A Phase II, Open-label Safety and Efficacy Study of an Autologous Neo-Kidney Augment (NKA) in Patients With Type 2 Diabetes and Chronic Kidney Disease
Phase: PHASE2
Conditions: Chronic Kidney Disease, Type 2 Diabetes
Sponsor: Prokidney

 
RegenMed (Cayman) Ltd. 
 
A PHASE II, OPEN-LABEL SAFETY AND EFFICACY STUDY OF AN 
AUTOLOGOUS NEO-KIDNEY AUGMENT (NKA) IN PATIENTS WITH 
TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE (RMCL-CL001) 
 
 
Protocol Date and Version: 28 April 2016, Version 1.3 
Replaces Protocol: 
 
27 August 2015, Version 1.2 
12 June 2015, Version 1.1 
30 April 2015, Version 1.0 
 
 
Study Team: 
Project Lead, 
RegenMed (Cayman) 
Ltd.  
Ashley H. Johns, MSHS 
Tel: 336-462-2293 
Fax: 919-294-8573 
Email: johnsclinicalconsulting@gmail.com  
Medical Monitor,  
CTI Clinical Trial 
and Consulting 
Services: 
William S. Aronstein, Ph.D., M.D., F.A.C.P. 
Tel: 513-598-9290 
Email: baronstein@ctifacts.com 
Manufacturing,  
Twin City Bio LLC 
Tom Spencer, PhD 
3929 Westpoint Blvd. Suite G 
Winston Salem, NC 27103 
Tel: 336-448-2857 
Email: tom.spencer@twincitybio.com  
 
 
 
Study Sponsor: RegenMed (Cayman) Ltd. 
Study References 
89 Nexus Way, Camana Bay 
NCT#: 02525263 
Grand Cayman, Cayman Islands 
EudraCT#: 2015-003156-49 
 
IND #: 16482 
 
 
 
 
This document is a confidential communication from RegenMed (Cayman) Ltd..  Acceptance of this document constitutes an agreement 
by the recipient(s) that no unpublished information contained herein will be published or disclosed without prior written approval from 
RegenMed (Cayman) Ltd., except that this document may be disclosed to appropriate Investigational Review Boards (IRBs) or Ethics 
Committees (EC) under the condition that they are also required to maintain confidentiality.    

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1 PROTOCOL SIGNATURE PAGE 
  
RMCL-CL001  
  
Protocol Version:  Version 1.3 
  
The signature of the Investigator below constitutes his approval of this protocol and provides the 
necessary assurances that this study will be conducted according to all stipulations of the 
protocol as specified in both the clinical and administrative sections, including all statements 
regarding confidentiality.  
This trial will be conducted in compliance with the protocol, in accordance with ICH GCP 
guidelines, in general in agreement with the most recent version of the Declaration of Helsinki, 
and in accordance with all applicable United States and European regulations.  
  
  
 
 
 
 
Sponsor:  RegenMed (Cayman) Ltd.,  
 
 
Date 
 
 
Investigator Name  
 
 
 
 
Investigator Signature   
 
Date 
 
 
  

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2 PROTOCOL SYNOPSIS 
  
Title:  A Phase II, Open-Label Safety and Efficacy Study of an Autologous Neo-Kidney Augment 
(NKA) in Patients With Type 2 Diabetes and Chronic Kidney Disease (RMCL-CL001)  
Therapeutic Product:  NKA is made from expanded autologous selected renal cell population 
(SRC) obtained from the patient’s kidney biopsy.  To manufacture NKA, kidney biopsy tissue from 
each enrolled patient will be sent to Twin City Bio, LLC, Winston Salem, North Carolina, where 
renal cells will be expanded and SRC selected.  SRC will be formulated in a gelatin based hydrogel at 
a concentration of 100 x 106 cells/mL, packaged in a 10 mL syringe, and shipped to the clinical site 
for use.    
Study Objectives:  
Primary Objective:  The primary objective of the study is to assess the safety and efficacy of NKA 
injected in one recipient kidney and determine if two injections of NKA provide stabilization of renal 
function.  
 
Primary Safety Outcome Measures:  procedure and/or product related adverse events (AE’s) 
through 12 months following the initial NKA injection.    
 
Primary Efficacy Outcome Measures: serial measurement of serum creatinine and estimation 
of GFR through 6 months following the second cell injection 
Secondary Objective:  The secondary objective of the study is to assess the safety and tolerability of 
NKA administration by assessing renal-specific adverse events over a 12 month period following a 
patient’s first NKA injection.  
 
Secondary Safety and Tolerability Outcome Measures:  renal-specific laboratory assessments 
through 12 months following the last NKA injection under this protocol, whether first or 
second.  
Exploratory Objective:  Exploratory objectives of the study are designed to assess the impact of 
NKA on renal function over a 12 month period following the initial NKA injection.  
 
Exploratory Outcome Measures:  clinical diagnostic and laboratory assessments of renal 
structure and function (including eGFR, serum creatinine, and proteinuria) to assess changes 
in the rate of progression of renal disease; and effect of method of injection on these 
parameters.  
 
Exploratory quality of life outcome measure will be the Kidney Disease Quality of Life 
survey obtained at baseline and at 1, 3, 6, 7, 9, 12, 15, 18, 30, and 42 months after a patient’s 
first NKA injection. 
Study Design:  Multi-center, prospective, open-label, single-group study. All enrolled subjects will 
be treated with up to two injections of NKA at least 6 months apart.  
Randomization:  Open-label, non-randomized.  

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Control Group:  Each subject will serve as his or her own control; the patient’s previous medical 
history, which must include a minimum 6 month period of observation of renal function, will serve as 
the comparator for rate of progression of renal insufficiency.    
Sample Size:  Up to 30 subjects will be injected with NKA.  As this is a Phase II safety and efficacy 
study, robust statistical analysis will not be performed.  Therefore, the sample size proposed for this 
study is a size typical for the active treatment group in Phase II studies, allowing for identification of 
safety outcomes and early efficacy in a limited population.  
Study Population:    
Male or female patients 30 to 70 years of age with Type 2 diabetes mellitus and CKD with eGFR 
between 20 and 50 mL/min/1.73m2. An enrolled patient should have sufficient historical clinical data 
to determine his or her individual rate of CKD disease progression.   
Inclusion Criteria:  Unless otherwise noted, inclusion criteria must be met at Screening and prior to 
injection.   
1. Male and female subjects, age 30 to 70 years on the date of informed consent.  
2. Patients with type 2 diabetes mellitus (T2DM). 
3. Patients with a well-established diagnosis of diabetic nephropathy as the underlying cause of 
their renal disease.    
4. At screening, patients not previously injected with NKA with CKD defined as a GFR of 20 – 
50 mL/min/1.73m2 inclusive. Patients previously treated with a single NKA injection with 
eGFR 15 to 60 mL/min may also enroll in this clinical trial. 
5. Microalbuminuria that cannot be explained by an alternative diagnosis.  Microalbuminuria is 
defined as urinary albumin-creatinine ratio (UACR) ≥ 30 mg/g or urine albumin excretion ≥ 30 
mg/day on 24 hour urine collection.    
6. Prior to biopsy, systolic blood pressure between 105 and 140 mmHg (inclusive) and diastolic 
blood pressure ≤90 mmHg.  
7. Ongoing and stable treatment with ACEI or ARB initiated at least 8 weeks prior to enrollment.  
Treatment must be stable for the 6 weeks immediately prior to injection.  Stable treatment is 
defined as dose adjustment to no less than ½ of the current dosage and no more than 2X the 
current dosage over the 6 week period immediately prior to injection; dose interruptions of up 
to 7 days due to medical necessity are allowed. Patients who are intolerant to ACEI or ARBs 
may be included as long as they have stable BP within the acceptable limits.  
8. Minimum of 2 measurements of eGFR or sCr taken at least 3 months apart (prior to screening) 
and within the previous 12 months to define the rate of progression of CKD.  The patient 
should have sufficient historical data to provide a reasonable estimate of the rate of progression 
of CKD as determined following consultation with the Medical Monitor (to insure sufficient 
data is available).  In addition, the rate of progression of CKD must be consistent over time.  
There is no defined rate of progression that is required to qualify for inclusion.    
9. Willing and able to refrain from use of NSAIDs (including aspirin) and clopidogrel, prasugrel, 
or other platelet inhibitors peri-procedure (i.e., before and after both the biopsy and injection).  
The wash-out period before and after each procedure should be 7 days.  Willing and able to 
refrain from use of fish oil and dipryridamole for 7 days before and 7 days after each procedure.  
10. Willing and able to cooperate with all aspects of the study.  
11. Willing and able to give signed informed consent.  
 

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Exclusion Criteria:  Patients may not be enrolled if they meet any of the exclusion criteria listed 
below.  Criteria should be assessed at Screening and before injection unless noted otherwise.   
1. Type 1 diabetes mellitus (DM).  
2. History of a renal transplant.  
3. HbA1c > 10% at Screening. Patients with HbA1c > 8% at the time of screening should be 
offered diabetic teaching and advised to consult their primary physicians for further diabetic 
management. 
4. Hemoglobin levels < 9 g/dL prior to injection.  Hemoglobin levels should be measured within 
48 hours before the procedure or per site standard practice.    
5. Known allergy to kanamycin or structurally similar aminoglycoside antibiotics (as kanamycin 
is used during manufacture of NKA).  
6. Abnormal coagulation status as measured by APTT, INR, and/or platelet count at Screening.  
7. Not a good candidate for the injection procedure (based on the assessment of the surgeon who 
will be performing the injection) including patients who are morbidly obese, have excessive fat 
surrounding the kidney, have BMI > 45, or who are otherwise at excessive risk for serious 
complications.    
8. Clinically significant infection requiring parenteral antibiotics within 6 weeks of injection.  
9. Patients with small kidneys (average size < 9 cm) or only one kidney, as assessed by MRI or 
renal US at screening or if previously done within 1 year of screening.   
10. Patients with a rapid decline in renal function over the last 3 months prior to injection or acute 
kidney injury.    
11. Patients with any of the following conditions prior to injection: renal tumors, polycystic kidney 
disease, renal cysts or other anatomic abnormalities that would interfere with injection 
procedure (e.g., cysts in the pathway of the injection), hydronephrosis, skin infection over 
proposed injection sites, or evidence of a urinary tract infection.    
12. Female subjects who are pregnant, lactating (breast feeding) or planning a pregnancy during the 
course of the study, or who are of child bearing potential and not using a highly effective 
method of birth control (including sexual abstinence). A highly effective method of birth 
control is defined as one that results in a low failure rate (i.e. less than 1 percent per year) when 
used consistently and correctly, such as implants, injectables, combined oral contraceptives, 
some intrauterine devices (IUDs), sexual abstinence, or a vasectomized partner. Subjects must 
be willing to continue birth control methods throughout the course of the study.  
13. History of cancer within the past 3 years (excluding non-melanoma skin cancer and carcinoma 
in situ of the cervix).  
14. Life expectancy of less than 2 years.  
15. Any contraindication or known anaphylactic or severe systemic reaction to either human blood 
products or materials of animal (bovine, porcine) origin or anesthetic agents.  
16. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C 
Virus (HCV) assessed at the Screening Visit.  
17. Subjects with active tuberculosis (TB) requiring treatment in the past 3 years.  
18. Immunocompromised subjects or patients receiving immunosuppressive agents (including 
patients treated for chronic glomerulonephritis) within 3 months of injection.  [Note:  inhaled 
corticosteroids and chronic low-dose corticosteroids [≤ 7.5mg per day] are permitted as are 
brief pulsed corticosteroids for intermittent symptoms (e.g. asthma).]  
19. Subjects with uncontrolled diabetes (defined as metabolically unstable by the PI), or with 
incapacitating cardiac and/or pulmonary disorders.  
20. History of active alcohol and/or drug abuse that in the investigator’s assessment would impair 
the subject’s ability to comply with the protocol.  
21. Patients with clinically significant hepatic disease (ALT or AST > 3.0 x ULN) at Screening.  

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22. Patients with bleeding disorders that would, in the opinion of the Investigator, interfere with the 
performance of study procedures; patients taking coumarins (e.g. Warfarin) or other 
anticoagulants (e.g. enoxaparin or direct thrombin inhibitors).    
23. Any circumstance in which the investigator deems participation in the study is not in the 
subject’s best interest.  
24. Use of any investigational product within 3 months of the injection without receiving prior 
written consent of the Medical Monitor.     
Number of Sites:  Up to 10 clinical centers will be included in the study.  
Study Duration: 18 months NKA injections follow up followed by 24 month long term follow up for 
a total study duration of 42 months.  
Study Enrollment: Up to 30 subjects undergoing NKA injection will be enrolled into the study.  
Patients who have received a single injection of NKA under previous research protocols may enroll in 
this clinical trial to receive a single additional injection.  Patients who have never received an NKA 
injection may enroll in this clinical trial for up to a total of two (2) NKA injections, temporally spaced 
at least 6 months apart. All biopsies are to be taken from a single kidney, and all NKA injections are 
to be given into the kidney that was biopsied. Patients who complete screening procedures satisfying 
all I/E criteria will be enrolled into the study immediately prior to the injection.  Patients who do not 
meet all criteria before injection will be considered screen failures.  Once a patient has been injected, 
the patient will have completed treatment and every effort should be made to ensure the patient 
completes all follow-up visits.  Injection dates for the first 3 patients receiving their second NKA 
injection will be staggered by a minimum of 3 week intervals to allow for assessment of acute adverse 
events and other safety parameters by the DSMB.  Subsequent second injections will continue to be 
staggered so as to occur no less than 3 weeks apart, but individual DMSB review will not be required. 
At the completion of the follow-up visits, patients will continue in a long-term follow-up study.  
Patients will be followed for a total of 36 months following the last NKA injection under this 
protocol, whether the first or second injection.  
Investigational Plan:   
Screening:  Subjects who satisfy eligibility criteria may be entered into the study.  Subjects must 
have sufficient historical data on renal function to allow for determination of the rate of progression 
of renal disease prior to injection (Inclusion Criterion 8).  Screening procedures will include a full 
physical examination, electrocardiogram, and laboratory assessments (hematology, serum chemistry, 
and urinalysis).  In addition, an MRI will be performed to assess kidney volume using site standard 
practices.  
Biopsy: Patients not previously enrolled in a Phase 1 trial will require a renal biopsy to obtain the 
cells for injection. The biopsy specimens obtained from patients previously enrolled in a Phase 1 trial 
and maintained in a frozen state will be used to generate the second quantum of NKA to be injected 
under this protocol, if sufficient cells are available after thawing.  If the number of cells obtained after 
thawing the frozen biopsy specimens is insufficient, the patient may need to have an additional biopsy 
procedure completed for this study.  
Injection:  Ten to 14 days before the scheduled injection date, subjects will report to the clinic for 
verification of final eligibility criteria.  In addition, a renal scintigraphy study will be performed to 
obtain a baseline assessment of split kidney function.  Subjects who meet appropriate I/E criteria will 

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be admitted to the hospital/clinical research unit early in the morning on the day of scheduled 
injection (Day 0).  NKA will be injected into the biopsied kidney, using one of two available options: 
(1) a laparoscopic approach; or (2) a percutaneous approach.  The laparoscopic method may utilize 
robotic assistance to stabilize the kidney while the injection is performed with laparoscopic viewing; 
while the percutaneous method will employ a standardized technique such as utilized in the ablation 
of renal masses by radiofrequency or cryogenic methods.  Subjects will remain hospitalized for a 
minimum of 2 nights and up to 4 nights following a laparoscopic injection (or until any procedure- or 
product-related AE’s have resolved or stabilized).   Patients may be discharged the same day 
following a percutaneous injection without complications.  An ultrasound study will be performed on 
Day 1 to verify the lack of subclinical adverse effects for both approaches. 
It is anticipated that all patients will be planned to receive 2 injections under this protocol, in order to 
allow dose-finding and to understand the duration of effect. Under certain circumstances a patient or 
investigator may decide to postpone or withhold the second dose.  In general, if there appears to be 
any untoward safety risk, in situations including rapid deterioration of renal function, the 
development of uncontrolled diabetes, or the development of uncontrolled hypertension, or if there is 
the intercurrent development of a malignancy, the patient should not receive the second dose. 
Second injections under this protocol will be staggered so that single injections in different patients 
occur no less than 3 weeks apart. The DSMB will review the clinical data regarding each of the first 3 
second injections under this protocol, and will consult with the Sponsor before the 2nd, 3rd, and 4th 
second injections are made.  Subsequent second injections will continue to be staggered so as to occur 
no less than 3 weeks apart, but individual DMSB review will not be required. 
No staggering will be required for first NKA injections under this protocol.  
Post-Injection Follow-up:   Subjects will return to the clinic for follow-up safety assessments on 
Days 7, 14, and 28 post-injection and at 2, 3, and 6 months post-injection.  At 6 months post-
injection, post-treatment MRI and renal scintigraphy studies will be conducted.  After patients 
complete the 6 month efficacy visit, they will be considered for a second NKA injection. Patients 
receiving a second dose will follow the same follow up visits that occurred after first injection. 
Patients 6 month post first injection visit will serve as the patients 14 to 10 day pre- second injection 
visit. Patients will return for their second injection and return to the clinic for follow up safety 
assessments on Days 7, 14, and 28 post-injection and at 2, 3, and 6 months post-injection  Patients 
will be followed up to 18 months in the post follow up phase with 6 months after first NKA injection 
and 12 months after second NKA injection. Refer to the time and events schedule on page 14 for 
additional post follow up time points. 
Long Term Follow-up:  Patients will be followed for safety and efficacy for 24 months after the 18 
month initial follow up period.  Telephone contact will be made 24 and 36 months after the last NKA 
injection, and visits will be made at 30 and 42 months after the last NKA injection.  
NKA Dose:  Kidney weight of the target/recipient kidney will be estimated from the results of the 
MRI taken during Screening.  Using the preclinical studies as a guideline, the dose of NKA for this 
study is 3 x 106 cells /g estimated kidney weight (g KWest).  Since the concentration of SRC per mL of 
NKA is 100 x 106 cells/mL, the dosing volume would be 3 mL for each 100 g or 6 mL for a 200 g 
kidney.  Based on this dosing paradigm, the following doses of NKA would be administered:  

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Estimated Kidney Weight (g KWest)  
Dose 
Volume 
(mL) 
SRC Delivered 
(cell number; x 
106) 
Median Weight 
(g) 
Weight Range 
(g) 
100  
95 – 108   
3  
300  
117  
109 – 125  
3.5  
350  
133  
126 – 141   
4  
400  
150  
142 – 158   
4.5  
450  
167  
159 – 175  
5  
500  
183  
176 – 191  
5.5  
550  
200  
192 – 208   
6  
600  
217  
209 - 225  
6.5  
650  
233  
226 – 241   
7  
700  
250  
242 – 258  
7.5  
750  
  
>259  
8  
800  
Safety Monitoring:  While unforeseen adverse effects may occur, the greatest recognized risk to 
subjects enrolled into the study is hemorrhage following the injection procedure.  Therefore, 
precautions have been taken to minimize the risk of excessive bleeding.  Patients with abnormal 
laboratory values predictive of an increased risk of bleeding will not be eligible for the study.  
Hemoglobin/hematocrit will be monitored a) before, b) 4 hours after, and c) the day after each 
procedure.  
Injection:  During the injection procedure, hemoglobin will be monitored on a regular basis and 
blood pressure will be monitored continuously using standard site practices.  Immediately following 
laparoscopic injection, the subject will remain supine for 8 hours with regular monitoring of blood 
pressure/pulse and hemoglobin.  The subject will remain in the hospital for 2 to 4 nights following 
laparoscopic injection for observation of adverse events.  On Day 1 following injection, an ultrasound 
study will be performed to verify there are no subclinical adverse effects.  If clinically warranted, an 
ultrasound may also be performed before discharge from the clinic to ensure no adverse events are 
ongoing.  After an injection via the percutaneous route, the patient may be discharged the same day if 
that is the site’s usual practice after similar procedures (i.e. percutaneous ablation), after no less than 2 
hours of observation and monitoring.  If product- or procedure-related AE’s occurred following 
surgery, the patient should not be released from the hospital until the AE’s have either resolved, 
stabilized, or returned to baseline.  After a laparoscopic injection, the patient should be observed in 
hospital for 2 to 4 nights to assess for AEs. Following discharge, subjects will be monitored at each 
visit for changes in renal function including the rate of progression of renal insufficiency.  Laboratory 
values predictive of renal function will be closely monitored.  Additional imaging studies may be 
conducted as needed in response to adverse changes in renal function.    
Data Safety Monitoring Board:  A Data Safety Monitoring Board (DSMB) will be chartered to 
oversee patient safety, especially as it relates to any unexpected product-related events.  The 
committee will include 3 members with expertise directly related to protocol activities.  The members 
of the DSMB will have no other engagement with RegenMed (Cayman) Ltd. or any of the study 

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centers, and the DSMB will function independently.  In general, the DSMB will advise RegenMed 
(Cayman) Ltd. on aspects concerning the safety to the patients who have enrolled as research subjects 
in the clinical trial.  The specific activities and responsibilities of the DSMB will be detailed in the 
DSMB charter. The DSMB’s recommendations will be communicated to the study centers, and where 
required to the IRBs/ECs, and to the regulatory authorities.  
Analysis Methods:  
Up to 30 subjects will be injected with NKA. As this is a Phase II safety and early efficacy study, 
formal sample size calculations were not performed.  The planned sample size allows for a 
preliminary characterization of both the safety profile and potential efficacy of the administered dose 
of NKA in patients with chronic kidney disease.  
Subgroup analyses will compare patients receiving a single injection with patients receiving two 
injections, and patients receiving laparoscopic injections with patients receiving percutaneous 
injections. 
The safety profile will consist primarily of an evaluation of adverse events, including events of 
special interest, laboratory parameters, including assessments of renal function, imaging results and 
vital signs.  

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3 TABLE OF CONTENTS 
1 
PROTOCOL SIGNATURE PAGE ..............................................................................2 
2 
PROTOCOL SYNOPSIS .............................................................................................3 
3 
TABLE OF CONTENTS ...........................................................................................10 
4 
TIME AND EVENTS SCHEDULE:  LABORATORY ASSESSMENTS ...............23 
5 
LIST OF ABBREVIATIONS.....................................................................................25 
6 
INTRODUCTION AND BACKGROUND ...............................................................28 
6.1 
Chronic Kidney Disease .............................................................................................28 
6.1.1 
Background .................................................................................................................28 
6.1.2 
Stages and Outcomes of CKD ....................................................................................28 
6.1.3 
Standard of Care .........................................................................................................29 
6.2 
Nonclinical Pharmacology Studies .............................................................................30 
6.2.1 
Pharmacodynamics .....................................................................................................32 
6.2.2 
Safety Pharmacology ..................................................................................................32 
6.2.3 
Kinetics, Migration and Persistence ...........................................................................33 
6.3 
Toxicology Studies .....................................................................................................34 
6.3.1 
ZSF Single Dose Study ...............................................................................................34 
6.3.2 
Single Dose Canine Study ..........................................................................................35 
6.3.3 
Repeat Dose Canine Study .........................................................................................37 
6.3.4 
Phase One Clinical Trials – Interim Results ...............................................................37 
6.4 
RegenMed (Cayman) Ltd.Overview of Efficacy ........................................................38 
6.4.1 
Phase 1 Studies of NKA .............................................................................................38 
6.5 
Study Rationale ...........................................................................................................46 
6.5.1 
Dose Selection ............................................................................................................47 
6.5.2 
Surgical Techniques ....................................................................................................47 
6.5.3 
Selection of Kidney for Biopsy/Injection ...................................................................48 
6.6 
Benefit: Risk Assessment ...........................................................................................48 
6.6.1 
Assessment of Potential Benefit .................................................................................48 
6.6.2 
Assessment of Potential Risks ....................................................................................48 
6.6.3 
Swedish Clinical Experience ......................................................................................50 
7 
STUDY OBJECTIVES ..............................................................................................50 

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7.1 
Primary Objectives and Outcome Measures ...............................................................50 
7.2 
Exploratory Objectives ...............................................................................................51 
8 
INVESTIGATIONAL PRODUCT ............................................................................51 
8.1 
Overview .....................................................................................................................51 
8.2 
Procurement and Manufacture of NKA ......................................................................52 
8.2.1 
Biopsy: Procurement of Renal Tissue ........................................................................52 
8.2.2 
Product for Injection ...................................................................................................52 
8.3 
NKA Dose ..................................................................................................................53 
8.4 
Accountability .............................................................................................................53 
9 
STUDY DESIGN .......................................................................................................54 
10 
STUDY POPULATION .............................................................................................56 
10.1 
Eligibility Criteria .......................................................................................................56 
10.1.1 
Inclusion criteria .........................................................................................................56 
10.1.2 
Exclusion criteria ........................................................................................................57 
10.2 
Prohibited and Concomitant Medications ..................................................................58 
10.3 
Subject Withdrawal and Replacement ........................................................................59 
11 
STUDY VISITS..........................................................................................................60 
11.1 
Screening Assessments (Within 45 Days of the Biopsy) ...........................................60 
11.2 
Biopsy (4 to 14 Weeks before Injection) ....................................................................60 
11.3 
Injection (Study Days -14 to 4) ..................................................................................61 
11.4 
Follow-up (Days 7, 14, and 28, 2month, 3month, 6month ± 3 days first 
injection and second injection) ...................................................................................62 
11.5 
Long term Follow-up ..................................................................................................63 
11.5.1 
Telephone Contact ......................................................................................................63 
11.5.2 
Visits at 30 and 42 Months .........................................................................................63 
12 
STUDY PROCEDURES AND ASSESSMENTS......................................................64 
12.1 
Demographics, Baseline Values, and Medical History ..............................................64 
12.2 
Clinical Evaluations ....................................................................................................64 
12.2.1 
ECG ............................................................................................................................64 
12.2.2 
Physical Examination (PE) .........................................................................................64 
12.2.3 
Vital Signs ..................................................................................................................64 
12.2.4 
Concomitant Medications ...........................................................................................64 
12.3 
Laboratory Assessments .............................................................................................65 

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12.4 
Renal Imaging .............................................................................................................67 
12.4.1 
Ultrasound ...................................................................................................................67 
12.4.2 
Magnetic Resonance Imaging .....................................................................................67 
12.4.3 
Renal Scintigraphy ......................................................................................................67 
12.5 
Surgical Procedures ....................................................................................................68 
12.5.1 
Biopsy .........................................................................................................................68 
12.5.2 
Injection ......................................................................................................................69 
13 
SAFETY ASSESSMENTS AND MANAGEMENT .................................................72 
13.1 
Event Definitions ........................................................................................................72 
13.1.1 
Adverse Events ...........................................................................................................72 
13.1.2 
Serious Adverse Reaction/Event ................................................................................72 
13.2 
Assessment and Grading of AE’s/SAE’s ...................................................................73 
13.2.1 
Relationship Assessment ............................................................................................73 
13.2.2 
Severity of Adverse Events ........................................................................................74 
13.3 
Recording, Follow-up and Reporting of Adverse Events ...........................................74 
13.3.1 
Recording of Adverse Events .....................................................................................74 
13.3.2 
Recording of Serious Adverse Events ........................................................................75 
13.3.3 
Follow-Up of AE’s/SAE’s ..........................................................................................75 
13.3.4 
Reporting of Serious Adverse Events .........................................................................75 
13.4 
Events of Special Interest ...........................................................................................76 
13.4.1 
Procedure-related Events ............................................................................................76 
13.4.2 
Product-related Events ................................................................................................77 
13.5 
Data Safety Monitoring Board ....................................................................................77 
13.6 
Stopping Criteria .........................................................................................................78 
14 
STATISTICAL CONSIDERATIONS .......................................................................79 
14.1 
Samples Size ...............................................................................................................79 
14.2 
Analysis Objectives ....................................................................................................79 
14.3 
Endpoints ....................................................................................................................80 
14.4 
Analysis Conventions .................................................................................................81 
14.4.1 
Analysis Sets ...............................................................................................................81 
14.4.2 
Handling Missing Data ...............................................................................................81 
14.5 
Demographic and Baseline Characteristics ................................................................81 
14.6 
Efficacy Analysis ........................................................................................................81 

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14.7 
Safety Analysis ...........................................................................................................81 
14.7.1 
Biopsy, NKA Injection, Patient Disposition...............................................................81 
14.7.2 
Adverse Events ...........................................................................................................81 
14.7.3 
Laboratory Evaluations ...............................................................................................82 
14.7.4 
Other Safety Evaluations ............................................................................................82 
14.8 
Exploratory Analysis ..................................................................................................82 
15 
STUDY ADMINISTRATION ...................................................................................82 
15.1 
Ethical and Regulatory Standards ...............................................................................82 
15.1.1 
Institutional Review Board and Ethics Committee ....................................................83 
15.1.2 
Subject Informed Consent ..........................................................................................83 
15.2 
Data Collection and Review .......................................................................................83 
15.2.1 
Data Collection ...........................................................................................................83 
15.2.2 
Study Monitoring ........................................................................................................83 
15.2.3 
Quality Assurance .......................................................................................................83 
15.3 
Retention and Disclosure of Information ...................................................................84 
15.3.1 
Records Retention .......................................................................................................84 
15.3.2 
Disclosure of Information ...........................................................................................84 
16 
REFERENCES ...........................................................................................................86 
 
 
 

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List of Figures  
Figure 1: 
Change in Mean Estimated Glomerular Filtration Rate ......................... 38 
Figure 2: 
Estimated Glomerular Filtration Rate Pre- and Post-NKA Injected- 
Entire Cohort .......................................................................................... 39 
Figure 3: 
Individual Changes in Estimated Glomerular Filtration Rate ................ 40 
Figure 4: 
Estimated Glomerular Filtration Rate Pre- and Post-NKA Injected- 
Patient 2 .................................................................................................. 41 
Figure 5: 
Rate of Decline of Renal Function Pre- and Post-NKA Injection .......... 42 
Figure 6: 
Serum Creatinine Pre- and Post-NKA Injection- Entire Cohort ............ 43 
Figure 7: 
Individual Serum Creatinine Pre- and Post-NKA Injection ................... 44 
Figure 8: 
Kidney Cortical Thickness Over Time ................................................... 46 
Figure 9: 
Hemoglobin Pre- and Post-NKA Injection- Patients 2, 3, and 6 ............ 46 
Figure 10: Study Design ........................................................................................... 54 
  
  
List of Tables  
Table 1: 
KDIGO Classification of CKD ............................................................... 29 
Table 2: 
Summary of Preclinical Pharmacology Studies ..................................... 31 
Table 3: 
Change in Estimated Glomerular Filtration Rate by Patient .................. 41 
Table 4: 
Change in Serum Creatinine by Patient .................................................. 45 
Table 5: 
Dose Summary:  Safety and Efficacy in Animal Studies ....................... 47 
Table 6: 
Serious Adverse Events Reported in TNG-010 ...................................... 50 
Table 7: 
NKA Dosing Paradigm ........................................................................... 53 
Table 8: 
Laboratory Assessments ......................................................................... 66 
 
 
 
 
 
 
 
 

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Time and Events Schedule: Patients receiving Second Dose NKA Only Laparoscopic Approach 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Screening assessments should be conducted within 45 days before the injection; if assessments fall outside of the 45 day window, rescreening should be conducted as discussed 
in Section 11.1  
2 The biopsy will only be obtained if there are not enough frozen SRC from the previous study. If there is enough for NKA product to be made skip this visit and proceed to Pre-
Injection visit (14d to 10d). 
3 Monthly visit dates for follow-up visits should be based on the calendar day (± 7 days).    
4 Inpatient hospital days, Days 1 and possibly Days 2 and 3.  
5 The patient will be discharged as early as Day 2 and as late as Day 4 following laparoscopic injection 
6 Conduct End-of-Study (EOS) assessments at the 18 mo visit post second injection, or when the subject discontinues from the study (See Section 11.4 ) 
7 The informed consent form (ICF) must be signed prior to conducting any study-specific procedures.  
8 Appropriate selected Inclusion/Exclusion criteria should be reviewed at Screening, and pre-injection.    
9 Medical and surgical history should be obtained at Screening.    
10 The physical examination (PE) is described in Section 12.2.2 .  
Event 
Scr1 
Biopsy2 
 
Pre-
Impl. 
2nd Injection 
(Hosp.) 
Follow-up 
(± 3 day) 
2nd Injection Follow-up (±7days) 
 
Long Term  
Follow Up3 
(±7days) 
Assessment 
≤45d 
pre- 
biopsy 
3 to 
1 
day 
Biopsy 
1 
day 
14 to 
10d 
D0 Inpt.4 Disch.5 D7 D14 D28 2mo 3mo 
6mo (14 
to 10 
day) 
8mo 9mo 12mo 15mo 
 
18mo6 
EOS 
 
24mo 
Call 
 
30mo 
Visit 
 
36mo 
Call 
 
42mo 
Visit 
ICF7  
X  
 
 
 
4--14 weeks: Renal cell 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria8 
X  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. Hist.9 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG  
X  
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Comp. Phy. Exam10 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Phy Exam10 
  
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Vital Signs11 
X  
X 
X 
X 
X 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ultrasound/CT  
  
 
X 
X  
X13 
X 
X 
X14 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
MRI  
X15 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Renal Scint. 
  
 
 
  
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Biopsy16 
 
X 
X16 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to Hosp.  
  
 
X 
  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection NKA17 
  
 
 
  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge  
  
 
 
X  
 
 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE’s 18 
  
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMeds  
X  
X  
X  
X   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
KDQoL Survey19 
 
 
 
  
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 

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11 Vital signs include heart rate, resting BP, and body temperature.  (See section 12.2.3 ) 
12 Vital signs should be measured throughout the procedure.  
13 An ultrasound should be performed 10 to 14 days before injection to verify continued eligibility and on Day 1 following injection to verify lack of adverse events/safety 
concerns.  
14 If clinically indicated due to, for example, bleeding during the procedure or a drop in hemoglobin, an ultrasound may be performed prior to discharge to assess safety concerns.  
15 To determine kidney size and volume, an MRI study should be performed between screening and the injection.  
16 The patient may be released same day as biopsy per site standard practice, if released same day as biopsy skip day 1 procedures after biopsy. 
17  NKA product should be handled and injected according to procedures described in the Study Reference Manual. 
18 Record NKA-related SAE’s, NKA-related and significant CKD-related AE’s reported by the patient at the visit, and ongoing CKD-specific medications. 
19 KDQOL Survey will be completed at pre-injection and at day 28 and months 3, 6, 9, 12, 15, 18, 30 and 42 months after second NKA injection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Time and Events Schedule: Patients receiving Second Dose NKA Only Percutaneous Approach 
 
Event 
Scr1 
Biopsy2 
 
Pre-
Impl. 
2nd 
Injection 
Follow-up 
(± 3 day) 
2nd Injection Follow-up (±7days) 
Long Term  
Follow Up3 
(±7days) 
Assessment 
≤45d 
pre- 
biopsy 
3 to 
1 
day 
Biopsy 
1 
day 
14 to 
10d 
D04 
 
D1 
D7 
D14 D28 2mo 3mo 
6mo (14 
to 10 
day) 
8mo 9mo 12mo 15mo 
 
18mo5 
EOS 
 
24mo 
Call 
 
30mo 
Visit 
 
36mo 
Call 
 
42mo 
Visit 
ICF7  
X  
 
 
 
4--14 weeks: Renal cell selection and manufacture of NKA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria8 
X  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. Hist.9 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG  
X  
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Comp. Phy. Exam10 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Phy Exam10 
  
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Vital Signs11 
X  
X 
X 
X 
X 
X12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ultrasound/CT  
  
 
X 
X 
X13 
X14 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
MRI  
X15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Renal Scint. 
  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Biopsy16 
 
X 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to Hosp.  
  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection NKA17 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge  
  
 
 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Call 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
AE’s 18 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMeds  
X  
X  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
KDQoL Survey19 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
1 Screening assessments should be conducted within 45 days before the injection; if assessments fall outside of the 45 day window, rescreening should be conducted as discussed 
in Section 11.1  
2 The biopsy will only be obtained if there are not enough frozen SRC from the previous study. If there is enough for NKA product to be made skip this visit and proceed to Pre-
injection visit (14d to 10d). 
3 Monthly visit dates for follow-up visits should be based on the calendar day (± 7 days).    
4 The patient may be discharged same day as percutaneous injection. 
5 Conduct End-of-Study (EOS) assessments at the 18 mo visit post second injection, or when the subject discontinues from the study (See Section 11.4 ) 
6 24hours post discharge a follow up phone call from the clinic will be conducted to do a wellness check on the subject. 
7 The informed consent form (ICF) must be signed prior to conducting any study-specific procedures.  
8 Appropriate selected Inclusion/Exclusion criteria should be reviewed at Screening, and pre-injection.    
9 Medical and surgical history should be obtained at Screening.    
10 The physical examination (PE) is described in Section 12.2.2 .  

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11 Vital signs include heart rate, resting BP, and body temperature.  (See section 12.2.3 )  
12 Vital signs should be measured throughout the procedure.  
13 An ultrasound should be performed 10 to 14 days before injection to verify continued eligibility and on Day 1 following injection to verify lack of adverse events/safety 
concerns.  
14 If clinically indicated due to, for example, bleeding during the procedure or a drop in hemoglobin, an ultrasound may be performed prior to discharge to assess safety concerns.  
15 To determine kidney size and volume, an MRI study should be performed between screening and the injection.  
16 The patient may be released same day as biopsy per site standard practice, if released same day as biopsy skip day 1 procedures after biopsy. 
17  NKA product should be handled and injected according to procedures described in the Study Reference Manual. 
18 Record NKA-related SAE’s, NKA-related and significant CKD-related AE’s reported by the patient at the visit, and ongoing CKD-specific medications.   
19 KDQOL Survey will be completed at pre-injection and at day 28 and months 3, 6, 9, 12, 15, 18, 30 and 42 months after second NKA injection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Time and Events Schedule: New Patients Receiving Laparoscopic Approach 
Event 
Scr1 
Biopsy 
 
Pre-
Impl. injection (Hosp.) 
Follow-up 
(± 3 day) 
1st 
Injection 
Follow-up 
(±7days) 
Pre-2nd 
Injection
2 
2nd Injection 
(Hosp) 
2nd Injection 
Follow-up 
(± 3 day) 
Follow-up (±7days) 
Long Term  
Follow Up3 
(±7days) 
Assessment 
≤45d 
pre- 
biopsy 
3 to 
1 
day 
Biopsy 
1 
day 
14 to 
10d 
D0 Inpt.4 Disch.5 D7 D14 D28 2mo 3mo 
6mo (14 
to 10 
day) 
D0 Inpt. 4 Disch5 D7 D14 D28 8mo 9mo 12mo 15mo 18mo6 
EOS  
 
24mo 
Call 
 
30mo 
Visit 
 
36mo 
Call 
 
42mo 
Visit 
ICF7 
X  
 
 
 
4--14 weeks: Renal cell selection and manufacture of NKA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria8 
X  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. Hist.9 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG  
X  
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Comp. Phy. Exam10 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Phy Exam10 
  
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Vital Signs11 
X  
X 
X 
X 
X 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ultrasound/CT  
  
 
X 
X 
X13 
X 
X 
X14 
 
 
 
 
 
X 
X 
X 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
MRI  
X15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Renal Scint. 
  
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Biopsy16 
 
X 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to Hosp.  
  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inject NKA17 
  
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge  
  
 
 
X 
 
 
 
X5 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE’s 18 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMeds  
X  
X  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
KDQoL Survey19 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
1 Screening assessments should be conducted within 45 days before the injection; if assessments fall outside of the 45 day window, rescreening should be conducted as discussed 
in Section 11.1   
2 If at 6 month visit the PI determines a second dose is not going to be completed patient should return to the clinic at month 9 visit and resume TES. 
3 Monthly visit dates for long-term follow-up visits should be based on the calendar day (± 7 days).    
4 Inpatient hospital days, Days 1 and possibly Days 2 and 3.  
5 The patient will be discharged as early as Day 2 and as late as Day 4 following laparoscopic injection 
6 Conduct End-of-Study (EOS) assessments at the 18 mo visit post second injection, or when the subject discontinues from the study (See Section 11.4 ) 
7 The informed consent form (ICF) must be signed prior to conducting any study-specific procedures.  
8 Appropriate selected Inclusion/Exclusion criteria should be reviewed at Screening, and pre-injection.    
9 Medical and surgical history should be obtained at Screening.    
10 The physical examination (PE) is described in Section 12.2.2 .  
11 Vital signs include heart rate, resting BP, and body temperature.   (See section 12.2.3 ) 
12 Vital signs should be measured throughout the procedure.  

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13 An ultrasound should be performed 10 to 14 days before injection to verify continued eligibility and on Day 1 following injection to verify lack of adverse events/safety 
concerns.  
14 If clinically indicated due to, for example, bleeding during the procedure or a drop in hemoglobin, an ultrasound may be performed prior to discharge to assess safety concerns.  
15 To determine kidney size and volume, an MRI study should be performed between screening and the injection.  
16 The patient may be released same day as biopsy per site standard practice, if released same day as biopsy skip day 1 procedures after biopsy. 
17  NKA product should be handled and injected according to procedures described in the Study Reference Manual. 
18 Record NKA-related SAE’s, NKA-related and significant CKD-related AE’s reported by the patient at the visit, and ongoing CKD-specific medications. 
19 KDQOL Survey will be completed at pre-injection and at day 28 and months 3, 6, 9, 12, 15, 18, 30 and 42 months after second NKA injection.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Time and Events Schedule: New Patients Receiving Percutaneous Approach 
Event 
Scr1 
Biopsy 
 
Pre-
Impl. 
1st 
Injection 
Follow-up 
(± 3 day) 
1st 
Injection 
Follow-
up 
(±7days) 
Pre-2nd 
Injection2 
2nd 
Injection 
2nd Injection 
Follow-up 
(± 3 day) 
2nd Injection Follow 
up(±7days) 
Long Term  
Follow Up3 
(±7days) 
Assessment 
≤45d 
pre- 
biopsy 
3 to 
1 
day 
Biopsy 
1 
day 
14 to 
10d 
D04 D1 D7 D14 D28 2mo 3mo 6mo (14 
to 10 day) D04  D1 D7 D14 D28 8mo 9mo 12mo 15mo 18mo5 
EOS  
 
24mo 
Call 
 
30mo 
Visit 
 
36mo 
Call 
 
42mo 
Visit 
ICF7 
X  
 
 
 
4--14 weeks: Renal cell selection and manufacture of NKA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria8 
X  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. Hist.9 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG  
X  
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Comp. Phy. Exam10 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Phy Exam10 
  
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Vital Signs11 
X  
X 
X 
X 
X 
X12 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ultrasound/CT  
  
 
X 
X 
X13 
X14 
 
 
 
 
 
 
X 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI  
X15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Renal Scint. 
  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Biopsy16 
 
X 
X16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to Hosp.  
  
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection NKA17 
  
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge  
  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Call 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
 
X 
 
X 
 
AE’s 18 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ConMeds  
X  
X  
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
KDQoL Survey19 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
1 Screening assessments should be conducted within 45 days before the injection; if assessments fall outside of the 45 day window, rescreening should be conducted as discussed 
in Section 11.1   
2 If at 6 month visit the PI determines a second dose is not going to be completed patient should return to the clinic at month 9 visit and resume TES. 
3 Monthly visit dates for long-term follow-up visits should be based on the calendar day (± 7 days).    
4 The patient may be discharged same day as percutaneous injection. 
5 Conduct End-of-Study (EOS) assessments at the 18 mo visit post second injection, or when the subject discontinues from the study (See Section 11.4 ) 
6 24hours post discharge a follow up phone call from the clinic will be conducted to do a wellness check on the subject. 
7 The informed consent form (ICF) must be signed prior to conducting any study-specific procedures.  
8 Appropriate selected Inclusion/Exclusion criteria should be reviewed at Screening, and pre-injection.    
9 Medical and surgical history should be obtained at Screening.    
10 The physical examination (PE) is described in Section 12.2.2 .  

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11 Vital signs include heart rate, resting BP, and body temperature.  (See section 12.2.3 )  
12 Vital signs should be measured throughout the procedure.  
13 An ultrasound should be performed 10 to 14 days before injection to verify continued eligibility and on Day 1 following injection to verify lack of adverse events/safety 
concerns.  
14 If clinically indicated due to, for example, bleeding during the procedure or a drop in hemoglobin, an ultrasound may be performed prior to discharge to assess safety concerns.  
15 To determine kidney size and volume, an MRI study should be performed between screening and the injection.  
16 The patient may be released same day as biopsy per site standard practice, if released same day as biopsy skip day 1 procedures after biopsy. 
17  NKA product should be handled and injected according to procedures described in the Study Reference Manual. 
18 Record NKA-related SAE’s, NKA-related and significant CKD-related AE’s reported by the patient at the visit, and ongoing CKD-specific medications.   
19 KDQOL Survey will be completed at pre-injection and at day 28 and months 3, 6, 9, 12, 15, 18, 30 and 42 months after second NKA injection.  
 

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4 TIME AND EVENTS SCHEDULE:  LABORATORY ASSESSMENTS  
Event 
Scr1 
 
Biopsy2 
 
Pre- 
Impl. 
Injection 
(Hosp.)3 
Follow-up 
(± 3 day) 
1st Injection 
Follow-up 
(± 7 day) 
Pre-2nd 
Injectio
n 
2nd Injection 
(Hosp.)3 
2nd Injection 
Follow-up 
(± 3 day) 
Follow-up 
(± 7 day) 
Long Term Follow Up 
(± 7 day) 
Laboratory 
Assessment  
≤45d 
pre-
biopsy 
3 to 
1 
day 
Biopsy 
1 
day 
14 to 
10 
days 
D0 Inpt4 Disch5 D7 D14 D28 2 mo 3mo 
6mo 
(14 to 
10 day) 
D0 Inpt.4 Disch5 D7 D14 D28 8mo 9mo 
 
12mo 
 
15mo 18mo 
EOS6 
24mo 
Call 
30mo 
Visit 
36mo 
Call 
42mo 
Visit 
Chemistry7 
 
 
 
 
4 – 14 weeks:  Renal cell selection and manufacture of 
NKA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Std. panel  
X 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
• Renal   
X 
X 
 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
• Pregnancy test8 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• HIV, HBV, HCV  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Lipid Panel  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology9 
X 
X 
 
X 
X 
 
X 
X 
X X 
X 
X 
X 
X 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
 
 
 
 
• Multiple10  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Coag. Status  
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 24 hour  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
• Spot urine  
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
• Test stick  
 
 
 
X 
X 
X11 
 
 
 
 
 
 
 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Add. Tests:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• HbA1c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
• Beta 
2microblobulin12  
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
• iPTH  
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
• Research (reserve) 
Samples13 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
1 
Screening assessments should be conducted within the 45 days prior to the injection; if assessments fall outside of the 45 day window, rescreening should be 
conducted as discussed in Section 11.1.  
2 
Patient may be released same day as biopsy per site standard practice, if released same day as biopsy skip day 1 procedures after biopsy. Note that returning 
patients may not need a biopsy to be completed and will go from screening to the pre-injection visit. 
3 
Patients receiving percutaneous approach will have Day 0 lab assessments and then skip to day 7 assessments. 
4 
Inpatient Hospital days, Days 1 and possibly Days 2 and 3 depending on day of discharge. 
5 
The patient will be discharged as early as Day 2 and as late as Day 4 following laparoscopic injection, or Day 1 following percutaneous injection.  Refer to 
Section 11.4  for discharge instructions.  
6 
Conduct End-of-Study (EOS) assessments at the 18 mo visit, or when the subject discontinues from the study (See Section 6.5).  Following the EOS visit, the 
patient should be rolled into the long-term observational follow-up phase.  

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7 
The Chemistry panel includes both standard and renal analytes as described in Table 8.  Laboratory assessments are described in detail in Section 12.3.    
8 
A urine pregnancy test should be performed using a urine dip-strip; if positive, then a confirmatory test should be performed by the central laboratory.  
9 
Hemoglobin levels must be verified to be > 9 g/dL within 48 hours of each procedure or per site standard practices for verifying Hb levels prior to an injection or 
surgical procedure.  
10 On procedure days, HCT and Hb should be measured per site standard practice at the site’s local lab so the results are immediately available for clinical care.  
Samples in lab kits for corresponding visit days should be sent to central laboratory for inclusion in database.     
11 Prior to injection, test stick should be performed to confirm absence of signs of infection.  
12 β 2-microglobulin should be assessed in both serum and urine samples.  
13 Research samples (serum/plasma and urine) will be collected, frozen, and stored for assay of renal specific analytes and/or biomarkers at a future date.  Results 
will not be available for reporting in the CSR for this study.   

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5 LIST OF ABBREVIATIONS   
  
ACEI  
Angiotensin-Converting-Enzyme Inhibitor  
ACR  
Albumin / Creatinine Ratio  
ADL  
Activities Of Daily Living  
AE  
Adverse Event  
ALT  
Alanine Transaminase  
APTT  
Activated Partial Thromboplastin Time  
ARB  
Angiotensin Receptor Blocker  
AST  
Aspartate Transaminase  
ATMP  
Advanced Therapy Medicinal Product  
AV (fistula)  
Arteriovenous  
BMI  
Body Mass Index  
BP  
Blood Pressure  
BUN  
Blood Urea Nitrogen  
CBC  
Complete Blood Count  
CKD  
Chronic Kidney Disease  
ConMed(s)  
Concomitant Medication(s)  
CRF  
Case Report Form  
CRO  
Contract Research Organization  
CRP  
C-Reactive Protein  
CSR  
Clinical Study Report  
CTA  
Clinical Trial Application  
CTCAE  
Common Terminology Criteria for Adverse Events  
CVP  
Central Venous Pressure  
DMSA  
Dimercaptosuccinic Acid  
DPBS  
Dulbecco’s Phosphate Buffered Saline  
eGFR  
Estimated Glomerular Filtration Rate   
ECG  
Electrocardiogram  
EC  
Ethics Committee  
EMEA  
European Medicines Agency  
EOS  
End Of Study Visit  
ESRD  
End Stage Renal Disease  
FDA  
Food And Drug Administration  
FIH  
First-In-Human (Clinical Trial)  
g  
Gram  

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GCP  
Good Clinical Practices  
GLP  
Good Laboratory Practices  
GMP  
Good Manufacturing Practices  
GFR  
Glomerular Filtration Rate  
HARS  
Hand Assisted Retroperitoneoscopic  
Hb  
Hemoglobin  
HbA1c  
Glycosylated Hemoglobin  
HBV, HBsAg  
Hepatitis B Virus, Hepatitis B Virus Surface 
Antigen  
HCV  
Hepatitis C Virus  
HCT  
Hematocrit  
HIV  
Human Immunodeficiency Virus  
IB  
Investigator’s Brochure  
ICF  
Informed Consent Form  
ICH  
International Conference On Harmonization  
I/E  
Inclusion / Exclusion  
IND  
Investigational New Drug  
INR  
International Normalization Ratio  
iPTH  
Intact Parathyroid Hormone  
i.v.  
Intravenous  
KDIGO  
Kidney Disease; Improving Global Outcomes  
KDOQI  
Kidney Disease Outcomes Quality Initiative  
KWest  
Kidney Weight, Kidney Weight estimated  
MedDRA  
Medical Dictionary for Regulatory Activities  
MRI  
Magnetic Resonance Imaging  
NCI  
National Cancer Institute  
NKA  
Neo-Kidney Augment  
NOAEL  
No-Observed-Adverse-Effect-Level  
NSAIDs  
Non-Steroidal Anti-Inflammatory Drugs  
Nx  
Nephrectomy, Nephrectomized  
PE  
Physical Examination  
PI  
Principal Investigator  
PT  
Prothrombin Time  
PTH  
Parathyroid Hormone  
QA  
Quality Assurance  
QP  
Qualified Person  
RBC  
Red Blood Cell  
SAE / SAR  
Serious Adverse Event / Serious Adverse Reaction  
sCr  
Serum Creatinine  

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SMC  
Safety Monitoring Committee  
SPIO  
Superparamagnetic Iron  
SRC  
Selected Renal Cells  
SUSAR  
Suspect, Unexpected Serious Adverse Reaction  
TB  
Tuberculosis  
UA  
Urinalysis  
WBC  
White Blood Cell  
 
 

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6 INTRODUCTION AND BACKGROUND  
RegenMed (Cayman) Ltd. is a regenerative medicine company whose principals have experience 
in developing regenerative medicine products (Atala et al., 2006; Basu et al., 2011; Basu and 
Ludlow, 2012; Genheimer et al., 2012; Jayo et al., 2008a; Jayo et al., 2008b; Jayo et al., 2008c; 
Kelley et al., 2012; Kelley et al., 2010).  RegenMed (Cayman) Ltd. is currently developing a 
regenerative cell-based product, Neo-Kidney Augment (NKA), designed to augment renal 
function in patients with chronic kidney disease (CKD).  Therapeutic intervention with NKA is 
intended to delay the need for renal replacement therapy (dialysis or transplant) which at this 
time, is inevitable in patients with CKD.  Therapeutic intervention with NKA entered clinical 
investigations with two similar Phase 1 studies, one at the Karolinska University Hospital 
Huddinge in Stockholm, Sweden (6 patients) and one at the University of North Carolina, Chapel 
Hill, NC (1 patient).  To date, 7 patients have been biopsied and injected safely with NKA.  This 
second study is designed to continue those clinical trials and assess the effect of a first and 
second injection of NKA in type 2 diabetic patients with CKD.    
6.1 Chronic Kidney Disease  
6.1.1 Background  
CKD is characterized by progressive nephropathy that, without therapeutic intervention, will 
worsen; ultimately the patient may reach end stage renal disease (ESRD).  Prevalence data from 
the U.S. to Europe show that approximately 10% of the general population have stage 1-3 CKD 
(ERA, 2009; USRDS, 2011).  Worldwide, the incidence and prevalence of CKD and ESRD are 
increasing while therapeutic outcomes remain poor. The greatest cause of ESRD is diabetes 
mellitus (Postma and de Zeeuw, 2009), and the incidence of CKD continues to increase, 
primarily due to the increases in the incidence of type 2 diabetes (Postma and de Zeeuw, 2009).  
CKD is often accompanied by adverse outcomes owing to underlying comorbidities and/or risk 
factors including hypertension and renovascular disease (Khan et al., 2002).  Due to serious 
comorbidities, patients with CKD are 5-11 times more likely to suffer premature death than 
survive to progress to ESRD (Collins et al., 2003; Smith et al., 2004).  In order to survive, ESRD 
patients require renal replacement therapy (dialysis or transplantation).  Preventing or delaying 
adverse outcomes of CKD by intervening early-on in the disease is the primary strategy in CKD 
management.  Unfortunately, early therapeutic approaches to prevent disease progression have 
not been successful.  
6.1.2 Stages and Outcomes of CKD  
The major causes of CKD are diabetes and hypertension; nearly half of all CKD cases arise from 
diabetes with or without hypertension (ERA, 2009; Postma and de Zeeuw, 2009). Other causes 
are glomerulonephritis (the inflammation and damage of the filtration system of the kidneys) 
caused by post-infectious conditions and autoimmune diseases such as lupus, polycystic kidney 
disease, long-term use of analgesics, atherosclerosis leading to ischemic nephropathy, ureteral 
obstruction or stricture leading to renal damage, HIV infection, sickle cell disease, amyloidosis, 
and chronic kidney infections.  
 
CKD is classified based on cause, GFR category and albuminuria category.  KDIGO (Kidney 
Disease: Improving Global Outcomes) recently published updated clinical practice guidelines 
with updated staging of CKD based on GFR and albuminuria as shown Table 1(KDIGO, 2013).  
 

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Table 1: 
KDIGO Classification of CKD  
A.  GFR Categories in CKD  
GFR Category  
Terms  
GFR (mL/min/1.73m2)  
G1  
Normal or high  
≥90  
G2  
Mildly decreased  
60-89  
G3a  
Mildly to moderately decreased  
45-59  
G3b  
Moderately to severely decreased  
30-44  
G4  
Severely decreased  
15-29  
G5  
Kidney failure  
<15 (or dialysis)  
B.  Albuminuria Categories in CKD  
Category  
AER  
(mg/24 hr)  
ACR (approximate equivalent)  
Terms  
(mg/mmol)  
(mg/g)  
A1  
<30  
<3  
<30  
Normal to mildly increased  
A2  
30 – 300    
3 – 30   
30 – 300   
Moderately increased  
A3  
>300  
>30  
>300  
Severely increased  
Abbreviations: CKD (chronic kidney disease), GFR (glomerular filtration rate), AER (albumin excretion rate), ACR (albumin-to-
creatinine ratio)  
  
The initial stage of diabetic nephropathy occurs over a period of several years and is marked by 
microalbuminuria (A2; 30 – 300 mg/24 hours) followed by macroalbuminuria (A3; > 300 mg/24 
hours), or proteinuria.  As the ability of the kidney to filter blood waste products declines, blood 
creatinine rises.  As kidney damage progresses, rising blood pressures further exacerbates kidney 
disease.  When the kidneys cease to function entirely (ESRD), renal replacement therapy 
(dialysis or transplant) is necessary.  
 
Mortality in CKD patients increases as GFR declines (Go et al., 2004; Kovesdy et al., 2006).  
Mortality among CKD patients in 2009 was 56% greater than among non-CKD patients.  The 
unadjusted mortality rate in Medicare CKD patients age 66 and older is approximately 16% 
(USRDS, 2011).  Death commonly results from cardiovascular events and in several studies of 
patients with advanced CKD was more common than progression to dialysis (Keith et al., 2004; 
Rahman et al., 2006).  
6.1.3 Standard of Care  
There is no cure for CKD or therapy which prevents progression of disease.  Therefore, 
treatment of patients with chronic kidney disease is focused on managing comorbid conditions 
including cardiovascular disease while slowing progression and preparing for kidney failure and 
kidney replacement.  
 
Co-morbidities:  Anemia, mineral and bone disorders, and cardiovascular events are the major 
comorbidities requiring treatment in CKD patients.  Anemia is often treated via recombinant 
human erythropoietin.  In addition, anti-inflammation medications may also be administered to 
temper inflammatory cytokines.  Treatment for mineral and bone disorders focus on maintaining 
phosphorous and calcium homeostasis (Lee et al., 2007).  Initial treatment restricts dietary 
phosphorus intake or uses specific phosphate binders when phosphate or parathyroid hormone 
levels begin to rise.  For chronic therapy, calcium-based phosphate binders are the most widely 
prescribed treatments for management of CKD-associated hyperphosphatemia.  Additionally, 

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vitamin D and its related compounds may be administered to raise serum calcium concentration 
sufficiently to suppress parathyroid hormone secretion.  Increased risk of cardiovascular disease 
can be a complication of CKD or an independent comorbidity, with the former being probable in 
advanced CKD cases (Gerstein et al., 2001). The use of 1) angiotensin converting enzyme 
inhibitors (ACEI) and/or angiotensin receptor blockers (ARBs) to reduce proteinuria and control 
hypertension, 2) insulin titration to achieve appropriate glycated hemoglobin, and 3) statin 
therapy to counter dyslipidemia, collectively aim to reduce cardiovascular risk and prevent or 
slow the progression of kidney failure.  
 
Renal replacement therapy:  When a patient reaches Stage 5 CKD, renal replacement therapy 
(i.e. dialysis or kidney transplant) is indicated.  The vast majority of Stage 5 individuals receive 
hemodialysis (Dhingra et al., 2001).  Dialysis replaces about 5-15% of kidney function 
depending on the intensity and frequency of use, and helps restore fluid and electrolyte balance 
when kidneys fail.   
 
However, the life-expectancy of an ESRD patient initiating hemodialysis is only 4-5 years 
(USRDS, 2011).  Additionally, hemodialysis is associated with multiple and serious 
complications and quality of life reductions such as arterio-venous graft infections, graft 
revision, and the need to undergo dialysis up to three times per week.    
 
Kidney transplantation remains the most effective form of therapy at this time; however, there is 
a chronic shortage of organs.  If a patient is able to secure a kidney for transplantation, long-term 
therapy with immunosuppressive agents is required to prevent rejection.  While newer 
immunosuppressive regimens are more potent leading to a reduction in immune-mediated graft 
loss, the use of these regimens has resulted in a higher incidence of medication-related problems 
including increased rates of infection.  
 
Therefore, there is a critical medical need for improved therapies for CKD which could 
dramatically slow the progression of disease, and significantly delay the need for renal 
replacement therapy.  
 
6.2 Nonclinical Pharmacology Studies  
NKA is composed of autologous, homologous selected renal cell population (SRC) formulated in 
a Biomaterial (gelatin-based hydrogel).  SRC are the biologically active component of NKA.  
The final composition of NKA is:  
 
 SRC: 100 x 106 cells per mL of NKA  
 Biomaterial:  0.88% solution of gelatin in Dulbecco's Phosphate Buffered Saline (DPBS)  
 
RegenMed (Cayman) Ltd.’s approach to developing NKA is based on extensive scientific 
evaluation of NKA and its active biological component SRC.  SRC are an autologous, 
homologous renal cell population naturally involved in renal repair and regeneration.  In 
pharmacology, physiology and mechanistic-biology studies, RegenMed (Cayman) Ltd. defined 
the pharmacological characteristics of SRC and demonstrated their ability to delay the 
progression of CKD by augmenting renal structure and function.  RegenMed (Cayman) Ltd. 

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subsequently conducted safety pharmacology and GLP toxicology safety studies with NKA in 
diabetic ZSF1 rats and normal mongrel canines.  An overview of the nonclinical studies is 
presented in Table 2.  A summary of these studies is presented below and a detailed description 
of the studies can be found in the Investigator’s Brochure (IB).  Of note, injection of NKA in 
rodent models was accomplished using a syringe affixed to a sharp needle which was used to 
pierce the capsule and deliver NKA.  In canine models, a piercing cannula was used to pierce the 
capsule and a blunt-ended cannula was used to deposit NKA directly in the kidney.    
 
Table 2: 
Summary of Preclinical Pharmacology Studies  
No  
Model  
No. 
Animals  
Study 
Length  
Dose 
per 
kidney 
weight1  
Kidneys 
Injected 
(# inj. per 
kidney) 
Total kidney 
weight  
Injected1 
Total  
Dose2  
Volume  
Total  
SRC  
SRC  
Conc.  
  
  
  
  
106Cell/g  
n  
g  
mL  
106  
106/mL  
Pharmacology (efficacy, kinetics, migration and persistence) of SRC  
 
 
1  
5/6 Nx, Lewis 
Rat  
3  
6 mo  
5 - 10  
1 (1)  
1  
0.1  
5-10  
50-100  
2  
70% Nx, Canine  
4  
10 mo  
6  
1 (2)  
57.7  
5  
334  
66.8  
3  
ZSF1  
7  
12 mo  
3  
2 (2)  
3.2  
0.4  
10  
25  
Safety Pharmacology (extra-renal effects) of NKA  
 
 
4  
5/6 Nx, Lewis 
Rat  
77  
4 d  
5-15  
1 (1)  
1  
0.1  
5-15  
50-150  
5  
Canine  
1  
30  min  
12.5  
2 (2)  
120  
10  
1500  
150  
6  
Canine  
4  
30  min  
1.5-9.2  
2 (1-2)  
120  
2.5-10  
92.7- 
553.5  
37-55  
GLP Toxicology of NKA  
 
 
7  
ZSF-1 rat  
5M/5F 
5M/5F  
5M/5F 
5M/5F  
3 mo 6 
mo  
3 mo 6 
mo  
3.13  
3.13  
6.25  
6.25  
2 (2) 2 
(2)  
2 (2) 2 
(2)  
2 2  
2 2  
0.25 
0.25  
0.25 
0.25  
6.25  
6.25  
12.5  
12.5  
25 25  
50 50  
8  
Canine  
2M/2F 
2M/2F  
2M/2F 
2M/2F  
1 mo 3 
mo  
1 mo 3 
mo  
2.75  
2.75  
11.0  
11.0  
1 
(1) 
1 (1)  
2 
(1) 
2 (1)  
60  
60  
120  
120  
3  
3  
12  
12  
330 
330  
1320 
1320  
110 
110  
110 
110  
9  
Canine3  
Dose 
1  
2M/2F  
n/a  
5.5  
2 (2)  
120  
6  
660  
110  
Dose 
2  
6 mo  
5.5  
2 (2)  
120  
6  
660  
110  
Abbr: Nx, nephrectomy; inj, injection; t, study duration  
1 Estimated kidney weight based on animal model.  Actual weights are listed in the study reports where 
applicable.  
2 Dose refers to SRC or NKA  
3 Two doses of NKA were administered in Study #9; one at 0 months and the second at 3 months   
  

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6.2.1 Pharmacodynamics  
Proof of principle for SRC as the biologically active component of NKA was established in 
multiple models of CKD (described in detail in the IB).  The 5/6th nephrectomy (Nx) rodent 
mass reduction model of CKD allowed for an optimized selection of a therapeutically relevant 
SRC cell population.  A 70% Nx canine model of CKD confirmed SRC activity in a large 
mammal, and the ZSF1 rat served as proof-of-principle for investigating the effects of SRC in 
the best model for meeting the criteria of human type 2 diabetes (Bilan et al., 2011).  SRC 
injected directly into the kidney cortex in multiple animal models of CKD were capable of 
affecting a regenerative response in multiple locations of the nephron through direct engraftment 
or tissue replacement, and through a putative paracrine mechanism involving the effect of 
secreted factors (Ilagan et al., 2010a; Ilagan et al., 2010b; Kelley et al., 2012; Kelley et al., 
2010).   
 
This intervention strategy elicited a regenerative response that significantly improved survival 
and stabilized disease progression to renal structure and function, and extended the longevity in 
both the 5/6th Nx model and the ZSF1 model of CKD.  Functional improvements included 
morphological normalization of multiple nephron structures and functions including, glomerular 
filtration, tubular protein handling, electrolyte balance and the ability to concentrate urine.  
Improvement to blood pressure, including reduced levels of circulating renin were also observed 
in the ZSF1 model.  These functional improvements following SRC treatment were accompanied 
by significant reductions in glomerular sclerosis, tubular degeneration and interstitial 
inflammation and fibrosis.  In each of these models where SRC were evaluated, no 
toxicologically significant in-life, clinical pathology, or histological changes were observed in 
the target organ or other tissues.  Based on results from multiple preclinical studies conducted in 
different animal models of CKD, SRC (active component of NKA) are effective in significantly 
delaying progression of CKD to ESRD when injected in the diseased organ prior to irreversible 
nephropathy.  These results provide a rationale for investigating the effects of this cell-based 
strategy in patients prior to fulminate, end-stage CKD or ESRD.  
 
6.2.2 Safety Pharmacology  
Extra-renal activity:  To evaluate extra-renal activity, in particularly the hemodynamic effects 
of NKA, (SRC formulated in gelatin-based hydrogel) was used in a series of in vivo studies to 
evaluate the immediate cardiovascular and respiratory effects from procedure under similar 
conditions reported in the pharmacology studies summarized above.  The rodent 5/6th Nx study 
(Study #4) was designed to test acutely the effects of a lower and higher SRC concentration in 
varying percentages of gelatin (0.75-1.0%), and the normal canine model was selected to 
evaluate blood pressure immediately before, during and shortly after NKA injection.  No studies 
on effects on the central nervous system were performed as animals showed normal behavior, 
and no direct effect on the nervous system is expected from a therapy consisting of injecting 
intact renal cells into the kidney.  
 
Hemodynamic effects:  The rats in the 5/6th Nx study (Study #4) were injected with NKA or 
controls and the short term effects of the procedure were followed to 4 days post-injection.  
Among the 77 animals treated in this NKA formulation screening study, 16 animals experienced 
apnea during or immediately after injection.  A total of nine animals died; the causes of death 
were classified as apnea (n=3), renal hemorrhage (n=2) and deaths associated with CKD (n=4).  

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Six of the 16 animals that experienced apnea were not pre-treated with atropine; of these animals 
that experienced apnea two died under the influence of anesthesia prior to the use of atropine, 
which included two of the three animals that died.  Ten of the 16 animals that experienced apnea 
were treated with atropine and all recovered from the surgical procedure and injection.    
Importantly, the apnea and bradycardia were not observed following the injection of SRC in the 
ZSF1 (Study #3), canine pharmacology study (Study #4), or in two (intact) canine pilot studies to 
assess the short-term effects of volume administration on blood pressure during and following 
NKA injection (Study #5 and Study #6).  This model-specific hemodynamic response can be 
potentially attributed to 1) altered hemodynamics of the severely mass-reduced rodent remnant 
kidney (Brenner,  
 
1985), 2) transient changes in kidney interstitial pressure administration triggering a central 
autonomic response (Montgomery et al., 1950; Swann et al., 1952), and possibly 3) under 
perfusion of tissue or acute hypoxia from bleeding following injection to the kidney.  That pre-
treatment with atropine (Field et al., 2010) (Field, 2010), a competitive antagonist of the 
parasympathetic nervous system, helped mitigate this species-specific volume-induced 
bradycardia and apnea with the associated death indicates an autonomic response to the injection 
strategy specific to severely mass-reduced rodent model of CKD.  
 
Dose Volume:  Using a range of NKA dose, volume and concentration (Study #5), the normal 
canine was selected to evaluate blood pressure immediately before, during and after NKA 
injection.  In this study, each pole of each kidney was injected with 2.5 mL of NKA; therefore a 
total of 10 mL/120 g, or 0.083 mL/g, was injected at a dosage of 12.5x106 cells / gram of kidney 
mass.  Injection was well tolerated, as there were no adverse systemic effects (physical or 
serological) findings, nor were there any toxicologically significant histomorphological changes 
indicative of kidney injury or other tissue injury as a result of NKA injection to the kidney.  
Notably and in contrast to the severe mass reduction rodent models of CKD, there were no 
hemodynamic changes (i.e. apnea) observed.  
 
6.2.3 Kinetics, Migration and Persistence  
Overview:  Given the cell-based nature of NKA, RegenMed (Cayman) Ltd. conducted studies to 
assess migration and persistence within the target organ over selected sampling times (Kelley et 
al., 2012; Kelley et al., 2010).  A brief summary of the studies is presented below; additional 
information is provided in the references and IB.  
 
No separate study to trace renal cells in tissues outside of the kidney has been performed to date 
based on: 1) significant renal cell retention following direct targeted injection into the kidney, 2) 
no negative effects from treatment have been observed with animal survival, and 3) no adverse 
systemic (physical or serological) findings were observed.  These results have been validated by 
GLP toxicology studies where data from interim QA-validated GLP reports comprehensively 
showed no gross, serological, macroscopic or microscopic histopathological test article-related 
adverse findings in the kidney nor in non-kidney tissues, and no traces of extra-renal test product 
distribution was observed.  Our results are in agreement with and supported by recent published 
reports demonstrating that both intravenous and targeted injection of hundreds of millions of 
allogeneic stem cells, that were neither native to the recipient or the targeted organ, posed little 
risk to cardiac insufficiency patients in human clinical trials (Hare et al., 2012; Hare et al., 2009).  

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Methods:  Renal biodistribution was performed via cell engraftment studies in the 5/6th Nx rat 
model and were determined through cell tracing experiments using male donors in female 
recipients post treatment through genomic detection of the male SRY gene, and by in situ 
hybridization detection of the engrafted male chromosome (Y/12) (Kelley et al., 2010).    
 
In the ZSF1 animal model, SRCs were labeled with the Rhodamine-B superparamagnetic iron 
oxide (SPIO) particle, a contrast agent that is specifically formulated for cell labeling and is 
readily internalized by non-phagocytic cells.  SPIO labeled cells were detected post-injection by 
MRI and whole organ optical imaging for the SPIO iron-labeling was performed 24 hours 
following injection.  In addition, ZSF1 injected with SRCs labeled with CelSense-19F were also 
quantified by Nuclear magnetic resonance (NMR) 3h, 24h, and 7 days after injection (Kelley et 
al., 2012).  
 
Results:  Both acute ZSF1 detection and long-term donor cell detection using the 5/6th Nx 
model of CKD showed significant retention of injected cells.  Clinically relevant MRI detection 
24 hr following cell injection reveals a region at the anterior pole of the kidney where the cells 
were injected with the SPIO Biopal ion particle. These data are consistent with whole organ 
fluorescent imaging highlighting cell detection at and around the site of injection located at the 
upper cortex of the anterior pole.  Sectioning of the whole kidney indicated a bolus of cells 
migrating and distributing from the cortical injection site, confirming their presence in tubular 
and peritubular spaces of the cortex and medulla.  The robust detection of 19F-labeled cells at 3 
and 24 hours following injection confirms their early retention in the kidney and the diminished 
yet significant detection of 19F 7 days following the transplantation procedure.  SRC retention 
was consistent with the detection of these cells previously reported in the 5/6 Nx model using 
both SRY gene detection and FISH for Y chromosome (male donor cell detection in female 
recipients), and cell-membrane PKH26 dye-labeled studies.  
 
Summary:  
 Donor SRC frequency estimated at ~1:30,000 at 6 months post-injection  
 SRC localized primarily to tubular and peritubular areas  
 Cellular proliferation and the 3-6 month half-life of a renal epithelial cell (Nadasdy et 
al., 1994)  in-part accounts for the dilution effect of retention of the SRC label 6 
months post-injection  
6.3 Toxicology Studies  
To assess the safety of NKA, three GLP safety studies were conducted; one in the rat ZSF1 
disease model of CKD and the other two in normal canines.  Details of the study designs are 
presented in the IB.  A brief description of the results are presented below.  
 
6.3.1 ZSF Single Dose Study  
The purpose of this study was to assess the safety of a single administration of NKA in ZSF1 
rats; a model of uncontrolled metabolic syndrome including type 2 diabetes, hypertension and 
severe obesity.  Rats were administered either a) high dose NKA, b) low dose NKA, c) PBS 
(sham-treated), or d) Biomaterial.  Each animal received 4 injections of test article, one into each 

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pole of each kidney.  Results were assessed at 3 and 6 months post-treatment.  An overview of 
the results are presented below.   
 
Renal-related findings:  No treatment-related kidney findings were noted following evaluation 
of 8 areas of each kidney (3 stains per area), including evaluation and scoring of 150 glomeruli 
per kidney.  Apart from changes related to injection and/or injection site linear scars, all kidneys 
were considered normal within the context of the disease model.  No test article-related kidney 
findings were observed at the 3 or 6 month time points.  All macroscopic and microscopic 
kidney changes were considered related to the natural progression of renal disease in the ZSF1 
obese rat, or to the injection procedure.    
 
Kidney changes in all groups were more severe in males, and consistent with differences in the 
disease stage between genders.  Overall, there was an apparent trend of lower renal histological 
severity scores (i.e., lower glomerular injury score, tubule-interstitial injury score, and global 
nephron score) that was consistently noted in the low-concentration NKA treatment group when 
compared to the Sham control group 6 months post-procedure.    
 
Based on the absence of differences across study groups, the No-Observed-Adverse-Effect-Level 
(NOAEL) was the high dose, 6.25 x 106 cells/g KWest.  
 
Non-renal findings:  No NKA safety-related findings were observed in non-target tissues.  No 
ureteral or bladder (primary routes of NKA excretion) NKA-related changes were observed.  
There were no NKA-related effects, and no observable NKA cellular materials, in any of the 
draining (lymph nodes) or filtering (liver, lung, spleen) tissues examined.  
 
Clinical Pathology:  The results of clinical laboratory tests (including hematology, clinical 
chemistry, and special urinalysis panels) were evaluated for differences between baseline and 
end of study (3 or 6 months post-treatment), and between treated and control groups.  No NKA-
related clinically significant laboratory abnormalities were identified.  Of note, a less severe 
decrease in hemoglobin and hematocrit was seen in the both male NKA treatment groups (i.e., 
high and low) as compared with the male Sham control.  Observations in this study support the 
safety of therapeutic uses of NKA.  
 
Conclusions:  
 All animals survived to the end of study (3 or 6 months post-treatment)  
 There were no significant safety-related clinical pathology findings attributable to 
treatment.  No test article safety-related findings of toxicological relevance were 
identified in any of the tissues evaluated.  
 No NKA-related clinically significant laboratory abnormalities were identified.  
 
6.3.2 Single Dose Canine Study  
The purpose of this study was to assess the safety of single administration of two different doses 
of NKA compared to PBS (sham treated) and Biomaterial.  Test article was delivered into one 
pole of each kidney approximately 1 month after bilateral renal injection.  A total of 32 normal 
mongrel dogs were entered into the study; 16 assessed at one month and 16 assessed at 3 months.  
Details of study design are presented in the IB.  An overview of the results are presented below.  

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General results:  All 32 animals survived to their designated termination time point (1 and 3-
month post-treatment).  The animals were in good health throughout the study duration.  There 
were no significant clinical pathology findings over the study duration.  None of the animals 
were azotemic at any point through the study duration and there were no indications of decreased 
GFR.  
 
Renal-related results:  No NKA injection-related macroscopic or microscopic findings were 
observed at the 1 or 3 month endpoint.  No treatment-related kidney findings were noted 
following enhanced evaluation of 8 areas of each kidney (3 stains per area), including evaluation 
and scoring of  
 
150 glomeruli per kidney.  Apart from changes related to injection site scars (fibrosis/chronic 
inflammation in the capsule; linear fibrosis/chronic inflammation and inflammatory cells in the 
cortex/medulla), all kidneys were normal.  All macroscopic and microscopic kidney changes 
were considered background findings or related to the injection procedures.  
 
Non-renal findings:  No test article-related findings were identified in other (non-kidney) 
tissues. All macroscopic and microscopic changes were considered background changes and 
within normal limits.   
 
Procedure-related findings:  The most common abnormalities included swelling at the incision 
sites (seroma formation) and weight loss at study termination.  With regard to incision site 
swelling, ten of sixteen (10/16) animals had sterile seroma formation post-injection, and nine of 
sixteen (9/16) post treatment.  The animals had varying degrees of swelling at their 
retroperitoneal incisions, and were treated as deemed necessary by a veterinarian.    
 
Numerous animals had mild inappetence post-operatively, following injection (29 of 32) and 
treatment (18 of 32) procedures.  Numerous (28 of the 32) animals had weight loss over the 
duration from baseline weight (prior to injection) to termination.  Of note, a greater amount of 
weight loss occurred between baseline (2 weeks prior to the injection) and treatment (day 0; 
renal injections) than between treatment and termination.  The weight loss was also noted across 
all treatment groups (DPBS, biomaterial, high dose, low dose), was not associated with 
intermittent inappetence, and was considered to be due to the stressful nature of this study.  The 
animals’ feed was increased only if the body condition deteriorated (1/16 animals), and weight 
gain was observed in those cases.    
 
Conclusions:  
 All animals survived to their designated termination time point and were in good general 
health throughout the study duration based on clinical pathology and veterinary 
assessment.        
 Pathological assessment showed no NKA safety-related (macroscopic or microscopic) 
findings in either target (kidney) or non-target organs examined.   
 NKA-treatment (low and high dose groups) showed no detrimental effects 1 month or 3 
months post treatment when compared to biomaterial control and sham (PBS) groups.  

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 Neither dose of NKA produced macroscopic or microscopic adverse effects.  Based on 
anatomic pathology, the no-observed-adverse-effect-level (NOAEL) is the high 
concentration of 11.7x106 cells/gram kidney.  
 
6.3.3 Repeat Dose Canine Study  
The purpose of this study was to assess the safety of administering two repeat doses of NKA; 
each dose was delivered into both kidneys at times 0 (baseline) and three months.  All animals 
were subjected to two renal biopsies per kidney (1 cranial and 1 caudal pole) 4 – 6 weeks prior to 
the initial injection procedure.  Control animals were injected with PBS.  Animals were 
monitored for 6 months following the baseline injection.  
 
Study Results:  All 8 animals were in good clinical health throughout the study duration and 
survived to their designated termination time point (6-months).  There was mild or insignificant 
weight loss in 5 of the 8 animals, with only 2 animals losing >3% body weight over the study 
duration.  Greater weight loss occurred between the renal injection and initial treatment than 
between the initial treatment and termination.  No abnormal trends were seen in clinical 
pathology or urinalysis data.  There were no signs of renal insufficiency in clinical pathology 
(azotemia), and no indications of decreased GFR.  
 
Kidney-Related Findings:  No NKA injection safety-related macroscopic or microscopic 
findings were observed at the 6-month time point.  No treatment-related kidney findings were 
noted following enhanced evaluation of 8 areas of each kidney (3 stains per area), including 
evaluation and scoring of 150 glomeruli per kidney.  All kidneys were essentially normal, apart 
from changes related to injection site scars (fibrosis/chronic inflammation in the capsule; linear 
fibrosis/chronic inflammation and inflammatory cells in the cortex/medulla).  
 
Non-Kidney Related Findings:  No test article safety-related findings were identified in other 
(nontarget organ) protocol-required tissues.  All macroscopic and microscopic changes were 
considered background changes and thus, considered within normal limits.  
 
Conclusions:  
 All animals survived to their designated termination time point and were in good general 
health based on clinical pathology and veterinary assessment data.        
 Pathological assessment showed no NKA safety-related (macroscopic or microscopic) 
findings in either the target organ (kidney) or non-target organs examined.   
 At the 6-month time point, no detrimental effects of repeat doses of NKA were seen 
when compared to the sham (PBS- injection) group.  
 
6.3.4 Phase One Clinical Trials – Interim Results 
In April 2013, a first-in-human (FIH) clinical trial was initiated at the Karolinska University 
Hospital Huddinge in Stockholm, Sweden, by Tengion, Inc. The trial was a Phase 1, open-label, 
safety and injection optimization study of NKA injected into patients with CKD. NKA was 
manufactured from SRC obtained from a patient’s biopsy, formulated with gelatin biomaterial, 
and injected back into the patient’s left kidney. The primary objective of the study was to assess 
the safety and optimal injection of NKA injected at one site in a recipient kidney as measured by 

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procedure and/or product related adverse events (AEs) through 12 months post-injection. The 
secondary objective of the study was to assess changes in renal function over a 12 month period 
following injection as measured by laboratory assessments. Six patients, recruited from the 
patient population at Karolinska University Hospital, were enrolled into the study. Each patient’s 
baseline rate of disease progression has been used as the control to monitor for adverse changes 
in the rate of disease progression following injection. The study was terminated due to a lack of 
funding on December 10, 2014. 
 
The patients enrolled in the Swedish study were recruited from the clinical practice at the 
Karolinska Institute and they continue to be closely monitored by the investigators.  When 
RegenMed (Cayman) Ltd. establishes regulatory and ethics committee approval to continue the 
clinical trial, the patients will be re-consented and further safety and efficacy data compiled, and 
the opportunity to receive a second injection of NKA offered.  
 
After the Swedish study had been under way, an IND for NKA was opened and a similar study 
started in the US, with one patient enrolled and treated at the University of North Carolina before 
the study was terminated due to a lack of funding on December 10, 2014. 
 
6.4 
RegenMed (Cayman) Ltd.Overview of Efficacy  
6.4.1 Phase 1 Studies of NKA  
Estimated Glomerular Filtration Rate (eGFR) 
Elderly male diabetic patients with CKD stage 3b/4 injected with NKA underwent a pre-
injection assessment of the progress of their kidney disease (data on file, RegenMed (Cayman) 
Ltd.).  This cohort of patients was consistent with Hemmelgarn Moderate Group decline in eGFR 
of 5-10ml/min/1.73m3 (Hemmelgarn et al, Kid Intern; 2006). 
 
Figure 1: 
Change in Mean Estimated Glomerular Filtration Rate 
 
This graph from Hemmelgarn 2006 shows the division of community-dwelling elderly patients 
in 5 groups based on the rate of change in mean eGFR. 
 

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Pre-injection information from this patient cohort indicated that their average decline in eGFR 
was 6.1 ml/min/year (red-line in graph below).  Post NKA administration, eGFR decline for the 
combined group of 7 patients (6 patients from the Swedish study and 1 patient from the 
American study) was -3.1 ml/min/year (green line in graph below).  The average post-injection 
rate-of-decline for eGFR in the cohort is shown by the green line and the shaded blue area 
represents the range of eGFR for the Hemmelgarn group of community-dwelling elderly patients 
with moderately severe CKD 3b/4 with an annual decline of 5-10 ml/min/year (blue shaded 
area). 
 
Figure 2: 
Estimated Glomerular Filtration Rate Pre- and Post-NKA Injected- Entire 
Cohort 
 
 
The eGFR changes for individual patients’ post-injection of NKA (green) along with the 
patient’s individual pre-injection decline (red-line) demonstrated that 6 of 7 patients had a 
reduction in the rate of decline in eGFR over the period patients were on study: 
 

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Figure 3: 
Individual Changes in Estimated Glomerular Filtration Rate 
 
 
 
 
 
 
The annual rate of eGFR decline pre and post injection for each patient is shown in the table 
below: 

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Table 3: 
Change in Estimated Glomerular Filtration Rate by Patient 
 
Change in eGFR (mL/min/year) 
Patient # Pre-NKA 
Post-NKA 
Patient 1 -14.8 
1.5 
Patient 2 -0.2 
-1.3 
Patient 3 -6.7 
-5.9 
Patient 4 -16.3 
-7.5 
Patient 5 -3.9 
-2.6 
Patient 6 -11.4 
-5.9 
Patient 7 -7.7 
1.4 
 
In summary, 6 of the 7 patients had a reduction in the rate (slope) of eGFR decline after NKA 
injection.  In Hemmelgarn’s study of community-dwelling elderly patients, patients were divided 
into 5 groups with different rates of eGFR decline. A moderate group was identified with a 
decline of 5-10 ml/min/year.  The pre-injection rate-of-decline in eGFR for the NKA cohort was 
6.1 ml/min/year, consistent with Hemmelgarn’s study of community-dwelling elderly patients.    
 
Of interest, patient #2 continued at approximately the same rate of decline as observed during the 
pre-injection period.  Over the short period of eGFR sampling prior to NKA injection in this 
patient, his eGFR measurements varied over a range of +3 ml/min/1.73m3.  When this patient’s 
eGFR was compared to the overall cohort of 7 patients, changes in his eGFR followed a similar 
pattern for post-injection as others in the study cohort (see figure).  Additionally, this patient’s 
serum creatinine increase was attenuated suggesting a potential stabilization of progression for 
CKD (see section on sCr below). 
 
Figure 4: 
Estimated Glomerular Filtration Rate Pre- and Post-NKA Injected- Patient 2 
 
 
The Phase I Clinical Trials with NKA were conducted using doses of NKA that were considered 
likely to be sub-therapeutic, to evaluate the effects of NKA when injected into a single kidney in 
a small cohort of elderly diabetic pre-dialysis patients with CKD 3b/4. In a diabetic animal 
model of aggressive chronic kidney disease, the optimal outcomes of delaying death from end-
stage kidney disease were obtained when animals were treated in both kidneys.  In the interest of 
safety, in the first clinical studies of NKA, only 1 kidney was injected with NKA, and therefore a 

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therapeutic signal was not necessarily expected.  However, after monitoring the progress of CKD 
in this cohort of patients for ~ 1 year, the decline in renal function projected for this cohort was 
modified by a single injection of NKA into a single kidney (left). When the rates of decline of 
renal function pre- and post-injection are compared, the NKA injected patients have an imputed 
delay in dialysis of over 1.5 years (see graph below). 
 
Figure 5: 
Rate of Decline of Renal Function Pre- and Post-NKA Injection 
 
 
Serum Creatinine (sCr) 
Serum creatinine levels for the cohort of patients pre-injection showed a general increase 
consistent with what would be expected in diabetic patients with moderate CKD (red-line). The 
overall pre-injection increase in sCr for the cohort of patients was >100 umole/L/yr. Post-
injection the cohort of patients had an increase <50 umole/L/yr (green line). The overall trends in 
SCr before and after injection are shown below. 
 

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Figure 6: 
Serum Creatinine Pre- and Post-NKA Injection- Entire Cohort 
 
 
Individual patient serum creatinine changes, post-injection of NKA (green) along with the 
patient’s individual pre-injection decline: 

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Figure 7: 
Individual Serum Creatinine Pre- and Post-NKA Injection 
 
 
 
 
 
The annual rates of increase of serum creatinine before and after NKA injection for each patient 
are shown in the table below: 

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Table 4: 
Change in Serum Creatinine by Patient 
 
Change in sCr (µmole/L/year) 
PT # 
Pre-NKA 
Post-NKA 
Patient 1 153 
-41 
Patient 2 17 
-21 
Patient 3 214 
200 
Patient 4 16 
-39 
Patient 5 69 
23 
Patient 6 216 
95 
Patient 7 48 
-40 
 
In summary, after NKA injection, all patients had a reduction in their individual rate of increase 
for sCr compared to the rate of sCr increase that had been observed in the pre-injection period. 
This change was consistent for each patient and supports the effects observed for eGFR in the 
after NKA injection period. 
 
Kidney Cortical Thickness 
Patients suffering from chronic kidney disease undergo a thinning of the functional portion of the 
kidney – the cortex.  Renal cortical thickness is reduced in CKD as a result of the fibrosis and 
scarring associated with progression of the disease process. 
This region of the kidney contains blood filtering (i.e. glomeruli), blood pressure control (i.e. 
juxtaglomerular apparatus for production of renin) and most of the metabolically active tubules 
(i.e. convoluted tubules) that transport electrolytes and other biomolecules scavenged out of the 
urine by the normal kidney. 
 
An increase in cortical thickness was associated with kidney regeneration in preclinical studies 
of NKA and was confirmed histologically in all 4 animal species studied (see description of 
preclinical study results as summarized in Section 6.4).  In the clinical studies, cortical thickness 
was evaluated using imaging technologies – no biopsies were taken to confirm the basis for the 
increased thickness.  Cortical thickness was measured in both the right and left kidney to 
determine if the injected left kidney exhibited any change in cortical thickness that could be 
attributed to NKA injection.  The right kidney served as a non-injected control. 
On average, cortical thickness increased in the left kidney from 14 mm at time of injection to 
~16mm after 1 year of injection (Figure 8; Line represents fitted trend). This change in cortical 
thickness was not sufficient to cause an increase in the total volume of the left kidney (data not 
presented).  No change in cortical thickness was observed in the right kidney cortex (Figure 8).   

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Figure 8: 
Kidney Cortical Thickness Over Time 
 
 
Hemoglobin 
Chronic Kidney disease can be associated with anemia linked to an alteration in renal 
erythropoietin production and from various metabolic abnormalities resulting from chronic 
uremia (Babbit and Lin, Mechanism of Anemia in CKD. J Amer Soc of Nephrology 23: 1631-
1634, 2012/ http://jasn.asnjournals.org/content/23/10/1631.full).  In the NKA patient trials 3 of 
the 7 patients showed improved hemoglobin levels after NKA injection and the remaining 
patients were shown to maintain normal levels during the study (Figure 9).  
 
Figure 9: 
Hemoglobin Pre- and Post-NKA Injection- Patients 2, 3, and 6 
 
 
Blood Pressure 
Blood pressure was monitored during the course of the clinical study and patients received 
medication to control their blood pressure. Antihypertensive medication has been reduced in 3 of 
6 Swedish patients during the first six months following the injection by NKA (Stenvinkel et al, 
World Congress of Nephrology, 2015; 
http://www.abstracts2view.com/wcn/view.php?nu=WCN15L_MON-336). 
 
6.5 Study Rationale  
When initiating the NKA program, it was hypothesized that autologous injection of renal cells 
would affect repair/regeneration of renal tissue in diseased organs.  Since that time, multiple 
animal studies conducted using a wide range of doses (3-15 million cells per gram of kidney 
tissue injected), and extended periods of time post-treatment (up to one year) have demonstrated 
the ability of NKA to positively affect renal outcomes in different models of renal insufficiency 
and disease.  In GLP safety studies, no unanticipated in-life, hematological, urinological, 
serological, or histological changes were found in kidney or other tissues.  
 

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Thus, the positive results from the pharmacology and toxicology studies presented above support 
evaluation of NKA as a therapeutic agent designed to slow the rate of disease progression in 
patients with CKD.  
 
6.5.1 Dose Selection  
Nonclinical efficacy and safety data is summarized in Table 5.  Based on this data, the NKA 
dose of 3x106 cells per g KWest will be delivered to patients in this clinical trial. This dose, 
equivalent to the low dose administered to ZSF1 rats in the GLP safety study, provides a 
minimum of a two-fold safety margin over doses delivered safely in safety pharmacology and 
toxicology studies (i.e., approximately two-fold lower than the identified NOAEL, which was the 
highest dose administered).   In addition, this dose demonstrated efficacy in an animal disease 
model.  Therefore, this dose provides a sufficient safety margin while having the potential to 
provide benefit to patients enrolled in the study.  
 
Table 5: 
Dose Summary:  Safety and Efficacy in Animal Studies  
Summary of Key Nonclinical Efficacy and Safety Data   
 
Context  
SRC Dose 
(106 cells 
per g 
KWest) 
Dose 
Volume 
(mL per g 
KWest) 
Ratio to Human 
Dose Regimen 
[SRC dose (vol)] 
Study No. 
(ref. Table 
2) 
Efficacy (SRC)  
 
Lowest effective doses tested in 5/6th Nx rats  
5-10  
0.1  
1.67 – 3.33 (3.33)  
Study 1  
Lowest effective dose tested in ZSF1 rats  
3  
0.125  
1 (4.167)  
Study 3  
Lowest effective dose tested in dog (70% Nx)  
5.2  
0.087  
1.73 (2.9)  
Study 2  
Safety (NKA)  
 
Cardiovascular acute reactions in 5/6th Nx rat  
5-15  
0.1  
1.67 – 5 (3.33)  
Study 4  
Safe dose /volume load in dog safety pharmacology  
12.5  
0.08  
4.167 (2.67)  
Study 5  
NOAEL in ZSF1 GLP toxicology study   
6.25*  
0.125  
2.1 (4.167)  
Study 7  
NOAEL in single dose dog GLP toxicology study   
11.0*  
0.1  
3.67 (3.33)  
Study 8  
NOAEL in repeat dose dog GLP toxicology study  
5.5*  
0.05  
1.83 (1.67)  
Study 9  
Reference: Human dose in this study  
3.0  
0.03   
NA  
  
*Maximum dose administered  
  
6.5.2 Surgical Techniques  
The biopsy will be collected using standard practices at each site.  A minimum of 2 tissue cores 
must be collected in order to provide sufficient material for manufacture of NKA.   
 
For injection, two methods are approved for use in this study. Each investigator team will select 
the method to be used based on the experience of the personnel at the site.   

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 Use of laparoscopic surgical techniques allows for direct visualization of the kidney so 
that any bleeding or other adverse events can be spotted during injection and addressed 
immediately.  
 Use of a percutaneous approach to the kidney has been in use for over a decade, primarily 
for ablating intrarenal masses.  These procedures insert an electrode or cryogenic needle 
into a defined mass in the kidney, and remain in contact for (typically) 10 to 20 minutes 
while the lesion is ablated.  For injection of NKA, the percutaneous instrumentation is no 
larger nor more complex, and this approach offers the safety advantages of no surgery 
(avoiding abdominal puncture wounds and inflation with gas) and minimal 
immobilization time.  Furthermore, the access track can have hemostatic biodegradable 
material left in place, to further reduce any chance of significant bleeding. 
 
6.5.3 Selection of Kidney for Biopsy/Injection  
Laparoscopic surgical techniques can be used to access either the right or left kidney.  However, 
the left kidney is more readily accessible and is most often accessed during nephrectomies, hence 
the first surgical team had more experience with accessing the left kidney, and the initial patients 
enrolled underwent left kidney biopsy and left kidney NKA injection.  Patients previously 
enrolled may have a second NKA injection in the left kidney.  Newly enrolled patients may have 
either the left or right kidney biopsied.  In any case, the NKA injection should be made into the 
kidney that was biopsied. 
 
6.6 Benefit: Risk Assessment  
6.6.1 Assessment of Potential Benefit  
NKA treatment provided a substantial clinical benefit to nephrectomized animals (rats and dogs) 
in nonclinical studies and in a ZSF1 rat disease model of type II diabetes.  The dose selected for 
this study is equivalent to the lowest effective dose assessed in animal studies (see Table 5).  
Therefore, the potential exists for patients in this study to realize some clinical benefit from 
participation; for example, a potential reduction in the rate of progression of CKD.  
 
6.6.2 Assessment of Potential Risks  
NKA Product:  RegenMed (Cayman) Ltd.’s platform utilizes the injection of the patient’s own 
cells; autologous renal cells obtained from the patient by a kidney biopsy procedure.  As a result, 
the risk of generating an immunological response (e.g., graft rejection) is similar to that seen for 
autologous stem cell transplants and is extremely unlikely.  Furthermore, a dose-limiting toxicity 
was not identified in animal studies.  Specifically, no unanticipated findings were observed in 
multiple animal studies, species, and disease conditions with administration or re-administration 
of syngeneic or autologous SRC to diseased or normal kidneys.    
 
Risks associated with escape of NKA to areas outside of the kidney cortex have also been 
considered; specifically, 1) the sub-capsular space, 2) systemic circulation, and 3) the urinary 
tract.  Leakage of SRC into the sub-capsular space is not expected to pose a risk to subject.  The 
sub-capsular space is commonly used for injecting endocrine tissue, most commonly islet tissue 
(Medarova et al., 2009).  The renal capsule also provides a niche for harboring native stem cells 
that are capable of migrating into the renal parenchyma (Park et al., 2009).    

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The possibility that SRC may enter systemic circulation is reduced by the targeted injection 
process.  Potential risk of an injected cell circulating systemically has been evaluated with 
heterologous allogeneic stem cells (i.e., mesenchymal stem cells) administered intravenously, 
and has been shown to present no significant risk to patients (Hare et al., 2009).  Importantly, 
direct injection to the target organ, the kidney, reduces the risk of systemically circulating cells 
and provides a natural route of elimination through the urinary tract.    
 
The Porcine Skin Type B gelatin used in the formulation of NKA meets Pharmaceutical and 
Edible Gelatin Monograph (European Pharmacopeia 7.0, US Pharmacopeia-National Formulary 
USP35 NF30) requirements.  Gelatin is widely used in pharmaceutical and medical applications, 
including cellular transplantation for regenerative products, because of its biocompatible nature.  
The extensive use of Gelatin described in the literature, coupled with the comprehensive 
evaluation of NKA containing porcine gelatin in GLP toxicology studies support its use in this 
context and would not be expected to result in an adverse effect in patients.  Additional 
information on the porcine gelatin used in the formulation of NKA can be found in the IB.    
 
NKA Injection:  A laparoscopic or percutaneous technique will be used to access the kidney for 
injection of NKA.  Laparoscopic techniques are routinely used to access the kidneys and adverse 
events resulting from such procedures have been published.  Patients will be closely monitored 
for these events as discussed in Section 8.2.2.  
 
Cain et al. (Cain et al., 1976) reported that renal cell homogenates injected intra-renally into 
rodent kidneys using a needle produced no significant adverse events.  Furthermore, 
morphological effects of NKA injection of the kidney are consistent with those reported for 
repeat kidney biopsies taken from canines - a mature connective tissue track and no functional 
deficits associated with these minimal structural changes (Groman et al., 2004).  In isolated 
cases, increasing intracapsular kidney water volume in canines resulted in elevated intra-kidney 
pressure and were associated with transient increases in kidney weight and systemic blood 
pressure (Montgomery et al., 1950; Swann et al., 1952); however, in our pilot canine study where 
blood pressure was monitored, no changes were observed following volume escalation of up to 6 
mL per kidney of NKA.   
  
Therefore, it is anticipated that the most significant risk associated with injection is from the 
surgical procedure; safety measures will be implemented throughout surgery and post-surgical 
follow-up to reduce the potential for excessive bleeding and other surgical adverse effects.  
This version of the protocol introduces an alternative procedure for injection of NKA: a 
percutaneous approach, rather than the laparoscopic procedure as used to date (see next section).  
The percutaneous procedure has been used for over a decade in ablation of renal masses, and it 
provides for a similar injection without requiring abdominal wounds for instrument ports, or 
abdominal inflation.  As the immobilization and recovery periods are generally substantially less, 
some investigators may find this method could be a safer option for some of their patients.  A 
concise review of this method can be found in Salagierski & Salagierski (2010).   

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6.6.3 Swedish Clinical Experience  
The first-in-human clinical trial with NKA was conducted in Sweden.  The patients enrolled in 
that study (TNG-010) were biopsied and injected in 2013.  As of the date of this protocol’s 
preparation (August 2015), all patients are doing well.  
 
Nine SAE’s were been reported in the trial in Sweden. A listing of the events is presented in 
Table 6; all events have resolved.  Of note, only two events were considered “possibly related” to 
NKA by the Investigator.  Both were of infectious origins (wound infection and pneumonia) and 
both resolved without sequelae.  As the two events occurred in the first two patients in the same 
time frame, assessing the events as possibly related to NKA was considered the most 
conservative approach.  
 
Table 6: 
Serious Adverse Events Reported in TNG-010  
Patient 
Number  
Event Term  
Event  
Intensity  
Outcome of Event  
Relationship to  
NKA  
001-002  
Fatigue  
Mild  
Recovered/Resolved  
Not Related  
001-001  
Fatigue  
Mild  
Recovered/Resolved  
Not Related  
001-001  
Postoperative wound 
infection  
Mild  
Recovered/Resolved  
Possible  
001-002  
Pneumonia  
Moderate  
Recovered/Resolved  
Possible  
001-003  
Urinary tract infection  
Mild  
Recovered/Resolved  
Not Related  
001-004  
Fatigue  
Mild  
Recovered/Resolved  
Not Related  
001-005  
Volvulus  
Moderate  
Recovered/Resolved  
Not Related  
001-003  
Fluid retention  
Moderate  
Recovered/Resolved  
Not Related  
001-005  
Anastomotic hemorrhage  
Moderate  
Recovered/Resolved  
Not Related  
 
7 STUDY OBJECTIVES  
7.1 Primary Objectives and Outcome Measures  
The primary objective of the study is to assess the safety and efficacy of NKA injected in one 
recipient kidney and determine if two injections of NKA provide stabilization of renal function.  
 Primary Safety Outcome Measures:  procedure and/or product related adverse events 
(AE’s) through 12 months following the initial NKA injection.    
 Primary Efficacy Outcome Measures: serial measurement of serum creatinine and 
estimation of GFR through 6 months following the second cell injection 
The secondary objective of the study is to assess the safety and tolerability of NKA 
administration by assessing renal-specific adverse events over a 12 month period following a 
patient’s first NKA injection.  
 Secondary Safety and Tolerability Outcome Measures:  renal-specific laboratory 
assessments through 12 months following the last NKA injection under this protocol, 
whether first or second.  

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7.2 Exploratory Objectives  
The exploratory objectives of the study are designed to assess the impact of NKA on renal 
function over a 12 month period following the initial NKA injection.  
 Exploratory Outcome Measures:  clinical diagnostic and laboratory assessments of renal 
structure and function (including eGFR, serum creatinine, and proteinuria) to assess 
changes in the rate of progression of renal disease; and effect of method of injection on 
these parameters.  
 
Exploratory quality of life outcome measure will be the Kidney Disease Quality of Life survey 
obtained at baseline and at 1, 3, 6, 7, 9, 12, 15, 18, 30, and 42 months after a patient’s first NKA 
injection. 
 
Additional exploratory endpoints include the following:  
1. Changes from baseline in BUN, β2 microglobulin and intact parathyroid hormone (iPTH) 
at 6 and 12 months post-injection.  
2. Changes from baseline in C-reactive protein (CRP) at 6 and 12 months post-injection.  
3. Need for initiation of renal replacement therapy.  
4. Comparison of pre-injection versus post-injection split functional differences between the 
left and right kidney based on renal scintigraphy.    
5. Comparison of pre-injection and post-injection kidney volume estimates based on 
comparative MRI assessments.  
6. Changes in the patient’s perception of quality of life, as measured by serial KDQoL 
surveys. 
8 INVESTIGATIONAL PRODUCT  
8.1 Overview  
NKA is an injectable product composed of SRC formulated in a Biomaterial (gelatin-based 
hydrogel).  A detailed description of SRC and NKA and the manufacturing process is provided 
in the IB.  A brief description of the process is described below, divided into three steps:  
 
Biopsy:  Renal cortical tissue obtained via kidney biopsy is sent to Twin City Bio LLC, Winston 
Salem, North Carolina, for manufacturing.    
 
Selection of SRC:  Renal cells are isolated from the kidney tissue by enzymatic digestion and 
expanded using standard cell culture techniques.  Cell culture medium is designed to expand 
primary renal cells and does not contain any differentiation factors.  Harvested renal cells are 
subjected to density gradient separation to obtain SRC which are composed a selected population 
of renal cells, cells well known for their regenerative potential (Humphreys et al., 2008).      
 
Formulation:  Gelatin-based hydrogel biomaterial is used to formulate SRC into NKA.  Porcine 
gelatin is dissolved in buffer to form the thermally responsive hydrogel.  This hydrogel is fluid at 
room temperature but gels when cooled to refrigerated temperature (2-8ºC).  SRC is formulated 

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in this gelatin-based hydrogel biomaterial to improve both cellular stability during transport and 
injection into the kidney cortex.   
 
8.2 Procurement and Manufacture of NKA  
NKA will be manufactured in a GMP facility at Twin City Bio LLC in Winston-Salem, NC.  
 
8.2.1 Biopsy: Procurement of Renal Tissue  
Those patients enrolling in this clinical trial after participation in the previous single-dose 
clinical trial will be injected with SRC cells obtained from their initial biopsies. Biopsy samples 
were obtained for these patients in a Phase 1 trial and maintained in a frozen state. These 
autologous samples will be used to generate the second dose of NKA that the patients are to 
receive under this protocol.   If there are not enough SRC cells obtained in the remaining sample, 
patients will be allowed to undergo another biopsy to prepare their second NKA injection dose. 
Patients who are enrolling in a clinical trial of NKA for the first time will have SRC cells 
prepared from kidney biopsy tissue obtained according to the usual standard of care procedures. 
 
8.2.2 Product for Injection  
Once the biopsy material is received at Twin City Bio LLC, the NKA product will be labeled and 
strict documentation measures will insure product traceability is maintained.  The site will notify 
Twin City Bio LLC of the date for injection and, following the pre-injection visit, of continuing 
patient eligibility so that manufacturing can adjust the in-process freezing step to accommodate 
the date of surgery.  If the patient still qualifies, cells will be thawed, NKA manufactured and 
subsequently shipped.  If the patient does not qualify, the PI should notify Twin City Bio LLC 
staff and renal cells will not be thawed for shipping.  In this case, the PI, Twin City Bio LLC, 
and RegenMed (Cayman) Ltd. staff will discuss available options including, for example, 
thawing of cells at a later date.  
 
Product will be packaged in sterile packaging in a 10 mL syringe for shipment and shipped to the 
address provided by the site.  It is the responsibility of the site to ensure NKA shipments can be 
delivered directly to site personnel so that product injection is not delayed.  NKA in the syringe 
must be warmed to 26.5 ± 1.5ºC before injection, in order to liquefy the gelatin-based hydrogel 
component of NKA.  Instructions for warming the product will be provided in the Study 
Reference Manual.  Detailed injection procedures can be found in Section 8.2.2 .    
 
Renal cells/SRC that were frozen but not used to manufacture NKA will be stored at Twin City 
Bio LLC’s GMP facility until the End-of-Study Visit for the patient.  At that time, if the cells 
have not been used and it is determined that they are no longer needed for that patient, then they 
will be designated for RegenMed (Cayman) Ltd. use and will be used for growth optimization, 
stability assessments, and other process improvement studies.  Some process improvement 
studies may include assessment of biomarker panels to assist in further characterization of 
specific cellular phenotypes present in each NKA sample.  Renal cells/SRC will be kept for a 
maximum of 5 years.  During the informed consent process, the patient will be alerted to the 
planned future use of his/her cells.  If the patient does not want his/her cells to be used for 
process improvement research, then during the informed consent process, he/she may request 
that the cells be destroyed after he/she has completed the study.  

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8.3 NKA Dose  
In nonclinical studies, harvested kidneys were weighed directly; dose was calculated based on 
the average weight of a dog or rat kidney.  Using the results from nonclinical studies, each 
patient will receive a dose of 3.0 x 106 SRC/g KWest.  For patients in the study, the dose of NKA 
will be based on kidney volume calculated using MRI.  As described in the literature, volume 
measurements of the kidney in mLs obtained by different methods are approximately 92 – 97% 
of dry weight measurements in grams obtained by measuring isolated organs trimmed of 
perirenal fat.  Therefore, as a conservative estimation, doses of NKA will be calculated using a 
conversion of 1 g equals 1 mL.  Using this ratio represents the safest approach as it guarantees 
patients will not receive doses higher than corresponding doses in animal studies.  Dosing 
volumes for a range of kidney weights are shown in Table 7 below.  The maximum volume for 
any patient will be 8.0 mL; that is, if any subject has a left kidney with a calculated weight ≥ 259 
g, then that subject will receive 8 mL of NKA.   
 
Table 7: 
NKA Dosing Paradigm  
Estimated Kidney Weight (g KWest)  
Dose Volume 
(mL)  
SRC Delivered  
 (cell number; x 106)  
Median Weight (g)  
Weight Range (g)  
100  
95 – 108   
3  
300  
117  
109 – 125  
3.5  
350  
133  
126 – 141   
4  
400  
150  
142 – 158   
4.5  
450  
167  
159 – 175  
5  
500  
183  
176 – 191  
5.5  
550  
200  
192 – 208   
6  
600  
217  
209 - 225  
6.5  
650  
233  
226 – 241   
7  
700  
250  
242 – 258  
7.5  
750  
  
>259  
8  
800  
  
8.4 Accountability  
Investigational product will be sent prepackaged in a sterile syringe.  The site should verify the 
subject information matches the subject to be injected.  If required by site practices, the site 
pharmacy may add a site-specific label prior to transport to the operating room.  The site should 
also verify the amount of NKA to be injected based on the kidney weight determined by MRI 
imaging at screening.  During injection, the amount of NKA delivered should be documented in 
source documents including estimates of the amount of product that leaked out of the kidney 
following injection, if any.    
 
Following injection, any excess NKA remaining in the syringe will be disposed of in the surgical 
suite immediately following surgery according to site standard practices.  

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9 STUDY DESIGN  
An overview of the study flow is shown in the diagram below.  
 
Figure 10: 
Study Design  
 
  
After patients have signed the ICF, they should be screened for entry into the study.  Screening 
assessments include laboratory assessments, physical examination, and an ECG and MRI study, 
all of which must be performed before the biopsy is taken.  If the patient meets all I/E criteria, a 
biopsy of the left/right kidney should be taken within 45 days of the first screening assessment.  
During the biopsy procedure, two tissue cores should be collected and sent to RegenMed 
(Cayman) Ltd. for manufacture of NKA.  If the patient experienced significant AE’s/SAE’s 
following biopsy (e.g., excessive bleeding, development of AV fistula) that, in the opinion of the 
PI would preclude safe injection, then the patient should be discontinued from the study.  Biopsy 
samples that were obtained from previously enrolled patients in a Phase 1 trial and maintained in 
a frozen state will be used to generate the second dose of NKA that the patients are to receive 
Screening 
Assessments 
Obtain Informed Consent 
Review Inclusion/ Exclusion Criteria 
Conduct screening assessments 
MRI 
Biopsy 

Confirm eligibility (Day -3 to D -1) 

Collect 2 cores for shipment to Twin City Bio LLC 

Discharge per SSP 
First Injection 

Day 0: Injection 
 
Conduct pre-injection qualification visits (-10 to -14 days) 
Up to 45 days 
4 to 14 weeks 
Second Injection 
Follow-up 

Days 7, 14, and 28 

Months 2, 3, 4, 6 
Follow-up 
Longterm 
Follow-up 

24 months  
 
Day 0: Injection 
Patient may or may not receive 2nd Dose 
Days 7, 14, and 28 
Months 2, 3, 4, 6, 9, 12, 15, and 18 

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under this protocol.  If there are not enough cells after thawing then these patients will be 
allowed to have the biopsy procedure completed for this study. 
 
One week after receipt at Twin City Bio LLC’s GMP facility in North Carolina, USA, 
RegenMed (Cayman) Ltd. will notify the site if the tissue received was of sufficient size and 
quality for manufacture of NKA.  If results are positive, the site should confirm the scheduled 
date of injection.  If the biopsy specimen is not able to be used for manufacture of NKA (for 
whatever reason), the patient should be discontinued from the study.  
 
Ten to 14 days before the scheduled injection, the patient should report to the clinic for a pre-
injection qualification visit including final review of I/E criteria and a renal scintigraphy study.  
If the patient is still eligible for injection, the site will notify Twin City Bio LLC to manufacture 
NKA product from frozen renal cells.  On the day of injection (Day 0), the patient should be 
admitted to the hospital and receive an NKA injection into the left (i.e., biopsied) kidney.  For 
injection, the kidney will be accessed either (a) laparoscopic approach, or (b) using a 
percutaneous approach.  The patient will remain in the hospital for two to four nights following 
the laparoscopic procedure, or 0-1 night following the percutaneous procedure, for observation 
and safety assessments.  The patient should not be discharged until any procedure- and/or 
product-related AE’s which may have occurred have stabilized or resolved.  
 
Post-injection Follow-up:   Subjects will return to the clinic for follow-up safety assessments on 
Days 7, 14, and 28 post-injection and at 3, 6, 9, and 12 months post-injection.  At 6 months post-
injection, post-treatment MRI and renal scintigraphy studies will be conducted. After patients 
complete the 6 month efficacy visit, they will be considered for a second NKA injection. Patients 
receiving a second dose will follow the same follow up visits that occurred after first dose. 
Patients 6 month post first injection visit will serve as the patients 14 to 10 day pre- second 
injection visit. Patients will return for their second injection and return to the clinic for follow up 
safety assessments on Days 7, 14, and 28 post- second injection and at 2, 3, and 6 months post- 
second injection.  Patients will be followed up to 18 months in the post follow up phase with 6 
months after first NKA injection and 12 months after second NKA injection. Refer to the time 
and events schedule on page 14 for additional post follow up time points. Subjects will complete 
an End-of-Study visit when they discontinue from the study or (for those who complete the 
study) at 18 months post-second injection.   
 
 

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10 STUDY POPULATION  
10.1 Eligibility Criteria  
Eligibility criteria should be assessed at Screening.  In addition, unless otherwise noted for the 
specific criterion, eligibility criteria should be also be reviewed before the biopsy and at the Day 
-10 to -14 pre-injection visit.    
 
Up to 30 subjects will be enrolled in this study, including subjects previously injected in either 
Phase 1 trial.  Note that a subject will be considered enrolled into the study at the time of 
injection.    
10.1.1 Inclusion criteria  
Unless otherwise noted, inclusion criteria must be met at Screening, Biopsy, and prior to 
injection.  
1. Male and female subjects, age 30 to 70 years on the date of informed consent.  
2. Patients with type 2 diabetes mellitus (T2DM). 
3. Patients with a well-established diagnosis of diabetic nephropathy as the underlying cause 
of their renal disease.    
4. At screening, patients not previously injected with NKA with CKD defined as a GFR of 20 
– 50 mL/min/1.73m2 inclusive. Patients previously treated with a single NKA injection 
with eGFR 15 to 60 mL/min may also enroll in this clinical trial. 
5. Microalbuminuria that cannot be explained by an alternative diagnosis.  Microalbuminuria 
is defined as urinary albumin-creatinine ratio (UACR) ≥ 30 mg/g or urine albumin 
excretion ≥ 30 mg/day on 24 hour urine collection.    
6. Prior to biopsy, systolic blood pressure between 105 and 140 mmHg (inclusive) and 
diastolic blood pressure ≤90 mmHg.  
7. Ongoing and stable treatment with ACEI or ARB initiated at least 8 weeks prior to 
enrollment.  Treatment must be stable for the 6 weeks immediately prior to injection.  
Stable treatment is defined as dose adjustment to no less than ½ of the current dosage and 
no more than 2X the current dosage over the 6 week period immediately prior to injection; 
dose interruptions of up to 7 days due to medical necessity are allowed. Patients who are 
intolerant to ACEI or ARBs may be included as long as they have stable BP within the 
acceptable limits.  
8. Minimum of 2 measurements of eGFR or sCr taken at least 3 months apart (prior to 
screening) and within the previous 12 months to define the rate of progression of CKD.  
The patient should have sufficient historical data to provide a reasonable estimate of the 
rate of progression of CKD as determined following consultation with the Medical Monitor 
(to insure sufficient data is available).  In addition, the rate of progression of CKD must be 
consistent over time.  There is no defined rate of progression that is required to qualify for 
inclusion.    
9. Willing and able to refrain from use of NSAIDs (including aspirin) and clopidogrel, 
prasugrel, or other platelet inhibitors peri-procedure (i.e., before and after both the biopsy 
and injection).  The wash-out period before and after each procedure should be 7 days.  
Willing and able to refrain from use of fish oil and dipryridamole for 7 days before and 7 
days after each procedure.  
10. Willing and able to cooperate with all aspects of the study.  

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11. Willing and able to give signed informed consent.  
10.1.2 Exclusion criteria  
Patients may not be enrolled if they meet any of the exclusion criteria listed below.  Criteria 
should be assessed at Screening, before the biopsy, and before injection unless noted otherwise.  
1. Type 1 diabetes mellitus (DM).  
2. History of a renal transplant.  
3. HbA1c > 10% at Screening. Patients with HbA1c > 8% at the time of screening should be 
offered diabetic teaching and advised to consult their primary physicians for further 
diabetic management. 
4. Hemoglobin levels < 9 g/dL prior to injection.  Hemoglobin levels should be measured 
within 48 hours before the procedure or per site standard practice.    
5. Known allergy to kanamycin or structurally similar aminoglycoside antibiotics (as 
kanamycin is used during manufacture of NKA).  
6. Abnormal coagulation status as measured by APTT, INR, and/or platelet count at 
Screening.  
7. Not a good candidate for the injection procedure (based on the assessment of the surgeon 
who will be performing the injection) including patients who are morbidly obese, have 
excessive fat surrounding the kidney, have BMI > 45, or who are otherwise at excessive 
risk for serious complications.    
8. Clinically significant infection requiring parenteral antibiotics within 6 weeks of injection.  
9. Patients with small kidneys (average size < 9 cm) or only one kidney, as assessed by MRI 
or renal US at screening or if previously done within 1 year of screening.   
10. Patients with a rapid decline in renal function over the last 3 months prior to injection or 
acute kidney injury.    
11. Patients with any of the following conditions prior to injection: renal tumors, polycystic 
kidney disease, renal cysts or other anatomic abnormalities that would interfere with 
injection procedure (e.g., cysts in the pathway of the injection for injection), 
hydronephrosis, skin infection over proposed injection sites, or evidence of a urinary tract 
infection.    
12. Female subjects who are pregnant, lactating (breast feeding) or planning a pregnancy 
during the course of the study, or who are of child bearing potential and not using a highly 
effective method of birth control (including sexual abstinence). A highly effective method 
of birth control is defined as one that results in a low failure rate (i.e. less than 1 percent per 
year) when used consistently and correctly, such as injections, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence, or a vasectomized 
partner. Subjects must be willing to continue birth control methods throughout the course 
of the study.  
13. History of cancer within the past 3 years (excluding non-melanoma skin cancer and 
carcinoma in situ of the cervix).  
14. Life expectancy of less than 2 years.  
15. Any contraindication or known anaphylactic or severe systemic reaction to either human 
blood products or materials of animal (bovine, porcine) origin or anesthetic agents.  
16. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis 
C Virus (HCV) assessed at the Screening Visit.  
17. Subjects with active tuberculosis (TB) requiring treatment in the past 3 years.  

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18. Immunocompromised subjects or patients receiving immunosuppressive agents (including 
patients treated for chronic glomerulonephritis) within 3 months of injection.  [Note:  
inhaled corticosteroids and chronic low-dose corticosteroids [≤ 7.5mg per day] are 
permitted as are brief pulsed corticosteroids for intermittent symptoms (e.g. asthma).]  
19. Subjects with uncontrolled diabetes (defined as metabolically unstable by the PI), or with 
incapacitating cardiac and/or pulmonary disorders.  
20. History of active alcohol and/or drug abuse that in the investigator’s assessment would 
impair the subject’s ability to comply with the protocol.  
21. Patients with clinically significant hepatic disease (ALT or AST > 3.0 x ULN) at 
Screening.  
22. Patients with bleeding disorders that would, in the opinion of the Investigator, interfere 
with the performance of study procedures; patients taking coumarins (e.g. Warfarin) or 
other anticoagulants (e.g. enoxaparin or direct thrombin inhibitors).    
23. Any circumstance in which the investigator deems participation in the study is not in the 
subject’s best interest.  
24. Use of any investigational product within 3 months of the injection without receiving prior 
written consent of the Medical Monitor.     
 
10.2 Prohibited and Concomitant Medications  
Use of investigational drugs is prohibited during the course of the study unless preapproved for 
use by the Medical Monitor.  Investigational drugs are defined as drugs which have not been 
approved for any use by the FDA.    
Patients should avoid taking drugs with nephrotoxic potential during the course of the study, 
including for example chronic use of ibuprofen and other NSAIDs.  Aspirin, up to a dose of 100 
mg/day, may be taken for cardiovascular prophylaxis.  NSAIDs may be taken PRN but the site 
should emphasize with patients the need to minimize use of NSAIDs during the course of the 
study.    
 
Patients who are not intolerant of such agents must be on an ACEI or ARB for 8 weeks prior to 
enrollment (i.e., at the time of injection) and a stable regimen for 6 weeks prior to injection.  
Requiring a minimum of 8 weeks treatment prior to enrollment ensures that the patient will be on 
an ACEI or ARB for a minimum of 12 weeks before administration of the Investigational 
Product.  Stable regimen is defined as a dose no less than ½ of the current dosage and no more 
than 2X the current dosage over the course of the 6 weeks immediately prior to injection.  The 
ACEI or ARB dose should be the maximum tolerated dose for that patient.  In addition, except 
where medically necessary, no changes should be made to ACEI or ARB dosing regimen from 
baseline through the 12 month EOS visit.  A dose interruption of up to 7 days for medical 
necessity is allowed.  Patients who are intolerant to ACEI or ARB therapy and, therefore, not 
taking an ACEI or ARB may be enrolled as long as their blood pressure is stable and within the 
acceptable range.  
 
Medications which specifically interfere with measurements of sCr should be avoided including 
trimethoprim, dronedarone, and cimetidine.  If such medications are required based on medical 
necessity, then the circumstance should be discussed with the medical monitor and the 
medication noted on the CRF.  
 

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10.3 Subject Withdrawal and Replacement  
Subjects may withdraw from the study at any time and for any reason.  If the PI determines that 
continuing in the study is no longer in the best interest of the subject, then the PI should 
withdraw the subject from the study.  If a subject withdraws from the study, the reason for 
withdrawal should be documented.    
 
If a subject withdraws from the study before having a biopsy, the subject will be considered a 
screen failure.  If a subject withdraws from the study after having the biopsy, but before injection 
of NKA, the subject will not be a screen failure, but will not be considered enrolled, and may be 
replaced.  If a subject withdraws from the study after injection but before the end of the follow-
up period, the subject cannot be replaced.  A maximum of 30 subjects, including subjects 
previously injected in the two previous Phase 1 trials, will be injected with NKA.  
Every effort should be made to ensure that patients who have been injected with NKA return for 
all subsequent follow-up visits and procedures.    
 

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11 STUDY VISITS   
Subjects will be screened, enrolled, injected and followed according to the Time and Events 
Schedule and the Time and Events Schedule: Laboratory Assessments.  
 
Before any study specific assessments are performed, the patient must agree to participate in the 
study by signing the ICF.  Informed consent must be obtained following ICH GCP guidelines 
and 21 CFR Part 50.  
11.1 Screening Assessments (Within 45 Days of the Biopsy)  
All screening assessments should be scheduled in a timeframe that will allow for scheduling of 
the biopsy within 45 days of the first screening assessment conducted specifically for this 
protocol.  For example, if a patient signs the consent and then goes to the laboratory for his/her 
blood draw two days later, then the date of the blood draw would be considered the date of the 
first screening assessment (not the date the ICF was signed).  An MRI study should be conducted 
as part of the screening assessments.  If the patient changes his/her mind after signing the ICF 
and refuses to have the MRI, then the patient must be discontinued from the study as the MRI 
will be used to define the dose of NKA.      
 
To qualify for participation in the study, a patient’s GFR must be between 20 – 50 
mL/min/1.73m2 inclusive.  To define the GFR for entry criteria, the site should use the eGFR 
assessed during screening procedures and calculated using sCr and the CKD-EPI equation.    
If a patient does not meet a specific eligibility criterion, but the Investigator believes that the 
patient would be an excellent candidate for the trial, then that criterion may be reassessed one 
time.  In general, a patient who does not qualify may be rescreened once as long as the 
Investigator has sufficient clinical justification for rescreening the patient.  If the Investigator has 
any questions concerning appropriateness of rescreening a patient, then he/she should contact the 
Medical Monitor.  
 
If, for whatever reason, the biopsy cannot be conducted within 45 days of the screening 
assessments, then the PI and Medical Monitor should discuss and agree upon the need for 
repeating screening assessments on a case by case basis.  In some cases (e.g., if the biopsy will 
be a few days out of the protocol specified window), the laboratory assessments performed 
between 1 and 3 days before the biopsy may be used in place of the screening assessments to 
satisfy final eligibility criteria.  In some cases, it may not be appropriate or necessary to repeat 
the clinical diagnostic procedures including the ECG or MRI studies.        
 
11.2 Biopsy (4 to 14 Weeks before Injection) 
The biopsy should be scheduled within 45 days following the first screening assessment.  The 
biopsy should be scheduled so that the injection procedure can be scheduled at 4 weeks or later.  
Due to shipping and manufacturing schedules, the preferred days for collecting the biopsy are 
Wednesday or Thursday.  Biopsies should not be collected on a Friday.  
 

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Patients should report to the site one to three days before the biopsy for pre-biopsy assessments.  
As much as possible, pre-biopsy laboratory samples may be collected and assessed to verify 
patient eligibility prior to biopsy.   
 
Following final review of appropriate eligibility criteria, the biopsy should be performed as 
described below in Section 12.5.1.  The biopsy should be sent to RegenMed (Cayman) Ltd. in 
the shipping container provided by RegenMed (Cayman) Ltd. according to procedures detailed 
in the Study Reference Manual.  After the biopsy, the patient should remain in the hospital 
overnight for observation.  As long as any biopsy-related AEs have resolved, stabilized, or 
returned to baseline, the patient may be discharged the same day as biopsy per site standard 
practice. 
 
Once the biopsy is received at RegenMed (Cayman) Ltd., the biopsy will be assessed and 
processed according to RegenMed (Cayman) Ltd.’s SOPs for product manufacturing.  One to 
two weeks after receiving the biopsy in North Carolina, RegenMed (Cayman) Ltd. will notify the 
site concerning the adequacy of the sample for manufacture of NKA.  Following the notification 
to proceed, the site can confirm the injection date.  If the biopsy cannot be used for manufacture 
of NKA, the patient should be discontinued from the study. 
 
11.3 Injection (Study Days -14 to 4)  
Due to shipping and manufacturing schedules, NKA injection should be scheduled for 
Wednesday, Thursday, or Friday.  If it is necessary to schedule the injection for Tuesday, the site 
should contact RegenMed (Cayman) Ltd. before scheduling the injection to make sure Tuesday 
injection can be accommodated.  NKA injection should not be scheduled on a Monday.  
 
Patients should report to the clinic ten to 14 days before the scheduled injection (Day -10 to -14) 
for pre-injection assessments to verify the continued eligibility of the patient.  If the patient is 
still eligible following review of the results of the assessments, the site will conduct the baseline 
renal scintigraphy study and contact RegenMed (Cayman) Ltd. indicating that NKA product 
should be produced.  If the patient is not eligible for injection, the site should contact RegenMed 
(Cayman) Ltd. to alert manufacturing staff not to thaw the patient’s frozen renal cells and 
manufacture NKA.  The PI should contact RegenMed (Cayman) Ltd. to discuss the reason(s) the 
patient did not qualify and determine the best course of action.  For example, if the patient was 
excluded for a temporary condition (e.g., active infection) then it may be possible to manufacture 
NKA at a later date such that the patient could be injected when he/she became eligible.  If the 
patient’s results indicate that it is highly unlikely that the patient would become eligible within 
an acceptable time frame, then the patient should be discontinued from the study.  [Note that in 
the latter case, the patient can be replaced.]  If injection is delayed, the renal scintigraphy study, 
if conducted, does not need to be repeated prior to injection.     
 
For injection, patients should arrive at the clinic the day of the scheduled injection day (Day 0).  
The patient should be injected according to procedures discussed below (Section 8.2.2 ).  On Day 
1 post-injection, an ultrasound should be performed to verify lack of subclinical adverse effects 
(e.g., swelling, fluid accumulation).  If clinically warranted, an additional ultrasound may be 
performed prior to discharge to verify lack of subclinical events.  
 

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Discharge:  After an injection via the percutaneous route, the patient may be discharged the 
same day if that is the site’s usual practice after similar procedures (i.e. percutaneous ablation), 
after no less than 2 hours of observation and monitoring.  If product- or procedure-related AE’s 
occurred following surgery, the patient should not be released from the hospital until the AE’s 
have either resolved, stabilized, or returned to baseline.  After a laparoscopic injection, the 
patient should be observed in hospital for 2 to 4 nights to assess for AEs. 
 
11.4 Follow-up (Days 7, 14, and 28, 2month, 3month, 6month ± 3 days first 
injection and second injection)  
The patient should return to the clinic for follow-up visits one week after injection (Day 7) and 
on Days 14 and 28.  The patient should make every attempt to return for the first follow-up visit 
on the protocol-specified day (i.e., Day 7) although a 3 day window will be allowed in the case 
of extenuating circumstances.  A 3-day window is allowable for visits on Days 14 and 28, and on 
Months 2, 3, 6, and 12.    At Month 6 visit the same procedures as the pre-injection visit should 
occur to prepare for the second injection of NKA, if the patient and investigator wish to proceed. 
The month 6 visit should occur -14 to -10 days before second injection and within 3 days of 6 
months post first injection. Patients will return to the clinic Days 7, 14, and 28 after second 
injection and Months 2, 3, 6, 9, and 12 after second injection. 
 
The monthly visit dates should be calculated using the calendar date of injection.  For example, if 
the patient was injected on April 30th, then the protocol-specified date of the 2 month follow-up 
visit would be June 30th and the 3 month visit date would be July 30th, etc.  The visit window for 
the long-term monthly follow-up visits is ± 7 days.    
 
End-of-Study Visit (EOS):  Patients will complete the EOS Visit as noted below:  
 If a patient discontinues the study after having the biopsy but before injection, then 
he/she should complete all EOS assessments except for the imaging studies; the MRI 
and/or renal scintigraphy should only be performed if the PI feels one and/or the other 
would provide critical safety information needed for management of the patient.  If the 
patient has an ongoing study procedure-related SAE, then the patient should not be 
discontinued until the SAE has resolved, stabilized, or returned to baseline.  If the SAE 
continues for 18 months, then the patient should be discontinued from the study at 18 
months and followed as discussed in Section 13.3.3.  
 If a patient discontinues from the study after injection but before completing all of the 
protocol-specified follow-up visits, then he/she should have the EOS Visit at the time of 
discontinuation.  For these patients, the PI will determine whether or not it is clinically 
prudent to perform one or both of the imaging studies (i.e., MRI and renal scintigraphy).  
If the patient has a procedure- or product-related SAE(s) that is ongoing, the patient 
should not be discontinued until the SAE(s) has resolved, stabilized, or returned to 
baseline.  If the SAE(s) is still ongoing at the time of the 18 month visit, the subject 
should be discontinued from the clinical trial and the SAE followed as discussed in 
Section 13.3.3.   
 Patients who complete all visits including all of the follow-up visits will return at 18 
months following second injection for the EOS visit.  If the patient has any procedure- or 
product-related SAE’s that are ongoing at the 18 month visit (i.e., not resolved, stabilized 

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or returned to baseline) the subject should be discontinued from the clinical trial and the 
SAE followed as discussed in Section 13.3.3.   
11.5 Long term Follow-up 
A limited assessment for long term follow-up will continue for 24 months after the initial 18 
month follow up period is completed. Telephone contact will be made with patients at 24 months 
and 36 months after the injection, and patients will be examined at 30 and 42 months after the 
injection as long term follow up. At the 24 and 36 month visits, urine and blood specimens will 
be obtained for standard chemistry and renal panel, spot urine, and HbA1c test, an interim 
physical examination will be conducted, AEs will be reviewed, and the KDQOL will be 
completed (see Time and Events Schedule).  
 
11.5.1 Telephone Contact 
Patients will be contacted via telephone at 24 and 36 months after the NKA injection in order to 
inquire about SAEs. 
 
11.5.2 Visits at 30 and 42 Months 
Long term follow-up will extend to 30 and 42 months after the NKA injection and will include a 
physical exam, CBC, blood chemistries, and KDQOL. 
 
 

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12 STUDY PROCEDURES AND ASSESSMENTS  
12.1 Demographics, Baseline Values, and Medical History  
Demographics and baseline characteristics including medical history will be obtained from each 
subject.  All CKD-related medical history and all other significant medical history should be 
recorded in the CRF.  As a general rule, more recent events are more likely to be considered 
significant than similar events which occurred in the more distant past.  Any items in the history 
that are still ongoing should be noted.  Methods of contraception, if applicable, should be 
documented in the source documentation.   
12.2 Clinical Evaluations   
12.2.1 ECG  
A 12-lead ECG should be performed at the visits indicated in the Time and Events Schedule.  
For each assessment, the recording should be obtained after the patient has been seated, both feet 
on the ground, back supported, and arms comfortably on armrests, with the blood pressure cuff 
applied but not inflated at the level of the heart for at least 5 minutes.   ECG recordings should be 
assessed by qualified personnel and the results entered into the CRF as explained in the CRF 
Completion Guidelines found in the Study Reference Manual.  
12.2.2 Physical Examination (PE)  
The Investigator or designee will perform the PE.  The comprehensive examination will include 
assessment of all pertinent body systems while the interim examination will include specific 
assessments of those body systems deemed appropriate for that subject by the PI.  As a general 
rule for the interim examination, the PI should review the patient’s reported adverse events prior 
to or in conjunction with the examination and include assessment of related body systems as 
appropriate.  Only clinically significant abnormalities should be recorded in the CRF.  Weight 
should be measured as part of the PE.    
12.2.3 Vital Signs  
Vital signs will include heart rate, body temperature and blood pressure (BP).  Blood pressure 
should be measured after the subject has rested in a chair with back supported and both feet on 
the ground for a minimum of 5 minutes. Height should be measured once at screening.    
12.2.4 Concomitant Medications  
Concomitant medications (ConMeds) should be recorded as follows:  
ICF to Biopsy / Biopsy to Injection:  Record any CKD-specific medication, medications that may 
affect renal hemodynamics, and medications that may affect serum creatinine measurements.  A 
list of these medications will be provided in the Study Reference Manual.  Record any ConMed 
that is used to treat an AE that is recorded in the CRF during this time (see Section 13.3.1).  Surgical 
medications used during the injection procedure do not need to be recorded unless their use falls 
outside of the expected dosages and/or frequencies.    
Injection to Month 12 Follow-up:  Any ConMed taken following injection through the 12 
month follow-up visit should be recorded on the CRF.  Surgical medications do not need to be 
recorded unless their use falls outside of the expected dosages and/or frequencies.  
 

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Month 12 to Month 18 Follow-up:  Following the 12 month visit to the 18 month follow-up 
visit, record any ConMed given to treat any AE that is recorded in the CRF as discussed in 
Section 13.3.1.  In addition, record CKD-specific medications, medications that may affect renal 
hemodynamics, and medications that may affect serum creatinine measurements as detailed in 
the CRF instructions.     
 
Month 18 to Month 42 Long-term Follow-up:  Following the 18 month visit to the 42 month 
follow-up visit, record CKD-specific medications, medications that may affect renal 
hemodynamics, and medications that may affect serum creatinine measurements that are ongoing 
at the time of the visit.   
12.3 Laboratory Assessments  
Laboratory assessments are listed below in Table 8.  All samples will be collected as shown in 
the Time and Events Schedule:  Laboratory Assessments will be assayed at a central laboratory 
designated by RegenMed (Cayman) Ltd. Laboratory results will be graded using the NCI 
CTCAE grading scale.  

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Table 8: 
Laboratory Assessments  
Chemistry  
Hematology  
•  Standard Panel  
Hemoglobin - Hb  
Alanine Aminotransferase: ALT  
Hematocrit - HCT  
Alkaline Phosphatase: ALP  
Platelets  
Aspartate Aminotransferase: AST  
RBC Count  
Bilirubin  
WBC Count  
Creatine Kinase: CK  
WBC Differential  
Gamma-glutamyl Transferase: GGT  
Coagulation Status  
Lactate Dehydrogenase: LDH  
Activated Partial Thromboplastin Time: APTT  
•  Renal Analytes  
INR  
Albumin, serum  
 
Calcium, serum  
Urine Chemistry  
CO2, total  
Protein & Albumin   
Creatinine, serum  
Creatinine  
Cystatin-C  
Protein & Albumin:Creatinine Ratio (PCR & ACR)  
C Reactive Protein: CRP  
NeutroPhase 1l Gelatinase-associated Lipocalin 
(NGAL)  
Glucose, serum  
Routine Urinalysis: UA*  
Phosphorus, serum  
Additional Selected Analytes  
Potassium, serum  
ß2-Microglobulin, serum & urine  
Sodium, serum  
Hemoglobin (Hb) A1c  
BUN  
(intact) Parathyroid hormone; PTH  
 
Virology   
Lipid Panel  
HIV-1, HBV, HCV   
Cholesterol  
 
LDL  
Research (Reserve) Analytes  
HDL  
Serum/plasma and urine sample  
LDL:HDL ratio  
Example: Fibroblast Growth Factor 23, Pentaxin 3  
Triglycerides  
Pregnancy (urine)  
*Routine UA using a urine test strip (dipstick).  Microscopic analysis should only be performed if albumin, 
leukocytes, erythrocytes, or nitrites are positive.  
  
eGFR:  For comparison of all subjects across the study, GFR will be estimated using the CKD-
EPI equation.  The specific assay for measuring creatinine will be defined by RegenMed 
(Cayman) Ltd. and the samples will be analyzed by the central laboratory.  For comparison to 
each subject’s historical values, it may be necessary to perform a second analysis at the site 
laboratory used to generate the historical data.   
 
Virology:  The biopsy samples collected from the patients will be used for selection of SRC and 
manufacture of NKA.  Therefore, the patient will be tested for viral blood-borne pathogens 
including HIV, HBV, and HCV.  
 
Urine Chemistry:  Over the course of the study, urine will be collected over two different time 
periods; 24 hour collection and spot urine.  Spot urine collections will be used for urine dipstick 
(test stick) assessments.  The times for collection of each type of sample are illustrated in the 
Time and Events Schedule: Laboratory Assessments.  To provide a comprehensive picture of 

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protein and albumin excretion, both total protein and albumin should be assessed in all samples 
as appropriate for that type of sample.  
 
Research (Reserve) Analytes:  Additional urine and serum/plasma samples will be collected, 
aliquotted, and stored for analysis of renal specific analytes and/or biomarkers of renal disease at 
a future time point.  Potential analytes include fibroblast growth factor 23 (FGF23) and pentaxin 
3 (PTX3).  Results from these analyses will not be available, nor will they be included in the 
Clinical Study Report (CSR) for this study.  
 
Pregnancy:  A urine pregnancy test will be performed at the site using a test-strip.  If the test is 
positive, then a confirmatory test will be performed at the clinical laboratory.  If site practices do 
not accept the results of a test-strip, then a urine sample should be sent to the central laboratory 
for analysis.  
 
12.4 Renal Imaging  
12.4.1 Ultrasound  
Ultrasound will be performed according to standard site procedures and will be used to assess 
safety during injection, prior to and following injection.  An ultrasound may be conducted at 
other times if required for safety assessment or guidance of instrumentation during procedures.  
Findings from the ultrasound (e.g., resistance index, length, etc.) will be recorded on the CRF.  
12.4.2 Magnetic Resonance Imaging  
MR imaging will be performed according to site standard practices.  During the site initiation 
visit, the MRI process will be defined for each site as dependent upon the MRI equipment in use. 
Generally, a 1.5-T unit should be used.  Images will be used to determine kidney volume (for 
dosing calculations) and may be used to measure renal cortical thickness.  MRI will be 
performed using standard sequences without injection of contrast agents.  Volume measurements 
may be calculated, for example, using a fast 3D gradient-echo sequence, VIBE, with an 
acquisition time of 22 sec. and spatial resolution of 2x1.4x1.2 mm.  The imaging parameters may 
be adjusted between patients; but the same parameters must be used for before and after images 
on any one patient.  The specific parameters used will be recorded in the source documents and 
appropriate fields completed in the CRF.  
12.4.3 Renal Scintigraphy  
Renal scintigraphy has been used for a long time to measure relative kidney function.  
Historically, the method was performed with different radiopharmaceuticals such as 
dimercaptosuccinic acid labeled with Technetium-99m  (99mTc-DMSA), diethylenetriamine 
pentaacetic acid (99mTc-DTPA), mercaptoacetyltriglycine (99mTc-MAG3), ethylenedicysteine 
(99mTc-EC) and orthoiodohippurate labeled with 131-J ( 131J-OIH).  Among these, 99mTc-
DMSA, a static renal agent, is considered as the most reliable method to measure relative renal 
function and is the preferred agent for this study.    
 
Renal scintigraphy using 99mTc-DMSA is being advocated as the preferred method for 
assessment of renal function following several types of kidney disease.  Its uptake correlates with 
effective renal plasma flow, glomerular filtration rate and creatinine clearance.  Its quantitative 
measurement is therefore a good index for relative renal function.  Previous studies have shown 

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that 99mTc-DMSA uptake differentiates normal from diseased kidney.  If the site routinely uses 
a different agent, then the method should be reviewed at the site initiation visit.  
 
The site should use their standard site procedure.  Outline of an example procedure is below:  
 
 Patient should receive an intravenous injection of 50MBq 99mTc-DMSA with 
imaging performed 3 hours after injection.   
 Patient will be placed in supine position and an acquisition of posterior view with 
preset time of 15 minutes, 256x256 matrix will be performed with ultra- high 
resolution collimator.   
 Differential renal function will be calculated using region-of-interest drawings.  
 
Note:  If site standard practice is to use a labeled agent other than 99mTc-DMSA, then the site 
must discuss the procedure with RegenMed (Cayman) Ltd. staff prior to site initiation.  If the 
procedure is considered sufficiently equivalent to the procedure listed in the protocol, then the 
site will be allowed to use their standard procedure.  In this case, the procedure will be signed by 
the RegenMed (Cayman) Ltd. Project Leader and a copy kept in the site’s regulatory binder.  
 
12.5 Surgical Procedures  
12.5.1 Biopsy  
The biopsy should be collected from the left/right kidney under sterile conditions using an 
ultrasound or CT guided method as dictated by site standard practices.  The only difference from 
the standard procedure may be collection of 2 tissue cores and use of a 16 gauge needle.  Two 
biopsy renal tissue cores are needed to insure sufficient cortical tissue is collected for selection of 
SRC and manufacture of NKA.  Likewise, a 16 gauge biopsy needle should be used to insure 
sufficient cortical material is collected for manufacture of NKA.  If site standard practices dictate 
use of a 15 gauge biopsy needle, then a 15 gauge needle may be used following consultation with 
the Medical Monitor.  In any case, it is imperative that as much cortical tissue is collected as 
possible.  If available at the site, bedside examination of the biopsy cores may be performed to 
ensure sufficient cortical material is obtained.  
 
It is important to remember that the biopsy tissue will be used to manufacture NKA, an 
injectable product.  Therefore, the site should ensure that individuals collecting the biopsy are 
aware that the tissue cores must be harvested using sterile conditions so that the risk of 
contamination during cell expansion and selection is minimized.  Product with microbial 
bioburden cannot be released for injection, so contamination of the tissue cores during collection 
could significantly jeopardize RegenMed (Cayman) Ltd.’s ability to manufacture an NKA 
product for that patient.  
 
Guidance on wound care and pain management following the injection procedure will be 
provided in the Study Reference Manual.  Importantly, pain medication administered to the 
patient post-biopsy should selected carefully, avoiding as possible medications with nephrotoxic 
potential as discussed in Section 10.2.  Specialized patient care surrounding the injection will 
focus on minimizing potential bleeding events.  The subject will remain supine for 4 hours with 
monitoring of hemoglobin, blood pressure, gross hematuria, abdominal/flank pain, and flank 

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ecchymosis.  In addition, the patient may be discharged the day of biopsy per site standard 
practice.  
 
If a subject experiences significant adverse events following the biopsy that, in the opinion of the 
PI would put the subject at increased risk for significant adverse effects following biopsy, then 
he/she will not be injected with NKA, but will be followed until resolution of the event(s) and 
then discontinued from the study.    
12.5.2 Injection  
NKA in a sterile syringe will be sent to the site from RegenMed (Cayman) Ltd.  Once received at 
the site, NKA should be stored in the Shipping Container until it is transported to the surgical 
suite.  NKA must be equilibrated to 26.5±1.5 ºC for a minimum of 30 minutes but not more than 
120 minutes immediately prior to injection into the patient.  Instructions for equilibration will be 
provided by RegenMed (Cayman) Ltd. in the Study Reference Manual.  
 
Patients will be injected with NKA using either: (1) a percutaneous minimally-invasive image-
guided direct-needle approach, or (2) a laparoscopic technique similar to that used to deliver 
NKA in the canine studies and already utilized 6 or more times in the Swedish study in humans.  
The objective in either case is to approach at an angle allowing deposition of NKA in the renal 
cortex, distributed as widely as feasible.  This could require imaging the kidney in a longitudinal 
or transverse approach, depending upon individual patient characteristics. Ideally the injection 
will involve multiple deposits as the injection needle/cannula is gradually withdrawn.  The 
volume to be injected is determined by the weight of the kidney as estimated from the MRI, up 
to a maximum of 8 mL.  For an 8 mL injection, it is anticipated that one to two mL will be 
deposited in 8 to 4 increments, respectively.  Up to two entry points may be used to deposit the 
full volume of NKA into the kidney (two entry points per kidney were routinely used in all of the 
animal studies).  NKA must be administered slowly at a rate no faster than 2 mL/min, ensuring 
viability of the NKA.  If possible, the injection procedure will be viewed by the sponsor and 
actual injection of the kidney will be recorded on video for use as an educational/training tool. 
 
Prior to surgery, the site must document the specific procedural approach that will be used to 
access the kidney.   
• 
Percutaneous procedure: 
Prior to the procedure, the operating physician will evaluate the patient, including: 
a. Physical evaluation, to determine the feasibility of the procedure in general; 
b. Evaluation of bleeding parameters, including coagulation panel, INR, platelets, 
hemoglobin, hematocrit, and other pertinent laboratory studies as indicates; 
c. Review of available imaging studies, including ultrasound, MRI, and/or CT, to 
determine route of access, depth of kidney, and appearance of cortical-medullary 
junction.  Mapping of potential sites of NKA cell deposition will be performed. 
d. Determination of ASA class from airway assessment, medical history, allergies, and 
medications. 
e. Interview of patient and family/supporters to discuss the procedure, its risks and 
possible complications, sedation, answer questions, and obtain documented informed 
consent. 
 
Procedural technique:  Specifically, a co-axial technique will be utilized (details below).  

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Image guidance:  The operator will determine which kidney was biopsied, and will plan his 
approach to that kidney via longitudinal, transverse, or both reference planes.  Imaging options 
during the procedure include ultrasound alone or ultrasound with complementary CT; the 
operator will verify and document the availability of adequate functionality, including color 
Doppler, measuring ability, probe frequency, and overall design.   
 
Prior to the procedure, abnormal coagulation values will be corrected.  Prophylactic antibiotics 
will be given intravenously according to the usual practices at the site.  An initial CT scan may 
be ordered if necessary, for evaluation of adjacent viscera, renal location, presence of renal cysts, 
and for determination of the cortical-medullary junction in conjunction with ultrasound.   
 
During the procedure, moderate conscious sedation will be employed, and patient monitoring 
will be continuous.   
 
NKA is targeted for injection into the kidney cortex via a needle (cannula) compatible with cells. 
The intent is to introduce NKA via penetration of the kidney capsule and deposit into multiple 
sites of the kidney cortex.  Initially, the kidney capsule will be pierced using a 15-20 gauge 
access trocar/cannula inserted approximately 1 cm into the kidney cortex (but not advanced 
further into the kidney).  NKA is contained in a syringe that will be attached to a blunt tipped 
inner needle or flexible cannula (18-26 gauge, as suitable for the access cannula).  In the Phase 1 
clinical study, NKA was delivered via an 18G needle. The proposed Phase II study will utilize an 
18 gauge or smaller needle (18-26 gauge) for NKA injection. The needle will be threaded inside 
the access cannula and advanced into the kidney, from which the NKA will be administered. 
Injection of the NKA will be at a rate of 1-2 ml/min.  After each 1-2 minute injection, the inner 
needle will be retracted along the needle course within the cortex to the second site of injection; 
and so forth until the needle tip is at the end of the access cannula or the entire cell volume has 
been injected.  This procedure can be used for both laparoscopic (used previously in Phase I 
study) and percutaneous injection of NKA.  For percutaneous injection of NKA, the placement 
of the access cannula/trocar and needle will be performed using direct, real-time image guidance. 
Injection of the NKA will be monitored with ultrasound image guidance to visualize the 
microbubble footprint of cell deposits. 
 
NKA injection will cease if there is imaging evidence of cell extravasation into central or 
peripheral renal blood vessels, the medullary portion of the kidney, or through the renal cortex 
and into the retroperitoneal soft tissues, or evidence of active bleeding.  At this point, the needles 
are withdrawn.  Additional renal injection sites may be chosen if NKA remains to be injected, 
along the same needle track, or at a new site in a different location in the kidney.   
 
Following completion of NKA injection, the inner needle will be withdrawn and the outer 
cannula will remain in place for track embolization.  During removal of the outer cannula 
(trocar), the site of the renal cortex puncture and needle track through the retroperitoneum will be 
embolized with absorbable gelatin particle/pledgets (e.g. Gelfoam [Pfizer]) or fibrin sealant (e.g. 
Tisseel [Baxter]) or other suitable agent to prevent renal bleeding.   
 
At completion of the procedure, non-contrast CT scan or ultrasound with color Doppler 
evaluation will be performed to assess for puncture site cell injection and any hematoma or 
bleeding.   

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For 2 to 3 hours post-procedure there will be observation in a recovery-room environment with 
nursing assessment and vital-sign monitoring.  The patient may be discharged after that, if all 
indices are normal.   
 
A follow-up phone call will be conducted at 24 hours post-discharge, and follow-up in clinic will 
continue per protocol. 
 
Minimally-Invasive Laparoscopic Procedure: 
Using the second method, the kidney will be accessed while the patient is under full anesthesia, 
using a robotic- or hand-assisted laparoscopic approach. (The site may choose to use HARS as 
described in Wadstrom et al., 2011a and 2011b, or else a standard robotically-assisted method).  
Using a robotic- or hand-assisted approach allows the surgeon to place the kidney in an optimal 
position for the injection.  It also allows the surgeon to visualize and stop bleeding if this should 
occur.  Blood pressure will be monitored continuously during surgery using standard site surgical 
practices.    
 
Once the kidney is accessed, NKA will be injected at an angle that allows for deposition of NKA 
into the kidney cortex.  The cannula should be inserted to a depth that allows for multiple 
depositions of NKA as the cannula is retracted from the kidney.  Entry points should be off the 
mid line of the kidney and angled to maximize deposition of NKA into kidney cortex.   
 
Immediately after injection, the patient will recover in a post-operative surgical recovery unit 
under supervision.  The patient will not be taken to his/her room until all vital signs are stable.  
Overall, the patient will be kept in the bed for at least 8 hours with monitoring of blood pressure 
and pulse.  The patient should be closely monitored for 24 hours by a skilled team of caregivers 
used to dealing with post-operative problems.  If pain, fever, dramatic decreases in blood 
pressure/hemoglobin, or any other clinical sign/symptom indicates potential adverse 
reactions/events, then further physical examinations (potentially including x-rays or ultrasound 
investigations) must be carried out liberally and swiftly for diagnostic purposes.  
 
In addition to standard safety measures, hemoglobin will be monitored before, 4 hours after, and 
then daily while hospitalized following injection.  Patients will remain in the hospital for 2 to 4 
nights following surgery.  Patients will not be released from the hospital until procedure- and/or 
product-related AE’s have resolved, stabilized, or returned to baseline. 
 
Post-procedure Evaluation of the injection: 
With either procedure, if NKA leaks from the kidney during deposition, then the amount leaked 
should be estimated and recorded in the CRF.  To prevent further leakage, the rate of injection 
may be slowed.    
• 
As part of this protocol, injection parameters including (but not limited to) rate of 
injection and angle of injection may be adjusted for optimization.  
 
 

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13 SAFETY ASSESSMENTS AND MANAGEMENT  
13.1 Event Definitions  
13.1.1 Adverse Events  
An Adverse Event (AE) is any untoward medical occurrence associated with the use of a drug or 
with study participation, regardless of the relationship of the occurrence to study drug or 
protocol. An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of the drug, whether or not 
considered related to the drug. An AE can arise from any use of the drug, and from any route of 
administration, formulation or dose, including an overdose. 
 
Disease or other specific clinical signs and symptoms which were ongoing prior to study entry 
(i.e., a “pre-existing” conditions) should be recorded on the Medical History CRF and are not 
considered AE’s unless the condition unexpectedly worsens during the study.  Specifically, CKD 
signs and symptoms which were present at study entry and had been worsening over time are not 
considered AE’s unless there is an unexpected worsening of the events.  This would include, for 
example, an unexpected increase in the rate of disease progression.   
 
Treatment emergent abnormal clinical laboratory findings or other abnormal assessments that are 
judged by the PI as clinically significant, involve therapeutic medical intervention, or lead to 
study discontinuation will be recorded as AE’s or SAE’s if they meet the definition of an AE or 
SAE presented in this section.  
 
To determine the presence of adverse events, patients should be questioned about the event in a 
general way, without asking about the occurrence of any specific symptom. The investigator 
should attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information.  In such cases the diagnosis should be documented as the AE and not the 
individual signs and/or symptoms.  
 
Following questioning and evaluation, all AE’s, whether believed by the investigator to be 
related or unrelated to study procedures and/or NKA, must be documented in the patient’s 
medical records in accordance with the investigator’s normal clinical practice and on the AE 
CRF. Each AE is to be evaluated for nature, duration, severity, seriousness, and causal 
relationship to NKA administration.  
 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final study report.  
13.1.2 Serious Adverse Reaction/Event  
An adverse event or suspected 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,  
• 
Inpatient hospitalization or prolongation of existing hospitalization,   
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  

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• 
A congenital anomaly/birth defect  
• 
An important medical event 
  
Life-threatening event: An adverse event or suspected adverse reaction is considered "life-
threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient 
or subject at immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.  Disability is 
defined as a substantial disruption in a person’s ability to conduct normal life functions.    
Hospitalization for elective treatment of a preexisting condition that did not worsen during the 
clinical investigation is not considered an AE/SAE.  Admittance to an emergency room for 
observation without being admitted to the hospital may be an AE but is not arbitrarily classified 
as an SAE.  Hospitalization or nursing home admission for the purpose of caregiver respite is not 
considered an AE/SAE.  Complications that occur during hospitalization are AE’s, and if a 
complication prolongs hospitalization, the event is considered serious.  
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 patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.    
13.2 Assessment and Grading of AE’s/SAE’s  
13.2.1 Relationship Assessment  
For each reported AE, the Investigator must make an assessment of the relationship of the event 
to study procedures and/or NKA using the following criteria:  
• 
Unrelated:  applicable to an AE that occurs when the subject was not exposed to 
study treatment or another cause is obvious.  
• 
Unlikely to be related:  applicable to an AE that meets the following criteria: 
o Does not follow a reasonable temporal sequence from injection of NKA  
o May readily have been produced by the patient’s clinical state, environmental, or 
toxic factors, or other therapy administered to the patient  
o Does not follow a known pattern of response to injection (based on animal data)  
• 
Possibly related:  applicable to AE’s where connection with NKA injection appears 
unlikely but cannot be ruled out.  Applicable to AE’s where:  
o It follows a reasonable temporal sequence following injection of NKA  
o It follows a known pattern of response to injection of NKA (based on animal 
studies)  
• 
Probably related:  applicable to AE’s that are considered, with a high degree of 
certainty, to be related to NKA.  Applicable to AE’s where  
o It follows a reasonable temporal sequence from injection of NKA  
o It cannot be reasonably explained by the know characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy  
o It follows a known patter of response to NKA injection (based on animal 
data).  

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13.2.2 Severity of Adverse Events  
All AE’s including SAE’s will be assessed for severity, using the following grading scale:    
 
Severity of symptoms and abnormal findings will be assessed in this study using the Common 
Terminology Criteria for Adverse Events (NCI CTCAE, version 4.03).  
 
In the event that an AE is not covered by the NCI-CTCAE grading system, the following 
definitions will be used:  
- Mild: awareness of sign, symptom, or event, but easily tolerated; does not interfere 
with usual daily activities or tasks  
- Moderate: discomfort enough to cause interference usual activity and may warrant 
therapeutic intervention  
- Severe: incapacitating with inability to perform usual activities and daily tasks;  or 
significantly affects clinical status, ; requires therapeutic intervention 
- Life-threatening: immediate risk of death  
- Death 
13.3 Recording, Follow-up and Reporting of Adverse Events  
13.3.1 Recording of Adverse Events  
Subjects will be required to report any AE that occurs after informed consent is signed. All AEs 
that occurred from the time of informed consent until the 18-month follow-up visit will be 
recorded with the following precisions. 
 
ICF to Biopsy:  Any AE occurring after the patient has signed the ICF but before biopsy should 
only be recorded on the AE page of the CRF if it is directly related to study procedures (e.g., 
nausea resulting from an agent used for an imaging study).  Any CKD specific event occurring 
during this time should be recorded (or updated) on the Medical History page.    
 
Biopsy to Injection:  Any AE occurring during or after the biopsy and before injection should be 
recorded on the AE page only if the event was considered possibly or probably related to the 
biopsy or other protocol-specified procedure.  CKD specific events should be recorded (or 
updated) on the Medical History page unless, in the opinion of the Investigator, the worsening of 
the CKD event could be related to the biopsy or other study procedure.  
 
Injection to Month 12 Follow-up:  Any AE occurring during or after injection until the 12 
month follow-up visit should be recorded on the CRF.  
 
Month 12 to Month 18 Follow-up:  Following the 12 month visit to the 18 month follow-up 
visit, all AE’s assessed as product- or procedure-related should be recorded in the AE CRF.  In 
addition, any AE’s with a severity assessment of “severe” or “life-threatening” should be 
recorded in the CRF, regardless of relationship.  Any CKD-related event that meets the definition 
of an AE (e.g., clinically significant increase in sCr) should be recorded in the AE CRF.  All 
other AE’s do not need to be recorded in the CRF; however, as the PI is responsible for patient 
safety, the site should record any event that the PI determines should be recorded in the AE CRF.     

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13.3.2 Recording of Serious Adverse Events  
All SAE’s should be recorded in the AE CRF from first study procedure through the 6 month 
follow-up visit.  In addition, any SAE’s that occur during the long-term observational phase 
AND are considered related to investigational product, should be recorded in the CRF.  All 
SAE’s should be reported according to the procedures discussed below (Section 13.3.4).  
13.3.3 Follow-Up of AE’s/SAE’s  
All AE’s that are assessed as related to Investigational Product (i.e., NKA) or study procedures 
(e.g. biopsy, laparoscopic surgery, or surgical or percutaneous injection) should be followed by 
the Investigator until the event resolves, stabilizes, or returns to baseline.  The investigator 
should continue to report any significant follow-up information to the Sponsor or Sponsor’s 
designee up to the point the event has been resolved.  
 
SAE’s should be followed until the event resolves, stabilizes, or returns to baseline.  If the 
patient insists on discontinuing from the study prior to resolution/stabilization/return to baseline 
of the SAE, then the patient will continue to be followed as part of the SAE reporting system.  
That is, the Investigator will continue to follow the patient on a schedule dictated by the clinical 
situation and submit appropriate follow-up SAE reports as discussed in Section 13.3.4.  If the 
patient refuses to continue to follow-up with the Investigator, then the Investigator may follow 
the patient through consultation with the patient’s primary physician if allowed by the site-
approved ICF and applicable regulations.  
 
SAE’s that are identified on the last scheduled visit must be recorded in the AE CRF and 
reported to the Sponsor or Sponsor’s designee as outlined in Section 13.3.4.  Subjects with 
unresolved, previously reported serious adverse events, or new serious adverse events identified 
on the last scheduled visit, should be followed by the investigator until the events are resolved, 
stabilized, or returned to baseline.    
 
13.3.4 Reporting of Serious Adverse Events  
8.3.4.1 Reporting of SAEs to the Sponsor 
It is the responsibility of the PI to insure all SAEs and follow-up SAEs, occurring from the 
signature of the ICF until the 18-month follow-up visit, are reported to the Sponsor or Sponsor’s 
designee within 24 hours of discovery or notification of the event or the follow-up information.  
For each SAE and follow-up to an SAE the site should ensure that critical AE CRFs are 
completed as of the onset date for the SAE (e.g. demographics, concomitant medications, and 
medical history) as described in the Study Reference Manual.  
At any time after completion of the AE reporting period, if the Investigator becomes aware of an 
SAE that is suspected by the Investigator to be related to the investigational product, the SAE 
must be reported to the Sponsor or Sponsor’s designee within the same timelines. 
 
SAEs shall be sent to CTI Safety preferably by Facsimile transmission, via secure e-fax specific 
to this study, with the SAE Report Form.  In circumstances where facsimile equipment is not 
available, notification by email to CTISafety@CTIFacts.com is acceptable. 
 
SAEs shall be sent by eFAX with the SAE report form to: CTI Safety 
Drug Safety Country-Specific Contact Numbers 

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Country 
E-Fax 
SAE Hotline  
United States 
1-800-541-1501 
877-755-0742 / 513-212-6804 
Sweden 
46 850 127 343 
 
CTI GSP EMAIL 
CTISafety@CTIfacts.com  
 
In circumstances where it is not possible to send the notification by the above-mentioned 
method, notification by telephone is acceptable, with a copy of the SAE Report Form sent by 
overnight mail. Initial notification via the telephone does not replace the need for the investigator 
to complete, sign and send the SAE form within the time frames outlined above. 
 
8.3.4.2 Reporting of SAEs to Competent Authorities  
SAEs that are considered as possibly or probably related to the investigational product, and as 
unexpected, will be reported to the Competent Authorities by the Sponsor or Sponsor’s designee 
as required by applicable local regulations; therefore it is critical that site personnel record SAEs 
in the eCRF in a timely manner.  Per regulation, any unexpected fatal or life-threatening AEs 
assessed as possibly or probably related to NKA will be reported to the Competent Authorities 
by the Sponsor or Sponsor’s designee within 7 calendar days. Additional information will be 
reported to the Competent Authorities within an additional 8 calendar days.  The Sponsor or 
Sponsor’s designee is required to submit any other unexpected SAEs assessed as possibly or 
probably related to NKA to the Competent Authorities within 15 calendar days of notification.      
13.4 Events of Special Interest  
The following events are considered “events of special interest” as they are events that have been 
reported in the past following one or more of the procedures performed during this study.  
Patients should be carefully monitored for appearance of these events at any time during the 
study.  
13.4.1 Procedure-related Events  
Post-procedure Pain:  If the subject experiences pain following the biopsy or injection, simple 
analgesia with paracetamol or paracetamol-codeine combinations usually suffices to control the 
pain.  More severe pain in the loin or abdomen requires ultrasonography to exclude significant 
perirenal hemorrhage.  Patients will be followed with regular hemoglobin and blood pressure 
monitoring.  If severe pain occurs, opiates may be necessary.  If analgesic doses higher than the 
maximum authorized doses are required to alleviate pain, then the Investigator must perform 
additional clinical evaluations to ascertain the probable cause(s) of excessive pain.  
 
Hemorrhage:  A degree of perirenal bleeding accompanies almost every renal biopsy.  
According to the literature (Whittier and Korbet, 2004b), mean hemoglobin decreases 
approximately 1.0 g/L to about 10 g/L after injection biopsy.  Macroscopic hematuria and painful 
hematomas are seen in about 3 % of patients after renal biopsy.  Therefore, following the biopsy 
and injection, patients will be followed with regular hemoglobin and blood pressure monitoring.  
Patients will be confined to bed and monitored for maintenance of normal coagulation indices.  If 
bleeding is brisk and the patient is hypotensive despite bed rest, blood transfusion will be 
considered.  If the bleeding is still not controlled, surgery may be considered.  In rare cases, renal 
angiography should be performed to identify the source of bleeding and coil embolization can be 
performed in such cases during the same procedure.  
 

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Arteriovenous (AV) fistula:  According to the literature (Abutaleb and Obaideen, 2007; Arora 
et al., 2012; Ham et al., 2012; Huang et al., 2011; Whittier and Korbet, 2004a; Whittier and 
Korbet, 2004b), AV fistulas can be found in about 18% of patients that have undergone renal 
biopsy.  However, as more than 95% of these resolve within 2 years, they should not be routinely 
pursued.  If patients have recurrent hematuria after a renal biopsy or injection, AV fistulas could 
be considered.  In these cases embolization may be indicated.  If an AV fistula is detected by 
ultrasound at the pre-injection qualification visit, then the PI should consider discontinuing the 
patient prior to injection.  
 
Other complications:  In very rare cases other organs, such as liver, gallbladder and lungs may 
have been penetrated during the procedure.  In these cases appropriate treatment and follow-up 
will be discussed with surgeons.  
 
Death:  Deaths resulting from renal biopsies occur in <0.01% of patients (Hergesell et al., 1998; 
Lin et al., 2006; Walker, 2009) but could be due to uncontrolled bleeding especially in patients 
with severe renal impairment.  Strict inclusion/exclusion criteria will be followed to ensure that 
patients who may be predisposed to uncontrolled bleeding would not be enrolled in the trial.  
 
13.4.2 Product-related Events  
No product-related events are expected to occur.  This is based on the autologous nature of NKA 
(i.e., NKA is manufactured from renal cells isolated from the same kidney to which they are to 
be returned), the lack of product-related events observed in the animal studies, and the lack of 
specific NKA related events seen during and following injection of the first 5 patients in Sweden 
(See Section 6.5.1).  However, patients will be extensively monitored throughout the course of 
the study for any unexpected events.  If an event occurs which is assessed as related to the 
investigational product, NKA, then the event will be immediately reviewed by the Medical 
Monitor and PI.   
13.5 Data Safety Monitoring Board  
Given the uniqueness of this product, an external data safety monitoring board (DSMB) will be 
convened to oversee patient safety, especially as it relates to any unexpected product-related 
events.  The committee will be composed of a minimum of 3 members whose expertise is such 
that the Board has adequate familiarity with reconstructive urological surgery, renal medicine, 
and monitoring emerging safety issues in clinical studies.  The DSMB will be an independent 
committee that is not otherwise engaged in the conduct of the clinical study and who do not have 
conflicts of interest.    
 
The DSMB will be governed by the DSMB charter.  The specific mandate of the DSMB will be 
to review any AE’s/SAE’s assessed by the PI as related to the investigational product, NKA.  
Thus, any events assessed as related to NKA will be forwarded to the DSMB by the study site or 
CRO.  If the event is rated mild or moderate, the DSMB will work with the PI and Medical 
Monitor to determine the best course of action.  The “best course of action” may range from no 
changes to adaptations of procedures to prevent future events, etc.  If the event is severe or life-
threatening, then the DSMB may consider halting future injections until a best course of action is 
devised.  If the event is an SAE that is considered severe or life-threatening, then no future 
patients may be injected until approved by the DSMB.  In addition to the above, the DSMB will 

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be charged with reviewing the safety data from the first two patients injected and providing 
consultation on enrollment of subsequent patients.  
 
The DSMB will be expected to advise RegenMed (Cayman) Ltd. regarding the study design and 
study conduct, and may recommend early study termination for safety reasons.  The DSMB will 
be expected to request additional information and analyses as they require. The DSMB’s 
recommendations will be communicated to the study centers, and where required to the 
IRBs/ECs and the Competent Authorities. If the DSMB recommends stopping the study, the 
Competent Authorities and the IRBs/ECs will be notified. 
 
The surgical procedures used in this study, renal biopsy, percutaneous needle insertion in the 
kidney, and laparoscopic or retroperitoneoscopic surgery, are established procedures with known 
adverse event profiles.  However, if unexpected procedure-related events occur, the DSMB will 
review the events on a case-by-case basis.  
13.6 Stopping Criteria  
Approximately two to three weeks following each of the first two injections, the PI, Medical 
Monitor, DSMB and RegenMed (Cayman) Ltd. staff will review the case to assess both positive 
and negative results of the injection.  If no clinically significant unexpected events are identified, 
the next patient may be injected such that the timing between the first 3 injections will be 
staggered by 3 weeks.  If any of the following events occur, no additional patients can be 
injected until review by the DSMB is completed:  
 
1. An SAE that is rated as severe or life-threatening and considered related to NKA or 
study procedures by the PI   
2. Death of an enrolled patient  
3. Similar SAE’s in more than one patient that are considered related to NKA by the 
investigator  
4. Inability to deliver a minimum of 50% of the dose of NKA in more than one 
patientdue to surgical or other issues  
5. DSMB recommendation to temporarily stop enrollment to allow for more precise 
review of case(s)  
 

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14 STATISTICAL CONSIDERATIONS  
14.1 Samples Size   
Up to 30 subjects will receive up to two doses with NKA.  As this is an early Phase II safety and 
efficacy study, formal sample size calculations were not performed.  The planned sample size 
allows for a preliminary characterization of the safety profile of the NKA in patients with 
chronic kidney disease.  
14.2 Analysis Objectives  
The primary objective of the study is to assess the safety and efficacy of NKA injected in one 
recipient kidney and determine if two injections of NKA provide stabilization of renal function.  
 Primary Safety Outcome Measures:  procedure and/or product related adverse events 
(AE’s) through 12 months following the initial NKA injection.    
 Primary Efficacy Outcome Measures: serial measurement of serum creatinine and 
estimation of GFR through 6 months following the second cell injection 
 
The secondary objective of the study is to assess the safety and tolerability of NKA 
administration by assessing renal-specific adverse events over a 12 month period following a 
patient’s first NKA injection.  
 Secondary Safety and Tolerability Outcome Measures:  renal-specific laboratory 
assessments through 12 months following the last NKA injection under this protocol, 
whether first or second.  
 
The exploratory objectives of the study are designed to assess the impact of NKA on renal 
function over a 12 month period following the initial NKA injection.  
 Exploratory Outcome Measures:  clinical diagnostic and laboratory assessments of renal 
structure and function (including eGFR, serum creatinine, and proteinuria) to assess 
changes in the rate of progression of renal disease; and effect of method of injection on 
these parameters.  
 
Exploratory quality of life outcome measure will be the Kidney Disease Quality of Life survey 
obtained at baseline and at 1, 3, 6, 7, 9, 12, 15, 18, 30, and 42 months after a patient’s first NKA 
injection. 
 
Additional exploratory endpoints include the following:  
 Changes from baseline in BUN, β2 microglobulin and intact parathyroid hormone (iPTH) 
at 6 and 12 months post-injection.  
 Changes from baseline in C-reactive protein (CRP) at 6 and 12 months post-injection.  
 Need for initiation of renal replacement therapy.  
 Comparison of pre-injection versus post-injection split functional differences between the 
left and right kidney based on renal scintigraphy.    
 Comparison of pre-injection and post-injection kidney volume estimates based on 
comparative MRI assessments.  
 Changes in the patient’s perception of quality of life, as measured by serial KDQoL 
surveys. 

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14.3 Endpoints 
The primary endpoint of the study is to assess the safety and efficacy of NKA injected in one 
recipient kidney and determine if two injections of NKA provide stabilization of renal function.  
 Primary Safety Outcome Measures:  procedure and/or product related adverse events 
(AE’s) through 12 months following the initial NKA injection.    
 Primary Efficacy Outcome Measures: serial measurement of serum creatinine and 
estimation of GFR through 6 months following the second cell injection 
Secondary Endpoint  
The secondary endpoint of the study is to assess the safety and tolerability of NKA 
administration by assessing renal-specific adverse events over a 12 month period following a 
patient’s first NKA injection.  
 Secondary Safety and Tolerability Outcome Measures:  renal-specific laboratory 
assessments through 12 months following the last NKA injection under this protocol, 
whether first or second.  
Exploratory Endpoints  
The exploratory endpoint of the study are designed to assess the impact of NKA on renal 
function over a 12 month period following the initial NKA injection.  
 Exploratory Outcome Measures:  clinical diagnostic and laboratory assessments of renal 
structure and function (including eGFR, serum creatinine, and proteinuria) to assess 
changes in the rate of progression of renal disease; and effect of method of injection on 
these parameters.  
 
Exploratory quality of life outcome measure will be the Kidney Disease Quality of Life survey 
obtained at baseline and at 1, 3, 6, 7, 9, 12, 15, 18, 30, and 42 months after a patient’s first NKA 
injection. 
 Changes from baseline in BUN, β2 microglobulin and intact parathyroid hormone (iPTH) 
at 6 and 12 months post-injection.  
 Changes from baseline in C-reactive protein (CRP) at 6 and 12 months post-injection.  
 Need for initiation of renal replacement therapy.  
 Comparison of pre-injection versus post-injection split functional differences between the 
left and right kidney based on renal scintigraphy.    
 Comparison of pre-injection and post-injection kidney volume estimates based on 
comparative MRI assessments.  
 Subgroup analyses will compare patients receiving a single injection with patients 
receiving two injections, and patients receiving laparoscopic injections with patients 
receiving percutaneous injections. 
 

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14.4 Analysis Conventions  
14.4.1 Analysis Sets  
Full Analysis Set:  The Full Analysis Set (FAS) will consist of all subjects who are enrolled in 
the study.  
Injection Analysis Set:  The Injection Analysis Set will include all patients who undergo a 
successful NKA injection.  
 
14.4.2 Handling Missing Data  
Values for missing data will not be imputed.  
 
14.5 Demographic and Baseline Characteristics  
Demographic data and baseline characteristics will be summarized using a typical 8-number 
summary (sample size, mean, standard deviation, median, Q1, Q3, minimum, and maximum) for 
continuous variables and frequency and proportion for categorical variables.  These summaries 
will be produced for both the FAS and the Injection analysis set.  Generating inferential statistics 
is not planned.  Demographic and baseline characteristics information will be provided in a data 
listing.  
 
14.6 Efficacy Analysis  
Not applicable.  
 
14.7 Safety Analysis  
14.7.1 Biopsy, NKA Injection, Patient Disposition  
Biopsy and NKA injection data will be provided in a data listing.  Patient disposition (e.g., 
Screen Failure, Enrolled/Underwent Injection, Withdrawn Pre-injection, Successful injection, 
Discontinued Early Post-injection, Completed Study) will be summarized by frequency and 
proportion and will be provided in a data listing.  
 
14.7.2 Adverse Events  
Clinical and laboratory AE’s will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  System Organ Class (SOC), High-Level Group Term (HLGT), High-
Level Term (HLT), Preferred Term (PT), and Lower Level Term (LLT) will be attached to the 
clinical database.  Adverse events will be graded using the NCI CTCAE scale.  
 
A treatment-emergent AE will be defined as any adverse event that begins on or after the date of 
enrollment up to 18 months post-injection.  
 
Summaries (frequency and proportion) of treatment-emergent AE’s will be presented by SOC 
and PT.   
 

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Additional summaries will include, but are not limited to, treatment-emergent AE’s by severity 
grade, Investigator’s assessment of relationship to procedure and/or product, serious AE’s 
(SAE’s), related SAE’s, and deaths.  AE summaries will be provided for both the FAS and the 
Injection analysis set.  There are no plans to generate inferential statistics.  AE data will be 
provided in a data listing.  
 
14.7.3 Laboratory Evaluations  
Baseline values will be collected immediately prior to injection.  Observed and change from 
baseline laboratory data will be summarized using a typical 8-number summary (sample size, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum) for continuous variables 
and frequency and proportion for categorical variables.  These summaries will be produced for 
both the FAS and the Injection analysis set.  Generating inferential statistics is not planned.  
 
Graded laboratory abnormalities will be defined using the NCI CTCAE grading scheme as 
defined in Section 12.3.  Incidence of treatment-emergent laboratory abnormalities, defined as 
values that increase at least 1 toxicity grade from baseline at any time post baseline up to six 
months post-injection will be summarized.  If baseline data are missing, then the latest value 
collected between biopsy and injection will be used as the baseline value.  If baseline and pre-
injection data are missing, then any graded abnormality, i.e., at least a Grade 1, will be 
considered treatment emergent.  
 
Laboratory data summaries will be provided for both the FAS and the Injection analysis set.  
There are no plans to generate inferential statistics, except for variables concerning the rate of 
renal insufficiency progression.  A paired t-test may be performed to assess the change in the rate 
of progression of renal insufficiency.  Laboratory data will be provided in a data listing.  
 
14.7.4 Other Safety Evaluations  
Data from ECG, physical exam, medical history, concomitant medication, vital signs, ultrasound, 
renal scintigraphy, and MRI assessments will be provided in a data listing.  Descriptive statistics 
for these evaluations will be generated as warranted.  
 
14.8 Exploratory Analysis  
As this study is a Phase II evaluation, hypothesis generating exploratory analyses may be 
conducted to help design future clinical studies. Subgroup analyses will compare patients 
receiving a single injection with patients receiving two injections, and patients receiving 
laparoscopic injections with patients receiving percutaneous injections. 
15 STUDY ADMINISTRATION  
15.1 Ethical and Regulatory Standards  
This study will be conducted in accordance with ICH E6 GCP guidelines, ethical principles 
outlined in the Declaration of Helsinki, and all appropriate US regulations including 21 CFR 
Parts 11, 50, 54, and 56, and all appropriate EU regulations. 

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15.1.1 Institutional Review Board and Ethics Committee 
It is the Investigator’s responsibility in the US and the sponsor’s (or sponsor’s designee’s) 
responsibility in the EU to ensure that this protocol is reviewed and approved by an appropriate 
IRB which conforms to US regulations found in 21 CFR Part 56, as well as EU and national 
regulations.  The PI in the US and sponsor/sponsor’s designee in the EU must also submit the 
ICF, any other written documentation provided to the subject and all advertisements that may be 
used for study-specific activities to the IRB/EC for approval.  If it is necessary to amend the 
protocol during the study, then it is the responsibility of the PI in the US and sponsor/sponsor’s 
designee in the EU to ensure that IRB/EC approval is obtained before implementation of the 
amended procedures.  It is also the responsibility of the PI in the US and sponsor/sponsor’s 
designee in the EU to provide the IRB/EC with any SAE or safety reports.  
15.1.2 Subject Informed Consent  
Prior to conducting any study-specific procedures, the site must obtain the informed consent of 
the patient, as indicated by his/her signature on the ICF.  The Investigator is responsible for 
informing the patient about the study and obtaining informed consent from the patient as 
indicated by his signature on the ICF to verify the task.  The ICF must contain all elements 
required by ICH guidelines and 21 CFR Part 50 in the US and EU and national regulations be 
approved for use in the study by the appropriate IRB/EC.    
15.2 Data Collection and Review  
15.2.1 Data Collection  
All observations relating to the study must be recorded by study site personnel in source 
documents.  In addition, specific Case Report Forms (CRFs) will be provided for this study.   A 
CRF must be completed for every patient who signs the ICF and has at least one protocol-
specified, study-specific assessment conducted.  CRF completion instructions will be provided to 
the site in the Study Reference Manual.  Every attempt should be made to enter patient visit data 
into the CRF within 3 days of the patient’s visit.  After the patient has completed the study, the 
PI must review and sign the CRF indicating that he has reviewed the completed CRF and 
pertinent clinical data for that patient and that, to the best of his knowledge, all data recorded in 
the CRF accurately reflects the patient’s clinical performance in the study.  
15.2.2 Study Monitoring  
A study monitor appointed by the Sponsor will periodically contact the site and conduct on-site 
monitoring visits as described in the Study Monitoring Plan.  The study monitor will insure that 
the investigation is conducted according to the protocol and regulatory requirements including 
ICH GCP guidelines.  
 
In addition, a DSMB will be convened to oversee patient safety.  The composition, role, and 
responsibilities of the DSMB will be as discussed in Section 13.5 and detailed in the DSMB 
charter.  
15.2.3 Quality Assurance  
At its discretion, RegenMed (Cayman) Ltd. or its designee may conduct a quality assurance audit 
of this study.  If such an audit occurs, the Investigator will give the auditor direct access to all 
relevant documents, and will allocate his time and the time of his staff to the auditor as required.  
In addition, regulatory agencies may conduct an inspection of this study.  If such an inspection 

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occurs, the Investigator will allow the inspector direct access to all source documents, CRFs, and 
other study documentation for source data check and/or on-site audit inspection.    
 
During any audit, the confidentiality of the data and the protection of patient confidential 
information will be respected and maintained.  
15.3 Retention and Disclosure of Information  
15.3.1 Records Retention  
Results from this study will be included in a US IND submission, therefore US FDA regulations 
for record retention will apply.  These regulations require that records and documents pertaining 
to the conduct of this study, including CRFs, consent forms, and laboratory test results must be 
kept on file by the PI for a minimum of two years after notification by RegenMed (Cayman) Ltd. 
that a marketing application has been approved.  If no application is filed or approved, these 
records must be kept for two years after the investigation has been discontinued and the U.S. 
FDA and applicable foreign authorities have been notified.    
 
EU regulations for record retention, in particular Directive 2005/28/EC, also apply and will be 
followed. 
15.3.2 Disclosure of Information  
Disclosure of Data:  The Investigator agrees by his/her participation that the results of this study 
may be used for submission to national and/or international registration and supervising 
authorities.  If required, these authorities will be provided with the names of Investigator, his 
address, qualifications and extent of involvement.  It is understood that the Investigator is 
required to provide RegenMed (Cayman) Ltd. with all study data, complete reports and access to 
all study records.  
 
Data generated by this study must be available for inspection by regulatory authorities, by 
RegenMed (Cayman) Ltd., and the US IRBs as appropriate.  At a patient’s request, medical 
information may be given to his or her personal physician or other appropriate medical personnel 
responsible for his or her welfare.  Patient medical information obtained during the course of this 
study is confidential and disclosure to third parties other than those noted above is prohibited.  
 
Confidentiality:  All information and materials disclosed or provided by the Sponsor (or any 
company/institution acting on their behalf), or produced during the study, including but not 
limited to the Investigational Product, Shipping Materials, protocol, CRFs, IB and the results 
obtained during the course of the study are confidential. The Investigator and any person under 
his/her authority agree to undertake to keep confidential and not to disclose the information to 
any third party without the prior written approval of the Sponsor.   
 
The Sub-investigators shall be bound by the same obligation as the Investigator.  The 
Investigator shall inform the Sub-investigators of the confidential nature of the clinical trial.  The 
Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account.  
 
Publication Policy:  Following completion of the study, the Investigators and Sponsor are 
expected to publish the results of this research in a scientific journal.    

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Property Rights:  All information, documents and Investigational Product provided by the 
Sponsor or its designee are and remain the sole property of the Sponsor.  
 
The Investigator shall not mention any information or the Investigational Product in any 
application for a patent or for any other intellectual property rights.   
 
All the results, data, and documents, which arise directly or indirectly form the study in any 
form, shall be the immediate and exclusive property of the Sponsor.  
 

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16 REFERENCES  
  
Abutaleb, N., and A. Obaideen. 2007. Renal tamponade secondary to subcapsular hematoma. 
Saudi J Kidney Dis Transpl. 18:426-429.  
Arora, K., R.S. Punia, and S. D'Cruz. 2012. Comparison of diagnostic quality of kidney biopsy 
obtained using 16g and 18g needles in patients with diffuse renal disease. Saudi J Kidney 
Dis Transpl. 23:88-92.  
Atala, A., S.B. Bauer, S. Soker, J.J. Yoo, and A.B. Retik. 2006. Tissue-engineered autologous 
bladders for patients needing cystoplasty. Lancet. 367:1241-1246.  
Basu, J., C.W. Genheimer, E.A. Rivera, R. Payne, K. Mihalko, K. Guthrie, A.T. Bruce, N.  
Robbins, D. McCoy, N. Sangha, R. Ilagan, T. Knight, T. Spencer, B.J. Wagner, M.J. Jayo, D. 
Jain, J.W. Ludlow, and C. Halberstadt. 2011. Functional evaluation of primary renal 
cell/biomaterial Neo-Kidney Augment prototypes for renal tissue engineering. Cell 
transplantation.  
Basu, J., and J.W. Ludlow. 2012. Developmental engineering the kidney: leveraging principles 
of morphogenesis for renal regeneration. Birth defects research. Part C, Embryo today : 
reviews. 96:30-38.  
Bilan, V.P., E.M. Salah, S. Bastacky, H.B. Jones, R.M. Mayers, B. Zinker, S.M. Poucher, and 
S.P. Tofovic. 2011. Diabetic nephropathy and long-term treatment effects of rosiglitazone 
and enalapril in obese ZSF1 rats. J Endocrinol. 210:293-308.  
Brenner, B.M. 1985. Nephron adaptation to renal injury or ablation. Am J Physiol. 249:F324337.  
Cain, H., E. Egner, and M. Redenbacher. 1976. Increase of mitosis in the tubular epithelium 
following intrarenal doses of various kidney homogenates and hemogenate fractions in 
the rat. Virchows Archiv. B: Cell pathology. 22:55-72.  
Collins, A.J., S. Li, D.T. Gilbertson, J. Liu, S.C. Chen, and C.A. Herzog. 2003. Chronic kidney 
disease and cardiovascular disease in the Medicare population. Kidney Int Suppl:S24-31.  
Dhingra, R.K., E.W. Young, T.E. Hulbert-Shearon, S.F. Leavey, and F.K. Port. 2001. Type of 
vascular access and mortality in U.S. hemodialysis patients. Kidney Int. 60:14431451.  
ERA. 2009. 2009 European Renal Association, European Dialysis and Transplant Association. 
ERA-EDTA Registry.  
Field, J.M., M.F. Hazinski, M.R. Sayre, L. Chameides, S.M. Schexnayder, R. HemPhase 1ll, 
R.A. Samson, J. Kattwinkel, R.A. Berg, F. Bhanji, D.M. Cave, E.C. Jauch, P.J.  
Kudenchuk, R.W. Neumar, M.A. Peberdy, J.M. Perlman, E. Sinz, A.H. Travers, M.D.  
Berg, J.E. Billi, B. Eigel, R.W. Hickey, M.E. Kleinman, M.S. Link, L.J. Morrison, R.E. 
O'Connor, M. Shuster, C.W. Callaway, B. Cucchiara, J.D. Ferguson, T.D. Rea, and T.L. 
Vanden Hoek. 2010. Part 1: executive summary: 2010 American Heart Association 
Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. 
Circulation. 122:S640-656.  
Genheimer, C.W., R.M. Ilagan, T. Spencer, R.W. Kelley, E. Werdin, S. Choudhury, D. Jain,  
J.W. Ludlow, and J. Basu. 2012. Molecular characterization of the regenerative  
response induced by intrarenal transplantation of selected renal cells in a rodent model of chronic 
kidney disease. Cells, tissues, organs. 196:374-384.  
Gerstein, H.C., J.F. Mann, Q. Yi, B. Zinman, S.F. Dinneen, B. Hoogwerf, J.P. Halle, J. Young, 
A. Rashkow, C. Joyce, S. Nawaz, and S. Yusuf. 2001. Albuminuria and risk of 
cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. 
JAMA. 286:421-426.  

RegenMed (Cayman) Ltd. Autologous Neo-Kidney Augment    
RMCL-CL001 
 
Confidential  
87  
v1.3 28APR2016 
 
Go, A.S., G.M. Chertow, D. Fan, C.E. McCulloch, and C.Y. Hsu. 2004. Chronic kidney disease 
and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 
351:1296-1305.  
Groman, R.P., A. Bahr, B.R. Berridge, and G.E. Lees. 2004. Effects of serial ultrasoundguided 
renal biopsies on kidneys of healthy adolescent dogs. Vet Radiol Ultrasound. 45:62-69.  
Ham, Y.R., K.R. Moon, H.J. Bae, H.J. Ju, W.I. Jang, D.E. Choi, K.R. Na, K.W. Lee, and Y.T. 
Shin. 2012. A case of urine leakage: an unusual complication after renal ibiopsy. 
Chonnam Med J. 47:181-184.  
Hare, J.M., J.E. Fishman, G. Gerstenblith, D.L. DiFede Velazquez, J.P. Zambrano, V.Y.  
Suncion, M. Tracy, E. Ghersin, P.V. Johnston, J.A. Brinker, E. Breton, J. Davis- 
Sproul, I.H. Schulman, J. Byrnes, A.M. Mendizabal, M.H. Lowery, D. Rouy, P.  
Altman, C. Wong Po Foo, P. Ruiz, A. Amador, J. Da Silva, I.K. McNiece, and A.W. Heldman. 
2012. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem 
cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: 
the POSEIDON randomized trial. JAMA. 308:2369-2379.  
Hare, J.M., J.H. Traverse, T.D. Henry, N. Dib, R.K. Strumpf, S.P. Schulman, G.  
Gerstenblith, A.N. DeMaria, A.E. Denktas, R.S. Gammon, J.B. Hermiller, Jr., M.A. Reisman, 
G.L. Schaer, and W. Sherman. 2009. A randomized, double-blind, placebocontrolled, 
dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) 
after acute myocardial infarction. Journal of the American College of Cardiology. 
54:2277-2286.  
Hergesell, O., H. Felten, K. Andrassy, K. Kuhn, and E. Ritz. 1998. Safety of ultrasound guided 
percutaneous renal biopsy-retrospective analysis of 1090 consecutive cases. Nephrol Dial 
Transplant. 13:975-977.  
Huang, C.W., K.J. Chou, H.C. Fang, C.L. Chen, P.T. Lee, C.Y. Hsu, and H.M. Chung. 2011. 
Unusual cause of postrenal biopsy anuria in a renal transplant patient. Am J Med Sci. 
341:250-252.  
Humphreys, B.D., M.T. Valerius, A. Kobayashi, J.W. Mugford, S. Soeung, J.S. Duffield, A.P. 
McMahon, and J.V. Bonventre. 2008. Intrinsic epithelial cells repair the kidney after 
injury. Cell Stem Cell. 2:284-291.  
Ilagan, R., S. Choudhury, A.T. Bruce, J. Basu, K.I. Guthrie, B.R. Cox, C. Genheimer, R. Kelley, 
J.W. Ludlow, and S.C. Presnell. 2010a. Exosomes derived from primary renal cells 
contain microRNAs that can potentially drive therapeutically-relevant outcomes in 
models of chronic kidney disease. TERMIS Conference, Orlando, FL.  
Ilagan, R., K.I. Guthrie, B.R. Cox, S. Choudhury, A.T. Bruce, B. Watts, D.D. O'Reilly, C. Tang, 
C.W. Genheimer, E.S. Werdin, R.W. Kelley, and S.C. Presnell. 2010b. Secreted Factors 
from Bioactive Kidney Cells Attenuate NF-kappa-B. TERMIS Conference, Orlando, FL.  
Kusek, J. Manzi, F. Van Lente, Y.L. Zhang, J. Coresh, and A.S. Levey. 2012. Estimating 
glomerular filtration rate from serum creatinine and cystatin C. The New England journal 
of medicine. 367:20-29.  
Jayo, M.J., D. Jain, J.W. Ludlow, R. Payne, B.J. Wagner, G. McLorie, and T.A. Bertram. 2008a. 
Long-term durability, tissue regeneration and neo-organ growth during skeletal 
maturation with a neo-bladder augmentation construct. Regenerative medicine. 3:671-
682.  
Jayo, M.J., D. Jain, B.J. Wagner, and T.A. Bertram. 2008b. Early cellular and stromal responses 
in regeneration versus repair of a mammalian bladder using autologous cell and 
biodegradable scaffold technologies. J Urol. 180:392-397.  

RegenMed (Cayman) Ltd. Autologous Neo-Kidney Augment    
RMCL-CL001 
 
Confidential  
88  
v1.3 28APR2016 
 
Jayo, M.J., D.D. Watson, B.J. Wagner, and T.A. Bertram. 2008c. Tissue engineering and 
regenerative medicine: role of toxicologic pathologists for an emerging medical 
technology. Toxicol Pathol. 36:92-96.  
KDIGO. 2013. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of 
Chronic Kidney Disease. Kidney International Supplement. 3:1 - 150.  
Keith, D.S., G.A. Nichols, C.M. Gullion, J.B. Brown, and D.H. Smith. 2004. Longitudinal 
follow-up and outcomes among a population with chronic kidney disease in a large 
managed care organization. Arch Intern Med. 164:659-663.  
Kelley, R., A. Bruce, T. Spencer, E. Werdin, R. Ilagan, S. Choudhury, E. Rivera, S. Wallace, K. 
Guthrie, M. Jayo, F. Xu, A. Rao, B. Humphreys, S. Presnell, and T. Bertram.  
2012. A Population of Selected Renal Cells Augments Renal Function and Extends Survival in 
the ZSF1 model of Progressive Diabetic Nephropathy Cell Transplantation (ePub).  
Kelley, R., E.S. Werdin, A.T. Bruce, S. Choudhury, S.M. Wallace, P. Tatsumi-Ficht, E.A. 
Rivera, T. Spencer, H.S. Rapoport, R. Ilagan, B.J. Wagner, K.I. Guthrie, M.J. Jayo, T.A. 
Bertram, and S.C. Presnell. 2010. A tubular cell-enriched subpopulation of primary renal 
cells improves survival and augments kidney function in a rodent model of chronic 
kidney disease. Am J Physiol Renal Physiol.  
Khajehdehi, P., S.M. Junaid, L. Salinas-Madrigal, P.G. Schmitz, and B. Bastani. 1999. 
Percutaneous renal biopsy in the 1990s: safety, value, and implications for early hospital 
discharge. Am J Kidney Dis. 34:92-97.  
Khan, S.S., W.H. Kazmi, R. Abichandani, H. Tighiouart, B.J. Pereira, and A.T. Kausz. 2002. 
Health care utilization among patients with chronic kidney disease. Kidney Int. 62:229-
236.  
Kovesdy, C.P., B.K. Trivedi, and J.E. Anderson. 2006. Association of kidney function with 
mortality in patients with chronic kidney disease not yet on dialysis: a historical 
prospective cohort study. Adv Chronic Kidney Dis. 13:183-188.  
Lee, G.H., D. Benner, D.L. Regidor, and K. Kalantar-Zadeh. 2007. Impact of kidney bone 
disease and its management on survival of patients on dialysis. J Ren Nutr. 17:38-44.  
Lees, G.E., R.E. Cianciolo, and F.J. Clubb, Jr. 2011. Renal biopsy and pathologic evaluation of 
glomerular disease. Top Companion Anim Med. 26:143-153.  
Lin, W.C., Y. Yang, Y.K. Wen, and C.C. Chang. 2006. Outpatient versus inpatient renal biopsy: 
a retrospective study. Clin Nephrol. 66:17-24.  
Manno, C., C. Bonifati, D.D. Torres, N. Campobasso, and F.P. Schena. 2011. Desmopressin 
acetate in percutaneous ultrasound-guided kidney biopsy: a randomized controlled trial. 
Am J Kidney Dis. 57:850-855.  
Medarova, Z., P. Vallabhajosyula, A. Tena, N. Evgenov, P. Pantazopoulos, V. Tchipashvili, G. 
Weir, D. Sachs, and A. Moore. 2009. In vivo imaging of autologous islet grafts in the 
liver and under the kidney capsule in non-human primates. Transplantation. 87:1659-
1666.  
Montgomery, A.V., J.C. Davis, Jr., J.M. Prine, and H.G. Swann. 1950. The intrarenal pressure; 
its relation to age, weight, blood pressure, and sex. J Exp Med. 92:637-642.  
Nadasdy, T., Z. Laszik, K.E. Blick, L.D. Johnson, and F.G. Silva. 1994. Proliferative activity of 
intrinsic cell populations in the normal human kidney. J Am Soc Nephrol. 4:20322039.  
Nass, K., and W.C. O'Neill. 1999. Bedside renal biopsy: ultrasound guidance by the 
nephrologist. Am J Kidney Dis. 34:955-959.  
Park, H.C., K. Yasuda, M.C. Kuo, J. Ni, B.B. Ratliff, P.N. Chander, and M.S. Goligorsky.  
2009. Renal Capsule as a Stem Cell Niche. Am J Physiol Renal Physiol.  

RegenMed (Cayman) Ltd. Autologous Neo-Kidney Augment    
RMCL-CL001 
 
Confidential  
89  
v1.3 28APR2016 
 
Postma, M.J., and D. de Zeeuw. 2009. The economic benefits of preventing end-stage renal 
disease in patients with type 2 diabetes mellitus. Nephrol Dial Transplant. 24:29752983.  
Rahman, M., S. Pressel, B.R. Davis, C. Nwachuku, J.T. Wright, Jr., P.K. Whelton, J.  
Barzilay, V. Batuman, J.H. Eckfeldt, M.A. Farber, S. Franklin, M. Henriquez, N. Kopyt, G.T. 
Louis, M. Saklayen, C. Stanford, C. Walworth, H. Ward, and T. Wiegmann. 2006. 
Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline 
glomerular filtration rate. Ann Intern Med. 144:172-180.  
Salagierski, M. & Salagierski, M.S., 2010.  Radiofrequency ablation: a minimally invasive 
approach in kidney tumor management.  Cancers 2:1895-1900. 
Smith, D.H., C.M. Gullion, G. Nichols, D.S. Keith, and J.B. Brown. 2004. Cost of medical care 
for chronic kidney disease and comorbidity among enrollees in a large HMO population. 
J Am Soc Nephrol. 15:1300-1306.  
Swann, H.G., J.M. Prine, V. Moore, and R.D. Rice. 1952. The intrarenal pressure during 
experimental renal hypertension. J Exp Med. 96:281-291.  
USRDS. 2011. 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal 
Disease in the United States. National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, Bethesda, MD.  
Wadstrom, J., A. Biglarnia, H. Gjertsen, A. Sugitani, and J. Fronek. 2011a. Introducing 
handassisted retroperitoneoscopic live donor nephrectomy: learning curves and 
development based on 413 consecutive cases in four centers. Transplantation. 91:462-
469.  
Wadstrom, J., A.L. Martin, R. Estok, C.J. Mercaldi, and M.D. Stifelman. 2011b. Comparison of 
hand-assisted laparoscopy versus open and laparoscopic techniques in urology 
procedures: a systematic review and meta-analysis. Journal of endourology / 
Endourological Society. 25:1095-1104.  
Walker, P.D. 2009. The renal biopsy. Arch Pathol Lab Med. 133:181-188.  
Whittier, W.L., and S.M. Korbet. 2004a. Renal biopsy: update. Current opinion in nephrology 
and hypertension. 13:661-665.  
Whittier, W.L., and S.M. Korbet. 2004b. Timing of complications in percutaneous renal 
injection. J Am Soc Nephrol. 15:142-147.