Conditions: Healthy Volunteers Chronic Kidney Disease
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 42
Healthy volunteers: yes

Brief summary:
This is a Phase 1b, single-center, dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effect of RBT-9 in healthy volunteers and in subjects with Stage 3/4 CKD.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: RBT-9
Intervention descriptions: intervention 1: intravenous administration

Protocol document:
Prot_000.pdf: 
  
 
Clinical Protocol REN-003 
 
A Phase 1b dose-escalating study with Stannous Protoporphyrin 
(SnPP), in healthy volunteers and subjects with chronic kidney 
disease stage 3-4 
 
 
IND 138109 
 
SPONSOR 
Renibus Therapeutics, Inc. 
950 E State Highway 114, Suite 160 
Southlake, TX 76092 
 
 
 
Original Protocol:  25 March 2019 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
Part or all of the information in this protocol may be unpublished material. Accordingly, 
this protocol is to be treated as confidential and restricted to its intended use. This 
material is the property of Renibus Therapeutics, Inc. and must not be disclosed or used 
except as authorized in writing by Renibus Therapeutics, Inc..
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 2 of 38 
Table of Contents 
1 
STUDY TITLE ............................................................................................................ 4 
2 
SPONSOR INFORMATION ...................................................................................... 4 
2.1 
Sponsor: ............................................................................................................... 4 
2.2 
Sponsor Representative:....................................................................................... 4 
3 
LIST OF ABBREVIATIONS ..................................................................................... 5 
4 
STUDY SYNOPSIS .................................................................................................... 7 
5 
EVENT SCHEDULE ................................................................................................ 14 
5.1 
Event Schedule – All subjects............................................................................ 14 
6 
INTRODUCTION ..................................................................................................... 15 
6.1 
Background Information .................................................................................... 15 
6.2 
Study Drug ......................................................................................................... 16 
6.3 
Preclinical Experience ....................................................................................... 16 
6.4 
Clinical Experience ............................................................................................ 16 
7 
STUDY OBJECTIVES ............................................................................................. 16 
7.1 
Primary Objectives............................................................................................. 16 
8 
INFORMED CONSENT ........................................................................................... 17 
9 
STUDY POPULATION ............................................................................................ 17 
9.1 
Healthy Volunteer (HV) .................................................................................... 17 
9.1.1 
HV Inclusion Criteria ................................................................................ 17 
9.1.2 
HV Exclusion Criteria............................................................................... 18 
9.2 
CKD Subjects..................................................................................................... 18 
9.2.1 
CKD Inclusion Criteria ............................................................................. 18 
9.2.2 
CKD Exclusion Criteria ............................................................................ 19 
9.3 
Study Design ...................................................................................................... 19 
9.3.1 
Stopping Rules .......................................................................................... 20 
9.4 
Recordkeeping and Monitoring ......................................................................... 20 
9.5 
Investigational Supplies ..................................................................................... 21 
9.5.1 
Study Drug Description ............................................................................ 21 
9.5.2 
Packaging .................................................................................................. 21 
9.5.3 
Investigational Product Dispensing .......................................................... 21 
9.5.4 
Dosage Preparation and Administration ................................................... 21 
9.5.5 
Storage Requirements ............................................................................... 22 
9.5.6 
Investigational Product Accountability ..................................................... 22 
9.5.7 
Retrieval and Destruction ......................................................................... 22 
9.6 
Study Visits ........................................................................................................ 22 
9.6.1 
General Information .................................................................................. 22 
9.6.2 
Screening (Within 14 Days Prior to Study Day 1) ................................... 22 
9.6.3 
Study Day 1............................................................................................... 23 
9.6.4 
Study Day 2............................................................................................... 24 
9.6.5 
Study Days 3,4,5,8 (Day 8 ± 1 day) .......................................................... 24 
9.6.6 
Study Day 14............................................................................................. 25 
9.6.7 
Study Day 29/End of Study Visit (28 ± 1 days following the SnPP dose) 25 
9.7 
Clinical Laboratory Evaluations ........................................................................ 25 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 3 of 38 
9.7.1 
Blood Chemistry, Hematology, Pharmacokinetic and Response biomarker 
Samples ..................................................................................................... 25 
9.7.2 
Urine Samples ........................................................................................... 25 
9.8 
Clinical Procedures and Observations ............................................................... 26 
9.8.1 
ECG........................................................................................................... 26 
9.8.2 
Concomitant Medications ......................................................................... 26 
9.8.3 
Physical Examination................................................................................ 26 
9.8.4 
Vital Signs ................................................................................................. 26 
9.8.5 
Meals and Dose Administration................................................................ 26 
9.8.6 
Prohibited Medications ............................................................................. 26 
10 ADVERSE EVENT REPORTING ........................................................................... 26 
10.1 Investigator Reporting Requirements ................................................................ 26 
10.2 Definitions.......................................................................................................... 27 
10.3 Breaking the Blind ............................................................................................. 29 
11 STATISTICAL CONSIDERATIONS ...................................................................... 29 
11.1 Study Populations .............................................................................................. 29 
11.2 Demographic and Baseline Characteristics ....................................................... 29 
11.3 Analysis of Efficacy Endpoints ......................................................................... 30 
11.4 Analysis of Pharmacodynamic/Safety Endpoints .............................................. 30 
11.5 Analysis of Pharmacokinetic (PK) Data ............................................................ 30 
11.6 Sample Size Calculations ................................................................................... 31 
11.7 Interim Analysis ................................................................................................. 31 
12 WITHDRAWAL FROM STUDY ............................................................................ 31 
13 DATA MANAGEMENT .......................................................................................... 32 
13.1 Database Lock .................................................................................................... 32 
14 ETHICAL CONSIDERATIONS .............................................................................. 32 
14.1 Ethical Conduct of the Study ............................................................................. 32 
14.2 Regulatory Considerations ................................................................................. 33 
14.3 Protocol Amendments and Study Termination .................................................. 33 
14.4 Safety Monitoring .............................................................................................. 33 
14.5 Quality Control and Quality Assurance ............................................................. 33 
15 GENERAL CONSIDERATIONS ............................................................................. 34 
15.1 Discontinuation of the Study ............................................................................. 34 
16 AGREEMENT WITH PROTOCOL ......................................................................... 35 
17 REFERENCES .......................................................................................................... 36 
 
 
Appendices 
 
Appendix 1 
Safety Clinical Chemistry, Hematology, and Urinalysis Tests Performed by the 
Laboratory at Screening, During the Study, and at Follow-up (EOS)……38 
 
 
 
 
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 4 of 38 
1 STUDY TITLE 
A Phase 1b dose-escalating study with Stannous Protoporphyrin (SnPP), in healthy volunteers 
and subjects with chronic kidney disease stage 3-4 
2 SPONSOR INFORMATION 
2.1 
Sponsor: 
Name: 
Renibus Therapeutics, Inc. 
Address: 
950 E State Highway 114, Suite 160 
 
Southlake, TX 76092 
2.2 
Sponsor Representative: 
Name: 
Bhupinder Singh, MD, FASN, FNKF, FCRS 
 
Title 
Chief Scientific Officer and Medical Monitor 
Affiliation: 
Renibus Therapeutics, Inc. 
Address: 
950 E State Highway 114, Suite 160 
Southlake, TX 76092 
Mobile: 
(480) 220-7084  
E-mail: 
medicalmonitor@renibus.com 
 
______________________________ 
 
_____________________ 
Bhupinder Singh, MD, FASN, FNKF, FCRS  
 
 
Date 
Chief Scientific Officer and Medical Monitor 
Renibus Therapeutics, Inc. 
 
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 5 of 38 
3 LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE  
Adverse event  
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ARB 
angiotensin-receptor blockers 
AST 
aspartate aminotransferase 
AUC(0-t) 
area under the concentration-time curve from time 0 to t 
AUC(0-inf) 
area under the concentration-time curve from time 0 to infinity 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CL 
clearance 
Cmax 
maximum serum or plasma concentration 
Cr 
creatinine 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FeS 
Iron sucrose 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
HO-1 
Heme oxygenase 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICSR 
Individual Case Safety Report 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
Ll-6 
Interleukin 6 
IL-10 
Interleukin 10 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
KDIGO 
KIM-1 
Kidney Disease: Improving Global Outcomes 
Kidney Injury Molecule-1 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 6 of 38 
Abbreviation 
Definition 
λz 
elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
NAG 
NGAL 
Modified Intent-to-Treat   
N acetyl-beta-D-glucosaminidase  
Neutrophil Gelatinase-Associated Lipocalin 
NOAEL 
no-observed-adverse-effect level 
PK 
Pharmacokinetic(s) 
POC 
Proof of Concept 
PP 
Per Protocol 
SnPP 
Stannous Protoporphyrin 
TEAE 
treatment emergent adverse event 
T½ 
elimination half-life  
Tmax 
time to maximum serum concentration 
Vz 
volume of distribution 
 
 
 
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 7 of 38 
4 STUDY SYNOPSIS 
Renibus Therapeutics, Inc. 
Protocol No. REN-003 
Name of Drug: Stannous Protoporphyrin (SnPP) 
Phase of Development: 1b 
Name of Active Ingredient:  
Stannous protoporphyrin (SnPP) 
Date of Study Synopsis 
25 March 2019 
Protocol Title: 
A Phase 1b dose-escalating study with Stannous Protoporphyrin (SnPP), in healthy volunteers 
and subjects with chronic kidney disease stage 3-4. 
Investigational Sites: 
One contract research organization in the US. 
Study Objectives: 
The primary objectives of the study are to evaluate: 
1. The safety and tolerability of SnPP in healthy volunteers and in subjects with stage 3-4 
chronic kidney disease (CKD). 
2. The effect of SnPP on biomarkers which are potential surrogates for cytoprotective 
activity in healthy volunteers and in subjects with stage 3-4 (CKD).  
3. To establish the optimal dose that could potentially be used in combination with iron 
sucrose for testing in subjects at risk for developing acute kidney injury (AKI). 
4. To study the Pharmacokinetics of SnPP 
Number Subjects to be Enrolled: 
Up to a total of 42 subjects consisting of 18 healthy volunteers and 24 subjects with chronic 
kidney disease will receive single escalating doses of SnPP. 42 subjects consisting of 18 healthy 
and 24 subjects with stage 3-4 CKD will be enrolled in one of three dose levels starting at the 
lowest dose of 9 mg SnPP for the Healthy volunteers and starting at the lowest dose of 27 mg 
SnPP for 3-4 CKD patients. 
Study Design: 
This is a Phase 1b, single-center, dose-escalating study to evaluate the safety, tolerability, PK and 
pharmacodynamic effect of SnPP in healthy volunteers and in subjects with stage 3-4 CKD. The 
following biomarkers will be used as surrogate measures of cytoprotective activity: Haptoglobin, 
Ferritin, Bilirubin, Hemopexin, IL-10, and Heme Oxygenase-1.  Additionally, the P21 biomarker 
will be monitored at various points of the study as well as urine biomarker response to SnPP.  
Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion 
criteria and none of the exclusion criteria are eligible to be enrolled into the study.   
The study is designed as follows: 
 
• 
A screening period with baseline evaluations for study eligibility. 
• 
Baseline for various biomarkers will be established by three different measurements in 
blood and urine prior to dosing. 
• 
If subjects meet eligibility criteria, they will receive a single dose of SnPP by slow 
intravenous injection over a 120-minutes on study day (SD) 1.  
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 8 of 38 
• 
Subjects will stay in the clinic for the initial 24 hours after administration of SnPP and 
will be discharged at the end of SD 2 if no safety issues appear. 
• 
The study will initially be dose-escalating in 3 groups of 6 healthy volunteers each, for a 
total of 18 healthy volunteers, evaluating escalating single dose of SnPP starting with a 
dose of 9 mg SnPP, followed by 27 mg SnPP, and 90 mg SnPP.  Dose-escalation from 
one dose level to the next will only be allowed after a careful review of the safety, 
tolerability and PK data from the prior dose group as determined by the Data and Safety 
Monitoring Board (DSMB). 
• 
After a careful review of the safety, tolerability and PK data from all dose groups from 
the healthy volunteer cohorts, the Data and Safety Monitoring Board (DSMB) will 
determine whether to proceed to the CKD cohorts. If the determination by the DSMB 
allows to proceed to the CKD cohorts, subjects with stage 3 CKD will be in 2 groups of 6 
each, for a total of 12 subjects, evaluating escalating single dose of SnPP starting with a 
dose of 27 mg SnPP followed by 90 mg SnPP.  Dose-escalation from one dose level to 
the next will only be allowed after a careful review of the safety, tolerability and PK data 
from the prior dose group as determined by the Data and Safety Monitoring Board 
(DSMB). 
• 
After a careful review of the safety, tolerability and PK data from all dose groups from 
the stage 3 CKD cohorts, the Data and Safety Monitoring Board (DSMB) will determine 
whether to proceed to the stage 4 CKD cohorts. If the determination by the DSMB allows 
to proceed to the stage 4 CKD cohorts, subjects with stage 4 CKD will be in 2 groups of 
6 each, for a total of 12 subjects, evaluating escalating single dose of SnPP starting with a 
dose of 27 mg SnPP followed by 90 mg SnPP.  Dose-escalation from one dose level to 
the next will only be allowed after a careful review of the safety, tolerability and PK data 
from the prior dose group as determined by the Data and Safety Monitoring Board 
(DSMB). 
• 
Subjects will be followed for 28 days after the dose of SnPP. Response biomarkers will 
be assessed at baseline and 2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 hours after study drug 
administration. Safety will be assessed for up to 28 days after study drug administration. 
• 
Blood samples for SnPP pharmacokinetic analysis will be assessed at baseline and 1, 2, 3, 
4, 6, 8, 12, 18, and 24 hours after study drug administration. These data will be used in 
the dose escalation decision making review process along with the safety and tolerability 
of the previous dose.  Urine samples will be collected and centrifuged and analyzed for 
subject responsiveness to SnPP therapy. 
• 
Urinary Clearance of SnPP will be assessed by the measurement of tin in a 24-hour urine 
sample 
• 
Total study duration will be 29 days for each subject, in addition to a screening period of 
up to 14 days. 
Endpoints: 
Pharmacodynamic/Safety Assessment: 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 9 of 38 
The safety and tolerability of SnPP will be assessed by determining the incidence, relationship to 
study drug, and severity of treatment-emergent adverse events (TEAEs), withdrawals due to 
adverse events (AEs), and changes in vital signs, laboratory tests, changes in concomitant 
medication use due to AEs, and other standard safety parameters. In addition, Blood Urea 
Nitrogen (BUN), creatinine, Cystatin-C, Kidney Injury Molecule-1 (KIM-1), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), albuminuria, N acetyl-beta-D-glucosaminidase 
(NAG), liver enzymes, and troponin I. 
Biomarker Monitoring 
The following biomarkers will be evaluated:  Haptoglobin (Hp), Ferritin and bilirubin, 
Hemopexin, IL-10, Heme Oxygenase 1 (HO-1) and P21, as well as urine biomarker response to 
SnPP. Biomarkers will be measured at baseline and 2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 hours 
after administration of SnPP. All biomarkers will be measured at the same time points. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 10 of 38 
Healthy Volunteer Subjects 
 
Inclusion Criteria: 
1. Male and female subjects age 18 to 80 years (inclusive, at time of ICF). 
2. Body weight <125 kg. 
3. Able and willing to comply with all study procedures. 
4. Female subjects must be either post-menopausal for at least 1 year or surgically sterile 
(tubal ligation, hysterectomy or bilateral oophorectomy) for at least 3 months, or if of 
childbearing potential, have a negative pregnancy test and agree to use dual methods of 
contraception, or abstain from sexual activity from Screening until 28 days after study 
drug administration.  
Male subjects with female partners of childbearing potential must agree to use a highly 
effective method of contraception from screening until 28 days after study drug 
administration. All fertile men with female partners of childbearing potential should be 
instructed to contact the Investigator immediately if they suspect their partner might be 
pregnant (e.g., missed or late menstrual period) at any time during study participation. 
Exclusion Criteria: 
1. History of malignancy except carcinoma in situ in the cervix, early stage prostate cancer 
or non-melanoma skin cancers. Cancer free for less than five years. 
2. Use of investigational drugs or participation in another clinical trial within 30 days or <5 
half-lives prior to screening, whichever is longer. 
3. Serum ferritin > 500 ng/ml or who have received IV iron within 28 days of screening. 
4. Women who are pregnant, breastfeeding, or planning to become pregnant while 
participating in the study. 
5. Any significant acute or chronic diseases.   
6. Subjects with abnormal baseline liver tests or hepatitis serologies that suggest 
active infection. 
7. Regular use of drugs of abuse and/or positive findings on urinary drug screening.  
8. Current tobacco use and/or positive findings on urinary cotinine screening.  
9. Subjects who are severely physically or mentally incapacitated and who, in the opinion of 
investigator, are unable to perform the subjects’ tasks associated with the protocol. 
10. Presence of any condition which, in the opinion of the investigator, places the subject at 
undue risk or potentially jeopardizes the quality of the data to be generated. 
11. Subjects with history of photosensitivity or active skin disease, which in the opinion of 
the investigator could increase the risk of photosensitivity. 
12. Known hypersensitivity or previous anaphylaxis to SnPP or tin based product. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 11 of 38 
CKD Subjects 
 
Inclusion Criteria: 
1. Male and female subjects age 18 to 80 years (inclusive, at time of ICF). 
2. Body weight <125 kg. 
3. Able and willing to comply with all study procedures. 
4. Female subjects must be either post-menopausal for at least 1 year or surgically sterile 
(tubal ligation, hysterectomy or bilateral oophorectomy) for at least 3 months, or if of 
childbearing potential, have a negative pregnancy test and agree to use dual methods of 
contraception, or abstain from sexual activity from Screening until 28 days after study 
drug administration.  
Male subjects with female partners of childbearing potential must agree to use a highly 
effective method of contraception from screening until 28 days after study drug 
administration. All fertile men with female partners of childbearing potential should be 
instructed to contact the Investigator immediately if they suspect their partner might be 
pregnant (e.g., missed or late menstrual period) at any time during study participation. 
5. CKD stage 3 as determined by a GFR between 30-59 ml/min as estimated using 
the CKD-EPI equation. 
6. CKD stage 4 as determined by a GFR between 15-29 ml/min as estimated using 
the CKD-EPI equation. 
Exclusion Criteria: 
1. History of malignancy except carcinoma in situ in the cervix, early stage prostate cancer 
or non-melanoma skin cancers.  Cancer free for less than 5 years. 
2. Use of investigational drugs or participation in another clinical trial within 30 days or 5 
half-lives prior to screening, whichever is longer. 
3. Serum ferritin > 500 ng/ml or who have received IV iron within 28 days of screening, or 
currently being treated with oral iron. 
4. Women who are pregnant, breastfeeding, or planning to become pregnant while 
participating in the study. 
5. Regular use of drugs of abuse and/or positive findings on urinary drug screening.  
6. Current tobacco use and/or positive findings on urinary cotinine screening.  
7. Subjects who are severely physically or mentally incapacitated and who, in the opinion of 
investigator, are unable to perform the subjects’ tasks associated with the protocol. 
8. Presence of any condition which, in the opinion of the investigator, places the subject at 
undue risk or potentially jeopardizes the quality of the data to be generated. 
9. Subjects with history of photosensitivity or active skin disease, which, in the opinion of 
the investigator could increase the risk of photosensitivity. 
10. Subjects with abnormal baseline liver tests or hepatitis serologies that suggest active 
infection. 
11. Subjects with CKD and not at their baseline of renal function and have significant acute 
or chronic illnesses. 
12. Known hypersensitivity or previous anaphylaxis to SnPP or to components thereof. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 12 of 38 
Drug, Dose and Mode of Administration: 
SnPP is supplied as a sterile liquid in vials for intravenous (IV) injection and intended for single 
use. Glass vials are plugged with Teflon-coated rubber stoppers and sealed with aluminum seals. 
Vials of 5 mL will be used for each cohort. 
SnPP at a dose of either 9 mg SnPP, 27 mg SnPP, or 90 mg SnPP will be administered on SD 1. 
The infusions will be given using a syringe pump over a 120-minute period. 
Rationale for the Dose and Schedule Selection: 
The proposed SnPP doses and administration schedules are based on previous human studies with 
SnPP and preclinical pharmacology and toxicology data. The proposed starting dose of 9 mg 
SnPP is 1/10 the NOAEL in rats and 1/36 the NOAEL in dogs based on body surface scaling 
in accordance with the conversion factors in Appendix A of the Guidance for Industry 
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers (2005) and a human body weight of 60 kg, and has previously 
been administered safely to human subjects.  
Study Duration: 
Study duration is for 29 days per subject. 
Criteria for Evaluation: 
Biomarkers 
• 
Key parameters: Haptoglobin, Ferritin, Hemopexin, IL-10, Heme Oxygenase 1 (HO-1) 
and Bilirubin. Urine samples will be collected and centrifuged and analyzed for subject 
responsiveness to SnPP therapy. 
• 
Additional secondary parameters: P21  
Pharmacodynamic/Safety parameters 
• 
Blood Urea Nitrogen (BUN), creatinine, Cystatin-C, Kidney Injury Molecule-1 (KIM-1), 
Neutrophil Gelatinase-Associated Lipocalin (NGAL), albuminuria, N acetyl-beta-D-
glucosaminidase (NAG), liver enzymes and troponin I at regular intervals 
• 
Adverse events, serious adverse events, suspected adverse reactions, and serious 
unexpected suspected adverse reactions  
• 
Laboratory safety data, vital signs, and temperature at regular intervals 
Pharmacokinetics 
• 
SnPP on SD 1 
Study Hypothesis: 
It is hypothesized that SnPP is safe and well tolerated up to the top dose of 90 mg SnPP. It is also 
hypothesized that SnPP will modulate biomarker levels in a dose-related fashion. 
Statistical Considerations 
Sample Size: No formal sample size calculation has been performed for this phase 1b study. 
However, it is believed that six subjects per dose group in the healthy volunteer cohorts (3) and 
the CKD stages 3 & 4 cohorts (2 each) will be adequate to establish POC based on biomarker 
response and identify an optimal dose for further testing, recognizing that a battery of different 
surrogate biomarkers will be evaluated 
Analysis Populations and General Methodology: All subjects who receive study medication 
will be included in the Safety population for safety analysis. Subjects who receive study 
medication and have a post-baseline efficacy assessment will be included in the Modified Intent-
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 13 of 38 
to-Treat (MITT) population for efficacy analysis. All subject data will be listed. When 
appropriate, summary statistics will be provided (number of non-missing values, mean, median, 
standard deviation, minimum, and maximum for continuous variables and number and percentage 
of subjects for categorical variables) by treatment group for all measures, including demographic 
and baseline assessments, safety, and efficacy endpoints. Baseline for all safety and efficacy 
endpoints is defined as the last observations before administration of the first IV infusion of study 
drug. No imputation will be used for missing data. 
Safety Analysis: Safety measures including AEs, infusion-related reactions, clinical laboratory 
tests, vital signs, physical exams, and concomitant medication usage will be summarized 
descriptively by treatment group and study visit, where appropriate.  
Biomarker Analysis: Biomarker response will be summarized by treatment group and study 
visit, comparing change from baseline at 2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 hours after start of 
infusion. 
Percent change from baseline will be analyzed using the mixed model for repeated measures 
(MMRM). The between-group comparison will be performed using the simple contrast at 2, 4, 8, 
12, 18, 24, 48, 72, 96 and 168 hours post-dosing 
In addition to absolute and percent changes from baseline, a responder analysis will also be 
considered. The responder definition and its appropriate analysis methodology will be detailed in 
the statistical analysis plan (SAP) for the study. Exploratory analysis using Cochran-Mantel-
Haenszel test stratified by baseline or primary diagnosis will be carried out. 
Pharmacokinetic Analysis: Pharmacokinetic parameters of each treatment group will be 
estimated using a non-compartmental analysis following completion of each dose and prior to 
dose escalation.  The maximum serum concentration (Cmax) and time to maximum serum 
concentration (Tmax) will be obtained directly from the data. The elimination rate constant (λz), 
elimination half-life (T½), area under the concentration-time curve from time 0 to time t (AUC[0-t]) 
and area under the concentration-time curve from time 0 to infinity (AUC[0-inf]), clearance (CL), 
and volume of distribution (Vz) will be calculated for each subject and summarized by treatment 
group. The renal excretion and renal clearance (CL) of tin will also be calculated. 
A compartmental model may be fit to the data if appropriate and used to predict plasma 
concentration-time profiles for other doses and regimens 
 
 
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
CONFIDENTIAL 
Page 14 of 38 
5 EVENT SCHEDULE 
5.1 
Event Schedule – All subjects 
Study Day 
Screening 
 
1 
2,3,4,5,81 
14** 
29/End of Study1 
Parameter 
Within 14 days prior to first dose 
 
 
 
 
Written informed consent 
X 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical examination and weight 
X 
X2 
 
 
X 
Electrocardiogram 
X 
X2,3 
 
 
X 
Vital signs 
X 
X2 
X 
 
X 
Serum chemistry8,9 
X 
X2 
X 
 
X 
Hematology8,9 
X 
X2 
X 
 
X 
Baseline determination13 
X 
X 
 
 
 
Response biomarkers8,11 
 
X2,4 
X 
 
 
Safety biomarkers8,12 
 
X2 
X 
X 
X 
SnPP PK4,11 
 
X 
 
 
 
Urinalysis including sediment9 
X 
X2 
X 
 
X 
Urine pregnancy test10 
X 
           X X at Day 8 
 
X 
Urine drug/alcohol/cotinine screen 
X 
 
 
 
 
Confinement in clinical testing unit5 
 
X5 
 
 
 
SnPP infusion 
 
X6 
 
 
 
Discharge from clinical testing unit 
 
 
X7 
 
 
Prior/Concomitant medications 
X 
X 
X 
 
X 
Adverse events 
 
X 
X 
 
X 
Investigational product reconciliation 
 
 
 
 
X 
 
1 
Day 8 visit will occur (± 1) days and End of Study (EOS) visit will occur 28 (± 1) days after administration of SnPP. 
2 
Baseline parameters performed prior to dosing on Study Day 1. 
3 
Two ECG’s will be performed on Study Day 1: the first at Baseline (prior to infusion) and the second within 10 minutes of 
infusion completion. 
4 
Blood samples for SnPP pharmacokinetic analysis will be assessed at baseline and 1, 2, 3, 4, 6, 8, 12, 18, and 24, hours (±15 
minutes) after start of infusion.  Additional biomarker samples will also be collected at 2, 4, 8, 12, 18 hours (±15 minutes) 
after start of SnPP. Urinary tin excretion will be measured on a 24-hour urine sample. 
5 
Subjects will be confined in the clinical testing unit a minimum of 24 hours from the morning of Study Day 1 until after 
collection of the 24-hour post-dose sample on Study Day 2. 
6 
SnPP will be administered by infusion over 120-minutes after Baseline ECG, vital signs and blood and urine samples are 
collected.  
7 
Discharge from unit following evaluations and sample collection required on Study Day 2 
8 
Measured fasting (nothing by mouth except water, coffee or tea, with or without milk and/or sugar, and essential medications 
only for a minimum of 8 hours prior to sample collection at the clinic).  
9 
Parameters to be measured are detailed in Appendix 1.  
10 For women of childbearing potential using kits supplied by the laboratory 
11 Haptoglobin, Ferritin, Bilirubin, Hemopexin, IL-10, P21 and HO-1. 
12 Cystatin-C, IL-6, SnPP, total porphyrin, Tin, Troponin I, albuminuria, Kidney Injury Molecule-1 (KIM-1), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), N acetyl-beta-D-glucosaminidase (NAG), (in addition to BUN/Cr which are part 
of the Serum Chemistry panel) 
13 Three measurements will be taken for the urinary safety biomarkers (albuminuria, Kidney Injury Molecule-1 (KIM-1), 
Neutrophil Gelatinase-Associated Lipocalin (NGAL),and N acetyl-beta-D-glucosaminidase (NAG)), eGFR, and response 
biomarkers prior to dosing. 
 
** Day 14 safety evaluation will be conducted at the request of the DSMB after each cohort safety review 
 
 
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6 INTRODUCTION 
6.1 
Background Information 
Acute kidney injury (AKI) is an abrupt loss of kidney function in which the body accumulates 
waste products and is unable to maintain electrolyte, acid-base, and water balance [Tögel 2014]. 
It is a major risk factor for morbidity, mortality, and the development of chronic kidney disease 
(CKD) [Goldberg 2009, Ishani 2009, Liangos 2006, Wald 2009, Xue 2006].  A meta-analysis of 
154 studies conducted worldwide in over 3.5 million subjects reported pooled incidence and 
mortality rates of AKI in hospitalized adult subjects of 21.6% and 23.9%, respectively 
[Susantitaphong 2013]. In cardiac surgery subjects, the incidence of postoperative AKI is 
approximately 30% and significantly increases the risk of death after cardiac surgery [Rosner 
2006]. Progression to advanced-stage CKD within 24 months occurs in approximately 15 to 20% 
of subjects who survive AKI [Chawla 2012]. 
Many different types of exposure may cause AKI; however, the chance of developing AKI after 
exposure depends on a number of susceptibility factors that vary widely among individual 
subjects [Kellum 2013].  Sepsis, critical illness, circulatory shock, burns, trauma, cardiac surgery 
(particularly with cardiopulmonary bypass), major non-cardiac surgery, nephrotoxic drugs, 
radiocontrast agents, and poisonous plants and animals are all recognized as causes of 
AKI.  Susceptibility factors that increase a subject’s risk of developing AKI include dehydration 
or volume depletion, advanced age, female gender, Black race, chronic kidney disease, chronic 
disease (heart, lung, liver), diabetes mellitus, cancer, and anemia. AKI can lead to a number of 
complications, including metabolic acidosis, hyperkalemia, uremia, changes in body fluid 
balance, and effects on other organ systems, including need for dialysis and possibly death. 
People who have experienced AKI have an increased risk of developing chronic kidney disease 
possibly requiring dialysis in the future. The annual cost to the US health care system is 
estimated at approximately $15B [Silver 2017]. 
The diagnosis of AKI is based on the following criteria introduced by the Kidney Disease: 
Improving Global Outcomes (KDIGO) AKI Work Group in 2012 [KDIGO 2012]: increase in 
serum creatinine ≥ 0.3 mg/dL within 48 hours; or increase in serum creatinine ≥ 1.5 times 
baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume 
< 0.5 mL/kg/hour for 6 hours. The management of AKI is purely symptomatic, with the aim of 
limiting damage and preventing further loss of function. No pharmacologic therapy is approved 
for the treatment or prevention of AKI. 
It has long been recognized that after an initial ischemic or toxic injury, the kidney develops 
marked resistance to subsequent damage [Honda 1987, Zager 1984, Zager 1995a, Zager 1995b, 
Zager 1995c]. This phenomenon, which is mediated in part by an upregulation of renal 
cytoprotective and anti-inflammatory stress proteins (e.g., heme oxygenase 1 [HO-1], ferritin, 
haptoglobin, hemopexin, alpha 1 antitrypsin, interleukin 10 [IL-10]), has been referred to as 
“ischemic preconditioning” or “acquired cytoresistance.” This phenomenon could be used in a 
clinical setting to preemptively protect organs, especially when a known insult is approaching. 
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6.2 
Study Drug 
A pharmacological intervention with the ability to stimulate the kidney’s natural protective 
pathways to prevent AKI would represent a significant medical advance. SnPP is under 
development as a prophylactic agent to induce cytoresistance in organs when a known insult is 
imminent. The initial target for development is the kidneys and prevention of AKI.  However, 
the phenomenon of acquired cytoresistance is also relevant to other bodily organs such as the 
heart and liver, and will be the focus of extended development of SnPP in combination with 
other agents, more specifically, Iron Sucrose (FeS.) 
Stannous protoporphyrin, a potent competitive inhibitor of heme oxygenase activity, is not 
commercially available, a 45 mg dose has been safely administered to healthy volunteers 
[Anderson 1986, Berglund 1988, Emtestam 1993], term newborns with hyperbilirubinemia 
[Kappas 1988], and adult subjects with hepatic dysfunction affecting heme metabolism or 
bilirubin conjugation [Anderson 1986, Berglund 1990] or porphyria [Dover 1993, Galbraith 
1989]. 
6.3 
Preclinical Experience 
Initial non-clinical pharmacology and toxicology studies have been conducted and are detailed in 
the Investigator’s Brochure.  Single-extended acute dose toxicity studies of intravenous SnPP 
demonstrated no-adverse-effect-levels of 10 mg/kg SnPP in the rat (human equivalent does of 96 
mg) and the dog (human equivalent dose of 324 mg).   
6.4 
Clinical Experience 
Safety data from intravenous SnPP administration at doses up to 3 mg/kg has shown 
photosensitivity in subjects when exposed to sunlight or UV-A light following dosing [Anderson 
1986, Berglund 1990, Dover 1993, Galbraith 1989, Kappas 1988].  No other adverse effects of 
SnPP administration have been consistently reported in the literature. 
7 STUDY OBJECTIVES 
7.1 
Primary Objectives 
The primary objectives of the study are to evaluate: 
1. The safety and tolerability of SnPP in healthy volunteers and in subjects with stage 3-4 
CKD. 
2. The effect of SnPP on biomarkers which are potential surrogates for cytoprotective 
activity in healthy volunteers and in subjects with stage 3-4 CKD.  
3. To establish the optimal dose for testing in subjects at risk for developing AKI. 
4. To study the Pharmacokinetics of SnPP 
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8 INFORMED CONSENT 
The investigator or designee will be responsible for obtaining a signed, written informed consent 
form (ICF) and providing a copy to each subject, legally authorized guardian, or a person with 
legal responsibility for the subject’s health care decisions prior to the performance of any clinical 
activities or procedures pursuant to this protocol. Subjects who are vision impaired may have the 
ICF read to them and their witnessed consent documented. Only the consent form approved by 
the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be used. If 
English is NOT the subject’s primary language, the subject will be consented using an IRB-
approved ICF in the requisite language. This consent will be conducted by a member of the 
research team who is fluent in the language and thus able to answer any scientific or procedural 
questions raised by a non-English speaking subject. 
Subject identity should be confirmed by the presentation of a photo identification to ensure the 
correct individual is consented, screened, and enrolled (if eligible). 
 
Only the PID, subject initials, and demographics will be recorded in the eCRF. If the subject 
name appears on any source document collected (e.g., hospital discharge summary), it must be 
removed from the document if the document will be viewed by the Sponsor or a sponsor-
contracted study vendor not permitted access to subject identifying information. All study 
findings will be stored in electronic databases. The subjects will give explicit written permission 
for representatives of the Sponsor, regulatory authorities, and the IRB to inspect their medical 
records to verify the information collected. Subjects will be informed that all personal 
information made available for inspection will be kept confidential to the extent permitted by all 
applicable state, local, and federal data protection/privacy laws and/or regulations and will not be 
made publicly available. If the results of the trial are published, the subject’s identity will remain 
confidential.  
 
At study check-in to the study site, subjects will be advised not to share their study information 
with other subjects. 
9 STUDY POPULATION 
9.1 
Healthy Volunteer (HV) 
9.1.1 HV Inclusion Criteria 
1. Male and female subjects age 18 to 80 years (inclusive, at time of signing the informed 
consent form [ICF]). 
2. Body weight <125 kg. 
3. Able and willing to comply with all study procedures. 
4. Female subjects must be either post-menopausal for at least 1 year or surgically sterile 
(tubal ligation, hysterectomy or bilateral oophorectomy) for at least 3 months, or if of 
childbearing potential, have a negative pregnancy test and agree to use dual methods of 
contraception, or abstain from sexual activity from Screening until 28 days after study 
drug administration.  
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Male subjects with female partners of childbearing potential must agree to use a highly 
effective method of contraception from screening until 28 days after study drug 
administration. All fertile men with female partners of childbearing potential should be 
instructed to contact the Investigator immediately if they suspect their partner might be 
pregnant (e.g., missed or late menstrual period) at any time during study participation. 
9.1.2 HV Exclusion Criteria 
1. History of malignancy except carcinoma in situ in the cervix, early stage prostate cancer 
or non-melanoma skin cancers. Cancer free for less than 5 years 
2. Use of investigational drugs or participation in another clinical trial within 30 days or 5 
half-lives prior to screening, whichever is longer. 
3. Serum ferritin > 500 ng/ml or who have received IV iron within 28 days of screening. 
4. Women who are pregnant, breastfeeding, or planning to become pregnant while 
participating in the study. 
5. Any significant acute or chronic diseases. 
6. Subjects with abnormal baseline liver tests or hepatitis serologies that suggest active 
infection. 
7. Regular use of drugs of abuse and/or positive findings on urinary drug screening.  
8. Current tobacco use and/or positive findings on urinary cotinine screening.  
9. Subjects who are severely physically or mentally incapacitated and who, in the opinion of 
investigator, are unable to perform the subjects’ tasks associated with the protocol. 
10. Presence of any condition which, in the opinion of the investigator, places the subject at 
undue risk or potentially jeopardizes the quality of the data to be generated. 
11. Subjects with history of photosensitivity or active skin disease 
12. Known hypersensitivity or previous anaphylaxis to SnPP. 
9.2 
CKD Subjects 
9.2.1 CKD Inclusion Criteria 
1. Male and female subjects age 18 to 80 years (inclusive, at time of ICF). 
2. Body weight <125 kg. 
3. Able and willing to comply with all study procedures. 
4. Female subjects must be either post-menopausal for at least 1 year or surgically sterile 
(tubal ligation, hysterectomy or bilateral oophorectomy) for at least 3 months, or if of 
childbearing potential, have a negative pregnancy test and agree to use dual methods of 
contraception, or abstain from sexual activity from Screening until 28 days after study 
drug administration.  
Male subjects with female partners of childbearing potential must agree to use a highly 
effective method of contraception from screening until 28 days after study drug 
administration. All fertile men with female partners of childbearing potential should be 
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instructed to contact the Investigator immediately if they suspect their partner might be 
pregnant (e.g., missed or late menstrual period) at any time during study participation. 
5. CKD stage 3 as determined by a GFR between 30-59 ml/min as estimated using the 
CKD-EPI equation. 
6. CKD stage 4 as determined by a GFR between 15-29 ml/min as estimated using the 
CKD-EPI equation. 
9.2.2 CKD Exclusion Criteria 
1. History of malignancy except carcinoma in situ in the cervix, early stage prostate cancer 
or non-melanoma skin cancers. Cancer free for less than 5 years. 
2. Use of investigational drugs or participation in another clinical trial within 30 days or 5 
half-lives prior to screening, whichever is longer. 
3. Serum ferritin > 500 ng/ml or who have received IV iron within 28 days of screening. 
4. Women who are pregnant, breastfeeding, or planning to become pregnant while 
participating in the study. 
5. Regular use of drugs of abuse and/or positive findings on urinary drug screening.  
6. Current tobacco use and/or positive findings on urinary cotinine screening.  
7. Subjects who are severely physically or mentally incapacitated and who, in the opinion of 
investigator, are unable to perform the subjects’ tasks associated with the protocol 
8. Presence of any condition which, in the opinion of the investigator, places the subject at 
undue risk or potentially jeopardizes the quality of the data to be generated. 
9. Subjects with abnormal baseline liver tests or hepatitis serologies that suggest active 
infection. 
10. Subjects with CKD and not at their baseline of renal function and have significant acute 
or chronic illnesses. 
11. Subjects with history of photosensitivity or active skin disease 
12. Known hypersensitivity or previous anaphylaxis to SnPP. 
9.3 
Study Design 
This is a Phase 1b, single-center, dose-escalating study to evaluate the safety, tolerability, PK 
and pharmacodynamic effect of SnPP in healthy volunteers and in subjects with stage 3-4 CKD. 
The following biomarkers will be used as surrogate measures of protective activity: Haptoglobin, 
Ferritin, Bilirubin, Hemopexin, IL-10, P21 and HO-1. 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion 
criteria and none of the exclusion criteria are eligible to be enrolled into the study.  A baseline 
for safety and response biomarkers will be established by taking three measurements between 
screening and prior to dosing. 
The study is designed as follows: 
• A screening period with baseline evaluations for study eligibility. 
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• If subjects meet eligibility criteria, they will receive SnPP by direct “push” infusion over 
a 120-minute period on SD 1.  
• Subjects will stay in the clinic for the initial 24 hours after administration of SnPP and 
will be discharged on SD 2 if no safety issues appear. 
• 
The study will initially be dose-escalating in 3 groups of 6 healthy volunteers each, for a total of 
18 healthy volunteers, evaluating escalating single dose of SnPP starting with a dose of 9 mg 
SnPP, followed by 27 mg SnPP, and 90 mg SnPP.  Dose-escalation from one dose level to the 
next will only be allowed after a careful review of the safety, tolerability and PK data from the 
prior dose group as determined by the Data and Safety Monitoring Board (DSMB). 
• 
After a careful review of the safety, tolerability and PK data from all dose groups from the 
healthy volunteer cohorts, the Data and Safety Monitoring Board (DSMB) will determine 
whether to proceed to the CKD cohorts. If the determination by the DSMB allows to proceed to 
the CKD cohorts, subjects with stage 3 CKD will be in 2 groups of 6 each, for a total of 12 
subjects, evaluating escalating single dose of SnPP starting with a dose of 27 mg SnPP followed 
by 90 mg SnPP.  Dose-escalation from one dose level to the next will only be allowed after a 
careful review of the safety, tolerability and PK data from the prior dose group as determined by 
the Data & Safety Monitoring Board (DSMB). 
• 
After a careful review of the safety, tolerability and PK data from all dose groups from the stage 3 
CKD cohorts, the Data and Safety Monitoring Board (DSMB) will determine whether to proceed 
to the stage 4 CKD cohorts. If the determination by the DSMB allows to proceed to the stage 4 
CKD cohorts, subjects with stage 4 CKD will be in 2 groups of 6 each, for a total of 12 subjects, 
evaluating escalating single dose of SnPP starting with a dose of 27 mg SnPP followed by 90 mg 
SnPP.  Dose-escalation from one dose level to the next will only be allowed after a careful review 
of the safety, tolerability and PK data from the prior dose group as determined by the Data and 
Safety Monitoring Board (DSMB). 
• The infusions will be given over a 120-minute period using a syringe pump.  
• Subjects will be followed for 28 days after the dose of SnPP. Response and Safety 
biomarkers will be assessed at baseline and (2, 4, 8, 12, 18, response biomarkers only) 
24, 48, 72, 96 and 168 hours after study drug administration. Safety will be assessed for 
up to 28 days after study drug administration.  Urine samples will be collected and 
centrifuged and analyzed for subject responsiveness to SnPP therapy. 
• Blood samples for pharmacokinetic analysis will be collected at baseline and 1, 2, 3, 4, 6, 
8, 12, 18 and 24 h post start of infusion. 
• Urinary excretion of SnPP will be assessed in a 24-hour urine sample by measuring tin in 
urine 
• Total study duration will be up to 29 days per subject. 
9.3.1 Stopping Rules 
There are no pre-established stopping rules for the study.   
9.4 
Recordkeeping and Monitoring 
All subject data will be reported in the electronic data capture (EDC) system with the exception 
of the laboratory reports, which will be uploaded by electronic transfer by the laboratory. All 
original source documents should be available for periodic monitoring and/or retrieval by a 
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Sponsor representative designee. The investigator is responsible for the accuracy of all data 
entered in the electronic case report forms (eCRFs) and for the timely completion of the 
electronic case report forms (eCRFs). The supporting documentation will be maintained at the 
site for a minimum of either: 
1. Two (2) years following notification by Renibus Therapeutics, Inc. to the FDA of the 
termination of the entire investigation. 
The Sponsor must be contacted and give written authorization prior to any study records being 
destroyed at investigative sites. 
This study will be conducted in compliance with Good Clinical Practice (GCP), which includes 
the Sponsor and Institutional Review Board (IRB) -approved protocol and ICF and the FDA and 
International Conference on Harmonisation (ICH) regulatory guidelines and requirements. No 
changes will be made without prior approval unless it is imperative for subject safety. Any such 
departures from the protocol will be reported immediately to the Sponsor and relevant IRB. 
All subjects’ medical records and study-related documents will be made available to the Sponsor 
for regular monitoring and audits as well as to the IRB and FDA or other governmental agency 
with oversight or compliance responsibilities for assuring subject rights and welfare. 
9.5 
Investigational Supplies 
Subjects will be dosed with open-label SnPP. 
9.5.1 Study Drug Description 
The investigational product is a mixture of Stannous protoporphyrin IX dichloride (SnPP) in a 
solution of sodium hydroxide 
The term investigational product refers to SnPP. 
9.5.2 Packaging 
SnPP will be packaged and labeled in filled vials of 5 ml at Patheon, Inc.. SnPP will be packaged 
in a clear vial protected from light. 
Following receipt of Form FDA 1572 and IRB approval for a given site, investigational product 
will be sent to the study site.  
9.5.3 Investigational Product Dispensing 
All investigational product will be dispensed by designated and trained site pharmacy staff.  
9.5.4 Dosage Preparation and Administration 
The vials of SnPP will be directly infused over a 120-minute period, further instructions will be 
included in the Pharmacy Manual.  
Total infusion time will be 120 (± 5) minutes as detailed in the Pharmacy Manual. 
Subjects will be observed for signs and symptoms of hypersensitivity during and after 
administration for at least 30 minutes and until clinically stable following completion of each 
administration. SnPP will only be administered when personnel and therapies are immediately 
available for the treatment of serious hypersensitivity reactions. 
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9.5.5 Storage Requirements 
The investigational product should be stored at controlled room temperature conditions (defined 
as 20 - 25°C/68 - 77°F with excursions of less than 24 consecutive hours permitted between 15 - 
30°C/59 - 86°F) and protected from light. 
9.5.6 Investigational Product Accountability 
The investigator or designee is responsible for maintaining accurate records accounting for the 
receipt, dispensing, and final disposition of all investigational products using the appropriate 
investigational product logs provided by Renibus Therapeutics, Inc. 
9.5.7 Retrieval and Destruction 
Periodically throughout the study, sites will perform investigational product reconciliation on a 
per-subject basis. The Renibus site monitor will review the log and once any discrepancies have 
been resolved, authorize destruction/disposition of the supplies associated with a given subject 
by signing the reconciliation log and will witness the destruction/disposition. 
9.6 
Study Visits 
9.6.1 General Information 
• All recorded clock times should utilize a 24-hour clock. 
• In accordance with the clinical site’s standard operating procedures, an intravenous 
catheter or a butterfly needle (of a sufficient gauge to avoid sample hemolysis) may be 
inserted for the purpose of collection of blood samples. Alternatively, the site preference 
may be to use direct venipuncture for the purpose of collection of blood samples. Either 
method is acceptable. 
• There are no dietary restrictions in this study. Subjects should continue to eat their 
normal diet.  
• Subjects will be encouraged to remain well hydrated during the study to promote sample 
collection. 
• Blood samples for Chemistry, Hematology, biomarkers and pharmacokinetic analysis 
will be collected into the appropriate collection tubes and processed in accordance with 
the instructions specified in the laboratory manual. 
• The ICF must be signed before any of the Screening or Study procedures are performed. 
9.6.2 Screening (Within 14 Days Prior to Study Day 1) 
1. Subjects will arrive at the clinical testing unit in the morning after fasting (defined as 
nothing by mouth except water) for at least 8 hours prior to the collection of any blood 
samples. 
2. Eligibility will be confirmed. 
3. Demographic characteristics and medical history will be obtained. 
4. Physical examination (including height and weight), vital signs (after sitting ≥ 5 minutes), 
and 12-lead ECG (after sitting ≥ 5 minutes) will be performed. 
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5. Blood and urine will be collected for clinical laboratory tests (Appendix 1) and 
drug/alcohol/cotinine screen. 
6. For women of childbearing potential, urine pregnancy test will be performed. 
7. Eligible subjects will return to the clinical testing unit within 14 days for confinement and 
dosing. 
8. An additional blood and urine sample will be taken between screening and prior to dosing 
on Study Day 1 in order to establish a baseline measurement for safety and efficacy 
biomarkers (a total of three measurements). 
9.6.3 Study Day 1 
1. 
Subjects will arrive at the clinic at 8:00am (± 60 minutes). 
2. 
All eligibility criteria will be assessed. 
For CKD subjects, subjects whose GFR value does not meet the inclusion criteria may 
be re-screened 2 more times during the trial. If the ICF has been signed within 30 days 
and there are no new revisions, a new ICF is not necessary. If a subject is re-screened, 
the subject will be given a new screening number in the eCRF system and source 
documents.  
3. 
If all eligibility criteria are met, the following Baseline samples will be collected 
(Appendix 1): 
• 
Blood samples for standard assessment of hematology and serum chemistry. 
• 
Blood samples for measurement of response biomarkers (Haptoglobin, Ferritin, 
Bilirubin, Hemopexin, IL-10, P21 and HO-1). 
• 
Blood samples for measurement of Safety biomarkers (Tin, Total Porphyrins, IL-6, 
Troponin I and Cystatin-C). 
• 
Blood samples for measurement of SnPP. 
• 
Urine for standard assessment of urinalysis parameters and safety biomarkers 
(albuminuria, Cystatin-C,  Kidney Injury Molecule-1 (KIM-1), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), and NAG). 
• 
Urine samples for measurement of response biomarkers (Hemopexin, Ferritin, P 21 
and HO-1), and for urinary clearance of SnPP.  Urine samples will be collected and 
centrifuged and analyzed for subject responsiveness to SnPP therapy. 
2. A Baseline ECG will be performed (Section 9.8.1). 
3. A full physical examination including height, weight, and vital signs will be performed 
(Sections 9.8.3 and 9.8.4). 
4. Medical history and prior/concomitant medication information will be collected. (Section 
9.8.2) 
5. Subjects who meet all inclusion/exclusion criteria will be enrolled into the Study and the 
following procedures will take place: 
• The dose of SnPP will be administered in the clinic as a “push,” direct infusion over a 
120 ± 5-minute period.  Food may be given after the infusion.  
 
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Observe for signs and symptoms of hypersensitivity during and after 
administration for at least 30 minutes and until clinically stable following 
completion of each administration. Only administer when personnel and 
therapies are immediately available for the treatment of serious hypersensitivity 
reactions. 
 
Should a subject experience nausea during or after infusion, the investigator 
may order Ondansetron (Zofran®) per its label instructions. Zofran may also be 
given prophylactically if at lower doses nausea is observed in subjects. 
• Patients will be advised on other interventions necessary to mitigate the risk of 
phototoxicity such as wearing a hat, sunglasses, long sleeve shirts and sunscreen 
with an SPF≥30, when appropriate,. 
• A post-infusion ECG will be performed 10 minutes (± 15 minutes) after the end of 
the infusion. 
• The clinic staff will solicit any adverse events. 
• Response biomarker samples will be collected at 2, 4, 8, 12, and 18 hours (± 15 
minutes) after the start of the infusion. 
• Blood samples for pharmacokinetic analysis will be collected at 1, 2, 3, 4, 6, 8, 12, 18 
and 24 hours (± 15 minutes) after the start of the infusion. 
• Lunch and dinner will be provided by the clinic. 
9.6.4 Study Day 2 
The following procedures will be done at 24 hours (± 15 minutes) after dosing: 
1. Blood samples for standard assessment of clinical chemistry, hematology, and safety and 
response biomarkers will be collected (Appendix 1). 
2. Blood samples for pharmacokinetic analysis will be collected. 
3. Urine samples for standard assessment of urinalysis parameters and response biomarkers 
will be collected (Appendix 1). 
4. The clinic staff will solicit any adverse events and note any changes in concomitant 
medications. 
5. The subject will be discharged from the clinic per site discharge procedures. 
9.6.5 Study Days 3,4,5,8 (Day 8 ± 1 day) 
1. Subjects will arrive at the clinic at 8:00am (± 60 minutes). 
2. Blood samples for standard assessment of clinical chemistry, hematology, and safety and 
response biomarkers will be collected (Appendix 1). 
3. Urine samples for standard assessment of urinalysis parameters and response biomarkers 
will be collected (Appendix 1). 
4. A urine pregnancy test will be performed if the subject is a woman of childbearing 
potential at Day 8. 
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5. The clinic staff will solicit any adverse events and note any changes in concomitant 
medications since the last visit.  
9.6.6 Study Day 14 
Study Day 14 safety review will be conducted at the request of the DSMB after the data 
assessment from each cohort. 
9.6.7 Study Day 29/End of Study Visit (28 ± 1 days following the SnPP dose) 
1. Subjects will arrive at the clinic at 8:00am (± 60 minutes). 
2. Blood samples for standard assessment of clinical chemistry, hematology, and safety 
biomarkers will be collected (Appendix 1). 
3. Urine samples for standard assessment of urinalysis parameters and safety biomarkers 
will be collected (Appendix 1). 
4. A full physical examination including weight and vital signs will be performed (Sections 
9.8.3 and 9.8.4).  
5. The clinic staff will solicit any adverse events and note any changes in concomitant 
medications since the last visit.  
6. A urine pregnancy test will be performed if the subject is a woman of childbearing 
potential. 
9.7 
Clinical Laboratory Evaluations 
All samples for clinical laboratory evaluations will be collected under fasting conditions, defined 
as nothing by mouth except water, and essential medications only (for CKD patients) for a 
minimum of 8 hours prior to collection of the samples.  
9.7.1 Blood Chemistry, Hematology, Pharmacokinetic and Response biomarker Samples 
The chemistry, hematology and response biomarker parameters to be evaluated during the study 
are presented in Appendix 1. Detailed instructions regarding sample collection and processing 
are provided in the laboratory manual. Collection times are summarized in the Events Schedules 
(Section 5 and Section 9.6). 
9.7.2 Urine Samples 
The urine parameters, including SnPP urinary excretion, and response biomarkers to be 
evaluated during the Study are presented in Appendix 1. Detailed instructions regarding sample 
collection and processing are provided in the laboratory manual. Collection times are found in 
the Events Schedules (Section 5 and Section 9.6). All urine samples will be analyzed by the 
laboratory, except for urine pregnancy tests for women of childbearing potential. 
All women of childbearing potential (defined as not surgically sterile nor postmenopausal for at 
least 2 years) will have a urine pregnancy test performed at the clinic as part of the screening 
procedure prior to any investigational product administration and at an End of Study using the 
pregnancy kit supplied by the laboratory.  
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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9.8 
Clinical Procedures and Observations 
The research clinic will follow its own standard operating procedures for the daily ongoing 
monitoring of subjects while subjects are in the clinic (e.g. pulse, O2 saturation, etc.). Subjects 
will be monitored for any adverse events occurring at any time throughout the study. 
9.8.1 
ECG 
ECGs will utilize a 12-lead recording. Collection times are summarized in the Events Schedules 
(Section 5 and Section 9.6). ECG results will be assessed by the investigator/sub-investigator.  
9.8.2 
Concomitant Medications 
All concomitant medications taken by the subject from 30 days prior to Study Day 1 through the 
end of study (28 [± 1] days after the dose of investigational product) will be recorded.  
9.8.3 
Physical Examination 
A full physical examination, including height (Study Day 1 only) and weight (weighed on the 
same scale in the same state of dress), will be conducted at Day 1 and at end of the study. 
Collection times are summarized in the Events Schedules (Section 5 and Section 9.6). 
All physical examinations are to be performed by the investigator/sub-investigator or designee 
whose license permits the performing of physical examinations. 
9.8.4 
Vital Signs 
Blood pressure (systolic and diastolic), pulse, and body temperature will be measured before 
investigational product is administered and after the subject has been in a sitting position for ≥ 5 
minutes. Collection times are summarized in the Events Schedules (Section 5 and Section 9.6). 
9.8.5 
Meals and Dose Administration 
There are no dietary restrictions in this study. Subjects should continue to eat their normal diet.  
Breakfast may be eaten before or after the infusion of SnPP on Study Day 1. 
9.8.6 Prohibited Medications 
Medications which can cause photosensitivity are prohibited for subjects in the Study. 
 
Oral iron medication may be taken prior to screening but must be discontinued upon enrollment. 
10 ADVERSE EVENT REPORTING 
All adverse events will be recorded on the designated study eCRF for each subject beginning 
with the first administration of investigational product and ending with the date of the end of 
study treatment follow-up. Any unresolved adverse events will be followed by the investigator 
until event resolution, the subject is lost to follow-up, the adverse event is otherwise explained or 
not considered clinically significant by the investigator. 
10.1 
Investigator Reporting Requirements 
The investigator must immediately report (within 24 hours by telephone and followed by a 
written report sent by fax or e-mail) all serious adverse events to Renibus Therapeutics, Inc. 
regardless of whether the investigator believes that they are drug related, including those events 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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listed in the protocol as anticipated to occur in the study population independent of drug 
exposure (see Section 10.2).  
These serious adverse events must be reported to: 
Bhupinder Singh, MD, FASN, FNKF 
 
Medical Monitor 
 
Renibus Therapeutics, Inc 
950 E State Highway 114, Suite 160 
Southlake, TX 76092 
Cell: 
 
(480) 220-7084 
Fax 
 
(817) 549-1254 
E-mail:   
medicalmonitor@renibus.com 
Because the investigator is knowledgeable about the human subject (e.g., medical history, 
concomitant medications), administers the investigational drug, monitors the subject’s response 
to the drug, is aware of the subject’s clinical state and thus may be sensitive to distinctions 
between events due to an underlying disease process versus events that may be drug-related, and 
may have observed the event, the investigator must include an assessment of causality (i.e., 
whether there is a reasonable possibility that the drug caused the event) in the report to Renibus 
Therapeutics, Inc Copies of each report to Renibus Therapeutics, Inc. will be kept in the 
investigator’s study file. 
The investigator is responsible for complying with their IRB’s requirements for reporting serious 
adverse events. Any expedited safety report (i.e., serious unexpected suspected adverse reaction) 
received from Renibus Therapeutics, Inc. should be submitted to the IRB. Copies of each report 
and documentation of IRB notification will be kept in the investigator’s study file. 
The investigator must record non-serious adverse events in the eCRF and report them to Sponsor 
according to the timetable for reporting (e.g., end of study). The investigator’s assessment of 
causality is not required for non-serious adverse events. 
10.2 
Definitions 
Adverse Event:  Adverse event means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. An adverse event can be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, without any judgment about causality. 
Adverse Reaction:  Adverse reaction means any adverse event definitely caused by the drug. 
Suspected Adverse Reaction: Suspected adverse reaction means any adverse event for which 
there is a “reasonable possibility” (i.e., evidence indefinite but suggests a causal relationship 
between the drug and the adverse event) that the drug caused the adverse event. By definition, a 
suspected adverse reaction is identical to the definition of adverse drug reaction per ICH E2A. 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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Examples that would suggest a causal relationship: 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture) 
• An aggregate analysis of specific events observed in a clinical trial (e.g., known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
Unexpected Adverse Event or Unexpected Adverse Reaction:  An adverse event or adverse 
reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed 
at the specificity or severity that has been observed. 
Adverse events or adverse reactions that are mentioned as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug will be considered “unexpected” if 
they are not specifically mentioned as occurring with the particular drug under investigation. 
Until the investigator brochure is updated to include a new serious suspected adverse reaction, 
subsequent occurrences of similar serious suspected adverse reactions must be submitted 
expeditiously to FDA in IND Safety Reports and to other appropriate regulatory authorities in 
countries other than the US in an Individual Case Safety Report (ICSR) or using a Council for 
International Organizations of Medical Sciences (CIOMS) I form, as appropriate. 
Serious Adverse Event or Serious Adverse Reaction:  An adverse event or adverse reaction is 
considered “serious” if, in the view of either the investigator or Sponsor, it results in any of the 
following outcomes: 
• Death 
• A life-threatening adverse event 
• In subject hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
If either the investigator or Sponsor believes that the event is serious, it must be evaluated by the 
Sponsor for expedited reporting to regulatory authorities. 
Life-Threatening Adverse Event or Life-Threatening Adverse Reaction:  An adverse event or 
suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or Renibus, its occurrence places the subject at immediate risk of death. 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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Page 29 of 38 
Serious Unexpected Suspected Adverse Reaction:  An adverse event for which there is a 
reasonable possibility that the drug caused the adverse event, and it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed, and it 
results in any of the serious outcomes listed above. This criterion is consistent with the concepts 
of FDA 21 Code of Federal Regulation (CFR) 312 and the ICH E2A Guideline for expedited 
safety reports. 
The Sponsor must notify the appropriate regulatory authority(ies) and all participating 
investigators in an expedited safety report (e.g., IND Safety Report or ICRS) of potentially 
serious risks from clinical trials or any other source (i.e., a serious unexpected suspected adverse 
reaction), as soon as possible, but no later than 15 calendar days after Renibus Therapeutics, Inc. 
receives the safety information and determines that the information qualifies for reporting. 
During the course of drug development, the Sponsor may become aware of new safety 
information from a variety of sources and will decide if an individual case of a serious and 
unexpected adverse event meets the criteria for reporting to regulatory authorities. 
If the adverse event does not meet all criteria (i.e., reasonable possibility of causality, serious and 
unexpected), it should not be submitted as an expedited safety report. 
Any unexpected fatal or life-threatening suspected adverse reaction must be reported to 
regulatory authorities no later than 7 calendar days after Renibus Therapeutics, Inc. receives the 
safety information. 
10.3 
Breaking the Blind 
Not applicable as this is an open label study. 
11  STATISTICAL CONSIDERATIONS 
This section outlines the nature and rationale for the statistical methods to be used for the 
analysis of the data from the study. A separate Statistical Analysis Plan (SAP) will describe data 
handling and statistical techniques in full detail. 
11.1 
Study Populations 
All subjects who receive study medication will be included in the safety and PD analyses. All 
subjects who receive study medication and provided sufficient and valid serum SnPP 
concentration data to allow the determination of PK parameters will be considered as potential 
PK evaluable subjects. No imputation will be used for missing data. 
11.2 
Demographic and Baseline Characteristics 
Demographic and baseline variables that will be summarized by dose group include:  
• 
Demographics   
• 
Medical history 
• 
Complete PE 
• 
Efficacy and Safety variables including vital signs and laboratory tests, including 
chemistry, hematology, and urinalysis obtained at Screening. 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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11.3 
Analysis of Efficacy Endpoints 
Descriptive statistics will be used to summarize Response biomarker results at baseline, each 
visit, and the change from baseline for each visit. 
Percent change from baseline will be analyzed using the mixed model for repeated measures 
(MMRM). In this analysis, percent change from baseline at each post treatment time point will 
be the response variable; treatment, visit, and treatment-by-visit interaction as fixed factors, 
patient as repeated measure unit over visits, and baseline as covariate. The between-group 
comparison will be performed using the simple contrast at 2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 
hours post-dosing. 
 
In addition to the percent changes from baseline, absolute change from baseline will also be 
analyzed using MMRM. Moreover, a responder analysis will also be considered. The 
responder definition and its appropriate analysis methodology will be detailed in the statistical 
analysis plan (SAP) for the study. Exploratory analysis using Cochran-Mantel-Haenszel test 
stratified by baseline or primary diagnosis will be carried out. 
11.4 
Analysis of Pharmacodynamic/Safety Endpoints 
The evaluation of safety will include adverse events, clinical laboratory parameters, vital signs, 
physical examinations, and ECGs.  
The principle of treatment emergence will be employed for the analysis of adverse event data. A 
Treatment emergent adverse event (TEAE) is defined to be any event that occurs during the 
observation period of the study and was not present at baseline, or exacerbation of a condition 
present at baseline.   
TEAEs will be classified by the Medical Dictionary for Regulatory Activities (MedDRA). The 
type, incidence, timing (onset, duration), relationship, and severity of adverse events will be 
reported for treatment-emergent and serious adverse events. Reasons for withdrawal due to 
adverse events will also be reported.   
Descriptive statistics, including mean, mean change from baseline, standard deviation, minimum, 
maximum, and median, will be presented for laboratory parameters, vital signs, and ECG 
parameters. The numbers and percentages of subjects with treatment-emergent laboratory, vital 
sign, and ECG values that meet Sponsor-defined potentially clinically significant criteria will be 
summarized. Categorical (low, normal, and high relative to the normal range) shifts from 
baseline will be summarized with the number and percentage of subjects for laboratory 
parameters. 
All safety data will be displayed in listings. 
11.5 
Analysis of Pharmacokinetic (PK) Data 
Pharmacokinetic (PK) parameters will be calculated for each subject and summarized by 
treatment group. PK profiles in which the pre-dose concentration is > 5% of the corresponding 
Cmax (and therefore greater than the lower limit of quantification [LLOQ]) will be excluded from 
all descriptive statistics and statistical analyses. 
For the PK analysis performed, actual blood sampling times will be used in all PK analyses. 
Protocol-specified times will be used to calculate mean plasma or serum concentrations for 
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Protocol Number: REN-003 (Original) 
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tabular and graphical displays. All PK calculations and generation of individual subject plasma 
or serum concentration versus time graphs will be performed using SAS®. 
PK parameters will be calculated using non-compartmental analysis. The maximum serum 
concentration (Cmax) and time to maximum serum concentration (Tmax) will be obtained directly 
from the data. The elimination rate constant (λz), elimination half-life (T½), area under the 
concentration-time curve from time 0 to time t (AUC[0-t]) and area under the concentration-time 
curve from time 0 to infinity (AUC[0-inf]), clearance (CL), and volume of distribution (Vz) will be 
calculated for each subject and summarized by treatment group.. Only plasma samples with 
concentrations ≥ LLOQ will be used in the PK analysis. Plasma concentrations < LLOQ will be 
taken as 0 for the calculation of the descriptive statistics at each sampling time. For the PK 
analysis, plasma concentrations < LLOQ that occur from pre-dose to the first concentration 
≥ LLOQ will be taken as 0 and those that occur thereafter will be taken as missing. 
The first dose escalation, from 9 mg to 27 mg, will be based on assuming a dose-proportional 
increase in Cmax and AUC and will use the maximum values across the first cohort. The 
subsequent decisions to escalate to the next dose level will be based on the available 
pharmacokinetic exposure data from the previous dose cohort(s) and compared with the exposure 
levels at the NOAEL established in the acute dose toxicity study in male and female Sprague 
Dawley rats.  The dose escalation decision will utilize best available modelling practices, i.e. fitting 
the power model to the individual subject Cmax and AUC vs. dose.  A dose will not be 
administered that would result in an upper 95th percentile for the model-predicted Cmax and AUC 
values exceeding 39,250 ng/mL and 209,500 hr.ng/mL (mean of males and females), respectively. 
These values were the observed values at the NOAEL of 10 mg/kg/day in the GLP toxicology 
study performed in Sprague Dawley rats.  
 
11.6 
Sample Size Calculations 
No formal sample size calculation has been performed for the study. However, it is believed that 
4 subjects per dose group will be adequate to establish POC based on biomarker response and 
identify an optimal dose for further testing, recognizing that a battery of different surrogate 
biomarkers will be evaluated. 
11.7 
Interim Analysis 
No interim analysis is planned.   
12 WITHDRAWAL FROM STUDY 
Every reasonable effort should be made to maintain protocol compliance and participation in the 
study. Should a subject withdraw or be prematurely terminated from the study for any reason, the 
reason for early study withdrawal will be recorded. If withdrawal is the result of a serious 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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adverse reaction, the subject will be followed until the condition has resolved, as determined by 
the investigator. 
The investigator or Sponsor may withdraw any subject at any time for medical reasons or for 
administrative reasons (i.e., subjects unable or unwilling to comply with the protocol). If so, the 
subject will be censored at time of withdrawal and, if possible, a final evaluation (End of Study 
procedures) will be made. All treated subjects (those who have received at least 1 dose of 
investigational product) will be included in the ITT and safety analyses. 
In the unlikely event the Sponsor or FDA should determine it is appropriate to terminate the 
study early, every effort will be made for transitioning subjects with minimal disruption to the 
subject and investigator. The IRB will be notified of termination, and reason(s) and procedures 
for follow-up of research subjects will be developed by the study physician in consultation with 
the Sponsor and IRB. 
13  DATA MANAGEMENT 
The standard procedures for handling and processing records will be followed as per GCP and 
the data management standard operating procedures of the contract research organization (CRO). 
A comprehensive Data Management Plan will be developed and approved by a representative of 
the Data Management CRO and the Sponsor. 
13.1 
Database Lock 
The database will be locked in order to protect write access after the following preconditions are 
fulfilled: 
• All data are entered in the database 
• All data queries have been resolved to the satisfaction of the Lead Biostatistician 
• All decisions have been made regarding all protocol violators and ITT population 
exclusions 
• The eCRF will be signed off/approved by the Site Investigator 
• Written authorizations to lock the database are obtained from Renibus Clinical Data 
Management and the Chief Scientific Officer. 
14 ETHICAL CONSIDERATIONS 
14.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with United States Title 21 CFR and the ICH E6 (R1) 
Guidelines of Good Clinical Practice. The Declaration of Helsinki and its most recent updates 
(Seoul, 2008) will be observed. 
The investigator will provide the Sponsor/designee with documentation of IRB approval of the 
protocol and the sample informed consent document before the study may begin at the 
investigative site. The IRB will review the protocol as required. 
The investigator will supply the following to the IRB: 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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• The current Investigator’s Brochure and updates 
• Study protocol and amendments 
• Informed consent and assent document and updates 
• Relevant curricula vitae 
• Safety alerts 
• Serious adverse reaction reports 
The investigator must provide the following documentation to the Sponsor or designee: 
• The IRB original approval of the protocol and the informed consent, and re-approval of 
the study (annual or semi-annual, per IRB guidelines) 
• The IRB approvals of any revisions to the informed consent document or amendments to 
the protocol 
• All other documents that are required by local regulatory authorities 
14.2 
Regulatory Considerations 
After reading the protocol, each investigator/sub-investigator will sign a protocol signature page 
and return a copy of the signed page to the Sponsor/designee, while maintaining the original at 
the site. 
14.3 
Protocol Amendments and Study Termination 
The IRB must be informed and give approval for any amendments likely to affect the safety of 
the subjects or the conduct of the study. 
The IRB must be advised in writing of the study’s completion or early termination and a copy of 
the notification must be provided to the Sponsor. 
14.4 
Safety Monitoring 
The Sponsor’s Medical Monitor and will monitor safety data throughout the course of the study. 
Renibus Drug Safety, or their designee, will expedite to the regulatory authorities only the 
suspected adverse reactions that are product-related and unexpected in accordance with FDA 21 
CFR 312, FDA draft guidance (Sept 2010) on Safety Reporting Requirements for INDs, and the 
ICH E2A guideline. 
14.5 
Quality Control and Quality Assurance 
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining 
quality control and quality assurance systems with written standard operating procedures to 
ensure that the study is conducted and data are generated, documented, and reported in 
compliance with the protocol, accepted standards of GCPs, and all applicable federal, state, and 
local laws, rules and regulations relating to the conduct of the clinical study. 
By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol, generally accepted standards of GCP, and all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical study. 
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Protocol Number: REN-003 (Original) 
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The investigator also agrees to allow monitoring, audits, IRB review and regulatory agency 
inspection of study-related documents and procedures and provide for direct access to all study-
related source data and documents. Investigators will be given notice before a quality assurance 
audit occurs. 
The investigator shall prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules and 
regulations, and promptly submit to the Sponsor all forms and reports required by this protocol 
following completion or termination of the clinical study or as otherwise required due to any 
agreement with the Sponsor. 
15 GENERAL CONSIDERATIONS 
15.1 
Discontinuation of the Study 
The Sponsor reserves the right to discontinue this study or investigator’s participation in this 
study for safety or administrative reasons at any time. 
 
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Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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16 AGREEMENT WITH PROTOCOL 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all sub-investigators and other study staff members have read and understand all aspects of 
this protocol. I agree to cooperate fully with Renibus Therapeutics, Inc. and its appointed 
Contract Research Organizations (CROs) during the study. I will adhere to all Food and Drug 
Administration (FDA), International Conference on Harmonisation (ICH), revised Declaration of 
Helsinki (2008) and other applicable regulations and guidelines regarding clinical trials on a 
study drug during and after study completion. 
Principal Investigator: 
Printed Name: 
 
Signature: 
 
Date: 
 
Protocol REN-003 
A Phase 1b dose-escalating study with Stannous Protoporphyrin (SnPP), in healthy volunteers 
and subjects with chronic kidney disease stage 3-4. 
Original Protocol: 
25 March 2019 
 
 
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IND 138109, SN 0008


Protocol Number: REN-003 (Original) 
Date: 25 March 2019 
 
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Page 36 of 38 
17 REFERENCES 
Anderson KE, Simionatto CS, Drummond GS, Kappas A.  Disposition of tin-protoporphyrin 
and suppression of hyperbilirubinemia in humans.  Clin Pharmacol Ther.  1986;39(5):510-20. 
 
Berglund L, Angelin B, Blomstrand R, Drummond G, Kappas A.  Sn-protoporphyrin lowers 
serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and 
potently inhibits hepatic heme oxygenase activity in normal human subjects. Hepatology. 
1988;8(3):625-31. 
 
Berglund L, Angelin B, Hultcrantz R, et al.  Studies with the heme oxygenase inhibitor 
Sn-protoporphyrin in subjects with primary biliary cirrhosis and idiopathic haemochromatosis. 
Gut. 1990;31:899-904. 
 
Chawla L, Kimmel P. Acute kidney injury and chronic kidney disease: an integrated clinical 
syndrome. Kidney Int. 2012;82:516-24. 
 
Dover SB, Moore MR, Fitzsimmons EJ, Graham A, McColl KE. Tin protoporphyrin prolongs 
the biochemical remission produced by heme arginate in acute hepatic porphyria. 
Gastroenterology. 1993 Aug;105(2):500-6. 
 
Emtestam L, Angelin B, Berglund L, Drummond GS, Kappas A.  Photodynamic properties of 
Sn-protoporphyrin: clinical investigations and phototesting in human subjects. Acta Derm 
Venereol. 1993;73(1):26-30. 
 
Galbraith RA, Kappas A.  Pharmacokinetics of tin-mesoporphyrin in man and the effects of 
tin-chelated porphyrins on hyperexcretion of heme pathway precursors in subjects with acute 
inducible porphyria. Hepatology. 1989;9:882-8. 
 
Goldberg A, Kogan E, Hammerman H, Markiewicz W, Aronson D. The impact of transient 
and persistent acute kidney injury on long-term outcomes after acute myocardial 
infarction.  Kidney Int. 2009;76:900-6. 
 
Honda IK, Hishida A, Ikuma K, Yonemura K. Acquired resistance to acute renal failure: 
editorial review.  Kidney Int.  1987;31:1233-8. 
 
Ishani A, Xue JL, Himmelfarb J, et al. Acute kidney injury increases risk of ESRD among 
elderly.  J Am Soc Nephrol. 2009;20:223-8. 
 
Kappas A, Drummond GS, Manola T, Petmezaki S, Valaes T. Sn-protoporphyrin use in the 
management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO 
incompatibility. Pediatrics. 1988;81(4):485-97. 
 
Kellum J, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: A 
KIDGO summary (part 1). Crit Care. 2013;17(1):204. 
 
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KDIGO AKI Work Group. KDIGO clinical practice guideline for acute kidney injury.  Kidney 
Int Supp.  2012;17:1-138. 
 
Liangos O, Wald R, O’Bell JW, Price L, Pereira BJ, Jaber BL. Epidemiology and outcomes of 
acute renal failure in hospitalized subjects: a national survey.  Clin J Am Soc 
Nephrol.  2006;1:43-51. 
 
Silver, S, Chertow, G. The Economic Consequences of Acute Kidney Injury. Nephron Clinical 
Practice. 2017;137:297-301. 
 
Susantitaphong P, Cruz D, Cerda J, et al.  World incidence of AKI: a meta-analysis.  Clin J 
Am Nephrol. 2013;8(9):1482-93. 
 
Tögel F, Westenfelder C. Recent advances in the understanding of acute kidney 
injury.  F1000Prime Rep. 2014;6:83. 
 
Wald R, Quinn RR, Luo J, Li P, Scales DC, Mamdani MM, Ray JG. Chronic dialysis and 
death among survivors of acute kidney injury requiring dialysis. JAMA. 2009;302:1179-85. 
 
Xue JL, Daniels F, Star RA. Incidence and mortality of acute renal failure in Medicare 
beneficiaries, 1992 to 2001. J Am Soc Nephrol. 2006;17:1135-42. 
 
Zager RA, Baltes LA, Sharma HM, Jurkowitz MS.  Responses of the ischemic acute renal 
failure kidney to additional ischemic events.  Kidney Int.  1984;26:689-700. 
 
Zager RA, Burkhart KM, Gmur DJ. Postischemic proximal tubular resistance to oxidant stress 
and Ca2+ ionophone-induced attack.  Implications for reperfusion injury. Lab 
Invest.  1995a;72:592-600. 
 
Zager RA.  Heme protein-induced tubular cytoresistance: expression at the plasma membrane 
level.  Kidney Int. 1995b;47:628-37. 
 
Zager RA. Obstruction of proximal tubules initiates cytoresistance against hypoxic 
damage.  Kidney Int. 1995c;47:628-37. 
 
Zager RA, Johnson AC, Frostad KB. Combined iron sucrose and protoporphyrin treatment 
protects against ischemic and toxin-mediated acute renal failure. Kidney Int. 2016;90:67-76. 
 
 
 
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Date: 25 March 2019 
 
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Appendix 1 
Safety Clinical Chemistry, Hematology, and Urinalysis Tests Performed by 
the Laboratory at Screening, During the Study, and at Follow-up (EOS) 
Clinical Chemistry1 
Hematology2 
Total protein 
Hemoglobin 
Albumin 
Hematocrit 
Bicarbonate 
Erythrocyte count (red blood cells) 
Blood urea nitrogen (BUN) 5 
Differential leukocytes  
Creatinine5 
Total leukocytes (white blood cells) 
Total bilirubin 
Platelets 
Alkaline phosphatase 
Urinalysis3 
Glucose 
pH 
Sodium 
Specific gravity 
Potassium 
Glucose 
Inorganic phosphate 
Ketones 
Calcium (total and ionized) 
Bilirubin 
Magnesium 
Urobilinogen 
Gamma-glutamyl transferase 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Cystatin-C5 
Tin5 
Tin Protoporphyrin 
IL-6 
Total porphyrins 
Blood 
P21 
HO-1 
Hemopexin 
Ferritin 
Urine sediment 
Urine samples to test for SnPP response  
SnPP Urinary excretion3’ 
N acetyl-beta-D-glucosaminidase (NAG) 
Kidney Injury Molecule-1 (KIM-1) 
Neutrophil Gelatinase-Associated Lipocalin 
(NGAL) 
Cystatin-C 
Albuminuria 
Urine pregnancy test4 
 
 
Response Biomarkers 
 
Haptoglobin 
Ferritin 
Hemopexin 
IL-10 
P21 
HO-1 
Bilirubin5  
 
 
1 
Collect into serum separator tubes. 
2 
Collect into K2 EDTA tubes.  
3 
Approximately 10 mL of urine required for urinalysis including sediment. 
3’ 
Urinary excretion to be tested in a 24-hour volume sample 
4 
Urine dipstick: all women of childbearing potential prior to the first dose of SnPP on Study Day 1 and End of Study. Perform in 
the clinic using the pregnancy kit supplied by the laboratory. 
5       Biomarkers run with standard Chemistry samples  
Renibus Therapeutics, Inc., RBT-1
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 1b dose-escalating study with Stannous Protoporphyrin (SnPP), in 
healthy volunteers and subjects with chronic kidney disease stage 3-4 
Protocol No.: IND 138109 
Protocol Date/Version: 25 March 2019 
IND No.: 138109 
Study Phase: 1b 
Study Drug: SnPP 
Statistical Analysis Plan 
Date/Version 
28 July 2019 
Version .1.0 
Prepared by: Annetta Krebs, MS 
Sponsor: Renibus Therapeutics, Inc.Renibus Therapeutics 
950 E State Highway 114, Suite 160 
Southlake, TX 76092 
Tel: (480) 220-7084 
Confidentiality Statement 
The information contained in this document is confidential and the property of Renibus Therapeutics, Inc.  
It should not be reproduced, revealed, or sent to third parties other than Institutional Review 
Boards/Independent Ethics Committees and the Investigator’s research support staff participating in the 
conduct of the study without the prior written authorization of Renibus Therapeutics, Inc. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 3 of 21 
28 July 2019 
Table of Contents 
1 
INTRODUCTION 
6 
2 
STUDY OBJECTIVES 
6 
3 
STUDY OVERVIEW 
6 
4 
EFFICACY, PHARMOCOKINETIC, AND SAFETY VARIABLES 
8 
5 
DEFINITIONS 
9 
6 
ANALYSIS POPULATIONS 
9 
7 
STATISTICAL METHODS OF ANALYSIS 
10 
7.1 
General Principles 
10 
7.1.1 
Handling Missing Values 
10 
7.1.1.1 
Study Drug Administration Date or Time 
10 
7.1.1.2 
Adverse Event or Concomitant Medications Dates or Times 
10 
7.1.1.3 
Adverse Event Severity or Relationship to Study Drug 
11 
7.1.2 
Multiplicity Adjustments 
11 
7.1.3 
By-Center Analyses 
11 
7.2 
Subject Disposition 
11 
7.3 
Description of Demographics and Baseline Characteristics 
12 
7.3.1 
Demographics 
12 
7.3.2 
Baseline Characteristics 
12 
7.4 
Prior and Concomitant Medications 
12 
7.5 
Measurements of Treatment Compliance 
13 
7.6 
Efficacy Analysis 
13 
7.6.1 
Percent Chamge in Response Biomarkers 
13 
7.6.2 
Absolute Chamge 
14 
7.6.3 
Responder Analysis 
14 
7.6.4 
Exploratory analysis 
15 
7.7 
Safety Analyses 
15 
7.7.1 
Adverse Events 
15 
7.7.2 
Laboratory Test 
16 
7.7.3 
Vital Signs 
16 
7.7.4 
ECG 
16 
7.8 
Pharmacokinetic Analysis 
17 
7.8.1 
Sample collections for Pharmacokinetic Analysis 
17 
7.8.2 
Pharmacokinetic Parameter Calculation Methods 
17 
7.8.3 
Pharmacokinetic Concentrations and Variables 
18 
7.9 
Interim Analysis 
18 
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Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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28 July 2019 
8 
SAMPLE SIZE CALCULATIONS 
18 
9 
REFERENCES 
19 
10 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
20 
10.1 
Event Schedule – All subjects 
20 
11 
CONVENTIONS FOR THE PRESENTATIONS OF TABLES, FIGURES AND LISTINGS21 
12 
LIST OF TABLES 
21 
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Renibus Therapeutics, Inc. 
Protocol: REN-003 
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Statistical Analysis Plan 
 
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List of ACRONYMS/Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
ARB 
angiotensin-receptor blockers 
AST 
aspartate aminotransferase 
AUC(0-t) 
area under the concentration-time curve from time 0 to t 
AUC(0-inf) 
area under the concentration-time curve from time 0 to infinity 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CL 
clearance 
Cr 
creatinine 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FeS 
Iron sucrose 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
HO-1 
Heme oxygenase 
Hp 
Haptoglobin 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICSR 
Individual Case Safety Report 
IEC 
Independent Ethics Committee 
IL-6 
Interleukin 6 
IL-10 
Interleukin 10 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
KIM-1 
Kidney Injury Molecule-1 
λz 
elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intent-to-Treat 
NAG 
N acetyl-beta-D-glucosaminidase 
NGAL 
Neutrophil Gelatinase-Associated Lipocalin 
NOAEL 
no-observed-adverse-effect level 
POC 
Proof of Concept 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
SAS 
Statistical Analysis System 
SnPP 
Stannous Protoporphyrin 
TEAE 
treatment emergent adverse event 
T½ 
elimination half-life 
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Renibus Therapeutics, Inc. 
Protocol: REN-003 
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Statistical Analysis Plan 
 
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Abbreviation 
Definition 
TFL 
Tables, Figures, and Listings 
Tmax 
time to maximum serum concentration 
Vz 
volume of distribution 
 
1 INTRODUCTION 
This is a Phase 1b single-center, dose-escalating study to evaluate the safety, tolerability, PK and 
pharmacodynamic effect of SnPP in healthy volunteers and in subjects with stage 3-4 CKD. The 
following biomarkers will be used as surrogate measures of cytoprotective activity: Haptoglobin, 
Ferritin, Bilirubin, Hemopexin, IL-10, and Heme Oxygenase-1.  Additionally, the P21 biomarker 
will be monitored at various points of the study as well as urine biomarker response to SnPP.   
The purpose of this statistical analysis plan (SAP) is to specifying the statistical approaches for the 
data analysis prior to database lock. This SAP covers the planned analyses of all data collected on 
the electronic case report forms (eCRFs). This SAP supersedes the statistical methods described 
in the clinical protocol. Deviations/changes from the planned analyses described in this SAP will 
be identified, with justification, in the appropriate section of the clinical study report. This SAP is 
developed based on the clinical study protocol REN-003, dated 29 March 2019.  
The reader of this SAP is encouraged to also read the clinical protocol and other related documents 
for details on the planned conduct of this study.  Operational aspects related to the collection and 
timing of planned clinical assessments are not repeated in this SAP unless relevant to the planned 
analyses. 
 
2 STUDY OBJECTIVES 
The primary objectives of the study are to evaluate: 
1. The safety and tolerability of SnPP in healthy volunteers and in subjects with stage 3-4 
chronic kidney disease (CKD). 
2. The effect of SnPP on biomarkers which are potential surrogates for cytoprotective 
activity in healthy volunteers and in subjects with stage 3-4 (CKD).  
3. To establish the optimal dose that could potentially be used in combination with iron 
sucrose for testing in subjects at risk for developing acute kidney injury (AKI). 
4. To study the Pharmacokinetics of SnPP. 
 
3 STUDY OVERVIEW 
This is a Phase 1b, single-center, dose-escalating study to evaluate the safety, tolerability, PK 
and pharmacodynamic effect of SnPP in healthy volunteers and in subjects with stage 3-4 CKD. 
The following biomarkers will be used as surrogate measures of cytoprotective activity: 
Haptoglobin, Ferritin, Bilirubin, Hemopexin, IL-10, and Heme Oxygenase-1.  Additionally, the 
P21 biomarker will be monitored at various points of the study as well as urine biomarker 
response to SnPP.  
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Renibus Therapeutics, Inc. 
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Product: SnPP 
Statistical Analysis Plan 
 
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Subjects who meet all inclusion criteria and none of the exclusion criteria are eligible to be enrolled 
into the study.   
The study is designed as follows: 
• A screening period with baseline evaluations for study eligibility. 
• If subjects meet eligibility criteria, they will receive SnPP by slow intravenous injection 
over a 120-minutes on study day1.  
• Subjects will stay in the clinic for the initial 24 hours after administration of SnPP and will 
be discharged at the end of study day 2 if no safety issues appear. 
• The study will initially be dose-escalating in 3 groups of 6 healthy volunteers each, for a 
total of 18 healthy volunteers, evaluating escalating single dose of SnPP starting with a 
dose of 9 mg SnPP, followed by 27 mg SnPP, and 90 mg SnPP.  Dose-escalation from one 
dose level to the next will only be allowed after a careful review of the safety, tolerability 
and PK data from the prior dose group as determined by the Data and Safety Monitoring 
Board (DSMB). 
• After a careful review of the safety, tolerability and PK data from all dose groups from the 
healthy volunteer cohorts, the Data and Safety Monitoring Board (DSMB) will determine 
whether to proceed to the CKD cohorts. If the determination by the DSMB allows to 
proceed to the CKD cohorts, subjects with stage 3 CKD will be in 2 groups of 6 each, for 
a total of 12 subjects, evaluating escalating single dose of SnPP starting with a dose of 27 
mg SnPP followed by 90 mg SnPP.  Dose-escalation from one dose level to the next will 
only be allowed after a careful review of the safety, tolerability and PK data from the prior 
dose group as determined by the Data and Safety Monitoring Board (DSMB). 
• After a careful review of the safety, tolerability and PK data from all dose groups from the 
stage 3 CKD cohorts, the Data and Safety Monitoring Board (DSMB) will determine 
whether to proceed to the stage 4 CKD cohorts. If the determination by the DSMB allows 
to proceed to the stage 4 CKD cohorts, subjects with stage 4 CKD will be in 2 groups of 6 
each, for a total of 12 subjects, evaluating escalating single dose of SnPP starting with a 
dose of 27 mg SnPP followed by 90 mg SnPP.  Dose-escalation from one dose level to the 
next will only be allowed after a careful review of the safety, tolerability and PK data from 
the prior dose group as determined by the Data and Safety Monitoring Board (DSMB). 
• Subjects will be followed for 28 days after the dose of SnPP. Response biomarkers will be 
assessed at baseline and 2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 hours after study drug 
administration. Safety will be assessed for up to 28 days after study drug administration. 
• Blood samples for SnPP pharmacokinetic analysis will be assessed at baseline and 1, 2, 3, 
4, 6, 8, 12, 18, and 24 hours after study drug administration. These data will be used in the 
dose escalation decision making review process along with the safety and tolerability of 
the previous dose.  Urine samples will be collected and centrifuged and analyzed for subject 
responsiveness to SnPP therapy. 
• Urinary Clearance of SnPP will be assessed by the measurement of tin in a 24-hour urine 
sample. 
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Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
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• Total study duration will be 29 days for each subject, in addition to a screening period of 
up to 14 days..Up to a total of 42 subjects consisting of 18 healthy volunteers and 24 
chronic kidney disease (stage 3-4) subjects will receive single escalating doses of SnPP.  
For a complete list of assessments performed throughout the study, see Time and Events Schedule 
(Section 10). 
 
4 EFFICACY, PHARMOCOKINETIC, AND SAFETY VARIABLES 
Efficacy Variables 
• Percent change from baseline in biomarkers at each postbaseline time point 
• Change from baseline in biomarkers at each postbaseline time point 
The biomarkers include the following pharmacodynamic variables 
• Haptoglobin (Hp) 
• Ferritin 
• Bilirubin 
• Hemopexin 
• IL-10 
• Heme Oxygenase 1 (HO-1) 
• P21 
The urine biomarkers include the following pharmacodynamic variables 
• Hemopexin 
• Ferritin 
• P21 
• Heme-Oxygenase 1 (HO-1) 
Pharmacokinetic (PK) Variables 
• Maximum serum concentration (Cmax) 
• Time to maximum serum concentration (Tmax) 
• Area under the concentration-time curve from 0 to last time point (AUC0-t) 
• Area under the concentration-time curve from 0 to infinity (AUC0-inf) 
• Terminal elimination rate constant (λz) 
• Terminal elimination half life (T1/2) 
• Clearance (CL) 
• Volumn of distribution (Vz) 
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Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
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• Renal excretion and renal clearance (CL) of tin 
Safety Variables 
• Treatment-emergent adverse events 
• Infusion-related reactions 
• Clinical laboratory tests 
• ECG 
• Vital signs 
• Physical exams 
• Concomitant medications 
 
5 DEFINITIONS 
Terminology 
Definitions 
Enrolled 
Subjects who signed the informed consent, meet all inclusion criterian and none of 
the exclusion criteria are entered into the study 
Completer 
Subjects who complete the End of Study (EOS) visit 
Study Day 
Day 1 is defined as the date subject took the study medication. Study Day for event 
post Day 1 is calculated as Event Date – Day 1 Date +1.  Study Day for event prior 
to Day 1 is calculated as Event Date – Day 1 Date.  Note:  There is no Day 0. 
Baseline 
Baseline is defined as the non-missing value collected most recent to and before the 
study of the study medication infusion 
Prior Medication 
Medication started and ended prior to the study drug infusion 
Concomitant 
Medication 
Medication taken on/after the study drug infusion. Concomitant medication may 
start prior to study drug infusion 
Treatment-
emergent 
Adverse Event 
Adverse event with onset date/time on or after the start of study drug infusion.   
 
6 ANALYSIS POPULATIONS 
The Safety Analysis Population will include all subjects who received study medication. This 
population will be used for all demographics, baseline characteristics, and safety summaries.  
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Renibus Therapeutics, Inc. 
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Statistical Analysis Plan 
 
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The Modified Intent-to-Treat (MITT) Population will include all subjects who received study 
medication and have a post-baseline efficacy assessment.  This population will be used for all 
efficacy analysis. 
The PK Analysis Population will include all subjects who receive study medication and provided 
sufficient and valid serum SnPP concentration data to allow the determination of PK parameters.  
This population will be used for the PK parameter summaries. 
 
7 STATISTICAL METHODS OF ANALYSIS 
7.1 
General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs).  All 
analyses and tabulations will be performed using SAS Version 9.4 or later.  Continuous variables 
will be summarized using descriptive statistics (sample size [n], mean, standard deviation [SD], 
minimum, median, and maximum).  Categorical variables will be tabulated with number and 
percentage of subjects.  Unless otherwise noted, percentages will be based on the number of 
subjects from the population, as appropriate. 
Individual subject data will be provided in listings.  All listings will be sorted by dose group (1 = 
9mg SnPP, 2 = 27mg SnPP, 3 = 90mg SnPP), stratum (CKD Stage 3 patients and CKD Stage 4 
patients versus healthy volunteer subjects), and collection date and time, where applicable, 
Unless otherwise noted, tabulations of categorical data will present only those categories appearing 
in the data.  
7.1.1 Handling Missing Values 
7.1.1.1 Study Drug Administration Date or Time 
It is expected that all necessary information on study drug administration (start and stop date and 
time) will be complete.  Any such information that is missing and cannot be obtained through 
query resolution may be imputed, on a case-by-case basis, in a conservative manner that minimizes 
bias. 
7.1.1.2 Adverse Event or Concomitant Medications Dates or Times 
For AEs or concomitant medications with missing or partially missing start/stop date/time, the 
following imputation rules will be applied: 
For partial start date/time: 
• If the year is unknown, then the date will be assigned as the date and time of first dose of 
study treatment. 
• If the month is unknown, then: 
i) 
If the year matches the year of study drug administration, then the month and day 
will be imputed to be the first month and day on study. 
ii) 
Otherwise, ‘January’ will be assigned. 
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Statistical Analysis Plan 
 
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• If the day is unknown, then: 
i) 
If the month and year match the month and year of the dose of the study drug 
administration date, then the day of the dose of earliest study drug administration 
date with matching month and year will be imputed. 
ii) 
Otherwise, ‘01’ will be assigned. 
• If the time is unknown, then: 
i) 
If the date (day, month, and year) matches the date of an administration of study drug, 
then the time of dose of study drug time from that date will be imputed. 
ii) 
Otherwise, ’00:00’ will be assigned. 
For partial stop date/time: 
• If the year is unknown, then the date will be assigned as the date subject discontinued from 
study, and the time will be set to the last time of the day (‘23:59’). 
• If the month is unknown, then the month subject discontinued from study will be assigned. 
• If the day is unknown, then the last day of the month will be assigned. 
• If the time is unknown, then the last time of the day will be assigned (‘23:59’). 
7.1.1.3 Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the event will be classified 
as ‘Severe’ and clearly footnoted.  If relationship to study drug is not reported for an AE, then for 
tables of study-drug related AEs, the event will be assigned the relationship of ‘definite’.  Tables 
presenting related AEs will include all AEs with relationships of ‘possible’, ‘probable’ or ‘definite’ 
as assessed by the investigator or defined as ‘definite’ when no investigtor assessment is made. 
7.1.2 Multiplicity Adjustments 
Not applicable. 
7.1.3 By-Center Analyses 
This is a single-center study. 
 
7.2 
Subject Disposition 
Subject disposition will be tabulated by dose group and overall and will present the number and, 
when appropriate, percentage of subjects who were: 
• Enroled 
o Not treated 
o Treated 
• In the safety analysis set 
• In the PK analysis set 
• In the MITT analysis set 
• Completed the study as planned 
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Statistical Analysis Plan 
 
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• Discontinued from the study, and 
• Reasons for discontinuation from the study 
Percentages for all rows will use the number of subjects treated as the denominator.   
The reasons for exclusion of subjects from the MITT and PK analysis set will be included in the 
data listing.   
Data will be summarized for each dose group and overall as well as by stratum (CKD Stage 3 
patients and CKD Stage 4 patients versus healthy volunteers). 
Note that the reasons for exclusion of a subject from the MITT and PK analysis set are not mutually 
exclusive, thus a subject may be excluded for mutliple reasons. 
 
7.3 
Description of Demographics and Baseline Characteristics  
7.3.1 Demographics  
The summary of demographic data will present: 
• Age (years) – descriptive statistics 
• Sex – n (%) 
• Ethnicity – n (%) 
• Race – n (%) 
 
Age is calculated from the date the subject signed the informed consent form (ICF) and birth.  It 
is presented as the number of years, rounding down to the nearest integer year.  For partial 
birthdates, impute the first of the month for missing day and January for missing month to calculate 
age.  It is presumed that birth year is known. 
The demographic summary will present the data for each dose group and overall as well as by 
stratum (CKD Stage 3 patients and CKD Stage 4 patients versus healthy volunteers).  Summaries 
will be provided for all (safety, MITT and PK) analysis sets.   
7.3.2 Baseline Characteristics 
The summary of baseline characteristic data will present: 
• Physical examination and weight 
• Electrocardiogram 
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be provided by dose 
group for the Safety Analysis Set.  
 
7.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODD version March 2019) and will be classified according to the default 
anatomical therapeutic chemical (ATC) classification and preferred term. 
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Statistical Analysis Plan 
 
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Prior medications are defined as medications with a stop date and time prior to the start of study 
drug administration.   
Concomitant medications are defined as medications taken after the start of study drug 
administration (i.e., started prior to the start of study drug administration and continued after or 
started after the start of study drug administration).   
Prior and concomitant medications will be summarized separately using n (%) of subjects for each 
dose group by ATC class and preferred term for the safety analysis set.   
Subjects may have more than one medication per ATC class and preferred term.  At each level of 
subject summarization, a subject will be counted only once if one or more medications are reported 
by the subject at the same level.  
 
7.5 
Measurements of Treatment Compliance 
Study treatment is administered by the site personnel other than the subject him/herself, therefore 
compliance is assured.   
 
7.6 
Efficacy Analysis 
7.6.1 Percent Chamge in Response Biomarkers  
The efficacy endpoint is the percent change (PCHT) in each response biomarker relative to the 
Baseline period.  
PCHT will be calculated as 100 x (T – B)/B, where T and B are Response biomarker at 2, 4, 8, 12, 
18, 24, 48, 72, 96 and 168 hours post dose (T) and baseline period (B).  
PCHT will be analyzed using a Mixed-Effect Model for Repeated Measure (MMRM) as follows: 
• A 2-way MMRM pooling stage 3 and stage 4 CKD patients and healthy subjects together  
• A 2-way MMRM pooling stage 3 and stage 4 CKD patients together 
• A 2-way MMRM for Healthy subjects 
The model will include dose level, visit (2, 4, 8, 12, 18, 24, 48, 72, 96 and 168 hours), and dose-
by-visit interaction as factors and baseline response biomarker as covariate.  The model parameters 
will be estimated using the restricted maximum likelihood method with the toeplitz variance-
covariance matrix and Kenward-Roger estimate for the denominator degrees of freedom. The 
between dose comparison will be performed using constrast in the main effect and the simple 
contrast at each time point. Least squares mean (LSM) and the associated 95% confidence interval 
(CI) for each dose level will be presented.  The difference in LSM between doses and the 95% CI 
for the difference will also be presented. Results will be presented for the pooled population, as 
well as for the CKD and healthy populations separately.  
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Statistical Analysis Plan 
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Additionally, LSM for each dose group will be plotted over time for the CKD patients and healthy 
volunteers pooled population as well as for each population separately. Dose response relationship 
will be examined graphically and may be analyzed where appropriate. 
A sample SAS code is provided as follows. The code assumes that “visit” has 10 values (2, 4, 8, 
12, 18, 24, 48, 72, 96 and 168 hours), “dose” is coded as 1 = 9 mg SnPP, 2 = 27 mg SnPP, and 3 
= 90 mg SnPP, “ckd” is coded as 2= CKD patients and healthy volunteers pooled, 1 = patients 
with CKD, 0 = healthy colunteers, and “resp” = PCHT, the % change from baseline being analyzed. 
ODS OUTPUT LSMEANS=lsm DIFFS=diff ESTIMATE=estm; 
PROC MIXED DATA=XXXX; 
BY ckd; 
CLASS dose usubjid visit; 
MODEL resp = base visit dose dose*visit / DDF=KR;  
REPEATED visit / SUBJECT=usubjid(dose) TYPE=UN; 
ESTIMATE "90 mg v 27 mg overall" dose  1 0 -1; 
LSMEANS dose / DIFF CL; 
ESTIMATE "90 mg v 27 mg @ 168 hours " dose 0 -1 1 
dose*visi 0 0 0 0 0 0 0 0 0 0 
0 0 0 0 0 0 0 0 0  -1 
0 0 0 0 0 0 0 0 0  1 / CL; 
RUN; 
ODS OUTPUT CLOSE; 
Note: Depending on the convergence status in the computation, Toeplitz (toep), 1st order 
autoregressive AR(1), and compound symmetry (CV) variance-covariance matrix will be applied 
sequentially.  The final analysis will be based on the first matrix leading to the convergence in the 
computation. 
7.6.2 Absolute Chamge 
In addition to the percent changes from baseline, absolute change from baseline will also be 
analyzed using MMRM. The method of analysis will be identical after replacing variable “resp” 
with “T-B”in Section 7.6.1. 
7.6.3 Responder Analysis 
Repeated measures responder analyses will be fitted using the generalized estimating equations 
(GEE) with PROC GENMOD in SAS for the proportion of patients reporting a response (defined 
as a 50% or greater reduction in each response biomarker from baseline) at each Visit. 
The model set up is similar to MMRM (Section 7.6.1).  A logit link function will be used for this 
binary response variable. The unstructured within-subject variance-covariance matrix will be 
assumed.  If computational convergence is an issue, other types of variance-covariance matrices 
will be explored. Odds ratios and 95% confidence intervals will be presented comparing proportion 
of responders between dose levels at each assessment timepoint. Results will be presented for the 
pooled population, as well as for the CKD and healthy populations separately. 
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Statistical Analysis Plan 
 
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Sample SAS code is given below. Variable “resp” is coded as 1 = Responder and 0 = Non-
Responder. 
  ODS OUTPUT LSMEANS=lsm DIFFS=diff ESTIMATE=estm; 
PROC GENMOD DATA=dataset; 
  BY ckd; 
  CLASS visit dose usubjid; 
MODEL resp(EVENT=’1’) = base visit dose dose*visit / LINK=LOGIT DIST=BIN; 
  REPEATED SUBJECT = usubjid /TYPE=UN; 
  LSMEANS dose / DIFF CL; 
RUN; 
ODS OUTPUT CLOSE; 
  
7.6.4 Exploratory analysis 
Percent change and change in each response biomarker will be analyzed using the Cochran-
Mantel-Haensel (CMH) test stratified by baseline. In the stratification, baseline will be divided 
into quintiles based on the pooled CKD and Healthy subjects in the MITT population.  Between 
group comparison will be carried out at each time point using the CMH test for row mean score 
difference (RMS) with the modified ridit scores. Analysis will compare the 90 mg group to the 27 
mg group at each timepoint overall and for CKD patients and healthy volunteers separately. 
Sample SAS code is as follows:  
 
PROC FREQ;  
BY visit; 
TABLE base*dose*resp / SCORE=MODRIDIT;  
RUN; 
 
7.7 
 Safety Analyses 
No inferential statistics are planned for any safety assessment.  
7.7.1 Adverse Events 
Safety assessments will be based mainly on the nature, frequency, relationship, and severity of adverse 
events (AEs). AEs will be coded by primary system organ class (SOC) and preferred term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) version 22.0. The treatment-
emergent adverse events (TEAEs) will be summarized by the number and percentage (n and %) of 
subjects in each SOC and PT. For summaries by relationship to study drug, “possibly related” will be 
combined with “related”, and “unlikely/remotely related” will be combined with “not related.” When 
multiple AEs are reported with the same preferred term, the AE of the strongest relation will be 
included in the summary by relationship, and the AE of the most severe grade will be included in the 
summary by severity table. 
The following AE incidence tables will be presented.  
• 
Overview of TEAEs to include  
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Statistical Analysis Plan 
 
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o Number (%) of subjects who reported at least one TEAE  
o Number (%) of subjects who reported at least one treatment-related TEAE  
o Number (%) of subjects who reported at least one severe TEAE  
o Number (%) of subjects who reported at least one serious TEAE  
o Number (%) of subjects who reported at least one TEAE leading to treatment 
discontinuation  
• 
TEAEs by PT sorted by decreasing order of subject incidence in the combined dose groups  
• 
TEAEs by SOC and PT sorted alphabetically  
• 
Study Drug-Related TEAEs by SOC and PT  
• 
TEAEs with Grade 2+ Severity by SOC and PT  
All AEs will be listed with onset/stop day, relationship to study drug, severity, action taken, and 
outcome. Pertinent subject information including dose group and demographics will also be included. 
Separate listings will be provided for TEAEs leading to study discontinuation, treatment-emergent 
serious AEs (TESAEs), and infusion-related TEAEs. 
7.7.2 Laboratory Test 
Hematology, biochemistry, and urinalysis test results will be summarized by dose group and visit 
using descriptive statistics.  For quantitative laboratory parameters, both actual values and change 
from baseline values will be summarized. 
Laboratory test result will be classified as low, normal, high (LNH) according to whether the value 
is below (L), within (N), or above (H) the reference range provided by the laboratory. Within-
treatment comparisons for hematology and chemistry will be based on the 3x3 shift tables that, for 
a particular laboratory test, showing how the LNH classification at baseline shifts to the LNH 
classification at postbaseline visit.  
A complete lab data listing, including hematology, biochemistry, and urinalysis will be provided 
for all subjects. 
7.7.3 Vital Signs 
Vitals signs are resting pulse (beats per minute), oral body temperature (oC), systolic blood 
pressure (mmHg), and diastolic blood pressure (mmHg).  Vital signs will be summarized by dose 
group at each scheduled timepoint.  Summaries will present both actual and change-from-baseline 
results.   
7.7.4 ECG 
The investigator evaluation for the overall ECG findings by normal, abnormal not clinically 
significant (NCS), and abnormal clinically significant (CS) will be tabulated with number and % 
of subjects at each time point.  
Actual and change from baseline in PR, QRS, QT, RR, QTc, and HR will be summarized with 
descriptive statistics at each time point.  
Data listings will be presented for ECG parameters by time point. QTc meeting the criteria of >450 
but ≤480, >480 but ≤500 or >500 msec for the actual value, or >30 msec or >60 msec increase 
from baseline will be identified. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 17 of 21 
28 July 2019 
 
7.8 
Pharmacokinetic Analysis 
7.8.1 Sample collections for Pharmacokinetic Analysis 
Blood samples will be obtained for PK analysis at baseline, before dosing and again at 1, 2, 3, 4, 
6, 8, 12, 18, and 24 hours post-dosing. 
7.8.2 Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be calculated by the noncompartmental analysis method from 
concentration-time data following these guidelines: 
• Actual sampling times relative to the start time of the study drug infusion will be used for 
all calculations of the PK parameters.  If the actual time is not available, the scheduled time 
will be used. 
• Concentrations from unscheduled PK blood samples will be used in the derivation of the 
parameters. 
• There will be no imputation of missing data. 
For the calculation of the non-compartmental parameters, 
• Pre-dose concentration ≥5% of the corresponding Cmax will be excluded from analysis. 
• Concentration below the lower limit of quantification (LLOQ) occurring from the predose 
to the first concentration ≥LLOQ will be set to zero.   
• All remaining concentration below LLOQ (BLOQ) will be set to missing. 
Pharmacokinetic parameters will be estimated according to the following guidelines: 
• 
The maximum observed plasma concentration (Cmax) will be obtained directly from the 
concentration-time data.   
• 
Time to maximum concentration (Tmax) is the time at which Cmax is observed. 
• 
The apparent terminal elimination rate constant (λz) will be estimated at terminal phase 
by linear regression after log-transformation of the concentrations: 
o Only those data points that are judged to describe the terminal log-linear decline 
will be used in the regression.  
o A minimum number of three data points in the terminal phase will be used in 
calculating λz with the line of regression starting at post-Cmax data point (Cmax 
will not be part of the regression slope) and including Clast and tlast. 
o The adjusted correlation coefficient (R2 adjusted) in general should be greater 
than 0.90.  Any value less than 0.90 may be used according to the 
pharmacokineticist's best knowledge and judgment. 
o An appropriate number of decimal places should be used for λz to enable the 
reported value of half-life (t½) to be calculated. 
• 
Half-life (t1/2) will be calculated as Loge(2)/λz. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 18 of 21 
28 July 2019 
• 
AUC will be calculated as follows: 
o The linear trapezoidal method will be employed for all incremental trapezoids 
arising from increasing concentrations and the logarithmic trapezoidal method 
will be used for those arising from decreasing concentrations. 
o 
∫
=
−
 t
0
)
0
(
)
( dt
t
C
AUC
t
 
o 
z
t
t
t
O
C
AUC
dt
t
C
dt
t
C
AUC
λ
/
)
(
)
(
)
0
(
 t
0
)
(
+
=
+
=
−
∞
∞
−
∫
∫
 
• 
Ct is the last observed quantifiable concentration. 
• 
Volume of distribution (Vd) will be estimated based on the teriminal phase as Dose/(
λz‧AUC0-∞). 
• 
Apparent clearance CL will be estimated as Dose/AUC0-∞.  
7.8.3 Pharmacokinetic Concentrations and Variables 
The analysis of the PK data will be based on the PK analysis set. 
Concentrations will be listed by dose group, subject, nominal time, and actual time.  
Concentrations that are below LLOQ will be indicated by BLOQ in this listing.  
Concentrations will be summarized by dose group at each time point.  The following descriptive 
statistics will be presented at each nominal time point: n, arithmetic mean, SD, geometric mean, 
%CV, median, minimum and maximum.  
PK parameters will be summarized.  Descriptive statistics for calculated PK parameters will 
include: n, arithmetic mean, SD, geometric mean, %CV, median, minimum and maximum values.  
The geometric mean and %CV will not be presented for Tmax. Values of %AUC extrapolated > 
20% will be flagged in the listings. 
Individual plasma concentration versus actual times will be plotted by dose in linear and semi-
logarithmic scale.  Mean plasma concentration at the scheduled timepoints will be plotted by dose 
group in linear and semi-logarithmic scale with the associated standard errors (SE only for the 
linear scale) at each scheduled timepoint.    
 
7.9 
Interim Analysis 
No interim analyses are planned for this study. 
 
8 SAMPLE SIZE CALCULATIONS 
No formal sample size calculation has been performed for the study. However, it is believed that 
6 subjects per dose group will be adequate to establish differences in biomarker response between 
groups.  
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 19 of 21 
28 July 2019 
9 REFERENCES 
 
 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
CONFIDENTIAL 
Page 20 of 21 
28 July 2019 
10 TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
10.1 
Event Schedule – All subjects 
Study Day 
Screening 
1 
2,3,4,5,81 
14** 
29/End of Study1 
Parameter 
Within 14 days prior 
to first dose 
Written informed consent
X 
Eligibility criteria 
X 
Demographics 
X 
Medical history 
X 
Physical examination and weight 
X 
X2 
X 
Electrocardiogram 
X 
X2,3 
X 
Vital signs 
X 
X2 
X 
X 
Serum chemistry8,9 
X 
X2 
X 
X 
Hematology8,9 
X 
X2 
X 
X 
Baseline determination13 
X 
X 
Response biomarkers8,11 
X2,4 
X 
Safety biomarkers8,12 
X2 
X 
X 
X 
SnPP PK4,11 
X 
Urinalysis including sediment9 
X 
X2 
X 
X 
Urine pregnancy test10 
X 
  X 
X at Day 8 
X 
Urine drug/alcohol/cotinine screen 
X 
Confinement in clinical testing 
unit5
X5 
SnPP infusion 
X6 
Discharge from clinical testing unit 
X7 
Prior/Concomitant medications 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
Investigational product 
reconciliation 
X 
1 
Day 8 visit will occur (± 1) days and End of Study (EOS) visit will occur 28 (± 1) days after administration of SnPP. 
2 
Baseline parameters performed prior to dosing on Study Day 1. 
3 
Two ECG’s will be performed on Study Day 1: the first at Baseline (prior to infusion) and the second within 10 minutes of 
infusion completion. 
4 
Blood samples for SnPP pharmacokinetic analysis will be assessed at baseline and 1, 2, 3, 4, 6, 8, 12, 18, and 24, hours (±15 
minutes) after start of infusion.  Additional biomarker samples will also be collected at 2, 4, 8, 12, 18 hours (±15 minutes) 
after start of SnPP. Urinary tin excretion will be measured on a 24-hour urine sample. 
5 
Subjects will be confined in the clinical testing unit a minimum of 24 hours from the morning of Study Day 1 until after 
collection of the 24-hour post-dose sample on Study Day 2. 
6 
SnPP will be administered by infusion over 120-minutes after Baseline ECG, vital signs and blood and urine samples are 
collected.  
7 
Discharge from unit following evaluations and sample collection required on Study Day 2 
8 
Measured fasting (nothing by mouth except water, coffee or tea, with or without milk and/or sugar, and essential 
medications only for a minimum of 8 hours prior to sample collection at the clinic).  
9 
Parameters to be measured are detailed in Appendix 1.  
10 For women of childbearing potential using kits supplied by the laboratory 
11 Haptoglobin, Ferritin, Bilirubin, Hemopexin, IL-10, P21 and HO-1. 
12 Cystatin-C, IL-6, SnPP, total porphyrin, Tin, Troponin I, albuminuria, Kidney Injury Molecule-1 (KIM-1), Neutrophil 
Gelatinase-Associated Lipocalin (NGAL), N acetyl-beta-D-glucosaminidase (NAG), (in addition to BUN/Cr which are part of 
the Serum Chemistry panel) 
13 Three measurements will be taken for the urinary safety biomarkers (albuminuria, Kidney Injury Molecule-1 (KIM-1), 
Neutrophil Gelatinase-Associated Lipocalin (NGAL),and N acetyl-beta-D-glucosaminidase (NAG)), eGFR, and response 
biomarkers prior to dosing. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


Renibus Therapeutics, Inc. 
Protocol: REN-003 
Product: SnPP 
Statistical Analysis Plan 
 
CONFIDENTIAL 
Page 21 of 21 
28 July 2019 
 
** Day 14 safety evaluation will be conducted at the request of the DSMB after each cohort safety review 
 
11 CONVENTIONS FOR THE PRESENTATIONS OF TABLES, FIGURES 
AND LISTINGS  
The specification for the tables, Figures and Listings are provided in a separate document. 
12 LIST OF TABLES  
Note, all tables will be repeated for CKD Patients Population and Healthy Subjects Population with Table 
numbers. 
Renibus Therapeutics, Inc., RBT-1
IND 138109, SN 0017


                                                                        
Page 1 of 4 
Statistical Analysis Plan_Amendment#1_REN003_v.1.0        C3: PROTECTED       CONTROLLED COPY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CliniOps, Inc. 
Fremont, CA, USA 
Tel: +1 408 829 4677 
www.cliniops.com 
 
 
 
 
 
CliniOps 
 
STATISTICAL ANALYSIS 
PLAN (AMENDMENT # 1) of 
REN003 
 
Version 1.0 
 
 
 
 
Enabling end-to-end eSourcing, 
Monitoring & Patient Engagement 
 
 
 
STATEMENT OF CONFIDENTIALITY / 
DISCLAIMER 
This document is the property of CliniOps, Inc. No 
part of this document shall be reproduced, stored in 
a retrieval system, or transmitted by any means, 
electronic, mechanical, photocopying, recording, or 
otherwise, without prior written permission from 
CliniOps, In


 
 
Page 2 of 4 
Statistical Analysis Plan_Amendment#1_REN003_v.1.0              C3: PROTECTED                CONTROLLED COPY 
1. 
STATISTICAL ANALYSIS PLAN DETAIL ............................................................................................................................... 3 
2. 
PURPOSE OF AMENDMENT ............................................................................................................................................. 3 
3. 
AMENDMENT CHECKLIST ................................................................................................................................................ 3 
4. 
SIGNATURE ..................................................................................................................................................................... 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 3 of 4 
Statistical Analysis Plan_Amendment#1_REN003_v.1.0              C3: PROTECTED                CONTROLLED COPY 
 
1. Statistical Analysis Plan Detail 
 
Client Name: 
Renibus Therapeutics, Inc. 
Study Name: 
A Phase 1b dose-escalating study with Stannous 
Protoporphyrin (SnPP), in healthy volunteers and 
subjects with chronic kidney disease stage 3-4 
Protocol: 
REN003 
Protocol No.: 
IND 138109 
Protocol Date/Version: 
25 March 2019  
IND No.: 
138109  
Study Phase: 
1b 
Study Drug: 
SnPP 
Statistical Analysis Plan Date/Version 28 July 2019 
Version.1.0 
Prepared by: 
Annetta Krebs, MS 
 
Sponsor: 
Renibus Therapeutics, Inc. 
950 E State Highway 114, Suite 160 
Southlake, TX 76092 
Tel: (480) 220-7084 
 
 
2. Purpose of Amendment 
 
The purpose of this amendment is to adjust the section on the SAP to reflect the following changes: 
- 
Define the baseline 
 
3. Amendment Checklist 
 
1. UPDATE the table in “SECTION 5: DEFINITIONS” to reflect the updated definition of ‘Baseline’:  
 
Terminology 
Definitions 
Enrolled 
Subjects who signed the informed consent, meet all inclusion criterian and none of the 
exclusion criteria are entered into the study 
Completer 
Subjects who complete the End of Study (EOS) visit 


 
 
Page 4 of 4 
Statistical Analysis Plan_Amendment#1_REN003_v.1.0              C3: PROTECTED                CONTROLLED COPY 
Terminology 
Definitions 
Study Day 
Day 1 is defined as the date subject took the study medication. Study Day for event 
post Day 1 is calculated as Event Date – Day 1 Date +1.  Study Day for event prior to 
Day 1 is calculated as Event Date – Day 1 Date.  Note:  There is no Day 0. 
Baseline 
Baseline is defined as the mean of three values from screening, study day -1 (one day 
before study day) and study day 1 prior to dosing 
Prior Medication 
Medication started and ended prior to the study drug infusion 
Concomitant 
Medication 
Medication taken on/after the study drug infusion. Concomitant medication may start 
prior to study drug infusion 
Treatment-
emergent Adverse 
Event 
Adverse event with onset date/time on or after the start of study drug infusion.   
 
2. Update the Table 14.3-2.1.1.1, Table  14.3-2.1.1.2, Table 14.3-2.1.1.3, Table 14.3-2.2.1.1 , Table 14.3-2.2.1.2, 
Table 14.3-2.2.1.3, Table 14.3-2.3.1.1, Table 14.3-2.3.1.2, Table 14.3-2.3.1.3, Table 14.3-3.1, Table 14.3-3.2 and 
Table 14.3-3.3 based on  updated definition of ‘Baseline’ 
 
*All other contents remain the same* 
4. Signature 
 
The following signature confirms that the activity mentioned above are completed by the responsible 
parties. 
 
 
 
 
 
 
 
 
 
 
 
 
Jeffrey Keyser 
President and COO 
Renibus Therapeutics, Inc 
Date 
 
 
 
 
 
 
 
 
 
October 1, 2020 
 
 
Anuradha Ghosh 
Data Science Lead and Project Manager 
CliniOps, Inc. 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
10/02/2020