
strength, cerebellar functions, and sensory functions. 
4.5.6 
Weight and Height 
Body weight (in kg; wearing light clothes, no shoes) and height (in cm) will be measured. Height 
and weight measurements will be used to calculate body mass index (BMI). 
4.5.7 
Protocol Deviation Reporting 
If any issue relating to the safety of study participant arises that requires a deviation from the 
protocol, the study unit through the investigator may immediately make such a deviation. The 
nature and reasons for the protocol deviations/violations will be recorded in the participant’s 
eCRF. All protocol deviations/violations will be captured by the study unit. Failure to obtain 
samples due to clinical issues, such as problems with venous access, will not be considered 
protocol violations. Changes in dose levels or the implementation of additional cohorts as 
directed by the SRC will not be considered protocol deviations.  


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 16 of 27 
Procedural deviations found by the clinical research associate (CRA) during monitoring visits 
and data deviations captured on the case report form (CRF) and found through programming and 
examining the database will be listed by participant. 
4.6 
Pharmacodynamic Assessments 
The PD of RJX will be assessed by changes from baseline in blood pH, blood bicarbonate 
urinary pH, and exploratory biomarkers. 
4.6.1 
Blood pH, Bicarbonate, and Biomarkers 
Blood samples collected for the evaluation of pH, bicarbonate, and biomarkers including:  
ICAM-1, VCAM-1, hsCRP, and IL-6 will be collected for Part 1 cohort 6 and Part 2 as specified 
in Protocol Appendix 2. 
The PD blood samples can be collected at the same time as the PK sample where timepoints 
coincide. The sample required for the PD assessment will be aliquoted into separate PD tubes. 
Additional details on the collection of PD blood samples are included in the Laboratory 
Procedures Manual. 
4.6.2 
Urinary pH 
In Part 1 and Part 2, the pH of RJX will be evaluated in urine. The urine sample will be collected 
prior to infusion and at the first voluntary void post the end of infusion to evaluate urine pH and 
exploratory biomarkers. Additional details on the collection of PD urine samples are included in 
the Laboratory Procedures Manual. 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
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CONFIDENTIAL 
Page 17 of 27 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS 
No changes.  


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
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CONFIDENTIAL 
Page 18 of 27 
6 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS 
Case report forms will be monitored and collected by ICON. All monitored CRFs will be sent to 
the Data Management group at ICON and processed according to the ICON Study Specific 
Procedure SSP DM-39570002.01 Data Management Plan (DMP). The DMP describes CRF data 
processing, edit checks, data query management, medical dictionary coding, SAE reconciliation, 
data transfers, and data quality review through database lock or any necessary reopening of the 
database. After database lock, the data will be retrieved from the database using SAS® for 
Windows Version 9.4 or newer (SAS Institute, Inc., Cary, NC). 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 19 of 27 
7 
STATISTICAL METHODS 
7.1 
General 
All statistical analyses will be performed using the statistical software SAS for Windows 
Version 9.4 or newer (SAS Institute, Inc., Cary, NC). 
Continuous data will be summarized using descriptive statistics including number of participants, 
mean, median, standard deviation, standard error, 90% confidence interval, minimum, and 
maximum by treatment and timepoint, where appropriate.  
Data collected from all randomized participants will be presented in data listings. Both absolute 
values and change-from-baseline values for each participant will be given where applicable. All 
continuous data will be listed with the same precision as is presented in the database. Data 
listings will be sorted by part, treatment, participant identification, and timepoint.  
Categorical data will be summarized by both participant and timepoint. Participant data will be 
summarized using the count of distinct participants who fall into the category and the percentage 
of the total number of participants. Timepoint data will be summarized using the count of the 
assessments that fall into the category and the percentage of the total number of assessments. 
Percentages will be rounded up or down to the next integer percentage. Population counts (either 
number of participants or number of timepoints at the assessment) for each treatment group will 
be used as the denominator in the calculation of percentages unless otherwise specified. 
7.2 
Handling of Dropouts or Missing Data 
All data from withdrawn participants will be included in all analyses up to the time of 
withdrawal regardless of the duration of treatment. There will be no imputation for missing data 
unless otherwise specified. 
7.3 
Multicenter Studies 
This is a single-center study. 
7.4 
Examination of Subgroups 
No subgroup analyses are planned. 
7.5 
Analysis Populations 
Intent to Treat (ITT) Population: all randomized participants based on the randomized treatment, 
regardless of which treatment the participant actually received; used for all summaries of 
baseline and demographic data; all associated listings will be produced for the ITT population 
Safety Analysis Population: participants who received at least 1 dose of the investigational 
product (RJX or placebo); used for all summaries of baseline, demographic data, safety data and 
PD data; all listings regarding safety data will be produced for the safety analysis population  


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 20 of 27 
PK Analysis Set: participants who received at least one dose of the investigational product and 
provided at least one quantifiable plasma concentration of cyanocobalamin, ascorbic acid, 
thiamine, magnesium or niacinamide. 
PK Evaluable Analysis Set: participants who received at least one dose of the investigational 
product for whom at least one estimable PK parameter could be reliably estimated. 
The following analysis population is also defined in the clinical study protocol:  
• QT/QTc Analysis Set 
This analysis population will not be defined in this SAP, since the QT/QTc analyses will be 
prepared by ERT.  
7.6 
Participant Accountability 
Summaries of analysis populations and participant disposition will be presented by treatment and 
overall using ITT Population for each part separately and will contain the following information: 
• Number and percent of participants who were randomized 
• Number and percent of participants who were dosed and received treatment 
• Number and percent of participants who received all doses planned (Part 2 only) 
• Number and percent of participants who completed the study 
• Number and percent of participants who discontinued early and reason for early 
discontinuation 
• Number and percent of participants in each population 
Participant enrollment and disposition, including reasons for early withdrawal from the study, 
will be summarized by treatment. Participant disposition will be presented in listings. 
7.7 
Protocol Deviation Reporting 
Protocol deviations identified by the clinical research associate during monitoring visits and 
deviations captured on the CRF and identified through programming and examining the database 
will be listed by participant. 
7.8 
Participant Demographics and Baseline Characteristics 
Summaries of baseline and demographic characteristics will be based on the ITT Population as 
well as Safety Analysis Set. Baseline and demographic data (including gender, age, race, 
ethnicity, weight, height, and BMI) will be summarized by treatment.  
7.9 
Dose Proportionality Analysis  
The dose proportionality of the main PK parameters Cmax, AUC0-last (SAD), AUCtau (MAD), and 
AUC0-inf (SAD and MAD) will be investigated using the following power model: 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 21 of 27 
log(parameter) = a + b * log(dose), where a is the intercept, b is the slope and dose is the actual 
dose in mL/kg. 
Each log-transformed PK parameter for the RJX components cyanocobalamin, ascorbic acid, 
thiamine, magnesium and niacinamide will be fitted to a power model with fixed effect term for 
log-transformed dose and subjects as random effects. For each PK parameter, the slope and 
associated 90% CI will be presented. If the 90% CI for the slope of the regression line contains 1 
then it can be concluded that the PK parameter is dose proportional. 
Dose proportionality may be assessed within different dose ranges if deemed appropriate. All 
dose proportionality assessments will include data from at least three dose levels. 
Scatterplots including regression line for all PK parameters of all analytes versus dose in mg will 
be generated. 
7.10 
Analysis of Safety Data 
7.10.1 
General 
Safety parameters will be listed and summarized using standard descriptive statistics for values 
for each treatment at each timepoint as well as changes from baseline of each cohort separately.  
7.10.2 
Adverse Events 
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data (Aes) will be summarized using descriptive methodology.  
The incidence of symptoms for each treatment will be presented by severity and association with 
investigational product, as perceived by the investigator. Symptoms reported to occur prior to 
enrollment will be distinguished from those reported as new or increased in severity during the 
study. Each symptom will be classified by the most suitable term from the Medical Dictionary 
for Regulatory Activities (MedDRA).  
The Aes will be grouped by MedDRA system organ class (SOC) and preferred term (PT) and 
summarized by actual treatment/dose level.  
Treatment-emergent adverse events (TEAEs) are defined as Aes that commence on or after the 
time of start of first investigational product administration.  
All TEAEs will be summarized by actual treatment/dose level. The number and percentage of 
participants experiencing Aes and the number of TEAEs will be tabulated. The following 
summaries will be presented:  
• Overall summary of TEAEs 
• All TEAES by SOC and PT 
• All TEAEs by SOC, PT, and severity 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
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12FEB2020
 
 
CONFIDENTIAL 
Page 22 of 27 
• All TEAEs by SOC, PT, and relationship to investigational product 
• SAEs by SOC and PT 
Any SAEs, Aes with outcome of death, or Aes resulting in discontinuation of study or IP will be 
listed separately. A separate summary table of adverse events of interest will be tabulated for 
neurological and infusion related events. 
7.10.3 
Clinical Laboratory Assessments 
Observed values and actual changes from baseline (defined as last value prior to first IMP 
administration) of continuous laboratory parameters (hematology and clinical chemistry) will be 
summarized descriptively, by actual treatment/dose level, and visit/timepoint. Categorical 
outcomes will be summarized by frequency tables. Shift tables representing categorical change 
of laboratory results from baseline to each post-baseline visit will be presented. Urinalysis results 
will be summarized at each timepoint by actual treatment/dose level at each timepoint using 
frequency tables. Pregnancy and infertility related data will be listed. Lab normal ranges will also 
be listed. 
7.10.4 
Vital Signs 
Observed values and actual changes from baseline (defined as last value prior to first IMP 
administration) of vital signs will be summarized descriptively by actual treatment/dose level and 
visit/timepoint. Categorical outcomes will be summarized by frequency tables. 
7.10.5 
Safety Electrocardiograms 
Observed values and actual changes from baseline (defined as last value prior to first IMP 
administration) of ECG parameters will be summarized descriptively by actual treatment/dose 
level and visit/timepoint. Safety 12-lead ECG interpretations (categorical outcomes) will be 
summarized by frequency tables. 
7.10.6 
Physical and Neurological Examinations 
Physical examination data as well as neurological examination data will be listed only. 
7.10.7 
Concomitant Medications 
Prior medications are those medications that were stopped prior to first dose of investigational 
product. Concomitant medications are medications taken at least once after investigational 
product. Medications stopped on the same day as investigational product will be considered prior 
medications.  
Prior and concomitant medications will be listed. Concomitant medication summary tables will 
be grouped by PT and show the number and percentage of participants by PT for all participants 
overall. For the summaries of concomitant medications, participants who take the same 
medication (in terms of the PT) more than once will only be counted once for that medication. 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
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7.11 
Pharmacodynamic Analysis 
Pharmacodynamic parameters like blood bicarbonate and pH, urinary pH, and relevant 
exploratory biomarkers (Part 1 cohort 6 and Part 2 only) will be summarized at each timepoint 
by actual treatment and each dose level by using descriptive statistics, unless results are 
categorical. Categorical outcomes will be summarized by frequency tables (see section 9.1). Data 
will be assessed for clinical safety and clinical significant changes from baseline and additional 
statistical analyses and interpretations may be added in an amendment. 
7.12 
Sample Size 
The sample size for this study has been selected without performing a formal sample size 
calculation. The sample size was chosen empirically and is customary for Phase 1 studies 
evaluating safety and PK parameters; it is not based on statistical hypothesis testing. 
7.13 
Interim Analysis 
The SRC will review the safety data and PK data (only safety data in Cohorts 1 and 2 in Part 1) 
prior to escalation to the next cohort for both parts of the study. The safety and PK findings of 
the Part 1 (SAD) Cohorts 1 to 5 will be reviewed by the SRC prior to commencing Part 2 
(MAD). 
7.14 
General Conventions for Tables, Listings and Figures  
For summary tables, unless otherwise specified, the number of decimal places provided in the 
SAS output will be based on the accuracy of the least accurate value in the raw data as follows: 
n 
integer 
Arithmetic mean 
1 decimal place more than the least accurate number in the raw data 
SD 
2 decimal place more than the least accurate number in the raw data 
CV(%) 
2 decimal places 
Geometric mean 
1 decimal place more than the least accurate number in the raw data 
Median 
1 decimal place more than the least accurate number in the raw data 
Minimum 
same number of decimal places as raw data 
Maximum 
same number of decimal places as raw data 
Confidence interval  
same number of decimals as the associated statistic 
Geometric mean ratio 2 decimal places 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
Page 24 of 27 
8 
TABLES, FIGURES, AND LISTINGS 
Table/Figure Number 
Table/Figure Name 
Section 14.1 
Demographic and Subject Characteristics Data Summaries 
Table 14.1.1 
Summary of Subject Disposition (ITT Population) 
Table 14.1.2 
Summary of Analysis Populations (ITT Population) 
Table 14.1.3 
Demographic and Baseline Characteristics (ITT Population) 
Table 14.1.4 
Demographic and Baseline Characteristics (Safety Analysis 
Population) 
Section 14.2 
Pharmacodynamic/ Dose Proportionality Summaries 
Table 14.2.1 
Summary of Blood Bicarbonate and pH (Safety Analysis 
Population) 
Table 14.2.2 
Summary of Urine pH (Safety Analysis Population) 
Table 14.2.3 
Summary of Exploratory Biomarkers (Part 1 Cohort 6 and Part 2 
only) (Safety Analysis Population) 
Table 14.2.4 
Dose Proportionality Analysis of RJX AUC and Cmax (PK 
Evaluable Analysis Set) 
Figure 14.2.1.1 
Scatterplot Cmax versus dose in mg (PK Evaluable Analysis Set) 
Figure 14.2.1.2 
Scatterplot AUCinf versus dose in mg (PK Evaluable Analysis Set) 
Figure 14.2.1.3 
Scatterplot AUClast versus dose in mg (PK Evaluable Analysis Set) 
Section 14.3 
Safety Data Summaries 
Section 14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety 
Analysis Population) 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Analysis Population) 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by Severity 
Grade (Safety Analysis Population) 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
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Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Relationship 
to Investigational Product (Safety Analysis Population) 
Table 14.3.1.5 
Summary of Neurological Adverse Events of Interest by 
Relationship to Investigational Product (Safety Analysis 
Population) 
Table 14.3.1.6 
Summary of Infusion Related Adverse Events of Interest by 
Relationship to Investigational Product (Safety Analysis 
Population) 
Section 14.3.2 
Listings of Deaths, Other Serious and Certain Significant 
Adverse Events 
Table 14.3.2.1 
Listing of Adverse Events Leading to Death (Safety Analysis 
Population) 
Table 14.3.2.2 
Listing of Serious Adverse Events (Safety Analysis Population) 
Table 14.3.2.3 
Listing of Adverse Events Resulting in Discontinuation of Study or 
Study Drug (Safety Analysis Population) 
Section 14.3.3 
Narratives of Deaths, Other Serious and Certain Significant 
Adverse Events 
Section 14.3.4 
Abnormal Laboratory Value Listing 
Table 14.3.4.1 
Listing of Abnormal Laboratory Results (Safety Analysis 
Population) 
Table 14.3.4.2 
Observed and Change from Baseline for Clinical Laboratory 
Parameters (Safety Analysis Population) 
Table 14.3.4.3 
Hematology Laboratory Data Shift from Baseline to Post-Baseline 
Results by Part (Safety Analysis Population) 
Table 14.3.4.4 
Clinical Chemistry Laboratory Data Shift from Baseline to Post-
Baseline Results by Part (Safety Analysis Population) 
Table 14.3.4.5 
Urinalysis Laboratory Data Shift from Baseline to Post-Baseline 
Results by Part (Safety Analysis Population) 
Section 14.3.5 
Additional Safety Data Summaries 
Table 14.3.5.1 
Summary of Vital Sign Results by Part, Category, Treatment and 
Test (Safety Analysis Population) 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
Final  v3.0  
12FEB2020
 
 
CONFIDENTIAL 
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Table 14.3.5.2 
Absolute and Change from Baseline Vital Signs by Part, Treatment 
and Test (Safety Analysis Population) 
Table 14.3.5.3 
Observed and Change from Baseline for 12-Lead 
Electrocardiogram Parameters (Safety Analysis Population) 
Table 14.3.5.4 
12-Lead Safety ECG Interpretation (Safety Analysis Population) 
Table 14.3.5.5 
Listing of Abnormal or Out of Range QTcF Electrocardiogram 
Results (Safety Analysis Population) 
Table 14.3.5.6 
Summary of Concomitant Medication by Preferred Name (Safety 
Analysis Population) 
Listing Number 
Listing Name 
Section 16.1.7 
Randomization Scheme and Codes 
Listing 16.1.7 
Randomization Allocation (ITT Population) 
Section 16.2.1 
Discontinued Subjects 
Listing 16.2.1 
Subject Disposition (ITT Population) 
Section 16.2.2 
Protocol Deviations 
Listing 16.2.2 
Protocol Deviations (ITT Population) 
Section 16.2.3 
Subjects Excluded from Analysis 
Listing 16.2.3 
Exclusions from Analysis Populations (ITT Population) 
Section 16.2.4 
Demographic Data 
Listing 16.2.4.1 
Demographics and Baseline Characteristics (ITT Population) 
Listing 16.2.4.2 
Eligibility Criteria Satisfaction (ITT Population) 
Listing 16.2.4.3 
Consent Information (ITT Population) 
Listing 16.2.4.4 
Medical History (ITT Population) 
Section 16.2.5 
Compliance and/or Drug Concentration Data 
Listing 16.2.5.1 
Investigational Product Dosing Record (Safety Analysis 
Population) 


Reven Pharmaceuticals, Inc. 
Protocol No. RPI003 
 
ICON Project No. 3957-0002 
Statistical Analysis Plan 
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12FEB2020
 
 
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Listing 16.2.5.2 
Investigational Product Reconciliation (Safety Analysis Population) 
Section 16.2.7 
Adverse Event Listings 
Listing 16.2.7.1 
All Adverse Events (Safety Analysis Population) 
Listing 16.2.7.2 
Verbatim to Preferred Term Mapping of All Adverse Events 
Section 16.2.8 
Individual Laboratory Measurements by Subject 
Listing 16.2.8.1 
Normal Ranges for Laboratory Data 
Listing 16.2.8.2 
Clinical Laboratory Data by Category (Safety Analysis Population) 
Listing 16.2.8.3 
Urine Drug Screen/Drugs of Abuse (Safety Analysis Population) 
Listing 16.2.8.4 
Alcohol Breath Test (Safety Analysis Population) 
Listing 16.2.8.5 
Pregnancy and Follicle-Stimulating Hormone Tests (Women of 
Child-bearing Potential Only) (Safety Analysis Population) 
Listing 16.2.8.6 
Serology Results (Safety Analysis Population) 
Listing 16.2.8.7 
Vital Signs (Safety Analysis Population) 
Listing 16.2.8.8 
12-Lead Electrocardiogram Results (Safety Analysis Population) 
Listing 16.2.8.9 
12-Lead Electrocardiogram Results with Abnormal Clinically 
Significant Findings (Safety Analysis Population) 
Listing 16.2.8.10 
Physical Examination Findings (Safety Analysis Population) 
Listing 16.2.8.11 
Neurological Examination Findings (Safety Analysis Population) 
Listing 16.2.8.12 
Prior and Concomitant Medications (Safety Analysis Population) 
Listing 16.2.8.13 
Concomitant Procedures (Safety Analysis Population) 
Listing 16.2.8.14 
Pharmacodynamic Parameters (Safety Analysis Population) 
Listing 16.2.8.15 
Investigator Comments (Safety Analysis Population)