Conditions: Obesity Weight Loss Overweight and Obesity
Keywords: Obesity Overweight Thermogenesis Fat reduction
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
Obesity is a direct result of food-intake in excess of body energy expenditure. Thus, induction of increased energy expenditure via the activation of thermogenesis at targeted anatomical sites can counterbalance obesity. This trial aims to study RZL-012, a novel compound, in treating obesity by activating thermogenesis in subcutaneous fat.

Detailed description:
Obesity is a direct result of food-intake in excess of body energy expenditure. Therefore, a feasible approach to combat obesity is via energy-consuming activities, such as physical exercise. Unfortunately, our modern society is moving in the other direction, spending more time in immobilized positions, at work and at home. An alternative strategy for the induction of increased energy expenditure is via the activation of thermogenic cells that utilize fat to produce heat.RZL-012 is a novel molecule that enables de-novo generation of thermogenic tissue at favorable anatomical sites. As a result, the extra fat accumulated in obese persons will be turned into heat. This is a double blind, randomized, placebo controlled, dose escalation Phase 2a clinical trial for the evaluation of safety, efficacy and thermogenesis-induction of RZL-012 in overweight and obese volunteers. This trial aims to study the ability of RZL-012 in treating obesity via the induction of thermogenic foci in subcutaneous fat.

Arms:
arm 1: A single-time injection, multiple subcutaneous injections of RZL-012 administered into 8-36 sites (0.1mL per site):

1. 40mg RZL-012 -administered at 8 sites
2. 80mg RZL-012 - administered at 16 sites
3. 120mg RZL-012 - administered at 24 sites
4. 180mg RZL-012 - administered at 36 sited arm 2: A single-time injection, multiple subcutaneous injections of Placebo administered into 8-36 sites (0.1mL per site)

Interventions: intervention 1: RZL-012 intervention 2: Placebo
Intervention descriptions: intervention 1: Subject receive a single-time injection. Multiple injections of RZL-012 are administered at 8-36 sites (0.1mL per site) into the abdominal subcutaneous fat. intervention 2: Subject receive a single-time injection. Multiple injections of the Placebo are administered at 8-36 sites (0.1mL per site) into the abdominal subcutaneous fat.

Protocol document:
Prot_000.pdf: 
Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.4 
RZL-012 
 
Version: 1.4 
 
26 May 2017 
1 
CONFIDENTIAL 
RZL-012 Study Protocol 
Protocol Number RZL-012-P2aUS-001.4 
 
A Double Blind, Randomized, Placebo Controlled, Dose Escalation Phase 2a Clinical Trial 
for the Evaluation of Safety and Thermogenesis-induction of RZL-012 in Overweight and 
Obese Volunteers 
Principal Investigator: 
Carlos Sanabria, MD 
Sponsor: 
Raziel Therapeutics LTD 
Hadassah Ein-Karem, JBP building, P.O.B. 12157 
Jerusalem, Israel 9112101 
 
Confidentiality Statement 
This document is a confidential communication of Raziel Therapeutics Ltd. 
Acceptance of this document constitutes agreement by the recipient that no 
unpublished information contained herein will be published or disclosed without 
prior written approval, with the exception of disclosure to the appropriate 
Institutional Review Board and/or Regulatory Authority under the condition that 
confidentiality is maintained 
 
Protocol Date:  11 July 2017 
Version 1:  20 February 2017 
Version 1.1:  26 May 2017 
Version 1.2: 11 July 2017 
Version 1.3: 20Aug 2017 
Version 1.4: 4 March 2018 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
STATEMENT OF COMPLIANCE ...............................................................................................11 
INVESTIGATOR SIGNATURE PAGE .......................................................................................12 
PROTOCOL SYNOPSIS ..............................................................................................................13 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
BACKGROUND ........................................................................................................21 
1.1.1. 
Scientific Background and Clinical Rationale ............................................................21 
1.1.2. 
RZL-012 Formulation Development ..........................................................................23 
1.2. 
NONCLINICAL ASSESSMENTS ............................................................................24 
1.2.1. 
Pharmacology .............................................................................................................24 
1.2.1.1. 
Efficacy In-vivo and In-vitro Studies .........................................................................24 
1.2.1.2. 
Safety Pharmacology ..................................................................................................24 
1.2.2. 
Toxicology ..................................................................................................................25 
1.2.2.1. 
Extended Single Dose Toxicity Studies .....................................................................25 
1.2.3. 
Additional Nonclinical Studies ...................................................................................27 
1.2.4. 
Clinical Studies ...........................................................................................................27 
2. 
PURPOSE AND STUDY OBJECTIVES ..................................................................30 
2.1. 
PURPOSE ...................................................................................................................30 
2.2. 
STUDY OBJECTIVES ..............................................................................................30 
2.2.1. 
Primary .......................................................................................................................30 
2.2.2. 
Secondary ...................................................................................................................30 
3. 
STUDY DESIGN .......................................................................................................31 
3.1. 
DESCRIPTION OF STUDY DESIGN ......................................................................31 
3.2. 
DOSE RATIONALE ..................................................................................................31 
3.3. 
DOSING .....................................................................................................................31 


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3.3.1. 
Dosing Regimen .........................................................................................................31 
3.3.2. 
Intolerable Side Effect ................................................................................................32 
4. 
STUDY ENDPOINTS ................................................................................................34 
4.1. 
PRIMARY ENDPOINTS ...........................................................................................34 
4.2. 
SECONDARY ENDPOINTS .....................................................................................34 
5. 
STUDY POPULATION .............................................................................................35 
5.1. 
INCLUSION CRITERIA ...........................................................................................35 
5.2. 
EXCLUSION CRITERIA ..........................................................................................35 
5.3. 
SUBJECT IDENTIFICATION ..................................................................................36 
5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF 
SUBJECTS FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE 
EFFECTS ....................................................................................................................36 
6. 
STUDY PROCEDURES AND ASSESSMENT ........................................................37 
6.1. 
DEFINITIONS OF STUDY PROCEDURES ............................................................37 
6.1.1. 
Informed Consent .......................................................................................................37 
6.1.2. 
Medical History ..........................................................................................................37 
6.1.3. 
Concomitant Medication ............................................................................................38 
6.1.4. 
Physical Examination .................................................................................................38 
6.1.5. 
Vital Signs and Measurements ...................................................................................38 
6.1.6. 
Anthropometric Measurements ..................................................................................38 
6.1.6.1. 
Weight .........................................................................................................................39 
6.1.6.2. 
Height .........................................................................................................................39 
6.1.6.3. 
BMI .............................................................................................................................40 
6.1.6.4. 
Waist Circumference ..................................................................................................40 
6.1.6.5. 
Hip Circumference ......................................................................................................40 
6.1.6.6. 
Waist to Hip Ratio (WHR) .........................................................................................41 
6.1.7. 
Serology Assays ..........................................................................................................41 
6.1.8. 
Clinical Laboratory Tests ...........................................................................................41 
6.1.8.1. 
Hematology .................................................................................................................41 
6.1.8.2. 
Serum Chemistry Analysis .........................................................................................42 
6.1.8.3. 
Urine Drug Screen ......................................................................................................42 
6.1.8.4. 
Inflammatory Markers and Cytokines ........................................................................42 
6.1.8.5. 
Histamine ....................................................................................................................43 


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6.1.8.6. 
Urinalysis ....................................................................................................................43 
6.1.9. 
ECG ............................................................................................................................43 
6.1.10. 
Draize Score ................................................................................................................44 
6.1.11. 
Photography of the Injected Site .................................................................................44 
6.1.12. 
Thermal Imaging ........................................................................................................45 
6.1.13. 
Fat Tissue Imaging: Magnetic Resonance Imaging (MRI) ........................................45 
6.1.14. 
Biopsy .........................................................................................................................46 
6.1.15. 
Pharmacokinetics ........................................................................................................47 
6.1.16. 
Adverse Events ...........................................................................................................48 
6.1.17. 
Evaluation of Response ..............................................................................................48 
6.1.17.1. 
Evaluation of Primary Endpoints................................................................................48 
6.1.17.2. 
Evaluation of Secondary Endpoints............................................................................49 
6.1.17.3. 
Compliance Monitoring ..............................................................................................50 
6.1.17.4. 
Dispensing of RZL-012 Investigational Product ........................................................50 
6.1.17.5. 
Questioning of Study Subjects ....................................................................................50 
6.2. 
STUDY VISITS..........................................................................................................51 
6.2.1. 
Screening Procedures ..................................................................................................51 
6.2.2. 
Study Randomization ..................................................................................................52 
6.2.3. 
Study Treatment ..........................................................................................................52 
6.2.3.1. 
Treatment with RZL-012 Investigational Therapy .....................................................52 
6.2.3.2. 
Treatment with Placebo ..............................................................................................54 
6.2.4. 
Baseline Visit ..............................................................................................................54 
6.2.5. 
Subject Site Visits .......................................................................................................56 
6.2.6. 
Termination Visit ........................................................................................................57 
6.2.7. 
Unscheduled Visit .......................................................................................................57 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR 
INVESTIGATORS .....................................................................................................57 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT 
MEDICATIONS .........................................................................................................57 
7.2. 
SAFETY MEASUREMENTS....................................................................................57 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY............................................59 
7.4. 
PREMATURE STUDY TERMINATION .................................................................59 
7.5. 
DEVIATION FROM STUDY PROTOCOL..............................................................59 


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8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS ................60 
8.1. 
DESCRIPTION OF RZL-012 ....................................................................................60 
8.2. 
FORMULATION, PACKAGING AND LABELING ...............................................60 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE .................................60 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND 
VEHICLE ...................................................................................................................60 
8.4.1. 
Dosage ........................................................................................................................60 
8.4.2. 
Administration and Instructions for Use .....................................................................61 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE ...............................................61 
9. 
ADVERSE EVENTS..................................................................................................62 
9.1. 
ADVERSE EVENT DEFINITIONS ..........................................................................62 
9.1.1. 
Definition of Adverse Event (AE) ..............................................................................62 
9.1.2. 
Definition of Serious Adverse Event ..........................................................................62 
9.1.3. 
Definition of Adverse Drug Reaction .........................................................................62 
9.2. 
ADVERSE EVENT GRADING ................................................................................62 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS (AEs) ...............................63 
9.4. 
UNEXPECTEDNESS OF ADVERSE DRUG REACTIONS ...................................64 
9.5. 
ADVERSE EVENT REPORTING AND MONITORING 
REQUIREMENTS .....................................................................................................65 
9.5.1. 
General ........................................................................................................................65 
9.5.2. 
SAE Reporting ............................................................................................................65 
9.5.3. 
Expedited Reporting ...................................................................................................66 
10. 
STATISTICAL CONSIDERATIONS .......................................................................66 
10.1. 
STUDY DESIGN AND OBJECTIVE .......................................................................66 
10.2. 
STUDY ENDPOINTS ................................................................................................67 
10.2.1. 
Primary Safety Endpoint .............................................................................................67 
10.2.2. 
Primary Efficacy Endpoint .........................................................................................67 
10.2.3. 
Secondary Efficacy Endpoints ....................................................................................67 
10.2.4. 
Safety and Tolerability Endpoints ..............................................................................68 
10.3. 
SAMPLE SIZE JUSTIFICATION .............................................................................68 
10.4. 
ANALYSIS SETS ......................................................................................................69 
10.4.1. 
Safety Analysis Set (SA) ............................................................................................69 
10.4.2. 
Efficacy Analysis Set (EF) .........................................................................................69 


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10.4.3. 
PK (PKA) Analysis Set ..............................................................................................69 
10.4.4. 
Statistical Analysis of Analysis Sets...........................................................................69 
10.5. 
STATISTICAL ANALYSIS ......................................................................................69 
10.5.1. 
General ........................................................................................................................69 
10.5.2. 
Subject Disposition .....................................................................................................70 
10.5.3. 
Demographic and Baseline Characteristics ................................................................70 
10.5.4. 
Primary Safety Endpoint .............................................................................................70 
10.5.5. 
Efficacy Analysis ........................................................................................................70 
10.5.6. 
Pharmacokinetics (PK) Assessment ...........................................................................71 
10.5.7. 
Safety and Tolerability ...............................................................................................71 
10.6. 
HANDLING OF MISSING DATA ............................................................................72 
10.7. 
INTERIM ANALYSIS ...............................................................................................72 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE ............................................................................................................72 
11.1. 
DATA COLLECTION AND REPORTING ..............................................................72 
11.2. 
RECORD KEEPING ..................................................................................................73 
11.3. 
SOURCE DATA AND SOURCE DOCUMENTS ....................................................73 
11.4. 
STUDY MONITORING ............................................................................................73 
11.5. 
CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION ...................74 
12. 
HUMAN SUBJECTS .................................................................................................75 
12.1. 
DECLARATION OF HELSINKI ..............................................................................75 
12.2. 
INFORMED CONSENT ............................................................................................75 
12.2.1. 
LIABILITY AND INSURANCE CONDITIONS ......................................................75 
13. 
REFERENCES ...........................................................................................................75 
 


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LIST OF TABLES 
Table 1:  Phase 0 Clinical Trial Design .........................................................................................28 
Table 2:  Subject Information and Timeframes .............................................................................55 
Table 3:  RZL-012 and Vehicle Storage Conditions .....................................................................60 
Table 4:  Definition of Causality ...................................................................................................63 
 
LIST OF FIGURES 
Figure 1:  MRI: Distribution of 16 Consecutive Slices .................................................................46 
Figure 2:  Biopsy Site and Dimensions..........................................................................................47 
Figure 3:  RZL-012 Injection Sites ................................................................................................53 
Figure 4:  Design of the 24 Injection Sites ....................................................................................53 
 
 
LIST OF APPENDICES 
Appendix I:  Trial Schedule of Events ...........................................................................................77 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the concentration-time curve 
BAT 
Brown-like adipose tissue 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CBC 
Complete blood count 
CDC 
Center for Disease Control 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence Interval 
CK-MM 
Creatine Kinase - Muscle 
Cmax 
Maximum observed concentration 
CNS 
Clinically not significant 
CRF 
Case Report Form 
CPK 
Creatine phosphokinase 
CRP 
C-reactive protein 
CS 
Clinically significant 
CTC 
Common terminology criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DICOM 
Digital Imaging and Communications in Medicine 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Efficacy analysis set 
ER 
Emergency room 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIFO 
First In First Out 
FLASH 
Fast-low-angle shot 


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Abbreviation or Specialist Term 
Explanation 
FOB 
Functional Observational Battery 
GLP 
Good Laboratory Practice 
GTTP 
Gamma-glutamyltransferase 
HBV 
Hepatitis B virus 
HCRC 
Hadassah Clinical Research Center 
HCV 
Hepatitis C virus 
H&E 
Hematoxylin and eosin stain 
HDL 
High-density lipoprotein 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical 
Practice 
IFN 
Interferon 
IL 
Interleukin 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDL 
Low-density lipoprotein 
LDH 
Lactate dehydrogenase 
LPL 
Lipoprotein lipase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP 
Monocyte chemoattractant protein 
MCV 
Mean corpuscular volume 
MD 
Medical Doctor 
MPV 
Mean platelet volume 
MRI 
Magnetic Resonance Imaging 
NHANES 
National Health and Nutrition Examination Survey 
NOAEL 
No observed adverse effect level 
NSAIDs 
Non Steroid Anti-Inflammatory Drugs 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKA 
PK Analysis set 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 


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Abbreviation or Specialist Term 
Explanation 
RBC 
Red blood cells 
RDW 
Red cell distribution width 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SAT 
Subcutaneous adipose tissue 
SC 
Subcutaneous 
SFM 
Subcutaneous fat mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Terminal half-life 
TAG 
Triacylglycerols 
TBD 
To be determined 
TC 
Total Cholesterol 
TG 
Triglycerides 
TGF 
Transforming growth factor 
Tmax 
Time of maximum observed sample concentration 
TNF 
Tumor necrosis factor 
UCP1 
Uncoupling protein 1 
ULN 
Upper limit of normal 
US/USA 
United States/United States of America 
WAT 
White adipose tissue 
WBC 
White blood cells 
WHR 
Waist to hip ratio 
 


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STATEMENT OF COMPLIANCE 
This clinical trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 and the applicable regulatory requirements. 


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INVESTIGATOR SIGNATURE PAGE 
I have read and understood the protocol and agree to implement the study in accordance with the 
procedures set forth in the protocol and in accordance with the Sponsor's guidelines, all 
applicable government regulations and the International Conference on Harmonization Good 
Clinical Practice Guidelines E6 (ICH-GCP). 
I will provide adequate protocol training to my associates, colleagues and employees assisting in 
the conduct of the study.  
I will obtain Institutional Biosafety Committee (or equivalent) and Institutional Review Board 
(IRB)/Ethics Committee (EC) approval of the protocol and the Subject Informed Consent form 
prior to enrollment of subjects in the study.  I understand that any modifications to the protocol 
made during the course of the study must first be approved by the Institutional Biosafety 
Committee (or equivalent) and IRB/EC except when such modification is made to remove an 
immediate hazard to the subject.  
I will ensure that a fully executed Subject Informed Consent form is obtained from each subject 
prior to initiation of any study procedures.  
I will report (within 24 hours) any serious adverse event that occurs during the course of the 
study in accordance with the procedures described in Section 9 of the protocol.  
I will allow the Sponsor, Raziel Therapeutics Ltd. and its agents, as well as the United States 
(US) Food and Drug Administration (FDA) and other regulatory agencies, to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, ensuring subject 
confidentiality.  If I am notified that this study is to be inspected by a regulatory agency, I will 
notify the Sponsor as soon as possible thereafter (no later than one week).  
 
 
 
 
_____________________ 
____________________  
 
_____________________ 
Investigator's name 
 
 
Investigator’s Signature  
 
Date 


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PROTOCOL SYNOPSIS 
Protocol 
Number 
RZL-012-P2aUS-001.2 
Protocol Title 
A Double Blind, Randomized, Placebo Controlled, Dose Escalation Phase 2a Clinical Trial for the 
Evaluation of Safety and Thermogenesis-induction of RZL-012 in Overweight and Obese Volunteers  
Study Phase 
Phase 2a 
Study Drug 
RZL-012 
Study 
Objectives 
Primary objective:  Evaluation of the overall safety and preliminary efficacy of RZL-012 after 
injection into the subcutaneous fat.  
Secondary objective:  Determination of RZL-012 pharmacodynamics and pharmacokinetics.  
Evaluation of the existence of a thermogenic effect and the extent, duration and tissue associated 
changes of the thermogenic response to RZL-012, via minimal invasive means (injected-site 
thermogenesis imaging, Magnetic Resonance Imaging (MRI) and biopsy) after subcutaneous 
injection into fatty tissue below the skin. 
Sample Size 
32 subjects 
Study Design 
This is a consecutive 4 cohort, dose escalation placebo-controlled clinical trial in overweight and 
obese subjects.  All cohorts will be comprised of 6 active (RZL-012) and 2 placebo subjects.   
Within each cohort, dosing of the first 3 subjects will progress consecutively from one individual to 
the other at 7-day intervals.  For additional precaution, the first 3 subjects will be forced randomized 
into 2 active and 1 control.  This study design will allow the physicians to monitor safety in a two 
subjects at each dose, nevertheless the blindness will remain intact.  The remaining subjects in a 
cohort will be randomized to either active treatment or placebo in a ratio determined by the number 
of subjects targeted for each cohort.  Dosing of the next subjects will be in couples and the last 
subjects will be in a triplet.  
If intolerable side effects in a cohort occurs, dosing will progress subject by subject, rather than in 
couples or triplet.  
The trial will proceed within a cohort and from one cohort to the next as long as no more than one 
subject experiences intolerable side effects in the lower-dose cohort, and based on the decision made 
by a Data and Safety Monitoring Board (DSMB).  The decision to proceed to the next cohort will be 
made after reviewing all safety data collected by Day 14 within 2 ± 1d of the last dosed subject in 
each cohort.  If two (2) intolerable side effects are observed in any dose cohort, further treatment at 
that dose will be stopped and only tolerable doses used for further subjects. 
The DSMB will be comprised of two independent MDs expert in early phase clinical trials. 
Study 
Population 
20-60 years old, overweight and obese by Body Mass Index (BMI) definition (27.5 < BMI ≤ 34.9), 
adult males. 


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Main Inclusion 
Criteria 
 
Subjects must meet all the following to be eligible for study participation: 
1. Adult male subjects, 20-60 years old.  
2. Subject is considered overweight and obese, with 27.5 < BMI ≤ 34.9. 
3. Significant subcutaneous abdominal fat as defined by Waist to hip ratio (WHR) ≥ 0.9.   
4. Subjects with stable weight in the last 3 months by medical history. 
5. Not one of the following eating disorders by subject's declaration: anorexia nervosa, bulimia 
nervosa. 
6. Generally considered healthy according to medical history, physical examination, 
electrocardiogram (ECG) and laboratory evaluation with a special emphasis on metabolic 
parameters (fasting glucose concentration < 100 mg, normal blood pressure). 
7. Subject is willing to refrain from sexual activity or agrees to use a double-barrier contraceptive 
device (e.g., condom and spermicide) for 4 weeks after treatment with RZL-012. 
8. Subjects must be able to adhere to the visit schedule and protocol requirements and be available 
to complete the study. 
9. Subjects must sign an informed consent indicating that they are aware of the investigational 
nature of the study. 
Main Exclusion 
Criteria 
Subjects meeting any of the following criteria will be excluded: 
1. Subjects weighing less than 75 kg.  
2. Subjects who have reduced/gained weight more than 5% of their current body weight in the last 
3 months.  
3. Unable to tolerate subcutaneous injection. 
4. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that in the 
opinion of the investigator put the subject at significant risk, are not eligible.  
5. Subjects who test positive to either Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human 
immunodeficiency virus (HIV) are not eligible. 
6. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune disease 
or subjects taking immunosuppressive drugs such as corticosteroids are ineligible.  
7. As a result of medical review, physical examination, the PI (or medically qualified nominee) 
considers the subject unfit for the study. 
8. Medication use on regular basis including blood and blood products. 
9. Positive drug and alcohol tests. 
10. Known sensitivity to components of the injection formulation.  
11. Prior wound, tattoo or infection in the treated area. 
12. Excessive growth of hair in the abdomen region. 
13. Claustrophobia or MRI incompatible device or implant. 


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Intolerable Side 
Effect Definition 
Safety will be the principal primary endpoint of this study, as such if there are 2 intolerable and at 
least possibly related side effects observed in any dose cohort, that dose cohort will be stopped and 
only tolerable doses used for future subjects 
An intolerable side effect defined as any of the following treatment-related adverse drug reactions 
(ADRs): 
• 
Any Grade 3 or greater event except for the following (For the following entities, a 
discussion will be held by the PI, DSMB and Sponsor to decide whether considered 
as:intolerable side effects): 
o 
Flu-like symptoms and fever that responds to standard treatment within 72 hours 
o 
Localized edema and erythema 
o 
Pruritus 
o 
Pain 
o 
Skin/soft tissue inflammation 
o 
Fat Atrophy 
o 
Liver enzymes abnormality 
o 
Non-significant lab abnormalities, lasting less than 7 days (see Section 3.3.2) 
Study discontinuation is to be considered by the investigator in any case of an intolerable side effect, 
and the actions taken are to be fully documented in source documents and Case Report Forms 
(CRFs). 
To be considered an intolerable side effect, such an event must be considered to be possibly or 
probably related to the study drug 
Subjects experiencing an intolerable side effect will be withdrawn from the study, but followed for 
toxicity. 
The study may also be prematurely terminated in any of the following cases:  
• 
Recurring serious or severe adverse drug reaction (ADR) clinically evaluated by DSMB as 
warranting study termination.  
• 
A decision made by Sponsor and/or IRB/EC and/or local regulatory agency to terminate the 
study.  
Study Drug 
Dosage and 
Administration 
Subjects will receive single doses of the investigational product (RZL-012) or the placebo in 
accordance with the following: 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Number of Subjects – 
Active/Placebo 
6/2 
6/2 
6/2 
6/2 
Total Dose RZL-012 
(mg) 
40 
80 
120 
180 
Dose per NOAEL* 
1/6.25th  
1/3.125th  
1/2.34th  
1/1.39 
Number of Injections 
8 
16 
24 
36 
* based on Human Equivalent Dose (HED) from GLP toxicology study) 
The initial dose will be 40 mg RZL-012 (1/6.25th the no observed adverse effect level (NOAEL) 
based on Human Equivalent Dose (HED) from GLP toxicology study) with subsequent doses of 
80 mg and 120 mg (1/3.125th and 1/2.34h the NOAEL based on HED).  The final dose will be 180 mg 
RZL-012, (1/1.39the NOAEL based on HED).  Subjects will receive a single treatment in multiple 
sites (8-48) of injection diagonally (45 °) to the skin surface at 5 cm lateral to the umbilicus lateral 
wall.  The distance between injected sites will be 2 cm (see picture below) in the first three cohorts 
and 1cm in the fourth cohort. 
The first cohort of 6 subjects will receive 8 injections (0.1 mL each in a 2 x 4 cluster and 2 cm apart) 
of 40 mg RZL-012 (~1/6.25th of the NOAEL).  Additional 2 subjects in the cohort will serve as 
control and will be injected placebo (vehicle). 
If no more than 1 subject experiences intolerable side effects within 14 days following the injection of 
the last dosed subject, according to schedule and following the DSMB approval an additional cohort 
(Cohort 2) of six volunteers, as above, will receive 16 injections (0.1 mL each in a 4x4 cluster and 


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2 cm apart) adding up to 80 mg RZL-012 (~1/3.125th of the NOAEL).  Additional 2 subjects in the 
cohort will serve as control and will be injected placebo (vehicle).  
If no more than 1 subject experiences intolerable side effects within 14 days following the injection of 
the last dosed subject according to schedule and following the DSMB approval, an additional cohort 
(Cohort 3) of six volunteers will receive a cluster of 24 injections (0.1 mL each in a 6x4 cluster and 2 
cm apart) adding up to 120 mg RZL-012 (~1/2.34th of the NOAEL).  Additional 2 subjects in the 
cohort will serve as control and will be injected placebo (vehicle).  
If no more than 1 subject experiences intolerable side effects within 14 days following the injection of 
the last dosed subject according to schedule and following the DSMB approval an additional cohort 
(Cohort 4) of six volunteers, as above, will receive 36 injections (0.1 mL each in a 9x4 cluster and 
1cm apart) adding up to 240 mg RZL-012 (~1/1.39 of the NOAEL).. Additional 2 subjects in the 
cohort will serve as control and will be injected placebo (vehicle). 
 
 
 
Concomitant 
Medication 
All concomitant medication given 3 months prior to study entry, including blood and blood products, 
dietary supplements, and non-prescription drugs will be listed at screening/baseline.  The clinical 
significance of the medication use will be decided by the investigator.  Study subjects will be 
routinely questioned for changes in the administration of concomitant medication during the trial.  
Subjects may not receive the following medications while on study:  
• 
Chronic treatment with systemic steroids or immunosuppressive drugs.  
• 
Chronic treatment with Non Steroid Anti-Inflammatory Drugs (NSAIDs).  
• 
Any investigational product other than RZL-012.  
Before dosing, analgesic gels or creams such Lidocaine (e.g., Emla) or Pramoxine should be used to 
numb the injected site.  An ice pack may be applied on the site of injection following dosing to help 
reduce pain.  At day 3 following blood sampling for histamine, the anti-histamine Benadryl Gel 
(Dimethindene Maleate 0.1 %) for topical use only should be initiated prophylactically, according to 
drug instructions for use to avoid itching in the injected area.  Benadryl Gel should be applied for 7 
days. 
Use of supplements or complementary medicines/botanicals is prohibited, except for conventional 
multivitamin supplements. 
Study 
Procedure 
Study activities upon study entry will include, but not be limited to: 
Informed Consent, full medical history, physical examination, anthropometric measurements, vital 
signs measurements, ECGs, clinical laboratory tests, photography, thermal imaging and skin irritancy 
evaluation of site injection. 
Subjects will be randomized upon eligibility to RZL-012 or placebo and to a right side or left side 
injection according to a predefined randomization scheme. 
Periodical site visits will allow assessment of treatment safety and efficacy. 
Subjects will be advised to keep their regular diet and physical activity.  
Visit Schedule 
(See Table 2) 
 
Subject site visits will be performed ± 1 days from scheduled date for study visits Day 0-28 and 2± 1 
days from schedule date for follow-up visits (Day 56-168).  All data relevant for the visit needs to be 
obtained within 3 days (e.g., blood tests results) of visit.  
Screening Day 1 visit (Day -28 through -7): 
- 
Following signing the informed consent - assessment of subject eligibility will include: 
medical history, physical examination, anthropometric measurements (BMI, WHR), vital 


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signs, ECG, serology assays (HBV, HCV and HIV), clinical laboratory tests, drug screen.  
Subjects should come fasting (10-12 hr. fast) for the glucose and weight measurement. 
Clinical laboratory tests will include: 
1. 
Hematology:  Complete blood count (CBC including White blood cell [WBC] differential 
values), Fibrinogen, D-dimer, and coagulation (International normalized ratio [INR], Partial 
thromboplastin time [PTT] and Prothrombin time (PT).). 
2. 
Serum chemistry analysis:  sodium, calcium, potassium, phosphorus, glucose, liver 
enzymes (Aspartate aminotransferase [AST], Alanine aminotransferase [ALT], Lactate 
dehydrogenase [LDH], Creatine-kinase MM [CK-MM], Gamma-glutamyltransferase 
[GTTP], Alkaline phosphatase [ALP]), Bilirubin, Creatinine, Urea/Blood urea nitrogen 
[BUN[, Total protein, Albumin, Amylase, Creatine phosphokinase [CPK] and Leptin. 
3. 
Urinalysis: Nitrite, Sodium, Potassium, Calcium, Phosphate, Protein, RBC, WBC, Blood, 
Glucose, Ketone bodies, Bilirubin, Urobilirubin, Urine specific gravity, Osmolarity, and 
pH. 
- 
In addition, photography, infra-red imaging and evaluation of skin irritancy by Draize score 
of the injection site area and contra-lateral area. 
The relevance of RZL-012 for human treatment of obesity will be assessed by the monitoring of 
injected-site thermogenesis, utilizing infra-red imaging.  Thermal imaging with a sensitive (± 0.1 °C) 
Infra-Red thermal camera (FLIR A310) will include:  a view of the injected area and the contra-
lateral non-injected area – at a distance of 1 meter and in a horizontal line from the umbilicus.  The 
thermal camera can create a visual heat map of skin temperatures in real time with a precision of ± 
0.1 °C. 
Screening Day 2 visit (Day -14 through -2):  
- 
Subjects should come fasting (10-12hr. fast) for weight measurement and MRI scan. 
- 
MRI of 16 slices that include the injected site, for subcutaneous adipose tissue (SAT) 
evaluation. 
- 
Anthropometric measurements (BMI, WHR). 
Clinic Admission visit (Day -1):  
- 
Subject should come fasting (10-12 hr. fast) for weight measurement and for laboratory tests 
of: glucose, insulin and lipid profile. 
Lipid profile will include: Triglycerides [TG], High-density lipoprotein [HDL], Low-density 
lipoprotein [LDL], Total-cholesterol [TC] and Free fatty acids [FFA]. 
- 
Inflammatory markers and cytokines – Testing from the 2nd, 3rd and 4th cohorts (on 6 
RZL-012 treated and 2 placebo treated subjects in each cohort):  CRP, Adiponectin, CD-
163, Interleukin [IL]-1β, IL-4, IL-6, IL-10, IL12p70, IL-13, IL-23, Tumor necrosis factor 
[TNF] α and transforming growth factor [TGF] β1. 
- 
Medical history, BMI, WHR, urine drug test, infra-red thermal imaging of the injected area 
and the contra-lateral side. Blood sample for histamine, serum chemistry and hematology 
baseline level. 
Baseline visit (Day 0):  
- 
Baseline visit will be in an in-patient setting.  Subjects will be interned in the study site for 
visit baseline till the following day. 
- 
Pre-treatment: eligibility confirmation, randomization, vital signs, Draize score,  First blood 
sample for pharmacokinetics will be taken.  
- 
Treatment - All injections will be administered 45 ° to the skin surface using a 1 mL Luer-
lock syringe and a 30 G x 1/2" needle (the hole of the needle pointing into the fat layer).  
The first injection site will be at 5 cm lateral to the umbilicus lateral wall into the left or 
right abdominal subcutaneous fat.  
- 
Post treatment: ECG (4h and 12h ± 30min post injection), pulse rate (1h, 2h, 4h, 8h, 12h, 
24h post injection in the opposite hand of blood sampling), vital signs (2h ± 30 min post 
injection), Draize score (2h post injection ± 30 min), adverse events (AEs) will be recorded 
and pharmacokinetics. 


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Pharmacokinetics with cohorts 1-4– RZL-012 half-life was determined to be 5 hours in the 
exploratory phase 0 clinical trial (protocol RZL012-P0US-001.3), therefore blood samples will be 
taken after injection at the given time points: 0, 30, 60 min, 2h, 3h, 4h, 6h, 8h, 12h, 16h,24h, 30h.  
Schedule visits (Day 1-28): 
- 
Day 1 following treatment will include: ECG, vital signs including pulse rate, Draize score, 
photographs and thermal imaging of the treated area.  Last 2 blood sample for 
pharmacokinetics and blood sample for histamine (24hr ± 2hr following injection) will be 
taken. 
- 
For safety reasons 24hr ± 2hr following injection, Blood samples for serum chemistry and 
hematology will be taken 
- 
Day 3 following treatment will include Serum chemistry, hematology and histamine.  
Subjects will start applying an anti-histamine gel. 
- 
Visits will take place every 7 days ± 1d from treatment till Day 28.  On study visit Day 28 
subject will come fasting (10-12hr fast) for the glucose and lipid profile tests.  During visits 
all tests (physical exam, vital signs, anthropometric measurements, ECG, clinical laboratory 
tests, urinalysis, fasting glucose and insulin, lipid profile, FFA, inflammatory markers and 
cytokines, histamine, Draize score, photographs, thermal imaging and MRI will be 
performed according to schedule (Table 2). 
- 
Subjects will be questioned for adverse events every visit. 
- 
Subjects will record their weight following 8-12hr fast (overnight) and at bedtime once a 
week (days 7, 14 and 21) in a diary.  Diaries will be checked and data will be captured in the 
CRFs. 
 
Follow-up visits (Day 29-168):  
Subjects of the 1st and 2nd cohorts: 
- 
On visit Day 56 - will come after overnight fast (10-12hr fast) for the glucose, insulin, lipid 
profile tests and FFA levels.  Subjects will be followed up for anthropometric 
measurements, thermal imaging and adverse events. An MRI scan will be conducted on Day 
56 in subjects of the 2nd cohort.  
- 
Will continue to be followed for safety every 28 days till Day 112.  If Draize-score is 0 for 
edema and erythema by visit Day 56 then subjects will be followed by phone call for AE. 
Subjects of the 3rd and 4th cohorts (or treated with the highest dose achieved): 
- 
 Will be followed up for anthropometric measurements (e.g., BMI, WHR) every 28 days as 
long as the thermogenic effect is apparent and for a period that will not exceed 6 months 
from the beginning of treatment.  
- 
Subjects will record their weight following 10-12hr fast (overnight) fast and at bedtime once 
a week when not visiting the site, in a diary.  Diaries will be checked and data will be 
captured in the CRFs. 
- 
In addition, evaluation of the injected area and the contra-lateral side will be performed by 
Draize score, photographs and thermal imaging 
- 
Subjects will come fasting (10-12hr fast) for the glucose, insulin, lipid profile tests and FFA 
levels.    
- 
MRI of 16 slices that includes the injected site (SAT evaluation).  MRI will be conducted on 
Day 28 days and every 28 days for a period that will not exceed 6 months from the 
beginning of treatment in the 3rd and 4th cohorts. 
- 
On Day 56 (following MRI), in 3 randomly selected subjects treated with the 3rd cohort 
(2 RZL-012 treated that show a sustained thermogenic effect by thermal camera imaging 
and one subject treated with vehicle with no thermogenic effect), an abdominal 
subcutaneous (SC) adipose tissue biopsy will be taken from the injected side.  The biopsy 
site will be anesthetized with 1% lidocaine and will be performed by a trained medical 
professional.  The sample (an elliptical excision of 15-20mm deep and 4.5-6cm long) will be 
placed in a vial filled with a fixation solution (formaldehyde).  After 24h ± 2h, the fixation 
solution should be exchanged to ethanol 80% and further processed for histological analysis.  
Biopsies will be stained for hematoxylin and eosin (H&E) and further evaluated for BAT 


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markers and morphometry.  Subjects will be followed 7 days post biopsy and will terminate 
their study participation. 
Subjects of the 3rd and 4th cohorts or subjects of the highest dose achieved will be followed up for 
additional 5 months for safety and efficacy. In case of termination before study day 112 in these 2 
cohorts, subjects will be followed for safety as the first cohorts. Subjects of all other cohort will be 
followed for safety additional 3 months. 
Safety Analysis 
Safety data from the study will be summarized descriptively by treatment and cohort.  Descriptive 
statistics will be calculated for quantitative data and frequency counts and percentages will be 
provided for categorical data.  The nature, frequency, seriousness, severity and relation to study drug 
of adverse events (AE) will be tabulated for all subjects combined and by treatment.  Change-from-
baseline values for vital signs, clinical laboratory and ECG will be summarized.  Shift tables of 
normal / abnormal versus baseline may be presented as well. Draize scores will be presented in 
tabular format by visit, treatment, and cohort. Serious adverse events (SAEs) will be described in 
narratives as part of the study report. 
Study 
Endpoints 
Primary Endpoint: 
Safety: The main objective is the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat. Therefore, the primary safety endpoint will be the incidence of intolerable side 
effects and all adverse events of RZL-012 injection into the subcutaneous fat. The dose escalation 
scheme will be stopped if at any dose cohort, 2 patients will experience intolerable side effects. 
Efficacy:  The primary endpoint for efficacy is a significant thermogenesis at the injected site 
compared with the contra-lateral, non-injected site.  This was monitored by sensitive (± 0.1 °C) Infra-
Red thermal camera.  A thermogenic effect is defined by an increase of 1 °C in the injected site when 
compared to the surroundings and/or the non-injected site, apparent at least 28 days after injection 
and non-related to inflammatory response as determined by inflammatory cytokines.  The primary 
efficacy evaluation will be supported by results from secondary endpoints, including MRI, biopsy 
and biomarkers. 
Secondary Endpoints: 
1. Duration of the thermogenic effect, defined as a net-delta ≥ 1.  
2. Local reduction in fat mass as determined by MRI. 
3. Clinical laboratory changes from baseline, including improvement in fasting blood glucose and 
lipid profile. 
4. Establishing pharmacokinetic profile for RZL-012. 
5. Anthropometric changes from baseline, including body weight change. 
6. Elucidation of the histological changes account for the thermogenic effect by biopsy of the 
injection site. 
7. Change from baseline in inflammatory markers and cytokines. 


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Sample Size 
This study is planned as a dose escalation study following a 6 subjects per dose group paradigm with 
the addition of a 2 subjects vehicle control group, for all doses. A maximum of 32 evaluable subjects 
will be included in the study (24 in the RZL-012 treatment arm and 8 in the placebo arm) and 
followed for as long as 3 months in the 2 lowest dose cohorts, and in the 2 highest dose cohorts for 
up to 6 months 
Statistical 
Methods 
Statistical analyses will be mainly descriptive in nature where study data will be tabulated and 
summarized using the mean, standard deviation or standard error, median, minimum, maximum and 
number of subjects by cohort for continuous data.  For categorical data, results will be summarized 
via a count and percentage by cohort.  The effects of noncompliance, dropouts, and covariates, may 
be assessed to determine the impact on the general applicability of results from this study. 
If any statistical tests are performed, they will be two-sided.  The required significance level of 
findings will be equal to or lower than 5%.  Nominal p-values will be presented. 
Where confidence limits are appropriate, the confidence level will be 95%. 
Incidence of intolerable side effects will be tabulated by study drug by cohort along with 95% 
confidence intervals. 
The average temperature will be presented in a tabular form by visit, site (treated / not treated) and 
treatment received (RZL-012 / placebo) by cohort and overall.  Difference between the sites (treated 
– not treated) will be presented in a tabular form by visit treatment along with the change from 
baseline (net-delta) in these differences by cohort and overall. 
Non-parametric tests will be used to compare the net-delta between the study arms for the relevant 
cohorts and visits. 
AEs and tolerability data will be presented descriptively by treatment and cohort.  AEs will be 
tabulated by body system, preferred term, seriousness, severity and relation to study drug by cohort.  
Where applicable, changes in values over time (e.g., lab values, vital signs, electrocardiograms 
[ECGs]) will be presented, this will include clinical laboratory evaluations (including CBC, blood 
chemistry and urinalysis), coagulation (INR, PTT, PT), cytokines, vital signs, and ECGs.  Shift tables 
of normal / abnormal versus baseline may be presented as well. 
Draize scores will be presented in tabular format by visit, treatment, and cohort 
Study Duration 
Study duration is 6.5 months, including enrollment, treatment and follow-up period. 
Each subject will participate in the study for a up to 42 days as part of this protocol with an extension 
for up to 3 additional months for safety and 5 additional months for those subjects in the highest dose 
cohort or subjects in the 3rd and 4th cohort as long as a thermogenic effect is evident.  
Study Site 
Spaulding Clinical Research LLC, West Bent, Winsconsin 


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1. 
INTRODUCTION 
1.1. 
BACKGROUND 
1.1.1. Scientific Background and Clinical Rationale 
The prevalence of obesity continues to escalate worldwide and is becoming one of the most 
significant global health problems in the United States.  Obesity-related co-morbidities place a 
significant burden on the healthcare system and include type 2 diabetes, hypertension, 
cardiovascular disease and cancer.  While diet and exercise are the primary methods to help 
control weight gain, in many cases people either cannot or do not want to comply with 
recommendations for exercise and proper food consumption.  These persons who become obese 
may be candidates for pharmacologic or surgical interventions to help lose weight and prevent or 
reduce the impact of adverse health consequences.  Conventional preventive measures (i.e., diet, 
exercise, behavioral counseling) and current adjunctive pharmacotherapies have limited efficacy 
and often fail to provide long term solutions.  Few medications are available for the treatment of 
obesity and their treatment strategies are based on decreasing energy uptake by either appetite 
suppression or by impaired food absorption.  At present, the only FDA-approved drugs for the 
long-term treatment of obesity are Orlistat (Xenical), Lorcaserin (Belviq), and the combination 
of phentermine and extended-release Topiramate (Qsymia), as well as GLP-1 analogs. 
Orlistat - blocks the action of pancreatic lipase, reducing triglyceride digestion and, thus, 
absorption.  The drug may reduce absorption of some fat-soluble vitamins (A, D, E, and K) and 
beta-carotene, as well as absorption of some medications.  Adverse effects include flatulence, 
fatty/oily stool, increased defecation, and fecal incontinence. 
Lorcaserin - was approved by the FDA in June 2012 as an adjunct to a reduced-calorie diet and 
exercise for long-term weight management in individuals with an initial BMI of 30 kg/m2 or 
higher (obese) or 27 kg/m2 or higher (overweight) with at least 1 weight-related comorbid 
condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus).  Lorcaserin is a schedule 
IV substance, since it has potential for abuse.  Lorcaserin is thought to decrease food 
consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic 
pro-opiomelanocortin neurons in the hypothalamus.  Lorcaserin should be used with caution in 
patients with heart failure, and it has not been studied in patients with serious valvular heart 
disease. 
Liraglutide - is a glucagon like peptide-1 (GLP-1) analog.  GLP-1 is a physiological regulator of 
appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain 
involved in appetite regulation.  Liraglutide is approved for chronic weight management as an 
adjunct to diet and exercise in adults with a BMI of ≥ 30 (obese) or adults with a BMI of ≥ 27 
(overweight) who have at least 1 weight-related condition (e.g., hypertension, type 2 diabetes, 
dyslipidemia). 


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Phentermine and topiramate -The combination of phentermine and extended-release topiramate 
was approved by the FDA in July 2012 as an adjunct to a reduced-calorie diet and exercise for 
long-term weight management in individuals with an initial BMI of 30 kg/m2 or higher (obese) 
or 27 kg/m2 or higher (overweight) with at least 1 weight-related comorbid condition (e.g., 
hypertension, dyslipidemia, type 2 diabetes mellitus).  Topiramate, which was first licensed as an 
adjunctive antiepileptic agent, has been associated with profound weight loss (an average of 5-
7% of initial weight).  The amount of weight loss appears to be greater with higher baseline 
weights.  The exact mechanism of this effect is being actively investigated.  Although the degree 
of efficacy is exciting, the propensity for adverse effects, especially the central nervous system 
effects such as drowsiness, paresthesias, memory loss, and confusion, is cause for concern.  
Qsymia contains an extended-release form of topiramate. 
Collectively, that the effect of these medications is limited to 5% - 7% weight loss of the initial 
body weight after 1 year and is associated with significant side effects. 
Bariatric surgery is a drastic intervention, suitable for only a small fraction of the qualifying 
obese population.  Thus, at present, obesity constitutes an outstanding unmet medical need.  The 
World Health Organization has recently released a report on the significant concerns with 
obesity worldwide that clearly outlines the significant consequences and epidemic scale of the 
health problem facing mankind (1). 
Obesity is a direct result of food-intake in excess of body energy expenditure.  Therefore, a 
feasible approach to combat obesity is via energy-consuming activities, such as physical 
exercise.  Unfortunately, our modern society is moving in the other direction, spending more 
time in immobilized positions, at work and at home.  An alternative strategy for the induction of 
increased energy expenditure is via the activation of brown adipose-tissue (BAT).  Diametric to 
the common white-adipose-tissue (WAT), which stores energy, BAT burns it.  Thus, BAT-
associated thermogenesis can counterbalance obesity.  For a comprehensive review of the subject 
see reference (2).  BAT existence in humans has only been recently discovered; it is relatively 
scarce and requires hypothalamic hardwiring for its activation, e.g., upon exposure to low 
temperatures.  It was also found that under certain conditions; WAT could give rise to BAT-like 
cells functionally identical to BAT, namely, utilizing fat to produce heat.  These BAT-like cells 
are called brite or beige adipocytes.  Research labs are currently exploring a variety of 
experimental approaches to BAT or brite/beige activation (3) but none have an FDA-approved 
indication for the treatment of obesity.  
Moreover, it was discovered that under certain conditions, genuine WAT can become 
thermogenic, independent of BAT-related mechanisms and unrelated to brite/beige (cells with 
BAT phenotype, but derived from WAT).  It is well understood that BAT thermogenesis depends 
on up regulation of uncoupling protein 1 (UCP1).  This protein takes advantage of the proton 
gradient generated by the mitochondria and diverts it for heat production, thereby uncoupling 
oxidative phosphorylation.  Indeed, UCP1-defficient mice have defective BAT and are very 
sensitive to acute cold exposure.  However, it was also found that if such UCP1-null mice are 


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gradually shifted to low temperature, their WAT becomes thermogenic (4).  Moreover, UCP1-
deficient mice are actually resistant to diet-induced obesity (5).  Namely, in the absence of 
UCP1, the mouse is forced to use alternative thermogenic metabolic systems.  However, the 
spectrum of physiological or biochemical stimuli that can lead to such WAT thermogenic 
phenotype, have yet to be explored (6).  Although these studies were carried out in rodents, there 
are indications that WAT conversion into a thermogenic tissue exists in humans (7).  
Raziel Therapeutics has discovered that a novel synthetic molecule can convert WAT into BAT-
like, thereby activating thermogenesis at targeted anatomical sites.  A single injection of this 
compound, called RZL-012, into WAT, is sufficient to trigger outstanding tissue remodeling.  
This chain reaction begins with removal of WAT adipocytes by macrophages, with ensuing 
increased vascularization at the treated site and concomitant appearance of BAT-like adipocytes.  
Temperature measurements of the treated site reveal a persistent local increase in body 
temperature. 
In essence, Raziel Therapeutics technology enables de-novo generation of thermogenic tissue at 
favorable anatomical sites.  Thus, Raziel Therapeutics intends to treat obesity via the induction 
of BAT-like thermogenic foci in subcutaneous fat.  As a result, the extra fat accumulated in 
obese persons will be turned into heat.  
The overall clinical plan for RZL-012 includes the completed exploratory (phase 0) study to 
evaluate the safety, thermogenesis, and pharmacodynamic response to RZL-012.  The additional 
phase 2 study will be initiated to explore higher doses prior to the initiation of larger studies.  
The initial exploratory study (Study RZL-012-P0US-001.3) demonstrated that RZL-012 was 
well tolerated with no serious adverse events reported and that thermogenesis was evident at the 
injection site of RZL-012-treated subjects.  The current study will be in overweight and obese 
subjects to confirm the safety and pharmacodynamic effects of RZL-012 for the treatment of 
obesity. 
1.1.2. RZL-012 Formulation Development 
The active ingredient RZL-012 drug substance was manufactured by Pharmacore.  The drug 
product, 5 % RZL-012 in F12 liquid formulation (RZL-012 in F12 is 5 g/vial, RZL-012 is 
250 mg/vial) was manufactured and packed at Nextar Ltd, Ness-Ziona, Israel.  RZL-012 in F12 
which was once defined as RZL-012 F12 is now defined as RZL-012.  The active ingredient and 
formulation manufacturing and packing were in accordance with current Good Manufacturing 
Practices (cGMPs). 


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1.2. 
NONCLINICAL ASSESSMENTS 
1.2.1. Pharmacology 
Studies in rats and pigs concluded that RZL-012 triggers remodeling of WAT to BAT-like tissue 
thereby activating thermogenesis.  The dose of RZL-012 to be used in clinical trials was 
extrapolated from the safety data obtained during animal testing (NOAEL). 
1.2.1.1. 
Efficacy In-vivo and In-vitro Studies 
Nonclinical studies were conducted to prove the efficacy of RZL-012 in several in-vivo and in-
vitro models. 
The in vivo studies (in pigs and rats) involving local administration of RZL-012, focused on two 
main endpoints: fat tissue reduction and conversion of WAT to brown-like adipose tissue, 
measured by several parameters, including; 
1. Subcutaneous or epididymal fat reduction following RZL-012 treatment. 
2. Fat tissue remodeling involving non-inflammatory liponecrosis, followed by tissue 
"browning", where WAT is converted to brown-like adipose tissue.  This conversion can 
be determined by: 
a. Histological fat tissue changes:  While white adipocytes are large and resemble a 
single large oil drop, with a characteristic condensed nucleus, the cells of brown 
adipose tissue are smaller, contain multiple mitochondria and a euchromatic 
nucleus.  
b. UCP-1 levels: UCP-1 is a mitochondrial inner membrane protein present in BAT 
that can dissipate the proton gradient before it can be used to provide the energy 
for oxidative phosphorylation.  UCP-1 normally does not exist in WAT.  
3. Assessment of body-surface temperature: Classical brown-like adipose tissue is typified 
by futile burning of fatty acids (i.e., heat production instead of adenosine triphosphate 
(ATP)), which can be assessed with an infrared camera that can sense differences in body 
surface temperature. 
The objective of the in-vitro studies was to reveal the mechanism of action of RZL-012 in 
adipocytes.  Studies were conducted on the 3T3-L1 adipocytes line, which is considered a model 
for white adipose tissue.  
1.2.1.2. 
Safety Pharmacology 
The effect of RZL-012 on the central and peripheral nervous systems was evaluated using the 
Functional Observational Battery (FOB) in male Sprague Dawley rats.  RZL-012 was 
administered subcutaneously to rats (n = 8/group) as 10 mg/rat.  From the results it was 


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concluded that RZL-012 did not affect any of the central nervous system functions tested using 
functional observation battery in rats. 
The effect of RZL-012 was evaluated on respiratory functions in male Sprague Dawley rat using 
head-out plethysmography.  RZL-012 was administered subcutaneously at a fixed dose of 
10 recorded to cover the entire predetermined time points; Pre-dose, 1, 2, 3, and 4 h post dose.  
RZL-012 did not affect any of the parameters tested hence it was concluded that RZL-012 has no 
effects on the respiratory system at the tested dose of 10 mg/rat.  
A board-certified veterinary cardiologist conducted a qualitative and quantitative review of the 
electrocardiograms obtained pretest, pre-dose, 4 and 24 hours post-dose following the 
subcutaneous injection of 500 mg 5.0 % RZL-012 or vehicle in Domestic Yorkshire Crossbred 
Swine.  There was no effect of the subcutaneous injection of 5.0 % RZL-012 on qualitative or 
quantitative ECG parameters or blood pressure. 
1.2.2. Toxicology 
The study design was to evaluate the safety of RZL-012 according to FDA guidelines for 
Exploratory IND appropriate for first-in-man clinical trial.  An extended single-dose toxicity 
study was performed according to FDA guidance in two species (rat and pig) to establish the 
NOAEL. 
1.2.2.1. 
Extended Single Dose Toxicity Studies 
1.2.2.1.1. Rats 
Single subcutaneous administration of test item RZL-012 at the doses of 5, 10, and 20 mg/kg in 
Sprague-Dawley rats resulted in non-systemic effects and or local effects at the treated skin area.  
Few changes observed in haematological parameters (WBC count, neutrophils, monocytes and 
eosinophils) were considered secondary effects due to inflammatory response (local skin 
reactions).  The changes observed in clinical chemistry parameters (increased BUN in males and 
females and increased creatinine and AST levels in females) at all the doses tested and 
histopathological changes in kidneys (necrosis in tubular epithelium) at 20 mg/kg were 
considered systemic effects.  Methods and results from the extended single dose toxicity study 
are described in the Investigator's Brochure. 
Considering skin changes as non-systemic effects and or local effects, the NOAEL was 
determined at 10 mg/rat with an average body weight of 246.2 g for females and 255.2 g for 
male, under the test conditions and doses employed. 
1.2.2.1.2. Pigs 
This study was conducted to evaluate the potential local and systemic toxicity as well as efficacy 
of the test article, RZL-012 (50 mg/mL), in domestic Yorkshire crossbred swine following 


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subcutaneous injection into the subcutaneous abdominal fat on Day 0.  Methods and results from 
the extended single dose toxicity in pigs study are described in details in the Investigator's 
Brochure. 
Assessment of toxicity was based on mortality, clinical observations, body weight, qualitative 
food consumption, body temperature, subcutaneous fat temperature, blood pressure; physical and 
electrocardiographic examinations; and anatomic and clinical pathology.  Blood samples were 
collected and analyzed for porcine stress syndrome testing, histamine level analysis, and 
toxicokinetic assessment of the test article. 
Administration of the test article was not associated with any mortality, clinical observations 
(with the exception of transient redness and swelling at injection sites), body weight or food 
consumption changes, effects on electrocardiographic endpoints, or changes clinical chemistry or 
coagulation parameters.  It should be noted that three animals died during the post anesthesia 
recovery period.  The cause of death was considered to be related to perioperative complications 
associated with the anesthesia and not related to RZL-012 or saline administration.  These three 
animals were replaced on study.   
A slight elevation in body temperatures was noted in males treated with the test article from 
Days 14-16 until Days 77-79.  In addition, several animals were observed with perioperative 
hyperthermia and/or hypothermia.  To determine if the perioperative hyperthermia and/or 
hypothermia was caused by Porcine Stress Syndrome all remaining animals on study were tested 
and determined to be normal (negative). 
Administration of the test article was associated with changes in subcutaneous fat temperatures, a 
mild increase in neutrophils, and macroscopic and microscopic observations.  
A noticeable difference in subcutaneous fat temperatures was noted between treatment groups.  
Beginning as early as Day 4-5, an increase in temperature was noted at all test article treated sites 
in both males and females.  The increase in temperature was noted through Days 58-63.  At 
study termination, subcutaneous fat temperatures at treated sites were comparable to vehicle 
control. 
Subcutaneous administration of RZL-012 (50 mg/mL) to farm pigs resulted in mild increases in 
neutrophils in both sexes at the 24 hour post-dose collection, which were most typical of an 
inflammatory response.  Increases in neutrophils had resolved by the Day 14 collection. 
Analysis of the plasma samples following subcutaneous administration of RZL-012 (Group 4) 
found that both female and male farm pigs were exposed to RZL-012.  Mean systemic exposure 
(area under the concentration versus time curve between zero and the 24 hour timepoint 
[AUC0-24hr]) and maximum observed concentration (Cmax) values, were 3700 (hr*ng/mL) and 
529 (ng/mL), respectively, for males and mean systemic exposure (AUC0-24hr) and Cmax values, 
were 2940 (hr*ng/mL) and 528 (ng/mL), respectively, for females. 


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Upon evaluation of the injection site photographs, no irritation was observed but transient 
redness was noted.  Upon microscopic evaluation at 24 hours and 14 days, test article related 
findings in the injected subcutaneous tissue was noted.  These findings were characterized by 
necrosis of the subcutaneous fat and muscle accompanied by acute inflammation at 24 hours 
post-dose.  At 14 days, residual necrotic tissue in the injected areas was noted with evidence of 
on-going healing characterized by chronic inflammation and fibrosis.  There was no evidence of 
systemic toxicity at 24 hours or 14 Days 
The 14 day interim results of this study demonstrated that administration of 5.68 to 7.14 mg/kg 
to males and 5.32 to 6.33 mg/kg to females of RZL-012 (test article) over 20 injection sites in the 
pig was associated with expected changes in subcutaneous fat temperatures, transient changes in 
neutrophils, and marked localized irritation and tissue necrosis.  The increase in subcutaneous fat 
temperature was considered to be related to the mechanism of action of RZL 012, and an 
indication of the efficacy of the test article.  The microscopic changes noted at 24 hours were 
beginning to resolve at 14 days.  The results of the final time point at 84 days will allow for 
assessment of the resolution of these findings.  
Based upon the interim results of the study a NOAEL of 7.14 mg/kg in males and 6.33 mg/kg in 
females of RZL-012 has been established in the swine.  The establishment of the NOAEL was 
based upon the microscopic effects being limited to the subcutaneous tissue with no systemic 
effects and the evidence of on-going healing at 14 days. 
1.2.3. Additional Nonclinical Studies 
• Secondary pharmacology (searching for off-target receptors).  
• Establishing pharmacokinetic parameters and investigation of RZL-012 metabolism 
by liver enzymes and half maximal inhibitory concentration (IC50) in cell-culture.  
• Testing RZL-012 mutagenicity, utilizing the Ames test. 
• Pyrogenicity in rabbits. 
• Assessment of RZL-012 binding to the β3 receptor in cellular and nuclear receptor 
functional assays.  
• Assessment of RZL-012 uptake by the 5-HT neurotransmitter in the absence and 
presence of a 5-HT2B agonist. 
• Assessment RZL-012 effect on 5-HT neurotransmitter uptake and release in cellular 
and nuclear receptor functional assays. 
• ADME-Toxicology 
• Genotoxicity 
Methods and results from these safety studies are described in the Investigator's Brochure. 
1.2.4. Clinical Studies 
Raziel Therapeutics has conducted an Exploratory phase 0, randomized, double-blind, vehicle-
controlled study aimed at the evaluation of safety and thermogenesis-induction of three 


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escalating doses of RZL-012 drug product in overweight and obese volunteers.  In each cohort, 
8 subjects were enrolled, 6 active and 2 control.  Study design is presented in the following table: 
Table 1:  Phase 0 Clinical Trial Design 
 
Cohort 1 
Cohort 2 
Cohort 3 
Number of Subjects – Active/Placebo 
6/2 
6/2 
6/2 
Total Dose RZL-012 (mg) 
5 
10 
20 
Dose per NOAEL* 
1/50th  
1/25th  
1/12.5th  
Number of Injections 
1 
2 
4 
 
Primary objective:  Evaluation of the overall safety and preliminary efficacy of RZL-012 after 
subcutaneous injection and the existence of a thermogenic effect. 
Secondary objective:  Determination of RZL-012 pharmacodynamics and pharmacokinetics.  
Evaluation of the extent, duration and tissue associated changes of the thermogenic response to 
RZL-012, via minimal invasive means including injected-site thermogenesis imaging, Magnetic 
Resonance Imaging (MRI) and punch biopsy following injection into the subcutaneous fat. 
Primary Endpoints: 
Safety: The main objective was the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat. Therefore, the primary safety endpoint was the incidence of intolerable adverse 
events.  The dose escalation scheme was stopped if at any dose cohort, 2 patients experienced 
intolerable side effects. 
Efficacy:  The primary efficacy endpoint was a significant thermogenesis at the injected site 
compared with the contra-lateral, non-injected site.  This was monitored by sensitive (± 0.1 °C) 
Infra-Red thermal camera.  A thermogenic effect was defined by an increase of 1 °C in the 
injected site when compared to the surroundings and/or the non-injected site, apparent at least 28 
days after injection and non-related to inflammatory response as determined by inflammatory 
cytokines.  The primary efficacy evaluation was supported by results from secondary endpoints, 
including MRI, biopsy and biomarkers. 
Secondary Efficacy Endpoints: 
1. Duration of the thermogenic effect, defined as a net-delta ≥ 1.  
2. Local reduction in fat mass as determined by MRI. 
3. Clinical laboratory changes from baseline, including improvement in fasting blood glucose 
and lipid profile. 
4. Establishing pharmacokinetic profile for RZL-012. 


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5. Anthropometric changes from baseline, including body weight change. 
6. Elucidation of the histological changes account for the thermogenic effect by biopsy of the 
injection site. 
7. Change from baseline in inflammatory markers and cytokines. 
Results: 
This was a dose escalation exploratory clinical trial of RZL-012, a first-in-class, new chemical 
entity.  
RZL-012 was generally found to be safe in all cohorts.  There were no clinically significant 
changes in vital signs, ECG and almost all blood laboratory tests.  Most AEs associated with 
RZL-012 injection occurred confined to the injection site and were transient.  Biopsy from the 
injected site revealed no damage to the skin 56 days following RZL-012 injection.  The only 
significant local AE was an abscess in one subject in the lower abdomen on the injected side, but 
at a considerable distance from the site of injection. 
In another patient, a severe elevation of ALT blood levels and a moderate elevation of AST 
blood levels were seen 14 days following injection.  This elevation was transient (resolved 
within 14 days).  In light of the pre-clinical findings (increased AST blood levels in female rats 
sacrificed on Day 2 following RZL-012 injection) and in light of the findings in this clinical trial, 
Raziel therefore plans to monitor closely (on 24hr, Day 3, Day 7, Day 14, Day 21, Day 28 and 
will follow further if necessary) liver functions in the next clinical trial.  There were no other 
systemic clinically significant AEs. 
The exploration of thermogenesis induction by RZL-012 in humans was successful.  A raise in 
temperature at the injection site was mostly evident in cohort 3 (the highest dose) at Day 14 or 
Day 21 following injection in RZL-012 treated subjects only.  This change in temperature was 
captured and recorded by the infra-red camera.  
Although not statistical significant, a drop in the change from baseline in Subcutaneous Fat Mass 
(SFM) ratio (treated/control) over time by MRI in RZL-012 treated subject of cohort 3 was 
evident in 5 of 6 treated subjects.  The drop in subcutaneous fat associated with a drop in weight 
(more than 1 kg) and BMI when compared to baseline and is evident in 4 of 6 RZL-012 treated 
subjects of cohort 3 on Day 28 and/or Day 56, while controls gained weight and increased BMI.  
Biopsy did not yield enough tissue (because punch biopsy did not penetrate deep enough to reach 
the remodeled tissue), and therefore, it was not possible to demonstrate that thermogenesis is due 
to adipose tissue remodeling by. 
Although not statistical significant, a decrease in TC and FFA blood levels was evident in 
subjects of the RZL-012 treated group in cohort 3.  This may imply to the mode of action of 
RZL-012 as stimulation of a thermogenic tissue such as BAT, is known to cause a systemic 


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effect via the mobilization of glucose and FFA from the blood stream to feed the ongoing local 
thermogenesis.  Thus, lipolysis of WAT triacylglycerols (TAG) stores is accelerated and the 
uptake of FA derived from blood-born lipoproteins is increased due to the action of lipoprotein 
lipase (LPL).  Raziel assumes that circulating FFA utilization by the RZL-012-induced 
thermogenic tissue resulted in lower levels of FFA in the blood, a process that may be beneficial 
for health.  There was no consistent pattern to suggest a connection between inflammation 
markers and cytokines levels and changes in thermogenic activity reflecting the intended effect 
of the drug as opposed to local inflammation and distinguish between events related to M1 and 
M2 macrophages.  Though, an increase in Adiponectin blood level was evident at Day 21 and 
Day 28 in 3 of 6 subjects treated with RZL-012, but not in controls.  Adiponectin was found to 
be an obligatory mediator of cold-induced browning of WAT (8).  Adiponectin can be elevated 
under various conditions, including those that trigger tissue remodeling in favor of 
thermogenesis such as chronic cold exposure.  Although we do not know what triggered 
elevation of adiponectin in this study, it is known that downstream effects of adiponectin can 
promote the type of tissue remodeling we are expecting. 
Raziel concludes that the potential risk-benefit balance for RZL-012 is favorable, and that it is 
likely that higher doses of RZL-012 will generate better results.  This will be assessed in the next 
clinical trial 
Methods and results of this exploratory study are described in the Investigator's Brochure. 
2. 
PURPOSE AND STUDY OBJECTIVES 
2.1. 
PURPOSE 
This phase 2a clinical trial aims to test safety and efficacy of a new chemical entity, RZL-012, in 
converting WAT into a thermogenic tissue and reducing fat-mass in overweight and obese males. 
2.2. 
STUDY OBJECTIVES 
2.2.1. Primary 
The primary objective is the evaluation of the overall safety and preliminary efficacy of RZL-
012 after subcutaneous injection. 
2.2.2. Secondary 
The secondary objective is the determination of RZL-012 pharmacodynamics and 
pharmacokinetics.  Evaluation of the existence of a thermogenic effect and the extent, duration 
and tissue associated changes of the thermogenic response to RZL-012, via minimal invasive 
means (injected-site thermogenesis, MRI and biopsy) after subcutaneous injection into fatty 
tissue below the skin. 


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3. 
STUDY DESIGN 
3.1. 
DESCRIPTION OF STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, consecutive 4 cohort, dose escalation 
clinical trial that will enroll 8 subjects, 6 active and 2 control in all cohorts.   
3.2. 
DOSE RATIONALE 
The initial dose was determined by the NOAEL established by the GLP extended single dose 
toxicology study and by the previous phase 0 clinical trial in which 20mg RZL-012 was the 
highest dose achieved.  This initial study is an escalating dose study.  If no more than 1 subject 
experiences intolerable side effects within 14 days following the injection of the last dosed 
group, according to schedule, an additional cohort of volunteers will be administrated the next 
dose level. 
Cohort 1: 40 mg RZL-012 (1/6.25th of the NOAEL determined in the GLP Toxicology studies). 
Cohort 2: 80 mg RZL-012 (1/3.125th of the NOAEL determined in the GLP Toxicology studies).  
Cohort 3: 120 mg RZL-012 (1/2.34375th of the NOAEL determined in the GLP Toxicology 
studies). 
Cohort 4: 180 mg RZL-012 (approximately the NOAEL determined in the GLP Toxicology 
studies). 
3.3. 
DOSING 
3.3.1. Dosing Regimen 
The dosing regimen will be a single dose treatment injection of RZL-012 in multiple sites. 
The first 6 subjects randomly assigned to the RZL-012 treatment group (cohort 1) will initiate at 
the dose of 40 mg RZL-012 (approximately 1/6.25th the NOAEL as determined in the GLP 
toxicology study) and 2 more subjects will be given placebo (vehicle). 
If no more than 1 subject experiences intolerable side effects within the 1st cohort, 14 days 
following the injection of the last dosed subject, an additional 6 subjects will receive a dose of 
80 mg RZL-012 (approximately 1/3.125th of the NOAEL) and 2 more subjects will be given 
placebo (vehicle). 
If no more than 1 subject experiences intolerable side effects within the 2nd cohort, 14 days 
following the injection of the last dosed subject, an additional 6 subjects will receive a dose of 
120 mg RZL-012 (approximately1/2.34th of the NOAEL) and 2 more subjects will be given 
placebo (vehicle). 


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If no more than 1 subject experiences intolerable side effects within the 3rd cohort, 14 days 
following the injection of the last dosed subject, according to schedule an additional cohort of 6 
volunteers, as above, will receive 180 mg RZL-012 (1/1.39 of the NOAEL).  Additional 2 
subjects in the cohort will serve as control and will be injected placebo (vehicle). 
Dosing of the first 3 subjects in each cohort will progress consecutively from one individual to 
the other at 7-day intervals.  For additional precaution, the first 3 subjects will be forced 
randomization with 2 active and 1 control.  This study design will allow the physicians 
to monitor safety in a single subject at each dose; nevertheless, the blindness will remain intact. 
The next subjects in the cohort will be randomized to either active treatment or placebo in a ratio 
determined by the number of subjects targeted for each cohort.  Dosing of the next subjects will 
be in couples and the last subjects will be in a triplet.  
If 1 subject had already experienced intolerable side effects in a cohort, then enrollment will 
progress consecutively from one individual to the other at 7-day intervals until that cohort is 
complete.  
The trial will proceed within a cohort and from one cohort to the next as long as no more than 
one subject experiences intolerable side effects in the lower-dose cohort, and based on the 
decision made by a DSMB.  The decision to proceed to the next cohort will be made after 
reviewing all safety data collected by Day 14 within 2 ± 1d of the last dosed subject in each 
cohort.  The DSMB will be comprised of two independent medical doctors (MDs) expert in early 
phase clinical trials. 
3.3.2. Intolerable Side Effect 
Safety will be the principal primary endpoint of this study, as such if there are 2 intolerable and 
at least possibly related side effects observed in any dose cohort, that dose cohort will be stopped 
and only tolerable doses used for future subjects.   
An intolerable side effect defined as any of the following treatment-related adverse drug 
reactions (ADRs): 
• Any Grade 3 or greater event except for the following (For the following entities, a 
discussion will be held by the PI, DSMB and Sponsor to decide whether considered as an 
intolerable side effects): 
o Flu-like symptoms and fever that responds to standard treatment within72 hours 
o Localized edema and erythema 
o Pruritus 
o Pain 
o Skin/soft tissue inflammation 
o Fat Atrophy 
o Liver enzymes abnormality 


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o Non-significant lab abnormalities, lasting less than 7 days 
To establish a threshold for clinical abnormalities and liver enzyme abnormalities the following 
tables were formed for main expected side effects. For the following abnormalities, intolerable 
side effect would be any Grade 3 or greater event: 
Clinical Abnormalities Table 
 
* Erythema – the measured local reaction at the greatest single diameter beyond the injected area surface of all 
injections (4x8 cm for the first cohort, 8x8cm for the second cohort and 12x8cm for the third and fourth cohort), the 
measurement should be recorded as a continuous variable.  
**Induration –– the measured local reaction at the greatest single diameter beyond the injected area surface of all 
injections (4x8 cm for the first cohort, 8x8cm for the second cohort and 12x8cm for the third and fourth cohort), the 
measurement should be recorded as a continuous variable.  
Liver Enzyme Abnormalities Table 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Liver Function Tests –ALT, AST 
increase by factor 
3 x ULN 
3 – 5 x ULN 
5-10 x ULN 
beyond 10 days  
> 10 x ULN 
beyond 10 days 
 
Study discontinuation is to be considered by the investigator in any case of an intolerable side 
effect, and the actions taken are to be fully documented in source documents and Case Report 
Forms (CRFs).  
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours 
Interferes with 
activity 
Any use of narcotic 
pain reliever beyond 
7 days following 
injection or prevents 
daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Discomfort to touch 
or with movement 
Significant 
discomfort at 
rest 
Prevents daily 
activity 
ER visit or 
hospitalization 
Erythema/Redness * 
2.5 - 7 cm 
7.1 - 15 cm 
> 15 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling 
** 
2.5 - 7 cm and does 
not interfere with 
activity 
7.1 - 15 cm or 
interferes with 
activity 
> 15 cm or prevents 
daily activity 
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To be considered an intolerable side effect, such an event must be considered to be possibly or 
probably related to the study drug. 
Subjects experiencing an intolerable side effect will be withdrawn from the study, but followed 
for toxicity. 
The study may also be prematurely terminated in any of the following cases:  
• Recurring serious or severe ADR clinically evaluated by DSMB as warranting study 
termination.  
• A decision made by Sponsor and/or IRB/EC and/or local regulatory agency to terminate 
the study.  
4. 
STUDY ENDPOINTS 
4.1. 
PRIMARY ENDPOINTS 
Safety: The main objective is the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat.  Therefore, the primary endpoint will be the incidence of intolerable side 
effects and all adverse events of RZL-012 injection into the subcutaneous fat.  The dose 
escalation scheme will be stopped if at any dose cohort, 2 patients will experience intolerable 
side effects. 
Efficacy:  The primary endpoint for efficacy is a significant thermogenesis at the injected site 
compared with the contra-lateral, non-injected site.  This was monitored by sensitive (± 0.1 °C) 
Infra-Red thermal camera.  A thermogenic effect is defined by an increase of 1 °C in the injected 
site when compared to the surroundings and/or the non-injected site, apparent at least 28 days 
after injection and non-related to inflammatory response as determined by inflammatory 
cytokines.  The primary efficacy evaluation will be supported by results from secondary 
endpoints, including MRI, biopsy and biomarkers.  
4.2. 
SECONDARY ENDPOINTS 
Following are the study's secondary endpoints:  
1. Duration of the thermogenic effect, defined as a net-delta ≥ 1, see definition in 
Section 6.1.17.2.1. 
2. Local reduction in fat mass as determined by MRI, see definition in Section 6.1.17.2.2. 
3. Clinical laboratory changes from baseline including improvement in fasting blood 
glucose and lipid profile, see definition in Section 6.1.17.2.3. 
4. Establishing pharmacokinetic profile for RZL-012, see definition in Section 6.1.15. 


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5. Anthropometric changes from baseline, including body weight change, see definition in 
Section 6.1.17.2.4. 
6. Elucidation of the histological changes account for the thermogenic effect by biopsy of 
the injection site, see definition in Section 6.1.17.2.5. 
7. Change from baseline in inflammatory markers and cytokines, see definition in 
Section 6.1.17.2.6. 
5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria will be eligible for study participation: 
1. Adult male subjects 20-60 years old. 
2. Subject is considered overweight and obese, with 27.5 < Body Mass Index (BMI) ≤ 34.9. 
3. Significant subcutaneous abdominal fat as defined by WHR ≥ 0.9. 
4. Subjects with stable weight in the last 3 months by medical history. 
5. Not one of the following eating disorders by subject's declaration: anorexia nervosa, 
bulimia nervosa. 
6. Generally considered healthy according to medical history, physical examination, ECG 
and laboratory evaluation with a special emphasis on metabolic parameters (fasting 
glucose concentration < 100 mg, normal blood pressure). 
7. Subject is willing to refrain from sexual activity or agrees to use a double-barrier 
contraceptive device (e.g., condom and spermicide) for 4 weeks after treatment with 
RZL-012. 
8. Subjects must be able to adhere to the visit schedule and protocol requirements and be 
available to complete the study. 
9. Subjects must sign an informed consent indicating that they are aware of the 
investigational nature of the study. 
5.2. 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded: 
1. Subjects weighing less than 75 kg. 
2. Subjects who have reduced/gained weight more than 5 % of their current body weight in 
the last 3 months. 
3. Unable to tolerate subcutaneous injection. 


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4. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that 
in the opinion of the investigator put the subject at significant risk, are not eligible.  
5. Subjects who test positive to Hepatitis B virus (HBV), Hepatitis C virus (HCV), or 
Human immunodeficiency virus (HIV) are not eligible.  
6. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune 
disease or subjects taking immunosuppressive drugs such as corticosteroids are ineligible. 
7. As a result of medical review, physical examination, the Principal Investigator (PI) (or 
medically qualified nominee) considers the subject unfit for the study. 
8. Medication use on regular basis including blood and blood products. 
9. Positive drug and alcohol tests.  
10. Known sensitivity to components of the injection formulation.  
11. Prior wound, tattoo or infection in the treated area. 
12. Excessive growth of hair in the abdomen region. 
13. Claustrophobia or MRI incompatible device or implant. 
5.3. 
SUBJECT IDENTIFICATION 
A unique code numbers will be assigned by the investigator to the trial subject rather than the 
subjects’ names, personal identification numbers, and/or addresses to protect the subject's 
identity.  The code numbers and initials will be used in lieu of the subject's name when the 
investigator reports adverse events and/or other trial related data. 
5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF SUBJECTS 
FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE EFFECTS 
In the first and second cohorts, if only one subject is withdrawn or removed from the study, and 
no more than one subject experience intolerable side effects, then the subject will not be 
replaced.  If more than one subject is withdrawn or removed from the study, and more than one 
subject experience intolerable side effects, then the subject will be replaced by new subject. 
In the third and fourth cohort, any withdrawal or removal not due to intolerable side effects 
within the first 28 days will be replaced by a new subject. 


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6. 
STUDY PROCEDURES AND ASSESSMENT 
6.1. 
DEFINITIONS OF STUDY PROCEDURES 
6.1.1. Informed Consent 
Prior to initiation of any study procedures, each subject will undergo an Informed Consent 
process in which the subject voluntarily confirms their willingness to participate in the trial, after 
having been informed of all aspects of the trial relevant to their decision to participate.  The 
investigator, or a person designated by the investigator, will fully inform the subject of all 
pertinent aspects of the trial.  In addition, the investigator, or a person designated by the 
investigator, will inform the subject that he is free to refuse to enter the study or to withdraw 
from the study at any time, for any reason. 
The Informed Consent Form (ICF) approved by the IRB/EC will contain a description of the 
study’s purpose, procedures, inconveniences and potential risks, and anticipated benefits.  
Prior to a subject’s participation in the trial, an ICF will be signed and personally dated by the 
subject and initialed by the person who conducted the Informed Consent discussion.  
If a subject is unable to read, an impartial witness should be present during the entire Informed 
Consent discussion.  After the written Informed Consent form is read and explained to the 
subject and after the subject has orally consented to participating in the trial and, if capable of 
doing so, has signed and personally dated the Informed Consent form, the witness should sign 
and personally date the ICF.  By signing the ICF, the witness attests that the information in the 
ICF was accurately explained to, and apparently understood by, the subject and that Informed 
Consent was freely given by the subject.  
Prior to participation in the trial, the subject will receive a copy of the signed and dated written 
ICF.  During participation in the trial, the subject will receive a copy of the signed and dated 
consent form updates and a copy of any amendments to the written information provided to 
subjects.  
The investigator should document in the source data that the Informed Consent was signed prior 
to subject's participation in the study and according to the ICH guidelines, as described above. 
6.1.2. Medical History 
Subjects' medical history should be fully documented at screening Day 1 (28 through 7days prior 
to baseline), to ensure compliance with study inclusion criteria and the absence of circumstance 
mentioned in the exclusion criteria.  Medical history information must include, but not be limited 
to past and present medical conditions, concomitant non-drug treatments and hypersensitivity to 
drugs. 


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6.1.3. Concomitant Medication 
All concomitant medication given 3 months prior to study entry, including blood and blood 
products dietary supplements, and non-prescription drugs will be listed at screening/baseline.  
Each entry will include the treatment's start date, treatment name (Generic), reason for use, 
dosing regimen (dose and frequency of use), route of administration, and stop date (if 
applicable).  The clinical significance of the medication use will be decided by the investigator.  
Study subjects will be routinely questioned for changes in the administration of concomitant 
medication during the trial.  
6.1.4. Physical Examination 
The investigator (or medically qualified nominee) will conduct a complete physical examination 
at screening Day 1 (performed 28 through 7 days prior to baseline).  Clinically significant 
abnormal findings except overweight and obesity should be discussed with the Sponsor. 
Additional physical examination to assess subject's safety will be performed on study visit on 
Day 28. 
6.1.5. Vital Signs and Measurements 
Subjects' vital signs will be measured at screening Day1 (performed 28 through 7 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  
Vital signs measurements will include systolic and diastolic sitting position blood pressure, pulse 
rate, respiratory rate, and body oral temperature.  
Additional vital signs measurements to assess subject's safety will be performed at baseline visit 
(Day 0) prior to drug injection, 2h ± 30min following drug injection, the following day (Day 1) 
after drug injection (24h ± 2h) and on study visits every 7 days thereafter, i.e., Day 7, Day 14 etc. 
Additional pulse rate measurements to assess subject's safety will be performed at baseline visit 
(Day 0) prior to drug injection and 1h, 2h, 4h, 8h, 12h, 24h following injection in the opposite 
hand of blood sampling. 
6.1.6. Anthropometric Measurements 
Subjects' anthropometric measurements will be measured at screening Day 1 (performed 28 
through 7 days prior to baseline) in order to ensure compliance with study inclusion and 
exclusion criteria.  Anthropometric measurements will include height, weight, waist 
circumference and hip circumference.  All anthropometric measurements will be measured in the 
morning following 10-12hr fast (overnight) and according to the Center for Disease Control 
(CDC) Anthropometry Procedures Manual of the National Health and Nutrition Examination 
Survey (NHANES) January 2007 edition (9). 


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Additional anthropometric measurements (apart from height) will be performed at Screening 
Day 2 before the MRI to ensure compliance with study inclusion and exclusion criteria, at -clinic 
admission visit (Day -1) and on study visit on Day 28.  In subjects that are followed for over than 
28 days, anthropometric measurements (apart from height) will be conducted on visit days 
attended at the study site every 28 days for a maximum period of additional 5 months. Additional 
weight measurements will be performed on weeks when weight is not measured at the site visits. 
In this case, weight will be measured by the subjects at their homes once a week in the morning 
following 8-12hr fast (overnight) and at bedtime. Subjects will be given a diary to record their 
weight. 
6.1.6.1. 
Weight 
Subjects' Weight will be measured in order ensure compliance with exclusion criteria and to 
calculate the BMI and ensure compliance with study inclusion criteria (27.5 < BMI ≤ 34.9). 
The subject will be instructed to stand completely still in the center of the scale platform with the 
feet close together hands at the sides and looking straight ahead.  The weight measurement will 
be taken for the electronic readout and is recorded in kilograms to one digit after the decimal 
point. 
6.1.6.2. 
Height 
Subjects' Height will be measured in order to calculate the BMI and ensure compliance with 
study inclusion criteria (27.5 < BMI ≤ 34.9). 
The standing height or stature measurement is an assessment of maximal vertical size.  This 
measure is for persons who are able to stand unassisted.  Standing height is measured with a 
fixed stadiometer with a vertical backboard, a fixed floorboard, and movable headboard.  Hair 
ornaments, jewelry, buns, braids and cornrows should be moved or removed from the top of the 
head in order to measure stature properly.  The subject will be instructed to stand on the 
floorboard with the heels of both feet together, touching the base of the vertical board.  The toes 
are pointed slightly outward at approximately a 60 ° angle.  Body weight is evenly distributed 
with both feet flat on the floor.  The technician will check the position of several points of body 
contact with the vertical board.  The first contact point is the heels, followed by the buttocks, the 
scapula or shoulder blades, and finally the back of the head.  Depending on the overall body 
conformation of the individual, all points may not touch.  In such case, the trunk of the body 
should be positioned vertically above the waist with the arms and shoulders relaxed.  The head 
should be aligned in the Frankfort horizontal plane.  The head is in the Frankfort Plane when the 
horizontal line from the ear canal to the lower border orbit of the eye is parallel to the floor and 
perpendicular to the vertical backboard.  Many people will assume this position naturally, but for 
some it may be necessary to make a minor adjustment.  If required the technician may gently tilt 
the head up or down until proper alignment is achieved with the eyes looking straight ahead.  
Once correctly positioned the headboard is lowered.  The subject is instructed to take a deep 


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breath and stand as tall as possible.  A deep breath allows the spine to straighten yielding a more 
consistent and reproducible stature measurement.  The headboard is positioned firmly on top of 
the head with sufficient pressure to compress the hair.  The measurement will be read in 
centimeter and recorded in meters. 
6.1.6.3. 
BMI 
Subjects' BMI will be calculated in order to ensure compliance with study inclusion criteria 
(27.5 < BMI ≤ 34.9) by the equation below: 
BMI = weight (in kilograms)/ (height)2 (in meters) 
BMI will be computed to one digit after the decimal point 
6.1.6.4. 
Waist Circumference 
Subjects' Waist Circumference will be measured in order calculate the WHR to ensure 
compliance with study inclusion criteria (WHR ≥ 0.9). 
The subject will be instructed to gather his gown shirt above the waist, cross the arms, and place 
the hands on opposite shoulders.  If necessary, lower the pants and underclothing to slightly 
below the waist.  The technician will stand on the subject’s right side and will palpate the hip 
area to locate the right ilium of the pelvis.  With a cosmetic pencil, draw a horizontal line just 
above the uppermost lateral border of the right ilium.  Cross this mark at the midaxillary line 
which extends from the armpit down the side of the torso.  If it is difficult to find the iliac crest, 
such as on subjects with larger waists, then begin inferior to the midaxillary line (toward the 
subject front) and palpate the ilium upward to the midaxillary line until the uppermost part of the 
bone is found.  Extend the measuring tape around the waist.  Position the tape in a horizontal 
plane at the level of the measurement mark.  Check that the tape sits parallel to the floor and lies 
snug but does not compress the skin.  Always position the zero end of the tape below the section 
containing the measurement value.  Take the measurement in centimeters to the nearest 0.1 cm at 
the end of the subject normal expiration (one digit after the decimal point). 
6.1.6.5. 
Hip Circumference 
Subjects' Hip Circumference will be measured in order calculate the WHR to ensure compliance 
with study inclusion criteria (WHR ≥ 0.9). 
The subject will be instructed to stand upright with feet together and weight evenly distributed.  
The buttocks or hip circumference is the only measure that is not taken directly on the skin.  The 
assistant technician stands in front of the subject and gathers the fabric of the pants.  The thumbs 
and index fingers hold the folded sides of the pants snugly.  This minimizes the amount of 
material included in the measurement and helps to define the maximum protuberance of the 
buttocks when viewed in profile.  The technician is positioned on the right side with eye level at 


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the hip region of the subject.  The measuring tape is place around the hips and anchored at the 
maximum protuberance of the buttocks.  The assistant then releases the folds of the pants and 
helps to adjust the tape so it is in a horizontal plane.  The measuring tape is held snugly, but not 
pulled tight.  The measure is recorded in centimeters to the nearest 0.1 cm (one digit after the 
decimal point). 
6.1.6.6. 
Waist to Hip Ratio (WHR) 
Waist to Hip Ratio (WHR) will be calculated in order to ensure compliance with study inclusion 
criteria (WHR ≥ 0.9) by the equation below: 
WHR = Waist Circumference (in centimeters) / Hip circumference (in centimeters) 
The WHR will be computed to two digits after the decimal point. 
6.1.7. Serology Assays 
Assays for Hepatitis C virus (HCV), Hepatitis B virus (HBV) and Human immunodeficiency 
virus (HIV) will be conducted at screening Day 1 (performed 28 through 7 days prior to 
baseline) in order to ensure compliance with study inclusion criteria. 
6.1.8. Clinical Laboratory Tests 
Clinical laboratory tests will be conducted at screening Day 1 (performed 28 through 7 days 
prior to baseline) in order to ensure compliance with study inclusion and exclusion criteria.  
Additional studies will be conducted on different study visits according to schedule as written 
below.  Clinical laboratory tests performed on Clinic Admission visit are performed in order to 
establish a baseline except from the following tests that are performed to confirm eligibility: 
urine drug screen and clinical significant results that the PI feels will risk the subject. 
The maximum total blood volume will be 30 -100 mL per visit.  Every out-of-range value will be 
assessed by a physician and deemed as either clinically significant (CS) or clinically not 
significant (CNS).  Values that represent a change from baseline in subject’s medical status 
according to the laboratory normal ranges will be adequately documented as an adverse event 
(AE) as described in Section 9. 
6.1.8.1. 
Hematology 
Hematology tests will be conducted at screening Day 1 (performed 28 through 7 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  Additional Hematology 
testing will be conducted to assess subject's safety on -clinic admission visit (Day -1), at 24hr ± 
2h following injection and on study visit Day -1, 1, 3, 7, 14 and 28. 
Hematology tests will include Complete blood count (CBC) (including White blood cells [WBC] 
differential values) and coagulation tests: White blood cells (WBC), Red blood cells (RBC), 


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Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin 
(MCH), Mean corpuscular hemoglobin concentration (MCHC), Red cell distribution width 
(RDW), Platelets, Mean platelet volume (MPV), Fibrinogen, D-dimer, International normalized 
ratio (INR), Partial thromboplastin time (PTT) and Prothrombin time (PT). 
6.1.8.2. 
Serum Chemistry Analysis 
Testing of blood chemistry values will be conducted at screening Day 1 (performed 28 through 7 
days prior to baseline) in order to ensure compliance with study inclusion criteria.  At screening 
Day 1, subjects should be notified to come fasting (10-12 hours of fast) for fasting glucose, blood 
test.   
Additional fasting glucose, insulin, leptin, lipid profile blood tests will be conducted at clinic 
admission visit (Day -1) and on study visit Day 28 and every 28 days during follow-up period.  
Additional Serum Chemistry testing will be conducted at clinic admission visit (Day -1) to 
establish baseline values, 24hr ± 2hr following injection and on study visit Day -1, 1, 3, 7, 14 and 
28. 
Serum chemistry will include:  Sodium, Calcium, Potassium, Phosphorus, Glucose, Liver 
enzymes (Aspartate aminotransferase [AST], Alanine aminotransferase [ALT], Lactate 
dehydrogenase [LDH], Creatine-kinase MM [CK-MM], Gamma-glutamyltransferase [GTTP], 
Alkaline phosphatase [ALP]), Bilirubin, Creatinine, Urea/Blood urea nitrogen [BUN], Total 
protein, Albumin, Amylase, Creatine phosphokinase [CPK] 
Lipid profile will include: (Triglycerides [TG], High-density lipoprotein [HDL], Low-density 
lipoprotein [LDL], Total-cholesterol [TC] and Free-fatty-acids [FFA]). 
In case of CK-MM >x5 ULN, subjects will undergo clinical assessment for symptoms and 
alternative causes, and renal function will be assessed (including urinalysis). 
6.1.8.3. 
Urine Drug Screen 
Urine drug screen will be conducted at screening Day 1 and at clinic admission visit (Day -1) in 
order to ensure compliance with study exclusion criteria.   
Drugs of abuse will include: amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, alcohol, opiates, phencyclidine and propoxyphene. 
6.1.8.4. 
Inflammatory Markers and Cytokines 
Testing of inflammatory markers and cytokines values from the 2nd, 3rd and 4th cohorts (on 
RZL-012 treated and placebo treated subjects in each cohort) will be conducted in order to 
explore the mode of action at clinic admission visit (Day -1)to establish baseline values (4 mL 


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blood per subject).  Additional cytokines testing will be conducted study visits Day 7, 14, 21 and 
28. 
Inflammatory and cytokines will include: CRP, Adiponectin, CD-163, Interleukin [IL]-1β, IL-4, 
IL-6, IL-10, IL12p70, IL-13, IL-23, Tumor necrosis factor [TNF] α, and TGFβ1. 
Inflammatory and cytokines level will be measured by multiplexed ELISA kits, called Q-Plex™.  
Q-Plex Arrays are able to measure the concentration of multiple proteins in each sample and to 
quantify cytokines levels.  Blood samples (4 mL) will be centrifuged at 1200 G in 4 ⁰C for 
10 minutes, plasma collected in aliquots (minimum of 2 aliquots of 500 µL each) within 
20 minutes of centrifugation and flash frozen on dry ice.  Processed samples will be frozen in -
80 ⁰C.  Plasma aliquots will be analyzed by Quansys Biosciences. 
6.1.8.5. 
Histamine 
Testing of subjects' blood histamine levels will be conducted at clinic admission visit (Day -1) 
visit before drug injection in order to establish a baseline (4 mL blood per subject).  Additional 
blood histamine levels will be conducted the day following drug injection (24h ± 2h following 
drug injection), at study visit Day 3 and 14. 
6.1.8.6. 
Urinalysis 
Urinalysis will be conducted at screening Day 1 (performed 28 through 7 days prior to baseline) 
in order to ensure compliance with study inclusion criteria and to allow differential diagnosis in 
case of urinary tract associated AE.  Additional urinalysis testing will be conducted on study visit 
Day 14 and 28. 
Urinalysis will include: Nitrite, Sodium, Potassium, Calcium, Phosphate, Protein, RBC, WBC, 
Blood, Glucose, Ketone bodies, Bilirubin, Urobilirubin, Urine specific gravity, Osmolarity, and 
pH. 
6.1.9. ECG 
Subjects' ECG will be performed at screening Day 1 (performed 28 through 7 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  ECG is to be performed on 
at least a triplicate of heartbeats for all measurements and will be recorded at a speed of 25 
mm/sec.  Additional ECGs will be performed at 4h ± 30min, 12h ± 30min and 24h ± 2h 
following drug injection (Day 0-1) and on Days 14 and 28. 
Computerized ECG analysis will include:  Heart rate, Rhythm, PR interval, QRS axis, and QRS 
duration.  QT interval and QTc will be calculated manually according to the Bazett formula.  
ECG will be recorded at a standard speed of 25 mm/sec and standard amplitude of 10 mm/mV. 


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6.1.10. Draize Score 
Subjects' skin irritancy will be evaluated by Draize score at screening Day 1 (performed 28 
through 7 days prior to baseline) in order to establish a baseline to compare following drug 
injection.  
Additional skin irritancy evaluation to assess subject's safety will be performed at baseline visit 
prior to injection, and on 2h ± 30min following injection, on the following day 24h ± 2h after 
drug injection and on study visits Day 7, 14, 21, and 28.  For the 1st and 2nd cohorts if by visit 
Day 56 Draize score is not 0 for erythema and edema, then subject will continue to be followed 
every 28 days till Draize score is 0.  If Draize score is 0 for erythema and edema, then subjects of 
these cohorts will be followed for additional 2 months (every 28 days) by phone for adverse 
events.  For the 3rd and 4th cohorts (or the highest dose achieved) Draize score will be assessed 
every 28 days during the follow-up period. 
Skin irritancy observations in the injected sites and contra-lateral sites will be scored using the 
Draize scale for scoring skin reaction: 
Erythema and eschar formation 
Edema formation 
No erythema 
0 
No edema 
0 
Very slight erythema (barely perceptible) 
1 
Very slight edema (barely perceptible) 
1 
Well defined erythema 
2 
Slight edema (edges are well defined by 
definite raising) 
2 
Moderate to severe erythema 
3 
Moderate edema (raised approximately 1mm) 
3 
Severe erythema (beet redness) to slight 
eschar formation (injuries in depth) 
4 
Severe edema (raised more than 1mm 
extending beyond area of exposure) 
4 
• Total possible erythema score = 4 
• Total possible edema score = 4 
6.1.11. Photography of the Injected Site 
Documentation of the skin condition and fat reduction effect in the injected area compared to the 
contra-lateral non-injected area will be conducted at screening Day 1 (performed 28 through 7 
days prior to baseline).  Additional photography will be performed at Day 1 (24h ± 2h following 
drug injection) and on study visits Day 7, 14, 21, and 28.  In subjects that are followed for over 
28 days, photographing will be conducted every 28 days. 
Photography with a digital camera will include:  
1. The injected area - at a distance of 20 cm and in a horizontal line from the umbilicus. 
2. The contra-lateral non-injected area - at a distance of 20 cm and in a horizontal line from 
the umbilicus. 


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3. The injected area and the contra-lateral non-injected area – at a distance of 1 m and in a 
horizontal line from the umbilicus. 
4. The injected area - at 45 degree angle from the camera and in a horizontal line from the 
umbilicus 
5. The contra-lateral non-injected area – at 45 degree angle from the camera and in a 
horizontal line from the umbilicus. 
6. The injected area - oblique views. 
7. The contra-lateral non-injected area - oblique views. 
 
Photography with a digital camera will be performed according to a detailed written manual. 
6.1.12. Thermal Imaging 
Evaluation of the thermal effect in the injected area compared to the contra-lateral non-injected 
area will be conducted at screening Day 1 (performed 28 through 7 days prior to baseline).  
Additional thermal imaging will be performed at clinic admission visit (Day -1), the day 
following drug injection (24h ± 2h following drug injection) and on study visits Day 7, 14, 21, 
28, and 56. 
For the 3rd and 4th cohort (or in the 2nd cohort if 2 subjects experience intolerable side effects in 
the 3rd cohort) additional thermal imaging will be conducted every 28 days for an additional 
maximum period of 5 months. 
Thermal imaging is non-invasive, non-radiating device that passively measures the emitting 
infra-red radiation of body surface with a sensitive (± 0.1 °C) Infra-Red thermal camera (FLIR 
A310, ISO 9001-2008 Certified).  Thermal imaging will include:  a view of the injected area and 
the contra-lateral non-injected area – at a distance of 1 meter and in a horizontal line from the 
umbilicus.  Thermal imaging will be performed in a room of 25 ± 1 °C to reduce environmental 
influences on temperature reading according to a detailed written manual. 
6.1.13. Fat Tissue Imaging: Magnetic Resonance Imaging (MRI) 
Evaluation of Magnetic Resonance Imaging (MRI) in all cohorts will be conducted in eligible 
subjects after 2-hour fast at screening Day 2 (performed 14 through 2 days prior to baseline) and 
on Day 28. 
For the 2nd cohort an additional MRI scan will be performed on Day 56. 
For the 3rd and 4th cohort (and for the 2nd cohort if subjects experience intolerable side effects in 
the 3rd cohort) additional MRI scans will be performed every 28 days for an additional maximum 
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MRI scans of the abdomen will be performed using a 1.5 Tesla machine (General Electric - 
Signa or Siemens) using a body coil.  Subjects will be examined after 2-hour fast in the supine 
position with arms positioned parallel along the lateral sides of the body.  A breath-hold 
technique will be used to avoid motion artifacts when chest and abdomen are scanned.  MRI 
scans demonstrating fat in the different compartments will be assessed using a MATLAB-based 
program.  Fat tissues of specific anatomical landmarks will be quantified.  In order to calculate 
the fat mass, 16 consecutive slices of 5mm width will be used: eight above the umbilicus and 
eight under the umbilicus (Figure 1).  The scanner will utilize a 3D modified DIXON 
(mDIXON) imaging technique without gaps (5mm thickness and spacing of 5mm), fast-low-
angle shot (FLASH) sequence with a multi-echo two-excitation pulse sequence for phase-
sensitive encoding of fat and water signals (TR,3.6ms; TE1,1.19ms; TE2,2.3ms; 
FOV 520×440×80mm; 2×1.4×1mm voxel size).  Sixteen images of the phantoms will be 
generated, including in-phase, out-phase, fat and water phase.  Images should be saved in a 
DICOM format with the information of date, subject's screening number and orientation 
(Left/Right) to be transferred by the Sponsor's request for analysis.  MRI will be performed 
according to a detailed written manual. 
Figure 1:  MRI: Distribution of 16 Consecutive Slices  
 
6.1.14. Biopsy 
On Day 56 (following MRI), in 3 randomly selected subjects of the 3rd cohort (or the 2nd if 
2 subjects experience intolerable side effects in the 3rd cohort) an abdominal SC adipose tissue 
biopsy will be taken from the injected side.  The Sponsor or designee will select 3 subjects to go 
under a biopsy: two subjects who will be demonstrating clear thermogenesis (assuming an 
active) and one subject who will not demonstrate thermogenesis (assuming a control).  Before 
biopsy the Sponsor representative who is un-blinded to the study will confirm that the selected 
subjects are indeed 2 RZL-012 treated and 1 vehicle treated.  Subjects will be followed 7 days 
post biopsy and will terminate their study participation. 


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After local anesthesia, an elliptical excision biopsy will be conducted by a trained medical 
professional 10 cm lateral to the umbilicus lateral wall (Figure 2).  A sample of fat tissue (a 
biopsy of an ellipse of 15-20 mm deep and 4.5-6 cm long, Figure 2) will be taken from the 
incision.  For optimal cosmetic results the incision will be made on a slant following Langer’s 
lines.  The incision will be stitched appropriately and the wound will be covered with a bandage 
or sterile dressing.  The sample will be divided in two. One half will be placed in a vial filled 
with a fixation solution (formaldehyde).  After 24h ± 2h, the fixation solution should be 
exchanged to ethanol 80% and further processed for histological analysis.  Each vial and lid will 
be labeled with: subject’s name, subject’s identification number and biopsy site. The other half 
of the biopsy will be embedded in a labeled cryomold with Optimum Cutting Temperature 
(OCT) compound and flesh frozen using a cryostat or liquid nitrogen. Each sample will be 
labeled with: subject’s name, subject’s identification number and biopsy site. Biopsies will be 
sent to the sponsor in an adequate manner and evaluated by a certified pathologist.  Biopsies will 
be stained for hematoxylin and eosin stain (H&E) and further evaluated for BAT and other 
markers and morphometry.  
Figure 2:  Biopsy Site and Dimensions 
 
6.1.15. Pharmacokinetics 
Testing of RZL-012 Pharmacokinetics will be conducted at the baseline visit till the following 
day (Day 0-1).  Subjects will stay overnight in the study center.  Blood samples (10 mL blood 
per sample in K2EDTA vials, 100 mL/subject/24h) will be taken after injection at the given time 
points: 0, 30, 60 min, 2h, 3h, 4h, 6h, 8h, 12h, 16h,24h, 30h in subjects from all cohorts.  Whole 
blood samples (10 mL x12 time points) will be stored on an ice block or wet ice until 
centrifuged.  Samples will be placed in the centrifuge and spin cycle started within 60 minutes of 
collection.  Samples will be centrifuged at 1200 g in 4 °C for 10 minutes.  Plasma will be 
removed and placed in aliquots (4 aliquots of 1 mL each) within 20 minutes of centrifugation and 
flash frozen on dry ice.  Processed samples will be placed in frozen (-60 to -90 °C) storage.  
Determination of RZL-012 in K2EDTA human plasma a validated method of Liquid 
Chromatography-Tandem Mass Spectrometry will be conducted and analyzed by Analyst 
Research Laboratories Ltd.  Samples (2 aliquots/subject/time point) will be sent to Analyst 
frozen on dry ice and 2 aliquots will be retained for possible future analysis. 


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6.1.16. Adverse Events 
The information obtained during weekly subjects questioning, review of subject’s compliance 
record, physical examinations, vital signs measurements, blood testing, and by any other means 
will be evaluated in light of baseline medical data and thus provide the basis for adverse events 
identification and grading.  
The trial will proceed within a cohort and from one cohort to the next as long as no more than 
one subject experiences intolerable side effects and based on the decision made by a DSMB.  
Proceeding from one cohort to the next will be based on the decision made after reviewing all 
safety data collected by Day 14 within 2 ± 1d of the last dosed subject in each cohort.  The 
DSMB will be comprised of two independent MDs expert in early phase clinical trials. 
The adverse events reported during the trial will be graded (see Section 9), documented, and 
assessed in light of their clinical significance and relation to investigational product.  In addition, 
the following information regarding the AE must be obtained: AE description, start date, end 
date (if applicable) or ongoing, severity, seriousness, relationship to study drug, outcome (e.g., 
resolved / unresolved), and action taken (e.g., concomitant medication).  The sponsor or the 
sponsor representative will provide information regarding SAE expectedness based on data 
included in the IB.  Adverse event monitoring will be conducted throughout subject’s 
participation up to 28 days after injection.  For the 1st and 2nd cohort subjects will be additionally 
followed for AE at visit Day 56.  If Draize score is 0 for erythema and edema, subjects of these 
cohorts and subjects of the 3rd and 4ths who terminate the study before visit Day 112, will be 
followed at Day 84 and Day 112 by phone-call questioning.  For the 3rd and 4th cohort (or the 
highest dose achieved) adverse events will be recorded after Day 28 every 28 days if subject did 
not terminate participation in the study. 
6.1.17. Evaluation of Response 
Evaluation of response will be conducted on Day 7 and every 7 days thereafter till Day 28. 
6.1.17.1. Evaluation of Primary Endpoints 
6.1.17.1.1. Safety and Tolerability Monitoring 
For determination of the study's primary end point, evaluation of safety and tolerability will be 
conducted according to definitions and guidelines below. 
Safety and tolerability will be assessed by the study medical staff (e.g., PI, site coordinator, and 
study nurse) and the study subjects on the basis of the following:  
1. AEs and Serious Adverse Events (SAEs), including severity, relation to study treatment 
and classification by whether or not these events comprise intolerable side effects. 
2. Physical exams, Draize score and vital signs measurements. 


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3. Urine testing. 
4. Blood laboratory testing for changes in hematology and chemistry values. 
5. ECG 
6. Subjects questioning - full medical history during screening, routine AE reporting and 
tolerability monitoring through review of subject’s weight diary. 
6.1.17.1.2. Efficacy Endpoint – Significant Thermogenesis 
The study primary efficacy endpoint, a significant thermogenesis at the injected site will be 
evaluated by comparing with the contra-lateral, non-injected site.  A significant thermogenic 
effect is defined as the increase of 1 °C from baseline in the difference in temperature (in °C) 
between the treated and not-treated sites (net delta).  This thermogenesis should be apparent by 
28 days after injection.  The sites temperatures will be measured with a sensitive (± 0.1 °C) 
Infra-Red thermal camera. 
6.1.17.2. Evaluation of Secondary Endpoints 
6.1.17.2.1. Sustained Thermogenic Effect 
Sustained thermogenic effect will be evaluated by thermal imaging.  A sustained thermogenic 
effect is defined as an evident thermogenic effect after 28 days.  A significant thermogenic effect 
is defined as the increase of 1 °C from baseline in the difference in temperature (in °C) between 
the treated and not-treated sites (net delta).  The duration of the thermogenic effect will be 
evaluated in the lower dose groups till Day 56 and in the higher dose groups by thermal imaging 
every 28 days in those subjects demonstrating clear thermogenesis by 28 days after injection for 
a maximum period of an additional 5 months. 
6.1.17.2.2. Local Fat Mass Reduction 
Local reduction in fat mass will be evaluated by MRI.  A local fat reduction is defined as a 
significant reduction (compared to baseline) in the average width of abdominal subcutaneous fat 
in the injected area compared to the contra-lateral area, SFM ratio, as evaluated by MRI.  Local 
fat reduction in cohort 4 will be defined as a significant reduction (compared to baseline) in the 
average width of abdominal subcutaneous fat in the injected area compared to the surroundings 
area, SFM ratio, as evaluated by MRI.  MRI will be evaluated in all groups at baseline and at 
Day 28.  MRI will be evaluated in the cohort 3 (or in cohort 2 if 2 subjects will experience 
intolerable side effects within the 3rd cohort) and cohort 4 every 28 days for up to 6 months from 
the beginning of treatment. 
6.1.17.2.3. Clinical Laboratory Changes 
Clinical Laboratory Changes will be evaluated comparing to baseline.  Clinical laboratory 
changes definition is a significant change from baseline according to the laboratory normal 


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ranges that affect the subject’s medical status as assessed by the investigating physician, 
including improvement in fasting glucose and lipid profile. 
6.1.17.2.4. Anthropometric Measurements Change 
Anthropometric measurements will be evaluated comparing to baseline.  Anthropometric 
measurements changes are defined as significant reduction in body weight, BMI and WHR at the 
end of the study compared to baseline. 
6.1.17.2.5. Histological Changes 
Histological changes will be evaluated comparing to known historical data.  Histological changes 
definition is an evident change from known historical data of normal subcutaneous adipose tissue 
as assessed by an expert pathologist. 
6.1.17.2.6. Inflammatory Markers and Cytokines Changes 
To determine drug mechanism of action, inflammatory markers and cytokines level in cohorts 2 
through 4 will be evaluated by comparing to baseline.  Inflammatory markers and cytokines 
changes definition is an apparent change from baseline. 
6.1.17.3. Compliance Monitoring 
Compliance monitoring will include the following procedures:  
• Compliance assessment by site coordinator at the study visit, including but not limited to 
subject questioning and review of the weight diary completed by the subject. 
• Completion of weight diary by the subject. 
6.1.17.4. Dispensing of RZL-012 Investigational Product 
The RZL-012 investigational product will be dispensed to the study site under monitored 
conditions by Nextar Ltd.  All procedures connected to investigational product's allocation (kits 
received at site, returned kits) will be properly documented, dated and signed in a designated site 
folder to allow full product tracking.  Source documents will be kept for the duration required by 
local regulations and ICH-GCP (whichever is longer). 
6.1.17.5. Questioning of Study Subjects 
Questioning of study subjects during site visits and any unscheduled conversations (e.g., by 
phone) with site staff will be fully documented in subject file.  Whenever possible, subject 
questioning should include, but not be limited to, inquiring information regarding occurrence and 
severity of AEs, treatment tolerability and compliance to future scheduled procedures and visits. 


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6.2. 
STUDY VISITS 
Study visits will be fully documented in the CRF as described in Section 11.  Documentation 
will be completed in a timely manner and within 5 working days to ensure protocol adherence 
and compliance with ICH-GCP. 
6.2.1. Screening Procedures 
All information collected and documented during screening procedures will be reviewed to 
ensure eligibility in reference to study inclusion and exclusion criteria, and fully documented in 
subject file. 
Screening visit Day 1 should be performed no later than 7 days prior to baseline visit for all 
cohorts.  
Subjects should be notified to come fasting (10-12 hours of fast) for the fasting glucose test and 
weight measurement.  Subjects screening visit Day 2 should be performed no later than 2 days 
prior to baseline visit.  Subjects who are alternates, and not dosed, the screening visit Day 2 
should be performed no later than 12-14 days prior to baseline. 
Study screening Day 1 procedures will include the following:  
• Informed Consent - Section 6.1.1 
• Medical History - Section 6.1.2 
• Concomitant Medication - Section 6.1.3 
• Physical Examination - Section 6.1.4 
• Vital Signs and Measurements - Section 6.1.5 
• Anthropometric Measurements - Section 6.1.6 
• Serology Assays – Section 6.1.7 
• Clinical Laboratory Tests - Section 6.1.8 
• ECG - Section 6.1.9 
• Draize Score – Section 6.1.10 
• Photography of Injected Site – Section 6.1.11 
• Thermal Imaging- Section 6.1.12 
• Fasting glucose 
Subjects may be rescreened if they were screened and not dosed within 14 days.  The following 
procedures will be performed: Clinical Laboratory Tests (hematology, serum chemistry, and 


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urinalysis), vital signs, weight, BMI, waist and hip circumference WHR, Draize score, 
photography and thermal imaging. 
Study screening day 2 procedure will include the following:  
• Anthropometric Measurements - Section 6.1.6 
• Fat Tissue Imaging: Magnetic Resonance Imaging (MRI) - Section 6.1.13 
6.2.2. Study Randomization 
Subjects will be randomized to each study group, i.e., investigational therapy or control, left side 
injection or right side injection according to a predefined randomization scheme.  The 
investigational therapy group will be treated with RZL-012 and the control group will be treated 
with the same formulation (vehicle) as with RZL-012, absent active medication. 
Masking will be used to blind the Investigator regarding randomization, i.e., assignment to study 
group will be disclosed only after subject eligibility is confirmed and immediately before 
treatment initiation.  The pharmacist will be unmasked and will be responsible to fill the syringes 
for injection. 
6.2.3. Study Treatment 
6.2.3.1. 
Treatment with RZL-012 Investigational Therapy 
RZL-012 is an investigational product supplied as a single dose single treatment injection in 
multiple sites (8-48) of injections.  Before injection, subjects will be advised to keep their regular 
diet and physical activity. 
The injection dosing regimen and technique is crucial for the therapy safety and efficacy.  
Syringes will be filled by the pharmacist with 0.1 mL RZL-012 or vehicle and the number of 
syringes will be compatible with the number of injections.  All injections will be administered 
diagonally in 45 °, using a 1 mL Luer-lock syringe and a 30 G x 1/2" needle. 
The injection will be administrated randomly into the left or right abdominal subcutaneous fat 
according to the randomization scheme (the hole of the needle pointing into the fat layer).  A grid 
line will be drawn with a makeup pencil in a horizontal plane 5 cm lateral to the umbilicus lateral 
wall so that it will cut the injected points symmetrically (Figure 3). 


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Figure 3:  RZL-012 Injection Sites 
 
For the 1st, 2nd and 3rd cohorts one to four (depends on the number of injection sites) tick marks 2 
cm apart will be drawn on the grid line.  For the 4th cohort nine tick marks 1 cm apart will be 
drawn on the grid line. Thus, the distance between injected points will be 2 cm for the first 3 
cohorts and 1 cm for the 4th cohort (Figure 4).  The injection sites will be drawn with a makeup 
pencil.  The needle will be inserted into the skin just above the pencil mark in a vertical manner 
towards earth.  The hole of the needle should be pointing into the fat layer.  An attempt to pull 
the plunger should be made before injecting to ensure that no blood is coming out.  If so, the 
plunger should be pushed down to inject the medicine.  The formulation is viscose; therefore, 
resistance is expected while injecting. 
Figure 4:  Design of the 24 Injection Sites 
 
This study will be performed in a dose escalation manner:  
Cohort 1:  The first 8 subjects randomly assigned to the study group will receive either RZL-012 
(6 subjects) or placebo (2 subjects).  The initial dose of 40 mg RZL-012 (1/6.25th the NOAEL) is 
based on HED from GLP toxicology study and safety results of the highest dose cohort (20mg 
RZL-012) from phase 0 clinical trial.  Subjects will receive 8 injections (0.1 mL in a 2x4 rows 
cluster) of 5 mg RZL-012.  If no more than 1 subject experiences intolerable side effects within 
14-days following the injection of the last dosed subject, according to schedule and following the 
DSMB approval an additional cohort will enter the study. 


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Cohort 2:  The next 8 subjects randomly assigned to the study group will receive either RZL-
012 (6 subjects) or placebo (2 subjects).  The dose of 80 mg RZL-012 (1/3.125th the NOAEL) is 
based on HED from GLP toxicology study and safety results of cohort 1.  Subjects will receive 
16 injections (0.1 mL each in a 4x4 rows cluster) adding up to 10 mg.  If no more than 1 subject 
experiences intolerable side effects within 14-days following the injection of the last dosed 
subject, according to schedule and following the DSMB approval an additional cohort will enter 
the study.  
Cohort 3:  The next 8 subjects randomly assigned to the study will receive either RZL-012 
(6 subjects) or placebo (2 subjects).  The dose of 120 mg RZL-012 (1/2.34th the NOAEL) is 
based on HED from GLP toxicology study and safety results of cohort 2.  Subjects will receive 
24 injections (0.1 mL each in a 6x4 rows cluster) adding up to 20 mg.  
. 
If no more than 1 subject experiences intolerable side effects within 14-days following the 
injection of the last dosed subject, according to schedule and following the DSMB approval an 
additional cohort will enter the study. 
Cohort 4: The next 8 subjects randomly assigned to the study will receive either RZL-012 
(6 subjects) or placebo (2 subjects).  The dose of 180 mg RZL-012 (1/1.39 the NOAEL) is based 
on HED from GLP toxicology study and safety results of cohort 3.  Subjects will receive 
36 injections (0.1 mL each in 9x4 rows cluster) adding up to 180 mg.  
The decision to proceed to the next cohort will be made by DSMB after reviewing all safety data 
collected by Day 14 within 2 ± 1d. 
Each RZL-012 kit contains 1 vial (250 mg/4.8 mL) corresponding to the number of subjects 
receiving treatment in each cohort. 
RZL-012 will be injected on baseline study visit. 
6.2.3.2. 
Treatment with Placebo 
Two subjects randomly assigned to the study in every cohort group will be injected placebo, 
which will be a vehicle control (tween-80, propylene glycol, benzyl alcohol and water) in the 
same manner as mentioned above (Section 6.2.3.1). 
6.2.4. Baseline Visit 
Baseline visit is defined in the study as Day 0.  Baseline visit will be performed to complete 
screening evaluation, and to review all procedures necessary to confirm subject eligibility.  
Subjects will stay overnight in the study center till 30h + 3h following drug injection. 


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Screening information may be considered for baseline data if acquired within the adequate 
timeframe as described in Table 2. 
Table 2:  Subject Information and Timeframes 
Information 
Timeframe 
Follow-up Timeframe 
Informed Consent Form 
Signed prior to any study 
dedicated procedure 
 
Medical History and Concomitant 
Medications 
At screening visit and at clinic 
admission visit (Day -1) 
 
Physical examination  
At screening Day1 visit and at 
Day 28 
 
Vital Signs  
At screening Day 1 visit and at 
Days 0 (pre and following 
injection), 1, 7, 14, 21, 28 
 
Pulse rate 
At Day 0 (pre and following 
injection) and at day 1 
 
ECG 
At screening Day 1 visit, at 
Day 0 (following injection) 
and at Days 1, 14, 28 
 
Anthropometric Measurements: weight, 
height (screening only),  BMI, waist 
circumference , hip circumference 
At screening Day 1 visit, 
screening Day 2, clinic 
admission visit (Day-1) and at 
Day 28 
Every 28 days.  
On Days 56, 84, 112, 
140, 168 
Weight – measured at home by the subjects 
at morning (8-12h fast) and at bedtime 
At Days 7, 14 and 21 
Every week when not 
visiting the site 
Draize Score at the Injected Site 
At screening Day 1 and at 
Days 0 (pre- and following 
injection), 1, 7, 14, 21, 28 
Every 28 days.  
 
Serology assays (HBV, HCV and HIV) 
At screening day1 visit   
 
Urine drug screen 
At screening Day 1 visit and at 
clinic admission visit (Day -1) 
 
Serum chemistry 
At screening Day 1, at clinic 
admission visit (Day -1) and at 
Day 1, 3, 7, 14 and 28 
 
Hematology  
At screening Day 1, at clinic 
admission visit (Day -1) and at 
Day 1, 3, 7, 14 and 28 
 
Fasting Glucose 
At screening Day 1 
 
Fasting Glucose, Insulin, Leptin, Lipid 
Profile and FFA 
At clinic admission visit (Day 
-1) and at Day 28 
Every 28 days.  
On Days 56, 84, 112, 
140, 168 
Urinalysis  
At screening Day 1 visit and at 
Days 14, 28 
 


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Information 
Timeframe 
Follow-up Timeframe 
Cytokines and inflammatory markers– in 
subjects from the 2nd, 3rd and 4th cohorts  
At clinic admission visit (Day 
-1) visit and at Days 7, 14, 21 
and 28 
 
Histamine 
At clinic admission visit (Day 
-1), and at Day 1, 3 and 14 
 
Pharmacokinetics in subjects from all 
cohorts 
At Day 0-1 
 
Photography of the Injected Sites 
At screening Day 1 visit and at 
Days 1, 7, 14, 21, 28 
Every 28 days.  
On Days 56, 84, 112, 
140, 168 
Thermal Imaging 
At screening Day 1 visit,at 
clinic admission visit (Day -
1)and at Days 1, 7, 14, 21, 28 
On Day 56 
Thermal Imaging - in subjects from the 3rd 
and 4th cohorts (or in cohort 2 if 2 subjects 
experience intolerable side effects within 
the 3rd cohort) 
 
Every 28 days.  
On Days 56, 84, 112, 
140, 168 
MRI 
At screening Day 2 and at Day 
28 
 
MRI - in subjects from the 2nd cohort 
 
On Day 56 
MRI - in subjects from the 3rd and 4th 
cohorts (or in cohort 2 if 2 subjects 
experience intolerable side effects within 
the 3rd cohort)  
 
Every 28 days.  
On Days 56, 84, 112, 
140, 168 
Biopsy – in subjects from the 3rd cohort or 
in cohort 2 if 2 subjects experience 
intolerable side effects within the 3rd cohort 
 
On Day 56 
AE Assessment  
At Days 1, 3, 7, 14, 21, 28 
Every 28 days 
Cohorts 1 and 2: AE Assessment by phone 
Days 84 and 112 
 
 
6.2.5. Subject Site Visits 
Subject site visits will be performed ± 1 days from scheduled date for study visits Day 0-28 and 
2± 1 days from schedule date for follow-up visits (Day 56-168).  All data relevant for the visit 
needs to be obtained within 3 days (e.g., blood tests) of visit.  
Subject sites visits will include procedures as described in Appendix I - Trial Schedule of Events. 
For site visit that results in study discontinuation, see termination visit in Section 6.2.6. 


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6.2.6. Termination Visit 
Once study is discontinued, all reasonable measures should be taken to perform a termination 
visit.  Termination visit should include all procedures necessary to complete subjects' records:  
AE reporting, any clinical laboratory test needed to evaluate unresolved AEs, evaluation of 
response, recovery of all clinical supplies and compliance diaries, and updating of subject 
contact information.  
6.2.7. Unscheduled Visit 
Unscheduled visits will be performed upon investigator's discretion, upon Sponsor request to 
redo tests with unusual results or complete missing results and may occur upon subject’s 
decision with no notification in advance.  Unscheduled visits will include any study procedure 
deemed necessary, as described in Section 6.1. 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR INVESTIGATORS 
Adherence to protocol monitoring procedures along with the following safety guidance will aid 
and promote subject safety. 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT MEDICATIONS 
Subjects may not receive the following medications while on study:  
• Chronic treatment with systemic steroids or immunosuppressive drugs.  
• Chronic treatment with Non Steroid Anti-Inflammatory Drugs (NSAIDs). 
• Any investigational product other than RZL-012.  
Before dosing, analgesic gels such as Lidocaine or Pramoxine should be used to numb the 
injected site.  An ice pack may be applied on the site of injection following dosing to help reduce 
pain.  At day 3 following blood sampling for histamine, the anti-histamine Benadryl Gel 
(Dimethindene Maleate 0.1 %) for topical use only should be initiated according to drug 
instructions for use to avoid itching in the injected area.  Benadryl Gel should be applied for 
7 days. 
Use of supplements or complementary medicines/botanicals and high energy supplements or 
drinks is prohibited, except for conventional multivitamin supplements. 
7.2. 
SAFETY MEASUREMENTS  
Simple measures may help avoid specific AEs associated with the use of the RZL-012 
investigational product.  Thus, study subjects must be informed of possible AEs that occurred in 
animal studies (rats and pigs): 


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• Any injection site reaction may occur.  Pain, swelling, itching, edema, erythema, 
hematoma etc. 
• Slight transient injection site bleeding following injection may occur. 
• Itching in the injected area may occur, and study subjects should be advised to use an 
antihistamine gel for topical use according to drug recommendations, wear wide cotton 
shirts, prevent touch with irritable clothing, avoid scratching and avoid exposure to direct 
sun.  Itching is expected till 7 days following drug injection. 
• Local erythema in the injected area. 
• Local heat in the injection area. 
• Study restrictions regarding concomitant medications are listed in Section 7.1.  
• The local subcutaneous fat reduction may appear as a slight dip in the skin surface.  This 
decline may be temporary and transient. 
• Transient increase (72%) in the WBC count by 24 hours following injection, which 
returned to basal level after 14 days.  Probably associated with the inflammatory response 
at the site of injection and involve neutrophils, monocytes and eosinophils.  
• Increased level of BUN and of creatinine and minimal single cell necrosis was observed 
in tubular epithelium at cortico medullary junction of kidney in rats receiving a dose 
higher 25 times the highest dose in this study.  All abnormalities were found to be 
reversible by Day 14. 
• Increased AST level which is most typical of myofiber injury associated with study 
related procedures.  This elevation was found to be reversible by Day 14. 
• Transient increase of serum CRP levels (in rats) which returned to the basic level by 
14 days. 
• Marked irritancy in the injected subcutaneous tissue resulting in coagulation necrosis of 
relatively large areas in the subcutaneous tissue planes acutely.  Necrosis persisted for up 
to 14 days and was accompanied by early evidence of healing in the form of chronic 
inflammation and fibrosis. 
• Local inflammation (minimal to moderate) with muscle degeneration, epidermal/dermal 
necrosis (minimal to severe) and parakeratosis (minimal).  Inflammation observed at 
injection site was also extended to adjacent subcutaneous adipose tissue.  By 56 days the 
inflammation was minimal, muscle degeneration was not evident and inflammation to 
adjacent subcutaneous adipose tissue was present.  
• A slight elevation in body temperatures was noted in male pigs. 
• Sinus tachycardia (in pigs), occurring at the 4 hour interval post dosing. 
• In addition, other acceptable treatment to relieve drug-related AE's should be used at 
Investigator's discretion. 
Study subjects must be informed of possible AEs that occurred in clinical studies (phase 0): 
• At the injection site -local and transient: erythema, oedema, pruritus, anesthesia, pain, 
mass (subcutaneous scar). 
• Abdominal abscess 


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• Transient moderate to severe elevation of the liver enzymes: Alanine aminotransferase 
(ALT) and Aspartate aminotransferase (AST). 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY 
Study will be prematurely discontinued in any of the following cases:  
• Subject's request.  
• Any life-threatening (i.e., Grade 4) adverse event may cause prematurely discontinuation.  
• Systemic hypersensitivity reaction may cause prematurely discontinuation.  
• Any Grade 3 or 4 ADR (defined in Section 9.3) clinically evaluated by the PI and/or 
Sponsor as warranting subject discontinuation.  
• Non-compliance: Subject's non-compliance with study procedures as evaluated by PI 
and/or Sponsor as warranting subject discontinuation.  
• Other reasons regarded by PI as warranting subject's discontinuation. 
• Premature study termination as described in Section 7.4.   
Subjects who discontinue the study prematurely will be queried whether an adverse event 
contributed to their decision. 
7.4. 
PREMATURE STUDY TERMINATION 
The study will be prematurely terminated in any of the following cases:  
• Recurring serious or severe ADR (defined in Section 9.1) clinically evaluated by PI 
and/or Sponsor as warranting study termination.  
• A decision made by Sponsor and/or IRB/EC and/or local regulatory agency to terminate 
the study.  
7.5. 
DEVIATION FROM STUDY PROTOCOL 
The investigator shall not deviate from the study protocol without first obtaining a written 
approval from the Sponsor, or its official designee, and if applicable, from the local IRB/EC 
according to local regulations.  
In the event of medical emergencies, the investigator shall use appropriate medical judgment and 
will remove the subject from any immediate hazard, then notify the Sponsor or its official 
designee and if applicable, the local IRB/EC, within 2 days, of the type of emergency and course 
of action taken.  
Any other changes to or deviations from the protocol will be made as an amendment to the 
protocol and must be approved by the Sponsor or its official designee and the local IRB/EC 
before they can be implemented.  Accordingly, the Sponsor will not assume responsibility or 
liability for any unauthorized deviation from or change to the protocol. 


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8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS 
8.1. 
DESCRIPTION OF RZL-012 
RZL-012 investigational drug is intended for a single dose in multiple injections into the 
subcutaneous fat.  The injection dosing regimen and technique is crucial for the therapy safety 
and efficacy. 
8.2. 
FORMULATION, PACKAGING AND LABELING  
The RZL-012 drug is a ready to use liquid to be injected to the subcutaneous fat, supplied in a 
1 vial kit.  1 vial contains 250 mg/4.8 mL RZL-012 in formulation F12. 
The vehicle is a ready to use liquid to be injected to the subcutaneous fat, supplied in a 1 vial kit.  
1 vial contains 1 mL of formulation F12. 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE 
The RZL-012 and vehicle kits will be stored in the site pharmacy at monitored room temperature 
conditions (22 ± 7 ᵒC) protected from light.  Storage space will be separate, designated and 
adequately labeled as containing investigational product.  
Stability program of RZL-012 is ongoing and site inventory will be managed by the Sponsor 
according to accumulating stability data.  Suitability of the product's expiration date must take 
into consideration and comply with FIFO (First In First Out) principals. 
The storage conditions are summarized in Table 3. 
Table 3:  RZL-012 and Vehicle Storage Conditions 
Storage Conditions 
Maximal Storage Duration 
Individual vials:  
Room temperature (15-30 ᵒC) 
According to expiration date as will be 
provided by manufacturer. 
* Stability program for RZL-012 is ongoing and site inventory will be managed by the 
Sponsor according to accumulating stability data. 
 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND VEHICLE 
8.4.1. Dosage 
RZL-012 therapy is available in vials of 250 mg/4.8 mL. 
The vehicle is available in vials of 4.8 mL. 


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8.4.2. Administration and Instructions for Use 
Each individual vial must be kept and handled at room temperature.  
The vial should be manually shaken before consumption.  
1 mL Luer-lock syringes with RZL-012 solution should be filled with 30 G 1/2" sterile needle as 
described below: 
• Cohort 1: 8 x 0.1 mL/syringe/subject 
• Cohort 2: 16 x 0.1 mL/syringe/subject 
• Cohort 3: 24 x 0.1 mL/syringe/subject 
• Cohort 4: 36 x 0.1 mL/syringe/subject 
One vial may be used for dosing of two subjects that are dosed together.  Dosing of both subjects 
will be within a maximum of 4 hours.  If only one subject is to be dosed, a single vial will be 
administered to that subject.  Breached vials will not be re-used for other subjects.  Each vial 
must be placed back into the container.  All open vials must be kept until the end of the study for 
the Sponsor to decide either to discard or return to the Sponsor. 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE 
The RZL-012 investigational product was manufactured by PharmaCore (USA) and complies 
with cGMP requirements.  Formulation and packing was done by Nextar (Israel) and complies 
with cGMP requirements. 
The vehicle was manufactured and packed by FusionRx (USA) and complies with cGMP 
requirements. 
The RZL-012 investigational product and vehicle will be supplied in kits, in quantities as needed 
to comply with the treatment of site subjects according to the study protocol. 
Site coordinator will notify the Sponsor or its official designee, in a timely manner and no less 
than 14 working days in advance, of any supply requirements to prevent shortage. 
Shipment, storage and inventory documentation will be updated regularly and kept in the 
investigation files at the site to allow inspection and trace of the supplied product.  


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9. 
ADVERSE EVENTS 
9.1. 
ADVERSE EVENT DEFINITIONS 
9.1.1. Definition of Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  This definition includes any abnormalities or anomalies that were not seen at 
baseline or which worsened during the course of the study, if present at baseline. 
9.1.2. Definition of Serious Adverse Event 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes:  
• death  
• a life-threatening AE, as defined below  
• subject hospitalization or prolongation of existing hospitalization  
• a persistent or significant disability/incapacity  
• a congenital anomaly/birth defect  
• important medical event, as defined below  
A life-threatening AE is any AE that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred (i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death).  
An important medical event is an AE that may not result in death, be life-threatening, or require 
hospitalization but may be considered a serious AE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above.  It can also include AEs otherwise judged to be serious by 
either the investigator or the Sponsor. 
9.1.3. Definition of Adverse Drug Reaction 
AEs associated with the use of investigational product (i.e., probably or possibly related to 
treatment as defined in Section 9.3) are also termed Adverse Drug Reactions (ADRs). 
9.2. 
ADVERSE EVENT GRADING 
AE will be documented and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 June 14, 2010) (10).  


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AE that do not appear in the CTCAE will be graded as follows:  
• Mild (Grade 1):  Sign or symptom, usually transient, requiring no special treatment and 
generally not interfering with usual activities.  
• Moderate (Grade 2):  Sign or symptom, which may be ameliorated by simple therapeutic 
measures, may interfere with usual activity.  
• Severe (Grade 3):  Sign or symptom that is intense or debilitating and that interferes with 
usual activities and/or requires hospitalization.  Recovery is usually aided by therapeutic 
measures and the discontinuation of the study product may be required.  
• Life-threatening or disabling (Grade 4):  Sign or symptom that is Life-threatening or 
disabling.  
• Death (Grade 5):  Death related to AE 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS (AEs) 
All AEs will be evaluated by the investigator and assigned an estimated relationship to the 
RZL-012 investigational product.  The terms "probable", "possible", "unlikely", or "unrelated" 
refer to the association with the use of the investigational product, as defined below in Table 4.  
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, confounding factors such as concomitant 
medication, concomitant diseases and relevant history.  
Assessment of causal relationship should be recorded directly in subjects CRF. 
Definition of AEs causality is specified in the table below (Table 4). 
Table 4:  Definition of Causality 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated  
This category applies to those AEs 
which, after careful consideration, 
are clearly due to extraneous 
causes (disease, environment, etc.) 
 
Unlikely 
Related 
In general, this category can be 
considered applicable to those 
AEs, which after careful medical 
consideration at the time they are 
evaluated, are judged to be 
unrelated to the study procedures/ 
investigational product. 
An AE may be considered unlikely related if or when (must 
have two):  
▪ It does not follow a reasonable temporal sequence from the 
study procedures/administration of the investigational 
product.  
▪ It could readily have been produced by the subject’s clinical 
state, environmental or toxic factors, or other modes of 
therapy administered to the subject.  
▪ It does not follow a known pattern of response to the study 
procedures/investigational product. 
Possibly 
Related 
This category applies to those AEs 
for which, after careful medical 
consideration at the time they are 
An AE may be considered possibly related if or when (at least 
two of the following):  


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TERM 
DEFINITION 
CLARIFICATION 
evaluated, a connection with the 
study procedures/investigational 
product administration appears 
unlikely but cannot be ruled out 
with certainty. 
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ A causal relationship to the experimental treatment cannot 
necessarily be reasonably excluded and an alternative 
explanation (e.g., concomitant investigational product or 
concomitant disease) cannot be reasonably suggested as 
causing the treatment emergent AE  
▪ It follows a known pattern of response to the study 
procedures/ investigational product. 
Probably 
Related  
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with a high 
degree of certainty to be related to 
the study 
procedures/investigational 
product. 
An AE may be considered probably related if or when (at least 
three of the following):  
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to 
the subject.  
▪ It disappears or decreases on cessation or reduction in dose.  
There are important exceptions when an adverse event does 
not disappear upon discontinuation of the investigational 
product, yet investigational product-relatedness clearly 
exists.  
▪ It follows a known pattern of response to the study 
procedures/investigational product. 
Definitely 
Related 
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with definite 
certainty to be related to the study 
procedures/investigational 
product. 
An AE may be considered definitely related if or when all of the 
following apply:  
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to 
the subject.  
▪ It disappears or decreases on cessation or reduction in dose.  
There are important exceptions when an adverse event does 
not disappear upon discontinuation of the investigational 
product, yet investigational product-relatedness clearly 
exists.  
▪ It follows a known pattern of response to the study 
procedures/investigational product. 
*In this protocol Unlikely is deemed as Unrelated.  
9.4. 
UNEXPECTEDNESS OF ADVERSE DRUG REACTIONS 
An ADR is considered unexpected when its nature or severity is not consistent with the 
applicable product information (i.e., RZL-012 Investigator's Brochure). 


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9.5. 
ADVERSE EVENT REPORTING AND MONITORING REQUIREMENTS 
9.5.1. General 
All adverse events, serious and non-serious, will be fully documented in both source documents 
and CRFs as described in Section 6.1.16, and each AE will be assessed in light of its clinical 
significance.  For each adverse event, the investigator will provide the onset, end, intensity, 
treatment required, outcome, seriousness and action taken with the investigational drug.  The 
investigator will determine the relationship to the investigational drug, i.e., causality assessment, 
for each AE.  
Any AE occurring prior to initiation of first dose, after initiation of the first dose and or during 
any point throughout the study should be recorded on the Adverse Event page of the CRF.  All 
adverse events occurring until subject is terminated from the study (28 days after the injection of 
RZL-012 and in the highest dose cohort until 6 months from injection of RZL-012), should be 
captured in the CRF.  AEs should be recorded in the CRF using the medical terminology found 
in the source documentation.  Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology. 
Occurrence of any Grade 4 and Grade 3 or 4 ADR must warrant clinical evaluation by the 
treating investigator and reported to the Sponsor within 7 calendar days.  
ADRs graded > 1 will be followed-up until resolution, or for a maximal duration of 6 months 
after RZL-012 injection, whichever occurs first. 
9.5.2. SAE Reporting 
The PI or his designee must report to the Sponsor any SAE occurring after injection of the study 
treatment, regardless of their relationship to the investigational product.  
Sponsor contact details for SAE reporting:  
Sharon Perles, sharon.perles@raziel-therapy.com, fax: 972-2-625-0901. 
An initial report must be faxed or emailed to sharon.perles@raziel-therapy.com, fax: 972-2-625-
0901 within 24 hours of becoming aware of the event and must include SAE general description, 
start date, end date (if applicable), the reason for evaluation as a SAE, basic subject information, 
assessment of the relationship to the investigational product, expectedness, and study therapy 
information.  
Follow-up information, including outcome, and treatment shall be faxed or emailed within 
48 hours.  Source documents to support the SAE (e.g., discharge summary, test results) shall be 
included in the report.  


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A complete SAE report must be sent to the Sponsor at the first possible date and no later than 
7 calendar days after SAE end date.  In addition to the information described in the initial report, 
this report will include AE common terminology criteria (CTC) description and grading, 
treatment given (if applicable), SAE outcome, an assessment of the relationship to the 
investigational product, and expectedness.  
SAE will be recorded on designated CRF forms in a timely manner and no later than 7 calendar 
days after its end date.  
The PI or his designee will submit the SAE report to IRB/EC according to applicable local 
regulations and will update the Sponsor. 
9.5.3. Expedited Reporting 
Expedited reporting by PI to IRB/EC is warranted for all Suspected Unexpected Serious Adverse 
Reactions (SUSAR), i.e., unexpected SAEs that are considered related to study product as 
defined in Sections 9.1.2, 9.1.3, and 9.4).  Additional cases will be communicated by PI to 
IRB/EC via expedited reporting when required by local regulation.  
Expedited reports will be submitted to the applicable regulatory authorities by the Sponsor or 
designee within the required timelines according to local regulations.  
Any pregnancy of a partner of a study male subject after dosing is considered an immediately 
reportable event.  
Such events must be reported within one (1) working day of the investigator becoming aware of 
the event.  Pregnancies shall be followed for the duration of the pregnancy.  It is the PI’s 
responsibility to provide to the Sponsor follow-up information on the outcome of the pregnancy 
including information about any sequelae. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. STUDY DESIGN AND OBJECTIVE 
The purpose of this phase 2a study is to find the tolerated dose that provides the largest 
thermogenic effect. 
The study is designed as a randomized, double-blind, two-arm clinical trial.  Eligible subjects 
will be randomized to receive either RZL-012 or placebo (vehicle).  In this feasibility study, 
different parameters of efficacy assessment will be measured in the all dose groups for a 
maximum period of up to 6 months.  Subject follow-up for safety will be up to 112 days after 
treatment administration for the two lower doses cohorts and up to 168 days after treatment 
administration for the last two highest dose cohorts or up to 112 as the first 2 cohorts in case of 
termination before visit Day 112. 


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10.2. STUDY ENDPOINTS 
10.2.1. Primary Safety Endpoint 
The main objective is the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat.  Therefore, the primary safety endpoint will be the incidence of intolerable side 
effects and all adverse events of RZL-012 injection into the subcutaneous fat.  The dose 
escalation scheme will be stopped if at any dose cohort, 2 patients will experience intolerable 
side effects. 
10.2.2. Primary Efficacy Endpoint 
The primary endpoint for efficacy is a significant thermogenesis at the injected site compared 
with the contra-lateral, non-injected site.  This was monitored by sensitive (± 0.1 °C) Infra-Red 
thermal camera.  A thermogenic effect is defined by an increase of 1 °C in the injected site when 
compared to the surroundings and/or the non-injected site, apparent at least 28 days after 
injection and non-related to inflammatory response as determined by inflammatory cytokines.  
The primary efficacy evaluation will be supported by results from secondary endpoints, 
including MRI, biopsy and biomarkers 
10.2.3. Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• Duration of the thermogenic effect, defined as a net-delta ≥ 1.  
• Local reduction in fat mass as determined by MRI. 
• Clinical laboratory changes from baseline in: 
o Fasting blood glucose, 
o Triglycerides (TG),  
o High-density lipoprotein (HDL), 
o Low-density lipoprotein (LDL),  
o Total-cholesterol (TC), and  
o Free-fatty-acids (FFA). 
• 
Pharmacokinetic profile for RZL-012. 
• Anthropometric changes from baseline in:  
o Body weight, 
o BMI,  
o Waist circumference, and 


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o WHR. 
• Change from baseline in inflammatory markers and cytokines: 
o CRP,  
o Adiponectin,  
o CD-163,  
o Interleukin (IL)-1β,  
o IL-4, IL-6,  
o IL-10,  
o IL12p70,  
o IL-13,  
o IL-23,  
o Tumor necrosis factor (TNF) α and  
o TGFβ1. 
• Elucidation of the histological changes account for the thermogenic effect by biopsy of 
the injection site. 
10.2.4. Safety and Tolerability Endpoints 
Safety endpoints include: 
• Incidence of AEs and SAEs, by severity and relation to study treatment.  AEs will be 
coded using MedDRA version 19.1 (or higher).  
• Physical examination (including Draize score)  
• Vital signs  
• Blood laboratory tests  
• ECG 
10.3. SAMPLE SIZE JUSTIFICATION 
This study is planned as a dose escalation study following a 6 subjects per dose group paradigm 
with the addition of a 2 subjects vehicle control group for the 2 all doses.  A maximum of 32 
evaluable subjects will be included in the study (24 in the RZL-012 treatment arm and 8 in the 
placebo arm) and followed for as long as 3 months in the 2 lowest dose cohorts, and in the 2 
highest dose cohorts for up to 5 months. 


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10.4. ANALYSIS SETS 
10.4.1. Safety Analysis Set (SA) 
The safety analysis set (SA) will consist of all enrolled subjects who received the study 
treatment, either RZL-012 or placebo (exposed population), including subjects prematurely 
withdrawn. 
All enrolled subjects receiving at least one study drug injection are considered evaluable for the 
SA set. 
10.4.2. Efficacy Analysis Set (EF) 
The efficacy (EF) will consist of all subjects from the SA analysis set without any major protocol 
violations measured at baseline.  Subjects will be analyzed according to the treatment received. 
10.4.3. PK (PKA) Analysis Set 
The PK analysis set will consist of all subjects with no major deviations related to study drug 
administration (e.g., incomplete injection of study drug). 
10.4.4. Statistical Analysis of Analysis Sets 
The SA analysis set will serve as the principal data analysis set for the analyses of the safety 
endpoints. 
The EF analysis set will serve as the principal data analysis set for the analyses of the efficacy 
endpoints. 
The PK analysis set will serve as the principal data analysis set for the PK analysis. 
10.5. STATISTICAL ANALYSIS 
10.5.1. General  
Statistical analysis will be performed using SAS V9.4 or higher (SAS Institute, Cary NC, USA). 
Statistical analyses will be mainly descriptive in nature where study data will be tabulated and 
summarized using the mean, standard deviation or standard error, median, minimum, maximum 
and number of subjects by cohort for continuous data.  For categorical data, results will be 
summarized via a count and percentage by cohort.  The effects of noncompliance, dropouts, and 
covariates, may be assessed to determine the impact on the general applicability of results from 
this study. 


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If any statistical tests are performed, they will be two-sided.  The required significance level of 
findings will be equal to or lower than 5%.  Nominal p-values will be presented. 
Where confidence limits are appropriate, the confidence level will be 95%. 
10.5.2. Subject Disposition 
A detailed description of subject accountability including count of subjects included, 
randomized, exposed, completed (i.e., subjects who complete the study treatment) and 
discontinued along with the main reason for discontinuation will be generated for each cohort 
and for all subjects.  All withdrawals from the study, taking place on or after study drug 
injection, will be fully documented in the body of the Clinical Study Report. 
Note that the actual study duration is for a period of maximum 6 months, with efficacy analyses 
being conducted at 28 days and 56 days for all dose levels and up to 6 months for the 3rd and 4th 
cohorts or for the highest dose level achieved. 
10.5.3. Demographic and Baseline Characteristics 
Baseline will be defined as the last available and evaluable parameter value before and closest to 
the injection.  If a rechecked value is used for baseline, it should be collected under the same 
conditions as for the planned baseline (e.g., fasting condition). 
Baseline safety data will be presented along with subsequent safety values assessed during or 
after dosing. 
10.5.4. Primary Safety Endpoint 
The incidence of intolerable side effects will be presented by treatment overall and by cohort 
along with two sided 95% exact binomial Confidence Interval (CI). 
The incidence of all adverse events will be presented by treatment overall and by cohort along 
with two sided 95% exact binomial Confidence Interval (CI). 
10.5.5. Efficacy Analysis 
The average temperature will be presented in a tabular form by visit, site (treated / not treated) 
and treatment received (RZL-012 / placebo) by cohort and overall.  Difference between the sites 
(treated – not treated) will be presented in a tabular form by visit treatment along with the change 
from baseline (net-delta) in these differences by cohort and overall. 
Non-parametric tests will be used to compare the net-delta between the study arms for the 
relevant cohorts and visits. 


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The number and percent of subjects with a thermogenic effect, defined as a net-delta ≥ 1, will be 
presented by cohort and visit for the subjects in the active arm.  The duration of the thermogenic 
effect after the Day 28 visit, for subjects in the active arm with thermogenic effect at the Day 28 
visit will be presented. 
Subcutaneous Fat Mass (SFM) ratio (treated sites / control sites) averaged over the MRI slices 
will be presented in tabular form by visit, treatment and cohort.  The change from baseline in this 
ratio (in % from the ratio at baseline) will be presented in the same manner, and compared 
between the treatment arms with non-parametric tests. 
Changes from baseline in fasting blood glucose, lipid profile, anthropometric changes, 
inflammatory markers and cytokines will be presented by visit, treatment, and cohort. 
Histology results will be presented in tabular form by treatment. 
10.5.6. Pharmacokinetics (PK) Assessment 
PK profile will be assessed as described below, and presented in a tabular form.  Individual PK 
parameters will also be presented in a listing. 
PK profile will be assessed by: Cmax, Tmax (time of maximum observed sample concentration) 
and if appropriate AUC values for the test article and from concentration-time data. 
Based on the data, appropriate parameters will be estimated and may include, C0/Dose and/or 
Cmax/Dose, AUC(Tlast) (area under the concentration-time curve from time zero to the time of final 
quantifiable sample), AUC(0-t) (area under the concentration-time curve from time zero to t, 
where t denotes a specific sample time following dosing), and AUC/Dose.  Based on the data, 
additional secondary parameters will be calculated, if appropriate, and include, AUCINF (area 
under the concentration-time curve from time zero extrapolated to infinity), and T1/2 (terminal 
half-life). 
10.5.7. Safety and Tolerability 
Safety analyses will be descriptive in nature.  
All reported adverse events will be coded to a standard set of terms using MedDRA coding 
dictionary (V19.1 or higher) treatment.  
AEs and tolerability data will be presented descriptively by treatment and cohort.  AEs will be 
tabulated by body system, preferred term, seriousness, severity and relation to study drug by 
cohort.  Where applicable, changes in values over time (e.g., lab values, vital signs, 
electrocardiograms [ECGs]) will be presented, this will include clinical laboratory evaluations 
(including CBC, blood chemistry and urinalysis), coagulation (INR, PTT, PT), cytokines, vital 
signs, and ECGs.  Shift tables of normal / abnormal versus baseline may be presented as well.  


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Draize scores will be presented in tabular format by visit, treatment, and cohort. 
10.6. HANDLING OF MISSING DATA 
No imputation of missing data will be performed. 
10.7. INTERIM ANALYSIS 
An interim analysis is planned at the end of each cohort for evaluation of efficacy. For this 
purpose, a data lock (except for externally collected data such as PK) will be implemented after 
each cohort is completed. Upon lack of trends in efficacy due to effect size, the Sponsor will 
consider study termination. 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
11.1. DATA COLLECTION AND REPORTING 
Each study subject will be assigned an individual CRF that will contain all of the relevant study 
information.  The investigator shall ensure that all data is completely and accurately recorded on 
the CRFs throughout trial duration.  
Data reported on the CRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained.  
All fields and blanks in the CRFs will be completed.  The following abbreviations are to be used 
when values or answers are not available: NA = Not applicable, ND = Not done, UNK = 
Unknown, CONT = Continued.  
White-out or erasure on the CRF is not permitted under any circumstances.  Any change or 
correction to a CRF should be dated, initialed, and explained (if necessary) and should not 
obscure the original entry (i.e., an audit trail should be maintained).  If an entry on a CRF form is 
changed, the correction will be made as follows:  A single line will be drawn through the 
incorrect entry, the date and initials of the reporting individual will be added beside the entered 
change and/or correction, and an explanation will be added when applicable.  
When a subject withdraws from the study, regardless of cause, all final study evaluations should 
be attempted.  
If a subject is lost to follow-up, (i.e., fails to return for scheduled visits) every reasonable effort 
must be made to contact the subject in order to determine why the subject failed to return.  All 
actions taken in this regard will be documented and dated in the CRF.  
Once completed, a copy of each completed CRF will be signed and dated by the investigator or a 
designated representative and submitted to the Sponsor. 


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11.2. RECORD KEEPING 
The investigator will maintain all records for this study including medical records, laboratory 
reports, informed consent forms, safety reports, subjects' CRF, and any other pertinent data.  All 
records are to be retained by the investigator for a period of fifteen years after completion of the 
study. 
11.3. SOURCE DATA AND SOURCE DOCUMENTS 
ICH-GCP defines source data as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies).  
Source documents are defined as original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, subject files, and records kept at departments 
involved in the clinical trial, etc.).  
The following data is to be recorded directly on the RZL-012 trial forms or CRF which will be 
considered to be the source data:  
• Subjects' weight diaries. 
• Subjects' questioning, e.g., pain, itching, topical antihistamine application.  
• Assessment of AEs relation to investigational product, i.e., causality assessment, and 
expectedness reported by investigator. 
The investigator should maintain the trial's essential documents as required by ICH-GCP 
guidelines and the applicable regulatory requirements, and take measures to prevent accidental or 
premature destruction of these documents.  
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the investigator will 
ensure direct access all requested trial-related records. 
11.4. STUDY MONITORING 
Monitoring procedures are required to assure compliance to ICH-GCP guidelines, the study 
protocol and local regulations.  
The investigator shall allow the Sponsor or its official designee to monitor and audit periodically, 
at mutually convenient times, all CRF and corresponding subject records.  The monitoring 
schedule will be based on Sponsor’s monitoring plan and will be done by competent monitors 
per GCP by either Sponsor personnel or sponsor’s designee such as CRO. 


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11.5. CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION 
In order to protect subject confidentiality, a consecutive identification number will be attributed 
to each subject enrolled to the trial.  In order to avoid identification errors, this number and 
subject’s initials (first letter of first name and the first letters of surname) will identify the subject 
and must be included on all CRFs.  The investigator will complete subject identification on a 
confidential site log, which will be used for subjects' traceability and follow-up.  
Individual subject medical information obtained as a result of this study is to be considered 
confidential and disclosure to third parties other than the regulatory authorities, or other persons 
or organizations designated by the Sponsor, is prohibited.  Any medical information may be 
provided to the subject’s personal physician or to appropriate medical personnel responsible for 
the subject’s care.  Additionally, data generated from this study is to be provided, upon request, 
to the Sponsor’s monitors, as well as to the local IRB/EC.  Subject confidentiality is to be further 
assured by utilizing subject identification code numbers to identify subject data.  
All information supplied by Raziel Therapeutics Ltd. in connection with this study and not 
previously published, is considered confidential information.  This information includes, but is 
not limited to, the Investigators' Brochure, clinical protocol, CRF, and other scientific data.  Any 
data collected during the study are also considered confidential.  This confidential information 
shall remain the sole property of Raziel Therapeutics Ltd, shall not be disclosed to others without 
the written consent of the Sponsor, and shall not be used except in the performance of this study.  
The information developed during the conduct of this clinical study is also considered 
confidential, and will be used by the Sponsor in connection with the development of the product.  
The information may be disclosed as deemed necessary by the Sponsor.  To allow the use of the 
information derived from this clinical study, the investigator is obliged to provide Raziel 
Therapeutics Ltd. with complete test results and all data developed in this study.  
The Sponsor has full ownership of the original case report forms completed as part of the study.  
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement.  
The information obtained during this study may be made available to other investigators who are 
conducting similar studies.  
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol.  
Raziel Therapeutics Ltd. will disclose the results of the trial on the basis of the final analysis and 
following the revision of a draft manuscript by the investigators, unless posting would 
compromise publication in a peer-reviewed medical journal or contravene national laws or 


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regulations.  Study results may also be disclosed through presentations and abstract submissions 
at professional scientific meetings. 
12. 
HUMAN SUBJECTS 
12.1. DECLARATION OF HELSINKI 
Both the PI and the Sponsor will ensure that the study is conducted in agreement with the 
Declaration of Helsinki, ICH Guideline for Good Clinical Practice (ICH-GCP), and the local 
laws and regulation. 
12.2. INFORMED CONSENT 
As described in Section 6.1.1. 
12.2.1. LIABILITY AND INSURANCE CONDITIONS 
Raziel Therapeutics Ltd. holds a clinical trial liability insurance policy.  
A copy of the policy summary will be filled in the investigator's site file. 
13. 
REFERENCES 
1. WHO. Obesity and overweight 2013 [Available from: 
http://www.who.int/mediacentre/factsheets/fs311/en/index.html. 
2. Cannon B, Nedergaard J. Nonshivering thermogenesis and its adequate measurement in 
metabolic studies. The Journal of experimental biology. 2011;214(Pt 2):242-53. 
3. Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different 
functions? Endocrinology. 2013;154(9):2992-3000. 
4. Ukropec J, Anunciado RP, Ravussin Y, Hulver MW, Kozak LP. UCP1-independent 
thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice. The Journal of biological 
chemistry. 2006;281(42):31894-908. 
5. Liu X, Rossmeisl M, McClaine J, Riachi M, Harper ME, Kozak LP. Paradoxical resistance to 
diet-induced obesity in UCP1-deficient mice. The Journal of clinical investigation. 
2003;111(3):399-407. 
6. Kozak LP, Anunciado-Koza R. UCP1: its involvement and utility in obesity. International 
journal of obesity. 2008;32 Suppl 7:S32-8. 
7. Huttunen P, Hirvonen J, Kinnula V. The occurrence of brown adipose tissue in outdoor 
workers. European journal of applied physiology and occupational physiology. 1981;46(4):339-
45. 


Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.4 
RZL-012 
 
Version: 1.4 
 
26 May 2017 
76 
CONFIDENTIAL 
8. Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, et al. Adiponectin Enhances Cold-Induced 
Browning of Subcutaneous Adipose Tissue via Promoting M2 Macrophage Proliferation. Cell 
metabolism. 2015;22(2):279-90. 
9. CDC. Abthropometric Procedure Manual of the National Health and Nutrition Examination 
Survey 2009-2010 [Available from: http://www.cdc.gov/nchs/nhanes/nhanes2009-
2010/current_nhanes_09_10.htm. 
10. NIH. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 2010 
[Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
 


Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.3 
RZL-012 
 
Version: 1.3 
 
26 May 2017 
77 
CONFIDENTIAL 
Appendix I:  Trial Schedule of Events 
Study Procedure 
Screening 
Day 1 
Screening 
Day 2 
Clinic 
Admission 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 28) 
Follow-up 
Schedule for 
the highest 
dose cohorts l 
(Days 29 - 168) 
Study Daya 
Daya-(-
28) 
through 
Day (-7) 
Daya-(-14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 56, 84, 
112, 140, 168 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
Complete physical 
exam 
X 
 
 
 
 
 
 
 
 
X 
 
Serology assays 
(HBV, HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
Fasting glucose 
X 
 
X 
 
 
 
 
 
 
 
 
Fasting glucose, 
insulin, leptin and 
lipid profile 
(including FFA) 
 
 
X 
 
 
 
 
 
 
X 
Every 28 days 
Inflammatory markers 
and Cytokines - In 
subject of the 2nd, 3rd 
and 4th  cohorts b 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Photography of site of 
injection and 
contralateral 
X 
 
 
 
X 
 
X 
X 
X 
X 
Every 28 days 
MRI section around 
the umbilicus 
 
X 
 
 
 
 
 
 
 
X 
 
MRI section around 
the umbilicus – for 
cohort 2 
 
 
 
 
 
 
 
 
 
 
On Day 56 


Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.3 
RZL-012 
 
Version: 1.3 
 
26 May 2017 
78 
CONFIDENTIAL 
Study Procedure 
Screening 
Day 1 
Screening 
Day 2 
Clinic 
Admission 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 28) 
Follow-up 
Schedule for 
the highest 
dose cohorts l 
(Days 29 - 168) 
Study Daya 
Daya-(-
28) 
through 
Day (-7) 
Daya-(-14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 56, 84, 
112, 140, 168 
MRI section around 
the umbilicus – for 3rd 
and 4th cohort or in 
cohort 2 if 2  subject 
experience intolerable 
side effects in cohort 
3) 
 
 
 
 
 
 
 
 
 
 
Every 28 days 
Anthropometric 
measurements: 
(weight, height) BMI, 
(waist & hip 
circumference) WHR 
X 
X 
X 
 
 
 
 
 
 
X 
Every 28 days 
Weight – by the 
subjects at home –
morning(8-12hr 
overnight fast) and 
evening 
 
 
 
 
 
 
X 
X 
X 
 
On weeks when 
not visiting the 
site 
Urine Drug Screen 
X 
 
X 
 
 
 
 
 
 
 
 
Infra-Red thermal 
imaging of the 
injected site 
X 
 
X 
 
X 
 
X 
X 
X 
X 
On Day 56 


Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.3 
RZL-012 
 
Version: 1.3 
 
26 May 2017 
79 
CONFIDENTIAL 
Study Procedure 
Screening 
Day 1 
Screening 
Day 2 
Clinic 
Admission 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 28) 
Follow-up 
Schedule for 
the highest 
dose cohorts l 
(Days 29 - 168) 
Study Daya 
Daya-(-
28) 
through 
Day (-7) 
Daya-(-14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 56, 84, 
112, 140, 168 
Infra-Red thermal 
imaging of the 
injected site -for 3rd 
and 4th cohort or in 
cohort 2 if 2 subjects 
experience intolerable 
side effects will in 
cohort 3)k 
 
 
 
 
 
 
 
 
 
 
Every 28 days 
Serum Chemistry, 
Hematology c 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Histamine levelsd 
 
 
X 
 
X 
X 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
X 
 
Pharmacokinetics f 
 
 
 
Pre e X post 
e 
X 
 
 
 
 
 
 
Draize score at the 
injected site g 
X 
 
 
Pre e X post e 
X 
 
X 
X 
X 
X 
Every 28 days 
Vital signs h 
X 
 
 
Pre e X post e 
X 
 
X 
X 
X 
X 
 
Injection of RZL-012 
 
 
 
X 
 
 
 
 
 
 
 
ECG i 
X 
 
 
X post e 
X 
 
 
X 
 
X 
 
Pulse rate j 
 
 
 
Pre e X post 
e 
X 
 
 
 
 
 
 
Adverse event 
assessment 
 
 
 
 
X-------------------------------------------------→ 
Every 28 days 


Raziel Therapeutics, Ltd. 
 
Protocol RZL-012-P2aUS-001.3 
RZL-012 
 
Version: 1.3 
 
26 May 2017 
80 
CONFIDENTIAL 
Study Procedure 
Screening 
Day 1 
Screening 
Day 2 
Clinic 
Admission 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 28) 
Follow-up 
Schedule for 
the highest 
dose cohorts l 
(Days 29 - 168) 
Study Daya 
Daya-(-
28) 
through 
Day (-7) 
Daya-(-14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Day 56, 84, 
112, 140, 168 
Adverse event 
assessment by phone 
for cohorts 1 and 2 
 
 
 
 
 
 
 
 
 
 
On Day 84 and 
112 
Subjects diary 
recording weight 
 
 
 
 
 
 
X 
X 
X 
 
On weeks when 
not visiting the 
site 
Biopsy – 
In subject of cohort 3 
(or in cohort 2 if 2 
subjects experience 
intolerable side 
effects in cohort 3)k,l 
 
 
 
 
 
 
 
 
 
 
On Day 56 
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
b. 
Inflammatory markers and cytokines from the 2nd, 3rd and 4th cohorts (on 6 RZL-012 treated and 2 placebo treated subjects in each cohort): CRP, Adiponectin, CD-163, 
Interleukin [IL]-1β, IL-4, IL-6, IL-10, IL12p70, IL-13, IL-23, Tumor necrosis factor [TNF] α and TGFβ1. 
c. 
CBC, coagulation, serum chemistry analysis, renal and liver function , urinalysis, CPK, amylase measurement: before injection,14d and 28d following injection 
d. 
Histamine blood level measurement: clinical admission, following drug injection (24h ± 2h), 3d and 14d following injection 
e. 
Pre/post – refers to before/after injection respectively 
f. 
Pharmacokinetics at the given time points: 0, 30, 60 min, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 30h in subjects from all cohorts. Pharmacokinetics will not be conducted in the 
fourth cohort as the injected dose is divided in 2 clusters 2 weeks apart. 
g. 
Draize score evaluation: before injection, 2h, 24h and 7d,14d,21d and 28d following injection 
h. 
Vital signs measurement: before injection, 2h, 24h and 7d,14d,21d and 28d following injection 
i. 
ECG is to be performed in triplicate for all measurements in given time point:  4h, 12h, 24h, Day 14 and 28 following injection 
j. 
Pulse rate measurements at given time points: 1h, 2h, 4h, 8h, 12h, 24h following injection in the opposite hand of blood sampling 
k. 
For 3 subjects of cohort 3 (in cohort 2 if 2 subjects experience intolerable side effects in cohort 3) - if thermogenesis is evident by thermal camera by Day 56, biopsy from the 
injected for histology and BAT characterization. 
l. 
For subjects from the 3rd (or in cohort 2 if 2 subjects will experience intolerable side effects within the 3rd cohort) and 4th cohort 
 

SAP_001.pdf: 
 
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Revision History 
 
Revision 
Revision Date 
Reason for Revision/Change Request 
Revised By 
1.0 
14-March-2018 
Original Release 
Daniel Manas, DMS 
2.0  
14-Nov-2018 
Updated version 
Daniel Manas, DMS 
 
 
 


 
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Final Statistical Analysis Plan 
 
A Double Blind, Randomized, Placebo Controlled, 
Dose Escalation Phase 2a Clinical Trial for the 
Evaluation of Safety and Thermogenesis-induction of 
RZL-012 in Overweight and Obese Volunteers 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
1. 
DEFINITIONS AND/OR ABBREVIATIONS ...................................................................... 4 
2. 
PURPOSE ............................................................................................................................. 10 
3. 
SCOPE .................................................................................................................................. 10 
4. 
RESPONSIBILITIES ........................................................................................................... 11 
5. 
PROCEDURE ....................................................................................................................... 12 
6. 
RELATED DOCUMENTS (optional) .................................................................................. 27 
7. 
RELATED FORMS (optional) ............................................................................................. 27 
8. 
REFERENCES ..................................................................................................................... 28 
9. 
Appendices (optional) ........................................................................................................... 28 
9.1 
APPENDIX I: TABLE SHELLS ................................................................................... 28 
9.2 
APPENDIX II: LISTINGS SHELLS ............................................................................. 30 
 


 
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SIGNATURES PAGE 
 
Daniel Manas, author  
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 
 
 
 
Daphna Goffer, reviewer 
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date:  
 
 
 
Rachel Gueta 
Raziel Therapy Ltd.                                                                         Date:  
 
 
 


 
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1. DEFINITIONS AND/OR ABBREVIATIONS  
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
ATP 
Adenosine triphosphate 
AUC 
Area under the concentration-time curve 
BAT 
Brown-like adipose tissue 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CBC 
Complete blood count 
CDC 
Center for Disease Control 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence Interval 
CK-MM 
Creatine Kinase - Muscle 
Cmax 
Maximum observed concentration 
CNS 
Clinically not significant 
CRF 
Case Report Form 
CPK 
Creatine phosphokinase 
CRP 
C-reactive protein 


 
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CS 
Clinically significant 
CTC 
Common terminology criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DICOM 
Digital Imaging and Communications in Medicine 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Efficacy analysis set 
ER 
Emergency room 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIFO 
First In First Out 
FLASH 
Fast-low-angle shot 
FOB 
Functional Observational Battery 
GLP 
Good Laboratory Practice 
GTTP 
Gamma-glutamyltransferase 
HBV 
Hepatitis B virus 
HCRC 
Hadassah Clinical Research Center 
HCV 
Hepatitis C virus 
H&E 
Hematoxylin and eosin stain 
HDL 
High-density lipoprotein 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
IC50 
Half maximal inhibitory concentration 


 
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ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical Practice 
IFN 
Interferon 
IL 
Interleukin 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDL 
Low-density lipoprotein 
LDH 
Lactate dehydrogenase 
LPL 
Lipoprotein lipase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP 
Monocyte chemoattractant protein 
MCV 
Mean corpuscular volume 
MD 
Medical Doctor 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MPV 
Mean platelet volume 
MRI 
Magnetic Resonance Imaging 
NHANES 
National Health and Nutrition Examination Survey 
NOAEL 
No observed adverse effect level 
NSAIDs 
Non Steroid Anti-Inflammatory Drugs 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKA 
PK Analysis set 
PT 
Prothrombin time 


 
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PTT 
Partial thromboplastin time 
QA 
Quality Assurance 
RBC 
Red blood cells 
RDW 
Red cell distribution width 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SAT 
Subcutaneous adipose tissue 
SC 
Subcutaneous 
SFM 
Subcutaneous fat mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Terminal half-life 
TAG 
Triacylglycerols 
TBD 
To be determined 
TC 
Total Cholesterol 
TG 
Triglycerides 
TGF 
Transforming growth factor 
Tmax 
Time of maximum observed sample concentration 
TNF 
Tumor necrosis factor 
UCP1 
Uncoupling protein 1 
ULN 
Upper limit of normal 
US/USA 
United States/United States of America 


 
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WAT 
White adipose tissue 
WBC 
White blood cells 
WHO 
World health organization 
WHR 
Waist to hip ratio 
 


 
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2. PURPOSE 
2.1 The purpose of this document is to describe in detail the Statistical Analysis Plan of clinical study 
procedures carried out by Medistat Ltd.  
2.2 This document serves Medistat Ltd. as a guiding document for all statistical analyses performed at 
the end of each clinical study. 
2.3 This SAP is specific to Raziel Therapeutics LTD, study RZL-012-P2aUS-001.4 
2.4 This SAP aims to provide details on: sample size calculation, efficacy analyses and safety analyses. 
3. SCOPE 
3.1 This document applies to all members of the statistical & data management units in Medistat Ltd.  
3.2 This document includes the main and interim study trial analysis. 


 
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4. RESPONSIBILITIES 
4.1 Medistat Ltd. Responsibilities  
The following personnel are responsible for these activities: 
Activities 
Responsible and 
accountable 
Title 
Statistical Analysis Plan 
(SAP) 
Daniel Manas 
Senior Biostatistician 
& SAS Programmer 
Statistical Report and listing 
appendix 
Daniel Manas 
Senior Biostatistician 
& SAS Programmer 
Quality Assurance (QA)  of 
SAP and programs 
David Israel 
Senior Biostatistician 
& SAS Programmer 
Quality Assurance (QA)  of 
final report 
Shimrit Herbst 
Quality & Data 
Assurance Manager 
 
4.2 Raziel’s Responsibilities 
4.2.1 To review and approve the SAP and related documents prior to database lock. 
4.2.2 To review and approve the draft and final statistical report and listing appendix. 
 


 
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5. PROCEDURE  
5.1 Introduction 
5.1.1 
This Statistical Analysis Plan (SAP) is based on the study protocol final version V1.4, dated 
4 March, 2018. 
5.1.2 
This Statistical Analysis Plan (SAP) contains details of the statistical analyses that will be 
performed, providing a more detailed description of the approach defined in the study 
protocol. Definitions of variables and populations used for the analyses are also included. 
The SAP will be finalized and signed prior to hard lock of the database. 
5.1.3 
General output specifications are provided; examples are given of calculations of derived 
variables. 
5.2 Rationale 
5.2.1 
The purpose of this study is to test safety and efficacy of a new chemical entity, RZL-012, 
in converting WAT into a thermogenic tissue and reducing fat-mass in overweight and 
obese males 
5.2.2 
RZL-012 investigational drug is intended for a single dose in multiple injections into the 
subcutaneous fat.  The injection dosing regimen and technique is crucial for the therapy 
safety and efficacy.  The RZL-012 drug is a ready to use liquid to be injected to the 
subcutaneous fat, supplied in a 1 vial kit.  1 vial contains 250 mg/4.8 mL RZL-012 in 
formulation F12.  The vehicle is a ready to use liquid to be injected to the subcutaneous fat, 
supplied in a 1 vial kit.  1 vial contains 4.8 mL of formulation F12. 
5.3 Study Objectives and Endpoints 
5.3.1 
Primary Objectives: 
5.3.2 
Evaluation of the overall safety and preliminary efficacy of RZL-012 after injection into 
the subcutaneous fat. 
5.3.3 
Primary Endpoints 


 
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5.3.4 
Safety: The main objective is the evaluation of the overall safety of RZL-012 injection into 
the subcutaneous fat.  Therefore, the primary endpoint will be the incidence of intolerable 
side effects and all adverse events of RZL-012 injection into the subcutaneous fat.  The 
dose escalation scheme will be stopped if at any dose cohort, 2 patients will experience 
intolerable side effects. 
5.3.5 
Efficacy:  The primary endpoint for efficacy is a significant thermogenesis at the injected 
site compared with the contra-lateral, non-injected site.  This was monitored by sensitive 
(± 0.1 °C) Infra-Red thermal camera.  A thermogenic effect is defined by an increase of 1 
°C in the injected site when compared to the surroundings and/or the non-injected site, 
apparent at least 28 days after injection and non-related to inflammatory response as 
determined by inflammatory cytokines.  The primary efficacy evaluation will be supported 
by results from secondary endpoints, including MRI, biopsy and biomarkers 
5.3.6 
Secondary Objectives: 
5.3.7 
Determination of RZL-012 pharmacodynamics and pharmacokinetics.  Evaluation of the 
existence of a thermogenic effect and the extent, duration and tissue associated changes of 
the thermogenic response to RZL-012, via minimal invasive means (injected-site 
thermogenesis imaging, Magnetic Resonance Imaging (MRI) and biopsy) after 
subcutaneous injection into fatty tissue below the skin.   
5.3.8 
Secondary Endpoints 
5.3.9 
Duration of the thermogenic effect, defined as a net-delta ≥ 1 
5.3.10 Local reduction in fat mass as determined by MRI. 
5.3.11 Clinical laboratory changes from baseline including improvement in fasting blood glucose 
and lipid profile. 
5.3.12 Establishing pharmacokinetic profile for RZL-012. 
5.3.13 Anthropometric changes from baseline, including body weight change. 
5.3.14 Elucidation of the histological changes account for the thermogenic effect by biopsy of the 
injection site. 
5.3.15 Change from baseline in inflammatory markers and cytokines. 
5.4 Overall study design and plan 


 
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5.4.1 
Study Design  
5.4.2 
This is a consecutive 4 cohort, dose escalation placebo-controlled clinical trial in 
overweight and obese subjects.  All cohorts will be comprised of 6 active (RZL-012) and 
2 placebo subjects.   
5.4.3 
Within each cohort, dosing of the first 3 subjects will progress consecutively from one 
individual to the other at 7-day intervals.  For additional precaution, the first 3 subjects will 
be forced randomized into 2 active and 1 control.  This study design will allow the 
physicians to monitor safety in a two subjects at each dose, nevertheless the blindness will 
remain intact.  The remaining subjects in a cohort will be randomized to either active 
treatment or placebo in a ratio determined by the number of subjects targeted for each 
cohort.  Dosing of the next subjects will be in couples and the last subjects will be in a 
triplet.  
5.4.4 
Schedule of Assessments 
Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Signed 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
X 
 
 
 
 
 
 
 
 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Complete 
physical exam 
X 
 
 
 
 
 
 
 
 
X 
 
Serology 
assays (HBV, 
HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
Fasting 
glucose 
X 
 
X 
 
 
 
 
 
 
 
 
Fasting 
glucose, 
insulin, leptin 
and lipid 
profile 
(including 
FFA) 
 
 
X 
 
 
 
 
 
 
X 
Every 
28 days 
Inflammatory 
markers and 
Cytokines - In 
subject of the 
2nd, 3rd and 4th  
cohorts b 
 
 
X 
 
 
 
X 
X 
X 
X 
 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Photography 
of site of 
injection and 
contralateral 
X 
 
 
 
X 
 
X 
X 
X 
X 
Every 
28 days 
MRI section 
around the 
umbilicus 
 
X 
 
 
 
 
 
 
 
X 
 
MRI section 
around the 
umbilicus – for 
cohort 2 
 
 
 
 
 
 
 
 
 
 
On Day 
56 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
MRI section 
around the 
umbilicus – for 
3rd and 4th 
cohort or in 
cohort 2 if 2  
subject 
experience 
intolerable side 
effects in 
cohort 3) 
 
 
 
 
 
 
 
 
 
 
Every 
28 days 
Anthropometri
c 
measurements: 
(weight, 
height) BMI, 
(waist & hip 
circumference) 
WHR 
X 
X 
X 
 
 
 
 
 
 
X 
Every 
28 days 
Weight – by 
the subjects at 
home –
 
 
 
 
 
 
X 
X 
X 
 
On 
weeks 
when 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
morning(8-
12hr overnight 
fast) and 
evening 
not 
visiting 
the site 
Urine Drug 
Screen 
X 
 
X 
 
 
 
 
 
 
 
 
Infra-Red 
thermal 
imaging of the 
injected site 
X 
 
X 
 
X 
 
X 
X 
X 
X 
On Day 
56 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Infra-Red 
thermal 
imaging of the 
injected site -
for 3rd and 4th 
cohort or in 
cohort 2 if 2 
subjects 
experience 
intolerable side 
effects will in 
cohort 3)k 
 
 
 
 
 
 
 
 
 
 
Every 
28 days 
Serum 
Chemistry, 
Hematology c 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Histamine 
levelsd 
 
 
X 
 
X 
X 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
X 
 
Pharmacokinet
ics f 
 
 
 
Pre e X 
post e 
X 
 
 
 
 
 
 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Draize score at 
the injected 
site g 
X 
 
 
Pre e X 
post e 
X 
 
X 
X 
X 
X 
Every 
28 days 
Vital signs h 
X 
 
 
Pre e X 
post e 
X 
 
X 
X 
X 
X 
 
Injection of 
RZL-012 
 
 
 
X 
 
 
 
 
 
 
 
ECG i 
X 
 
 
X post e 
X 
 
 
X 
 
X 
 
Pulse rate j 
 
 
 
Pre e X 
post e 
X 
 
 
 
 
 
 
Adverse event 
assessment 
 
 
 
 
X----------------------------------
---------------→ 
Every 
28 days 
Adverse event 
assessment by 
phone for 
cohorts 1 and 2 
 
 
 
 
 
 
 
 
 
 
On Day 
84 and 
112 


 
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Study 
Procedure 
Screening
Day 1 
Screeni
ng Day 
2 
Clinic 
Admissi
on 
Baseline 
(Treatme
nt) 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Schedu
le for 
the 
highest 
dose 
cohorts 
l (Days 
29 - 
168) 
Study Daya 
Daya-(-
28) 
throug
h Day 
(-7) 
Daya-(-
14) 
through 
Day (-2) 
Day (-1) 
Day a 0 
Da
y 1 
Da
y 3 
Da
y 7 
Day 
14 
Da
y 
21 
Da
y 
28 
Day 56, 
84, 112, 
140, 
168 
Subjects diary 
recording 
weight 
 
 
 
 
 
 
X 
X 
X 
 
On 
weeks 
when 
not 
visiting 
the site 
Biopsy – 
In subject of 
cohort 3 (or in 
cohort 2 if 2 
subjects 
experience 
intolerable side 
effects in 
cohort 3)k,l 
 
 
 
 
 
 
 
 
 
 
On Day 
56 
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
b. 
Inflammatory markers and cytokines from the 2nd, 3rd and 4th cohorts (on 6 RZL-012 treated and 2 placebo treated subjects 
in each cohort): CRP, Adiponectin, CD-163, Interleukin [IL]-1β, IL-4, IL-6, IL-10, IL12p70, IL-13, IL-23, Tumor necrosis 
factor [TNF] α and TGFβ1. 
c. 
CBC, coagulation, serum chemistry analysis, renal and liver function , urinalysis, CPK, amylase measurement: before 
injection,14d and 28d following injection 
d. 
Histamine blood level measurement: clinical admission, following drug injection (24h ± 2h), 3d and 14d following injection 
e. 
Pre/post – refers to before/after injection respectively 
f. 
Pharmacokinetics at the given time points: 0, 30, 60 min, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 30h in subjects from the 1st, 2nd 
and 3rd  cohorts. Pharmacokinetics will not be conducted in the fourth cohort as the injected dose is divided in 2 clusters 2 
weeks apart. 


 
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g. 
Draize score evaluation: before injection, 2h, 24h and 7d,14d,21d and 28d following injection 
h. 
Vital signs measurement: before injection, 2h, 24h and 7d,14d,21d and 28d following injection 
i. 
ECG is to be performed in triplicate for all measurements in given time point:  4h, 12h, 24h, Day 14 and 28 following 
injection 
j. 
Pulse rate measurements at given time points: 1h, 2h, 4h, 8h, 12h, 24h following injection in the opposite hand of blood 
sampling 
k. 
For 3 subjects of cohort 3 (in cohort 2 if 2 subjects experience intolerable side effects in cohort 3) - if thermogenesis is 
evident by thermal camera by Day 56, biopsy from the injected for histology and BAT characterization. 
l. 
For subjects from the 3rd (or in cohort 2 if 2 subjects will experience intolerable side effects within the 3rd cohort) and 4th 
cohort 
 
 


 
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5.4.5 
Randomization, Blinding and Un-blinding 
5.4.6 
Subjects will be randomized to each study group, i.e., investigational therapy or control, 
left side injection or right side injection according to a predefined randomization scheme.  
The investigational therapy group will be treated with RZL-012 and the control group will 
be treated with the same formulation (vehicle) as with RZL-012, absent active medication  
5.4.7 
Masking will be used to blind the Investigator regarding randomization, i.e., assignment to 
study group will be disclosed only after subject eligibility is confirmed and immediately 
before treatment initiation.  The pharmacist will be unmasked and will be responsible to 
fill the syringes for injection. 
5.5 Selection of study population 
5.5.1 
Study Population 
5.5.2 
Male subjects 
5.5.3 
Age 20 - 60 years old 
5.5.4 
The study population include subjects who are obese by Body Mass Index (BMI) 
definition (27.5 < BMI ≤ 34.9) 
5.5.5 
Rationale Sample Size Calculation 
5.5.6 
The planned sample size is 32 subjects (8 in each cohort). 6 subjects per dose group 
paradigm with the addition of a 2 subjects per control group for all doses.  A maximum of 
32 evaluable subjects will be included in the study (24 in the RZL-012 treatment arm and 
8 in the placebo arm) and followed for as long as 3 months in the 2 lowest dose cohorts, 
and in the 2 highest dose cohorts for up to 5 months.  
5.6 Statistical Analysis Software and Data Management 
5.6.1 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed using SAS® version 9.3 or higher for 
Windows. If the use of other software is warranted, the final statistical methodology report 
will detail what software was used for what purposes. 
5.6.2 
Data Management 
5.6.3 
Data management for the study is performed by Spaulding Clinical. 
5.6.4 
Medical Coding 


 
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5.6.5 
Concomitant medications entered into the database  are coded using the WHO (World 
Health Organization) Drug Public Website Dictionary named WHOCC-ATC/DDD 
index, which employs the Anatomical Therapeutic Chemical classification system.  
5.6.6 
Adverse events are coded using the most updated version of Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. 
5.6.7 
Medical history events are coded using the most updated version of Medical Dictionary 
for Regulatory Activities (MedDRA) terminology 
5.6.8 
Handling of Missing data 
5.6.9 
No imputation of missing data will be performed 
5.6.10 Protocol Violations and Deviations  
5.6.11 Departures from the protocol should be avoided unless required for the safety of the 
subject. Protocol deviations and, if possible, the reason for occurrence will be documented 
by the study monitor and included in the final clinical study report.  
5.6.12 The Investigator must report any protocol deviation to the Sponsor and, if required, to the 
IRB/IEC in accordance with local regulations, within reasonable time.  All violations and 
deviations must be recorded in the study site’s electronic system and signed by the 
Investigator (or designee). 
5.7 Subject Population for analyses 
5.7.1 
The safety analysis set (SA) will consist of all enrolled subjects who received the study 
treatment, either RZL-012 or placebo (exposed population), including subjects 
prematurely withdrawn.  All enrolled subjects receiving at least one study drug injection 
are considered evaluable for the SA set. 
5.7.2 
The SA analysis set will serve as the principal data analysis set for the analyses of the safety 
endpoints. 
5.7.3 
The efficacy analysis set (EF) will consist of all subjects from the SA analysis set without 
any major protocol violations measured at baseline  
5.7.4 
The EF analysis set will serve as the principal data analysis set for the analyses of the 
efficacy endpoints. 


 
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5.7.5 
The PK analysis set will consist of all subjects with no major deviations related to study 
drug administration (e.g., incomplete injection of study drug). 
5.7.6 
The PK analysis set will serve as the principal data analysis set for the PK analysis 
5.8 Statistical Analysis 
5.8.1 
General 
5.8.2 
All measured variables and derived parameters will be listed individually and, if 
appropriate, tabulated by descriptive statistics. For categorical variables summary tables 
will be provided giving sample size, absolute and relative frequency. For continuous 
variables summary tables will be provided giving sample size, arithmetic mean, standard 
deviation, standard error, coefficient of variation (CV%), median, minimum and 
maximum of variables, and 95% confidence intervals of means. 
5.8.3 
The data  is analyzed using the SAS ® version 9.3 or higher (SAS Institute, Cary North 
Carolina). Analyses presented in the clinical report but not mentioned in the SAP are 
unplanned or ad-hoc analyses. 
5.8.4 
Statistical methods presented in the SAP may be slightly different from those that are 
presented in the protocol. Differences are clearly stated and the SAP supersedes the 
protocol only with regard to the way data will be handled and analysed. 
5.8.5 
Derived Data 
5.8.6 
Definition of baseline 
5.8.7 
Baseline is defined as the last non-missing value prior to the patient start of treatment 
(screening or baseline visit). 
5.8.8 
End of Study  
5.8.9 
The end-of-study visit is defined as Day 168.  
5.8.10 Disposition of subjects (Table 14.1-1 – 14.1.2) 
5.8.11 The number of subjects that are randomized into the study, the number of subjects in the 
Safety, efficacy analysis set, and PK populations, and the number of study completers will 
be presented. 
5.8.12 The reasons for early termination/ withdrawal will be summarized. 
 


 
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5.8.13 Demographic and Baseline data (Tables 14.1-3 -14.1-4) 
5.8.14 Baseline and demographic data will be summarized in appropriate tables using the Safety 
population. The data includes demographic characteristics (age and gender) and medical 
history. 
5.8.15 Efficacy Analysis  
5.8.1 
The primary endpoint for efficacy is a significant thermogenesis at the injected site 
compared with the contra-lateral, non-injected site. 
5.8.2 
The average temperature will be presented in a tabular form by visit, side (treated / not 
treated) and treatment received (RZL-012 / placebo) by cohort and overall.  Difference 
between the sides (treated – not treated) will be presented in a tabular form by visit 
treatment along with the change from baseline (net-delta) in these differences by cohort 
and overall. 
5.8.3 
Kruskal-Wallis will be used to compare the net-delta between the study arms for the 
relevant cohorts and visits. 
5.8.4 
The number and percent of subjects with a thermogenic effect, defined as a net-delta ≥ 1, 
will be presented by cohort and visit for the subjects in the active arm.  The duration of the 
thermogenic effect after the Day 28 visit, for subjects in the active arm with thermogenic 
effect at the Day 28 visit will be presented. 
5.8.5 
Subcutaneous Fat Mass (SFM) ratio (treated sites / control sites) averaged over the MRI 
slices will be presented in tabular form by visit, treatment and cohort.  The change from 
baseline in this ratio (in % from the ratio at baseline) will be presented in the same manner, 
and compared between the treatment arms with Kruskal-Wallis test.  
5.8.6 
Changes from baseline in fasting blood glucose, lipid profile, anthropometric changes, 
inflammatory markers and cytokines will be presented by visit, treatment, and cohort. 
5.8.7 
Histology results will be presented in tabular form by treatment for relevant subjects. 
5.8.8 
Safety analysis 
5.8.9 
Safety data will be summarized for the Safety population.  
5.8.10 Adverse events will be coded according to coding dictionaries (the most updated version 
of  MedDRA) and presented in tables by System Organ Class (SOC) and Preferred Term 
(PT) and by treatment group.  


 
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5.8.11 The incidence of AEs, as well as the intensity and relationship to study drug will be 
summarized by treatment group. 
5.8.12 The incidence of all adverse events will be presented by treatment overall and by cohort 
along with two sided 95% exact binomial Confidence Interval (CI). 
5.8.13 The incidence of intolerable side effects will be presented by treatment overall and by 
cohort along with two sided 95% exact binomial Confidence Interval (CI). 
5.8.14 Concomitant medication verbatim terms (as recorded on the CRFs) will be coded to 
Anatomical Therapeutic Chemical (ATC) Level 2 and 4 using the World Health 
Organization (WHO) dictionary. 
5.8.15 Interim Analysis 
5.8.16 An interim analysis is planned at the end of each cohort for evaluation of efficacy. For this 
purpose, a data lock (except for externally collected data such as PK) will be implemented 
after each cohort is completed. Upon lack of trends in efficacy due to effect size, the 
Sponsor will consider study termination 
 
 
 
 
 
 
 
 
6. RELATED DOCUMENTS (OPTIONAL) 
6.1 Study Protocol:  RZL-012-P2aUS-001.4_track changes 04 Mrch 2018 
6.2 Randomization plan: RZL-012-P2aUS random plan final version 1.0 01-08-2017.pdf 
 
7. RELATED FORMS (OPTIONAL) 
Not Applicable 


 
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8. REFERENCES 
Not Applicable 
9. APPENDICES (OPTIONAL) 
9.1 APPENDIX I: TABLE SHELLS 
14.1 Demographic Data 
Table 14.1-1: Disposition of Subjects 
Table 14.1-2: Analysis populations 
Table 14.1-3: Demographic Data 
Table 14.1-4: Medical History 
14.2 Efficacy Assessment 
14.2.1 Primary Safety Endpoint 
Table 14.2.1-1: Summary of Thermal Imaging per visit 
Table 14.2.1-2: Summary of Thermal Imaging Changes per visit 
P-value for difference between groups 
Table 14.2.1-3: Frequency of Thermogenic Effect 
Table 14.2.1-4: Duration of Thermogenic Effect 
Table 14.2.1-5: Summary of MRI Results 
14.2.2 PK Assessments  
Table 14.2.2-1: Summary Statistics of RZL-012 Concentrations (ng/mL) by Treatment and time 
(hours) 
Table 14.2.2-2: Summary of RZL-012 PK Parameters by Treatment 
14.3 Safety Data 
14.3.1 Adverse Events 
Table 14.3.1-1: Frequency of Any Adverse Events 
Table 14.3.1-2: Frequency of any intolerable side effects 
Table 14.3.1-3: Summary of Adverse Events by SOC and PT by treatment 
Table 14.3.1-4: Summary of Adverse Events by SOC, PT, severity, and by treatment 
14.3.2 Other safety Assessments 


 
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Table 14.3.2-1: Summary of Vital signs 
Table 14.3.2-2: Changes from baseline - Vital signs 
Table 14.3.2-3: Summary of Chemistry 
Table 14.3.2-4: Changes from baseline – Chemistry 
Table 14.3.2-5: Summary of Hematology 
Table 14.3.2-6: Changes from baseline – Hematology 
Table 14.3.2-7: Summary of Coagulation 
Table 14.3.2-8: Changes from baseline – Coagulation 
Table 14.3.2-9: Summary of Glucose 
Table 14.3.2-10: Changes from baseline - Glucose 
Table 14.3.2-11: Summary of Lipids 
Table 14.3.2-12: Changes from baseline - Lipids 
Table 14.3.2-13: Summary of Plasma 
Table 14.3.2-14: Changes from baseline - Plasma 
Table 14.3.2-15: Summary of Serum 
Table 14.3.2-16: Changes from baseline – Serum 
Table 14.3.2-17: Summary of Urinalysis 
Table 14.3.2-18: Changes from baseline - Urinalysis 
Table 14.3.2-19: Summary of Urinalysis - Categorical results 
Table 14.3.2-20: Summary of Serology at Screening 
Table 14.3.2-21: Summary of Drug Screening 
Table 14.3.2-22: Summary of ECG Results 
Table 14.3.2-23: Changes from baseline - Urinalysis 
Table 14.3.2-24: Summary of Draize Score 
Table 14.3.2-25: Summary of Physical Examination 
Table 14.3.2-26: Any concomitant medications 
 
 
 
 
 


 
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9.2 APPENDIX II: LISTINGS SHELLS 
16.2.1 Subject Disposition 
Listing 16.2.1-1: Subject Disposition 
Listing 16.2.1-2: Visit dates per subject 
16.2.2 Protocol Deviations 
Listing 16.2.2-1: Inclusion/Exclusion Criteria 
16.2.3 Subjects Excluded from the Efficacy Analysis 
Listing 16.2.3-1: Subjects Excluded from the Efficacy and PK Analysis 
16.2.4 Demographic Data and Baseline Assessments 
Listing 16.2.4-1: Demographic Data 
Listing 16.2.4-2: Medical History 
16.2.5 Compliance/Exposure/Drug Concentration Data 
Listing 16.2.5-1: Index Procedure 
16.2.6 Individual Efficacy/PK/PD Response Data 
Listing 16.2.6-1: PK Collection 
Listing 16.2.6-2: Thermogenesis results 
Listing 16.2.6-2: RZL-012 Concentration (ng/mL) by Subject, Treatment and Time 
Listing 16.2.6-3: RZL-012 PK Parameters by subject and Treatment 
Listing 16.2.6-5: MRI results 
16.2.7 Adverse Events 
Listing 16.2.7-1: Adverse Events 
16.2.8 Laboratory and other safety parameters 
Listing 16.2.8-1: Chemistry 
Listing 16.2.8-2: Hematology 
Listing 16.2.8-3: Coagulation 
Listing 16.2.8-4: Urinalysis 
Listing 16.2.8-5: CK, Total+Isoenzymes, and Serum 
Listing 16.2.8-6: Plasma 
Listing 16.2.8-7: Glucose 
Listing 16.2.8-8: Lipids 


 
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Listing 16.2.8-9: Drugs of Abuse 
Listing 16.2.8-10: Serology 
Listing 16.2.8-11: Vital Signs 
Listing 16.2.8-12: ECG Findings 
Listing 16.2.8-13: ECG Quantitative Results 
Listing 16.2.8-14: Abnormal Physical Examination 
Listing 16.2.8-15: Draize Assessment 
Listing 16.2.8-16: Concomitant Medications