Clinical trial NCT04086823
Conditions: Submental Fat
Sponsor: Raziel Therapeutics Ltd.
Start date: 2020-02-25; Completion date: 2020-09-16
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Twenty-Eight (28) subjects (12 for cohort 1 and 16 for cohort 2 ) will be included in the study. Subjects in each cohort will be injected with a different dose of RZL-012. The total of 28 subjects will be enrolled in 2 clinical sites.

Detailed description:
This is a single blinded, randomized, placebo-controlled, 2-cohort clinical study in healthy volunteers. Cohort 1 will be comprised of 8 active (RZL-012) and 4 placebo subjects. Cohort 2 will be comprised of 16 subjects wuth at least 4 placebo subjects. All subjects will receive a single dose of RZL-012 or vehicle into the submental area, after which they will be monitored for safety and efficacy during 84 days of follow-up.

Subjects will be blinded to study treatment while physicians will not be blinded.

The study will be composed of 2 treatment cohorts, 12 in cohort 1 and 16 in cohort 2.

The study will be conducted in 2 clinical sites. Per each study cohort, subjects will be randomized to receive active or placebo treatment according to a randomization program that will be prepared prior to study initiation. Each clinical site will have at least one active and one placebo treatment subject per each study cohorts. In case of slow enrollment in one of the sites, other sites may complete the enrollment of subjects in each cohort.

Cohort 1 (N=12) - Each subject will be dosed with up to 120 mg RZL-012 (depending on submental fat area) or vehicle.

Cohort 2 (N=16) - Each subject will be dosed with up to 240 mg RZL-012 (depending on submental fat area) or vehicle.

Treatment of cohort 2 will start following cohort 1 day 28 data. An independent Data Safety Monitoring Board (DSMB) will review safety and tolerability data for cohort 1 subjects, 28 days after injection, and decide whether it is safe to increase the dose for the next study cohort. The decision to proceed to the cohort 2 will be made within 30 days (28 days + 2 days) after injection of the last dosed subject in cohort 1.

The DSMB will be comprised of two independent MDs with expertise in the aesthetic area and in conduction of clinical trials.

In case of serious safety concerns (e.g. prolonged severe swelling or severe pain following injection) among cohort 1 subjects receiving the 120mg dose, sponsor and DSMB may decide to reduce or stay with the 120mg/subject dose level for cohort 2 subjects.

Arms: arm 1: A single-treatment injection, multiple subcutaneous injections of RZL-012 administered into 48 sites in the submental fat (0.05/0.1mL per site):

1. Up to 120mg administered at 48 sites in a volume of 0.05 ml at each injection site (total injected volume 2.4mL)
2. Up to 240 mg administered at 48 sites in a volume of 1 ml at each injection site (total volume injected 4.8mL) arm 2: Subject receive a single-treatment injection. Multiple injections of the Placebo are administered at 48 sites (0.05/0.1mL per site) into the submental fat.

Up to a total of 2.4 mL will be injected for placebo subjects enrolled during cohort 1.

Up to a total of 4.8 mL will be injected for placebo subjects enrolled during cohort 2.
Interventions: intervention 1: RZL-012 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection to the submental fat area intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
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RZL-012 Study Protocol 
Protocol Number RZL-012-SMF-P2aUS-001 
 
A Single Blind, Randomized, Placebo-controlled, Phase 2, 2-cohort Study for the 
Evaluation of Efficacy and Safety of RZL-012 for Submental Fat Reduction in Healthy 
Volunteers 
Principal Investigator: 
Dr. Steven Dayan 
Sponsor: 
Raziel Therapeutics 
Prof. Menachem Plaut 10 
Rehovot, Israel 760000 
 
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, except for disclosure to the appropriate Institutional 
Review Board and/or Regulatory Authority under the condition that confidentiality 
is maintained 
Protocol Date:  05 September 2019 
 
Version 1:  05 September 2019 
 
Version 1.1: 02 December 2019 
Version 1.2: 06 April 2020 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
STATEMENT OF COMPLIANCE .................................................................................................8 
INVESTIGATOR SIGNATURE PAGE .........................................................................................9 
PROTOCOL SYNOPSIS ..............................................................................................................10 
1. 
INTRODUCTION ......................................................................................................15 
1.1. 
BACKGROUND ........................................................................................................15 
1.1.1. 
Scientific Background and Clinical Rationale ............................................................15 
1.1.2. 
RZL-012 Formulation Development ..........................................................................16 
1.2. 
NONCLINICAL ASSESSMENTS ............................................................................16 
1.2.1. 
Pharmacology .............................................................................................................16 
1.2.1.1. 
Efficacy In-vivo Studies .............................................................................................17 
1.2.1.2. 
Safety Pharmacology ..................................................................................................18 
1.2.2. 
Toxicology ..................................................................................................................18 
1.2.2.1. 
Extended Single Dose Toxicity Studies .....................................................................18 
1.2.3. 
Additional Nonclinical Studies ...................................................................................19 
1.2.4. 
Clinical Studies ...........................................................................................................19 
2. 
PURPOSE AND STUDY OBJECTIVES ..................................................................27 
2.1. 
PURPOSE ...................................................................................................................27 
2.2. 
STUDY OBJECTIVES ..............................................................................................27 
2.2.1. 
Primary .......................................................................................................................27 
2.2.2. 
Secondary ...................................................................................................................27 
3. 
STUDY DESIGN .......................................................................................................27 
3.1. 
DESCRIPTION OF STUDY DESIGN ......................................................................27 
3.2. 
DOSE RATIONALE ..................................................................................................28 
3.3. 
DOSING .....................................................................................................................28 
3.3.1. 
Dosing Regimen .........................................................................................................28 
3.3.2. 
Serious Adverse Events Considered Related to the Investigational Drug ..................30 


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4. 
STUDY ENDPOINTS ................................................................................................31 
4.1. 
PRIMARY ENDPOINTS ...........................................................................................31 
4.2. 
SECONDARY ENDPOINTS .....................................................................................31 
5. 
STUDY POPULATION .............................................................................................32 
5.1. 
INCLUSION CRITERIA ...........................................................................................32 
5.2. 
EXCLUSION CRITERIA ..........................................................................................32 
5.3. 
SUBJECT IDENTIFICATION ..................................................................................33 
5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF 
SUBJECTS FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE 
EFFECTS ....................................................................................................................34 
6. 
STUDY PROCEDURES AND ASSESSMENT ........................................................34 
6.1. 
DEFINITIONS OF STUDY PROCEDURES ............................................................34 
6.1.1. 
Informed Consent .......................................................................................................34 
6.1.2. 
Medical History ..........................................................................................................34 
6.1.3. 
Concomitant Medication ............................................................................................35 
6.1.4. 
Physical Examination .................................................................................................35 
6.1.5. 
Weight Measurement ..................................................................................................36 
6.1.6. 
Vital Signs Measurements ..........................................................................................36 
6.1.7. 
Draize Score ................................................................................................................36 
6.1.8. 
2D Standardized Photography ....................................................................................37 
6.1.9. 
MRI .............................................................................................................................37 
6.1.10. 
Subject’s Satisfaction Rating following Treatment ....................................................38 
6.1.11. 
Physician’s Evaluation of Improvement .....................................................................39 
6.1.12. 
Pregnancy Test ............................................................................................................39 
6.1.13. 
Submental Fat Thickness using Calipers ....................................................................39 
6.1.14. 
Adverse Events ...........................................................................................................40 
6.1.15. 
Evaluation of Response ..............................................................................................41 
6.1.15.1. 
Evaluation of Primary Endpoints................................................................................41 
6.1.15.2. 
Evaluation of Secondary Endpoints............................................................................42 
6.1.15.3. 
Compliance Monitoring ..............................................................................................42 
6.1.15.4. 
Dispensing of RZL-012 Investigational Product ........................................................42 
6.1.15.5. 
Questioning of Study Subjects ....................................................................................43 
6.2. 
STUDY VISITS..........................................................................................................43 


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6.2.1. 
Screening Procedures ..................................................................................................43 
6.2.2. 
Study Randomization ..................................................................................................43 
6.2.3. 
Study Treatment ..........................................................................................................44 
6.2.3.1. 
Treatment with RZL-012 Investigational Drug to Submental Fat..............................44 
6.2.4. 
Treatment with Placebo ..............................................................................................46 
6.2.5. 
Baseline Visit ..............................................................................................................46 
6.2.6. 
Subject Site Visits .......................................................................................................47 
6.2.7. 
Termination Visit ........................................................................................................47 
6.2.8. 
Unscheduled Visit .......................................................................................................48 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR 
INVESTIGATORS .....................................................................................................48 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT 
MEDICATIONS .........................................................................................................48 
7.2. 
SAFETY MEASUREMENTS....................................................................................48 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY............................................49 
7.4. 
PREMATURE STUDY TERMINATION .................................................................49 
7.5. 
DEVIATION FROM STUDY PROTOCOL..............................................................49 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS ................50 
8.1. 
DESCRIPTION OF RZL-012 ....................................................................................50 
8.2. 
FORMULATION, PACKAGING AND LABELING ...............................................50 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE .................................50 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND 
VEHICLE ...................................................................................................................51 
8.4.1. 
Dosage ........................................................................................................................51 
8.4.2. 
Administration and Instructions for Use .....................................................................51 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE ...............................................51 
9. 
ADVERSE EVENTS..................................................................................................52 
9.1. 
ADVERSE EVENT DEFINITIONS ..........................................................................52 
9.1.1. 
Definition of AE .........................................................................................................52 
9.1.2. 
Definition of Serious Adverse Event ..........................................................................52 
9.1.3. 
Definition of Adverse Drug Reaction .........................................................................53 
9.2. 
ADVERSE EVENT GRADING ................................................................................53 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS .........................................53 


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9.4. 
UNEXPECTEDNESS OF ADVERSE DRUG REACTIONS ...................................54 
9.5. 
ADVERSE EVENT REPORTING AND MONITORING 
REQUIREMENTS .....................................................................................................54 
9.5.1. 
General ........................................................................................................................54 
9.5.2. 
SAE Reporting ............................................................................................................55 
9.5.3. 
Expedited Reporting ...................................................................................................55 
10. 
STATISTICAL CONSIDERATIONS .......................................................................56 
10.1. 
STUDY DESIGN AND OBJECTIVE .......................................................................56 
10.2. 
STUDY ENDPOINTS ................................................................................................57 
10.2.1. 
Primary Safety Endpoints ...........................................................................................57 
10.2.2. 
Secondary Efficacy Endpoints ....................................................................................57 
10.2.3. 
Safety and Tolerability Endpoints ..............................................................................57 
10.3. 
SAMPLE SIZE JUSTIFICATION .............................................................................57 
10.4. 
ANALYSIS SETS ......................................................................................................58 
10.4.1. 
Safety Analysis Set (SA) ............................................................................................58 
10.4.2. 
Efficacy Analysis Set (EF) .........................................................................................58 
10.4.3. 
Statistical Analysis of Analysis Sets...........................................................................58 
10.5. 
STATISTICAL ANALYSIS ......................................................................................58 
10.5.1. 
General ........................................................................................................................58 
10.5.2. 
Subject Disposition .....................................................................................................59 
10.5.3. 
Demographic and Baseline Characteristics ................................................................59 
10.5.4. 
Primary Safety Endpoint .............................................................................................59 
10.5.5. 
Efficacy Analysis ........................................................................................................59 
10.5.6. 
Safety and Tolerability ...............................................................................................59 
10.6. 
HANDLING OF MISSING DATA ............................................................................60 
10.7. 
INTERIM ANALYSIS ...............................................................................................60 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE ............................................................................................................60 
11.1. 
DATA COLLECTION AND REPORTING ..............................................................60 
11.2. 
RECORD KEEPING ..................................................................................................61 
11.3. 
SOURCE DATA AND SOURCE DOCUMENTS ....................................................61 
11.4. 
STUDY MONITORING ............................................................................................61 
11.5. 
CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION ...................62 


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12. 
HUMAN SUBJECTS .................................................................................................63 
12.1. 
DECLARATION OF HELSINKI ..............................................................................63 
12.2. 
INFORMED CONSENT ............................................................................................63 
12.2.1. 
LIABILITY AND INSURANCE CONDITIONS ......................................................63 
13. 
REFERENCES ...........................................................................................................63 
 
LIST OF TABLES 
Table 1:  Overview of Ongoing and Completed Clinical Studies .................................................20 
Table 2:  Study Design ...................................................................................................................29 
Table 3:  Grading scales of bruising and induration ......................................................................41 
Table 4:  Subject Information and Timeframes .............................................................................47 
Table 5:  RZL-012 Storage Conditions ..........................................................................................50 
Table 6:  Definition of Causality ...................................................................................................54 
 
LIST OF FIGURES 
Figure 1:  Injection Sites for Phase 0 Study ...................................................................................21 
Figure 2:  Injection Sites for Phase 2A Study ................................................................................23 
Figure 3:  Injections Diagram According to Lipomas Size ...........................................................25 
Figure 4:  Injection Scheme Lipedema Subjects............................................................................25 
Figure 5:  Scheme of Injection Pattern that will be used by the Physician to Inject into 
the Submental Fat Area in Both Study Cohorts..........................................................29 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
ADR 
Adverse drug reaction 
AE 
Adverse event 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EF 
Efficacy analysis set 
FDA 
Food and Drug Administration 
GLP 
Good Laboratory Practice 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical 
Practice 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No observed adverse effect level 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QOL 
Quality of life 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SFM 
Subcutaneous fat mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US/USA 
United States/United States of America 
 


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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 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 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-SMF-P2aUS-001 
Protocol Title 
A Single Blind, Randomized, Placebo-controlled, Phase 2a, 2-cohort Study for the Evaluation 
of Safety and Efficacy of RZL-012 for Submental Fat Reduction in Healthy Volunteers. 
Study Phase 
Phase 2a 
Study Drug 
RZL-012 
Study 
Objectives 
Primary objective:  
To evaluate the safety of RZL-012 subcutaneous injections in the submental area, relative to 
placebo, as assessed by spontaneous adverse event reports and post injection evaluation of 
subjects by treating physician. 
 
Secondary objectives: 
To evaluate the efficacy of RZL-012 subcutaneous injections in the submental area, relative to 
placebo, by: 
1. Evaluation of treatment efficacy by using Physician’s global assessment 
questionnaire, on study days 28, 56 and 84 
2. Reduction from baseline in submental fat volume, as measured by MRI 
3. Improvement in subject’s satisfaction rating score of the FACE-Q questionnaire on 
study days 28, 56 and 84 vs. baseline 
Sample Size 
Twenty-Eight (28) subjects (12 for cohort 1 and 16 for cohort 2) will be included in the study. 
Subjects in each cohort will be injected with a different dose. The total of 28 subjects will be 
enrolled in 2 clinical sites. 
Study Design 
This is a single blinded, randomized, placebo-controlled, 2-cohort clinical study in healthy 
volunteers. Cohort 1 will be comprised of 8 active (RZL-012) and 4 placebo subjects. Cohort 
2 will be comprised of 16 subjects that will be randomized for active treatment and placebo. 
All subjects will receive a single dose of RZL-012 or vehicle into the submental area, after 
which they will be monitored for safety and efficacy during 84 days of follow-up. 
All subjects per cohort will be randomized to either active treatment or placebo at a ratio of 
2:1 per cohort.   
Subjects will be blinded to study treatment while physicians will not be blinded. 
The study will be composed of 2 treatment cohorts, 12 in cohort 1 and 16 in cohort 2. 
The study will be conducted in 2 clinical sites.  
In cohort 1, a total of 12 subjects and in cohort 2 a total of 16 subjects will be randomized to 
receive active or placebo treatment (2:1) according to a randomization program that will be 
prepared prior to study initiation. Each clinical site will have at least one active and one 
placebo treatment subject per each study cohorts. In case of slow enrollment in one of the 
sites, other sites may complete the enrollment of subjects in each cohort. 
Cohort 1 (N=12) – Each subject will be dosed with up to 120 mg RZL-012 (depending on 
submental fat area) or vehicle.   
Cohort 2 (N=16) – Each subject will be dosed with up to 240 mg RZL-012 (depending on 
submental fat area) or vehicle.  
Treatment of cohort 2 will start following cohort 1 day 28 data. An independent Data Safety 
Monitoring Board (DSMB) will review safety and tolerability data for cohort 1 subjects, 
28 days after injection, and decide whether it is safe to increase the dose for the next study 
cohort. The decision to proceed to the cohort 2 will be made within 30 days (28 days + 
2 days) after injection of the last dosed subject in cohort 1.   
The DSMB will be comprised of two independent MDs with expertise in the aesthetic area 


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and in conduction of clinical trials. 
In case of serious safety concerns (e.g., prolonged severe swelling or severe pain following 
injection) among cohort 1 subjects receiving the 120 mg dose, sponsor and DSMB may 
decide to reduce or stay with the 120 mg/subject dose level for cohort 2 subjects. 
Study 
Population 
Men and women 18-65 years old  
Main Inclusion 
Criteria 
 
Subjects must meet all the following to be eligible for study participation: 
1. Men and women 18-65 years old.  
2. Subjects with Body Mass Index <35. 
3. Subjects must have submental skin fold thickness greater than 1.5 cm as measured 
with calipers. 
4. Males must be willing to be clean shaved for all study visits. 
5. Patient weight must be stable (no fluctuation of >15 pounds in the past year). 
6. Males or females in the age of fertility agree to use a double-barrier contraceptive device 
(e.g., condom and spermicide) for 4 weeks after treatment with RZL-012. 
7. Subjects must be able to adhere to the visit schedule and protocol requirements and be 
available to complete the study. 
8. Subjects must sign an IRB approved informed consent indicating they are aware of the 
investigational nature of the study. 
Main Exclusion 
Criteria 
Subjects meeting any of the following criteria will be excluded from study participation: 
1. Unable to tolerate subcutaneous injection. 
2. Pregnant or lactating women.  
3. Subjects with dysfunctional gallbladder activity, e.g., underwent cholecystectomy or 
cholecystitis. 
4. Any uncontrolled systemic disease -a potential patient in whom therapy for a systemic 
disease is not yet stabilized will not be considered for entry into the study. 
5. Treatment with botulinum toxin injections in the neck or chin area within 6 months 
before screening. 
6. Excessive submental skin laxity. 
7. Any Scars, unshaven hair, tattoos or jewelry on or near the proposed treatment area. 
8. Significant history or current evidence of a medical, psychological or other disorder that, 
in the investigator's opinion, would preclude enrollment into the study. 
9. An active dermatitis or open wound in the proposed treatment area. 
10. An active bacterial, fungal, or viral infection in the proposed treatment area. 
11. Pre-existing skin condition in the submental region that may confound evaluation or 
analysis, at investigator discretion. 
12. Previously treated with focused ultrasound, radiofrequency, cryolipolysis, liposuction, 
sodium deoxycholate to the submental region within the previous 6 months. 
13. Pre-existing neurological or gastrointestinal condition leading to dysphagia, dysphonia or 
facial nerve palsy. 
14. Pre-existing medical condition other than increased submental fat that may result in 
increased submental fullness such as but not limited to thyroid enlargement, goiter, 
cervical lymphadenopathy etc., at investigator discretion. 
15. Must not have a planned fat reduction procedure of any variety to the submental region 
for the duration of the study. 
16. Must not have planned significant alterations in diet or physical activity that may result in 
significant fluctuations in weight. 
17. Subjects with medication or history of coagulopathy. 
18. Allergic subjects to Benadryl. 


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19. Subjects treated chronically at least 3 months prior to study entry with systemic steroids 
or immunosuppressive drugs.  
20. Subjects treated chronically at least one week prior to study entry with Non-Steroidal 
Anti-Inflammatory Drugs (NSAIDs).  
21. Current participation or participation within 3 months prior to the start of this study in a 
drug or other investigational research study. 
22. Claustrophobia or MRI incompatible device or implant. 
Study Drug 
Dosage and 
Administration 
All subjects will receive a single multi injection of the investigational product RZL-012 or 
placebo in accordance with the table below: 
 
 
N=28 
Cohort 1 
N=12 
Cohort 2 
N=16 
Number of 
 RZL-012/Placebo 
8/4 
At least 4 placebo 
subjects 
Total Maximal Dose RZL-012 
(mg)/vehicle (mL)  
Up to 120 mg/2.4 mL 
Up to 240 mg/4.8 mL 
Dose of RZL-012 (mg)/vehicle 
(mL) per single injection 
2.5 mg/0.05 mL 
5 mg/0.1 mL 
Maximal Number of Injections per 
subject 
48 
48 
 
Treatment area boundary: superiorly by a line 1 cm inferior to the mandibular margin, 
laterally by the sternocleidomastoid muscles, and inferiorly by the hyoid bone. 
Cohort 1 active subjects will receive a maximal dose of up to 120 mg RZL-012 in a series of 
up to 48 injections. Each injection point will be dosed with 2.5mg RZL-012 (0.05ml of RZL-
012 solution). Placebo (vehicle) subjects will be injected with 0.05 mL vehicle at each 
injection site, resulting in a total volume of up to 2.4 mL. 
Cohort 2 active subjects will receive a maximal dose of up to 240 mg RZL-012 in a series of 
up to 48 injections. Each injection point will be dosed with 5 mg RZL-012 (0.1 mL of RZL-
012 solution). Placebo (vehicle) subjects will be injected with 0.1 mL vehicle at each injection 
site, resulting in a total volume of up to 4.8 mL.  
The injection pattern in cohort 1 and cohort 2 will be based on a submental area shaped grid in 
which the distance between rows will be 1cm and distance between columns will also be 1 cm 
as seen in the figure below. Physician will choose two points at the edge of the 50-point 
pattern that will not be injected (up to 48 injections): 
 
Injection pattern to be used by the physician for precise dosing into submental fat area in both study 
cohorts. The dose at each injection site will be different between Cohort 1 and Cohort 2, i.e., 0.05 mL 
injection volume in cohort 1 and 0.1 mL injection volume in Cohort 2 for active treatment or vehicle. 
 
Twelve (12) subjects from cohort 1 (8 active and 4 placebo) will be injected with a maximal 
dose of 120 mg/subject or with up to 2.4 mL of vehicle. If no serious safety concerns will be 
noted within 28 days of follow-up post-dose of subjects from cohort 1, the study will proceed 


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to the additional 16 subjects of Cohort 2. These subjects  will be injected with a maximal dose 
of 240 mg/subject or with up to 4.8 mL of vehicle. 
In case of serious safety concerns (e.g., prolonged severe swelling or severe pain following 
injection) among Cohort 1 subjects receiving the 120 mg dose, sponsor and DSMB may 
decide to reduce or stay with the 120 mg/subject dose level for Cohort 2 subjects. 
Subjects will be injected with RZL-012 or vehicle perpendicularly (90) to the skin. An ice 
pack will be placed on the injected area for pain relief immediately after injection. Subjects 
will have to remain seated in the injection position for an additional 10 minutes after dosing. 
Study 
Procedure 
Activities upon study entry will include: 
Informed consent, medical history, physical examination, measurement of submental skin fold 
thickness with calipers, weight measurements, vital signs, MRI. 
Subjects will be randomized upon eligibility to RZL-012 or placebo at each clinical site and 
each cohort according to a predefined randomization scheme. 
Periodic site visits will allow assessment of treatment safety (skin adverse events) and 
efficacy. 
Subjects will be advised to continue their regular diet and physical activity.  
Visit Schedule 
 
Subject site visits will be performed ± 1 days from scheduled dates (from Day 7 visit to Day 
84 visit). 
Screening visit (Day -45 through -1): 
- 
Following signing the informed consent - assessment of subject eligibility will 
include: medical history, physical examination, weight measurements, height 
measurement, BMI record, pregnancy elimination by women subjects, vital signs, 
measurement of submental fat thickness using calipers, skin type by Fitzpatrick scale 
and MRI. 
MRI will be conducted within a window of 5 days from the screening visit but prior 
to baseline visit. 
Baseline visit (Day 0):  
- 
Pre-treatment: eligibility confirmation, concomitant medications, vital signs, weight 
measurement, Pregnancy test, Draize score of the injection site area, pain, bruising 
and induration grading, FACE Q questionnaire, 2D Photography.  
- 
Treatment - All injections will be administered 90° to the skin surface using a 0.5 mL 
(cohort 1) syringe or 1 mL (cohort 2) Luer-lock syringe and a 29/30 G x 1/2" needle, 
respectively (the hole of the needle pointing into the fat layer). The injection pattern 
will be performed according to physician evaluation of submental fat fullness. At the 
end of treatment, subjects will remain seated for an additional 10 minutes in the same 
position.   
- 
Post treatment: Draize score (2h post injection ± 30 min), adverse events (AEs)   
record (including pain, bruising and induration grading) . 
Schedule visits (Day 1-84): 
- 
At Day 1 following treatment: Concomitant medications, vital signs, Draize score, 
AEs (including pain, bruising and induration grading). 
- 
At Days 7 and 14 following treatment: Concomitant medications, vital signs, Draize 
score, 2D photography of face, AEs (including pain, bruising and induration 
grading). 
- 
At Day 28 following treatment:  Concomitant medications, vital signs, Draize score, 
2D photography of face, Subject’s satisfaction questionnaire (Face Q), Physician’s 
global assessment questionnaire, AEs (including pain, bruising and induration 
grading). 
- 
At Day 56 following treatment:  Concomitant medications, vital signs, weight, 
Draize score, 2D photography of face, Subject’s satisfaction questionnaire (Face Q), 
Physician’s global assessment questionnaire, AEs (including pain, bruising and 
induration grading). 
- 
Day 84 visit: Concomitant medications, Weight, Draize score, 2D photography of 


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face, Subject’s satisfaction questionnaire (Face Q), Physician’s global assessment 
questionnaire, MRI, AEs (including pain, bruising and induration grading). 
MRI at Day 84 visit will be performed at Day 84±5 Days.  
Safety Analysis 
Safety data from the study will be summarized descriptively by treatment and by cohort. The 
nature, frequency, seriousness, severity and relation to study drug of adverse events (AE) will 
be tabulated for all subjects combined and by treatment. Draize scores will be presented in 
tabular format by visit and cohort.  
Study 
Endpoints 
Primary Endpoint: 
The main objective is to evaluate safety following injection of RZL-012 vs. placebo into 
submental fat. Skin irritancy and AEs related to the injection procedure will be evaluated for 
frequency, severity and duration. Specifically, tolerability and assessment of the following 
AEs will be monitored: bruising, pain, induration erythema and swelling/edema at the 
injection site.  
Secondary Endpoints: 
Secondary endpoints will test the efficacy of RZL-012 vs. placebo according to the following 
measures: 
1.  Improvement of Physician’s global assessment questionnaire for treatment efficacy in 
active vs. placebo treated subjects on Days 28, 56 and 84 following injection. 
2.  Reduction from baseline in submental fat volume, as measured with MRI, in RZL-012 
treated subjects vs. placebo treated subjects on Day 84 following injection. 
3.  Improvement from baseline in the Face-Q satisfaction questionnaire rating score in RZL-
012 treated subjects vs. placebo treated subjects on Days 28 and 56 and 84.  
Statistical 
Methods 
Study data will be tabulated and summarized using the mean, standard deviation or standard 
error. 
AEs related to injection and Draize scores will be presented in tabular format by visit, cohort 
and treatment (active vs. placebo). 
Improvement in Global physician’s scale score pf RZL-012 treated subjects vs. placebo 
treated subjects by cohort and overall. 
The average change from baseline in submental volume as analyzed from MRI images will be 
presented in a tabular form by treatment received (RZL-012 / placebo), by cohort and overall. 
The average change from baseline in questionnaire score will be presented in a tabular form 
by treatment received (RZL-012 / placebo), by cohort and overall. 
Any statistical tests will be two-sided. The required significance level (P value) of findings 
will be equal to or lower than 5%.   
Study Duration 
Study duration is 4.5 months for each subject, including enrollment, treatment and follow-up 
period. 
Study Sites 
2 


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1. 
INTRODUCTION 
1.1. 
BACKGROUND 
1.1.1. Scientific Background and Clinical Rationale 
Submental fat represents an aesthetic problem in overweight males and females. Although 
localized fat deposits are present in many parts of the body, submental fat is particularly 
noticeable due to its location. Until recently, treatments of submental fat have been limited to 
invasive, surgical procedures such as liposuction or fat excision and even complete neck 
reconstruction. Because surgery is associated with the risks of anesthesia, infection, bleeding, 
bruising, and scarring, as well as the possibility of poor outcome, discomfort, and the prolonged 
“down time” for the patient, there is a large demand for nonsurgical alternatives (1-3). The 
submental area represents an ideal anatomical area for an injectable treatment for fat reduction. 
Recently, several treatments were developed and approved as ‘non-invasive’ treatments for fat 
reduction, i.e., freezing (medical device) and injection into the subcutaneous fat. Kybella, a drug 
which is based on sodium deoxycholate injection was approved as a treatment for submental fat. 
However, due to repeated treatments (every 4 weeks, 4-6 treatments) and adverse events such as 
swelling and bruising that repeats after every treatment, physicians and subjects are still 
searching for additional alternatives in the market.  
Raziel Therapeutics has discovered that a novel synthetic molecule (termed RZL-012) can help 
reduce fat content in human and pigs. Recent data has led Raziel to the understanding that the 
mechanism of action (MOA) of RZL-012 involves liponecrosis at the injection site, followed by 
a transient inflammatory response and finally by a healing process in which fibrotic tissue 
replaces previous fat tissue. A thermogenic effect is noted at the injection site probably due to a 
local inflammatory reaction. Studies in pigs show that necrosis of fat tissue at the injection site is 
seen as early as 24 hours after injection, and is still evident 2 weeks later but is completely 
cleared at 12 weeks post dosing. A macrophage-mediated inflammatory response was also very 
prominent at 24 hours and 14 days after injection with only minimal signs of inflammation 
remaining at 12 weeks post dosing. Fibrosis showed a different pattern compared with 
liponecrosis and inflammation - it started at 14 days post dosing and became much more 
prominent at 12 weeks post dosing. In essence, RZL-012 enables de-novo generation of fibrotic 
tissue to replace excess fat tissue at selected anatomical sites.   
Recently, RZL-012 was evaluated as a treatment for local fat reduction among obese and 
overweight subjects in two clinical studies and was evaluated for the treatment of fat disorders 
diseases such as Dercum’s Disease (DD) and lipedema.   
In the initial exploratory clinical trial that was conducted (RZL-012-P0US-001.3 under IND 
119941) to test safety and thermogenesis-induction of RZL-012 in overweight and obese 
subjects, RZL-012 was found to be safe with mainly transient and local adverse events (AEs). A 
thermogenic effect (a rise of 1 °C in temperature at the injected site compared to the untreated 
collateral side) was evident in the RZL-012-treated subjects of the highest dose cohort 


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(20 mg/subject). Moreover, MRI at 28 days after injection demonstrated that fat mass was 
reduced at the injection site compared to matched fat mass at the non-injected contralateral site, 
in RZL-012 but not in vehicle-treated subjects.  
In a Phase 2a study that was conducted in 32 overweight and obese subjects (RZL-012-P2aUS-
001.4 under IND 133324), the maximum injection dose of RZL-012 was 180 mg/subject. RZL-
012 demonstrated a dose dependent reduction in Subcutaneous Fat Mass (SFM) ratio at doses of 
80 mg/subject (8.6% ± 3.6% reduction), 120 mg/subject (10.5% ± 3.4% reduction) and 
180 mg/subject (18.1% ± 4.9% reduction) vs vehicle (3.6% ± 1.6% increase), 56 days following 
injection. The reduction of local fat mass was still evident 6 months following RZL-012 
injection. Safety and tolerability were good with only mild or moderate adverse events, mostly 
transient and localized to the injection site.  
An additional Phase 2a study (RZL-012-FD-P2aUS-001.7 under IND 135762) was conducted to 
evaluate the safety and pharmacodynamic response to RZL-012 in lipedema and DD patients. 
Interim analysis for 5 of 6 DD subjects demonstrated a 55% reduction in height of 18 injected 
lipomas. Safety and tolerability were good with mild or moderate adverse events. The Adverse 
Events (AEs) that were categorized as definitely related to the study drug were transient and 
localized to the injection site. 
Based on the above, Raziel concludes that the safety profile of RZL-012 is good and acceptable 
and the compound demonstrated efficacy in long-term reduction of local SFM. Thus, Raziel 
Therapeutics is being developed to be for aesthetic indications such as submental fat. 
1.1.2. RZL-012 Formulation Development 
The active ingredient RZL-012 drug substance was manufactured by Pharmacore, High Point 
NC, USA. The drug product, 5 % RZL-012 in F12 liquid formulation (RZL-012 in F12 
formulation is 250 mg RZL/5 mL vial = 50 mg RZL/mL) 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). 
1.2. 
NONCLINICAL ASSESSMENTS 
1.2.1. Pharmacology 
Studies pigs concluded that RZL-012 mechanism of action (MOA) following injection into the 
subcutaneous fat involves liponecrosis at the injection site, followed by a transient inflammatory 
response and finally by a healing process in which fibrotic tissue replaces previous fat tissue. The 
dose of RZL-012 to be used in clinical trials was extrapolated from the no observed adverse 
effect level (NOAEL) safety data obtained during animal testing. 


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1.2.1.1. 
Efficacy In-vivo Studies 
Several nonclinical studies in pigs, in which the subcutaneous fat tissue resembles that of 
humans, were conducted to prove the efficacy of RZL-012 following its injection to the 
subcutaneous fat. Each single administration was based on multi injection of RZL-012. 
1.  A non-GLP study where four domestic pigs (2 male/2 female) were injected with either a 
single dose of 350 mg (14 injections of 25 mg RZL-012) or vehicle. Study results 
demonstrated that body weight, body temperature, and physical examinations were all 
normal throughout the 14-day monitoring period. There seemed to be no clear difference in 
fat tissue depth regarding gender or treatments provided. 
2.  A non-GLP study was conducted to assess the influence of RZL-012 for the reduction of 
adipose tissue in two male pigs. One (1) was injected with a single dose of 200 mg 
(8 injections of 25 mg RZL-012) RZL-012 and the other with vehicle. Both pigs were 
injected in their right side and the left side of each pig was left untreated. Study results 
demonstrated that 28 days after treatment, no local injection site reactions were observed. 
Body weight, body temperature, and physical examinations were all normal throughout the 
monitoring period. No pathological findings were reported at necropsy. Post-treatment, 
measurements of the subcutaneous fat depth of the RZL-012-treated side was markedly lower 
(~30%) than that of the untreated side. This observation was not evident in the vehicle-
treated pig. 
3.  A GLP study was conducted to evaluate the potential local and systemic toxicity, as well as 
efficacy of RZL-012, in domestic Yorkshire crossbred swine. Twenty-eight pigs received 
either control (0.9% Sodium Chloride for Injection) or 500 mg (20 injections of 25 mg RZL-
012) RZL-012 and observed 24 hours (3/group/sex), 14 days (2/group/sex), or 84 days 
(2/group/sex) post dose.  Study results demonstrated that the mean fat thickness in RZL-012 
treated males was reduced approximately by 16.8% as compared to a 1.1% increase in males 
treated with Saline. The mean fat thickness in females treated with RZL-012 was reduced 
approximately by 19.1% as compared to a 3.7% increase in females treated with Saline. 
This study also contributed to the understanding of MOA. Since all injection sites (20 
injection sites/pig) were quantified for necrosis, inflammation and fibrosis it was possible to 
demonstrate injection-related fat tissue damage followed by an acute inflammatory response 
which was already evident at 24 hours after injection and very prominent at 14 days. 
This transient inflammatory response involved mostly macrophages with little or no apparent 
lymphocytes seen at the injection site. Stepwise clearance of fat cell debris by surrounding 
macrophages was ongoing and by about 84 days after dosing the tissue was fully healed. 
A process of fibrosis was an active participant in this healing process, initiating already at 
14 days after injection and becoming very prominent at 84 days post dose. In essence 
injection of RZL-012 resulted in a long-lasting replacement of fat tissue by fibrotic tissue at 
the injected areas causing shrinkage of treated tissues.  


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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 
concluded that RZL-012 did not affect any of the central nervous system (CNS) functions tested 
using FOB in rats. 
The effect of RZL-012 was evaluated on respiratory functions in male Sprague Dawley rats 
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 (ECGs) 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 Food and Drug 
Administration (FDA) guidelines for Exploratory Investigational New Drug (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 (changes in white blood cells [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 
blood urea nitrogen [BUN] in males and females and increased creatinine and aspartate 
aminotransferase [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 (IB). 
Considering skin changes as non-systemic effects and or local effects, the NOAEL was 
determined at 5 mg/rat (approximately 20 mg/kg) under the test conditions and doses employed. 


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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 
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 detail in the IB. 
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 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 in clinical chemistry 
or coagulation parameters.   
1.2.3. Additional Nonclinical Studies 
• Secondary pharmacology 
• ADME-Toxicology study: Establishing pharmacokinetic (PK) parameters, absorption, 
distribution and metabolism and excretion 
• RZL-012 genotoxicity (in-vitro and in-vivo) 
• Absorption studies in rats and pigs 
Methods and results from these safety studies are described in the Investigator's Brochure. 
1.2.4. Clinical Studies 
RZL-012 has been tested in several clinical trials. A total of 54 subjects were exposed to RZL-
012 at single doses of up to 180 mg. The currently planned clinical trial will be the first trial to 
test a single maximal dose of RZL-012 of up to 240 mg, (the NOAEL) and the first trial to assess 
the potential efficacy of RZL-012 in reducing submental fat. 
Two studies were completed and one study is still on-going.  


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Table 1:  Overview of Ongoing and Completed Clinical Studies 
Study ID 
STATUS 
Phase 
Country 
Study Title 
Study Design 
Dosing Regimen 
Study Population 
RZL-012-P0US-
001.3 
 
 
COMPLETED 
0 
USA 
Phase 0 Study of Three Cohorts Aiming at 
the Evaluation of Safety and 
Thermogenesis-induction of Three 
Escalating Doses of RZL-012 Drug Product 
in Overweight, Healthy Volunteers 
A randomized, double-blind, 
vehicle-controlled, dose-
escalation study that will 
enroll 8 subjects, 6 active 
and 2 control, in each of 3 
cohorts.  
Cohort 1: 5 mg 
Cohort 2: 10 mg 
Cohort 3: 20 mg 
 
Healthy, 20-40 years old, 
overweight by Body Mass Index 
(BMI) definition (25 < BMI 
≤ 34.9), adult males.  
 
RZL-012-
P2aUS-001.4 
 
COMPLETED 
2A 
USA 
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 
A randomized, double-blind, 
placebo-controlled, 
consecutive 4 cohort, dose 
escalation clinical trial 
Cohort 1: 40 mg 
Cohort 2: 80 mg 
Cohort 3: 120 mg 
Cohort 4: 180 mg 
Adult male subjects 20–60 years 
old, with 27.5 < BMI ≤ 34.9 
RZL-012-FD-
P2aUS-001.7 
 
ON GOING 
2A 
USA 
An Open Label, Phase 2a Clinical Trial for 
the Evaluation of Safety and Efficacy of 
RZL-012 for the Treatment of Women with 
Lipedema Involving Substantial Fat above 
the Knee or of Women and Men with 
Nodular Dercum’s Disease 
Open-label safety and 
efficacy clinical trial  
Cohort 1 DD: 
Subjects will receive 
up to 40 mg RZL-
012 
Cohort 2 Lipedema: 
Each 3 subjects will 
receive 60 mg or 
80 mg RZL-012 
Post-menopausal (at least 
2 years) women no more than 
65 years old, with lipedema 
involving substantial fat above 
the knee or nodular Dercum’s 
disease in such women and in 
men 20–65 years with nodular 
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1.2.4.1.1. Protocol No. RZL-012-P0US-001.3. Status: Completed 
The first-in-man clinical trial was an exploratory, randomized, double-blind, vehicle-controlled 
Phase 0 study, conducted under IND 119941 to evaluate the safety and thermogenesis-induction 
of three escalating doses of RZL-012 in overweight and obese subjects. This study also evaluated 
the RZL-012 pharmacokinetics at the baseline visit till the following day (Day 0-1). 
The primary objective of the study was the evaluation of the overall safety of RZL-012 after 
subcutaneous injection and the existence of a thermogenic effect. A thermogenic effect was 
defined by an increase of 1 °C in the injected site when compared to the surroundings and/or the 
contra-lateral (non-injected site), apparent at least 28 days after injection. This was monitored by 
sensitive (± 0.1 °C) Infra-Red thermal camera.   
The secondary objective was the determination of RZL-012 pharmacodynamics. The 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 are summarized 
below. 
The study was composed of 3 cohorts where in each cohort 8 subjects were injected (6 active and 
2 control). This was a dose escalation study, therefore RZL-012 was injected at doses of 5, 10, 
and 20 mg/subject at cohorts 1, 2, 3, respectively. 
Subjects received a single treatment in multiple sites (1-4) of injection diagonally (45°) to the 
skin surface at 3 cm lateral to the umbilicus lateral wall. The distance between injected sites was 
1 cm (see Figure 1). 
Figure 1:  Injection Sites for Phase 0 Study 
 
RZL-012-P0US-001.3 Study Results:  
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 were confined to the injection site and were transient. Biopsy from the 
injection site revealed no damage to the skin 56 days following RZL-012 injection. The only 


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significant local AE was an abscess in one subject in the lower abdomen at the surrounding of 
injected side (but away from the injected site).   
One systemic clinically significant AE involved a severe elevation of ALT blood levels and a 
moderate elevation of AST blood levels 17 days following injection of the highest dose (AST 
169 U/L; ALT 411 U/L) of active treatment. This elevation was transient. Resolution for AST 
elevated levels and reduction for ALT levels to Grade 1 according to MeDRA coding dictionary 
occurred 11 days following detection. ALT levels were normal on the next visit on Day 56. 
There were no other systemic clinically significant AEs. 
PK profile results demonstrated an association between dose and Cmax with values of 
13.11 ng/mL at the lower dose level (Cohort 1), 23.02 ng/mL at the next (double) dose level 
(Cohort 2) and 51.46 ng/mL at the highest (x4 of the lowest dose) dose level (Cohort 3).   
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. 
Magnetic Resonance Imaging (MRI) results demonstrated a decrease over time in Subcutaneous 
Mass Fat (SFM) ratio (injected/non-injected side) vs baseline in most RZL-012 treated subjects 
of Cohort 3. This reduction was not statistically significant. 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 changes in the adipose tissue. 
Raziel concludes that the potential risk-benefit balance for RZL-012 is favorable, and it is likely 
that higher doses of RZL-012 will generate better results.   
1.2.4.1.2. Protocol No. RZL-012-P2aUS-001.4 Status: Completed  
An additional clinical trial was a double blind, randomized, placebo controlled, dose escalation 
Phase 2a study, conducted under IND 133324 to evaluate the safety and thermogenesis-induction 
of RZL-012 in overweight and obese subjects.  
The primary objective of the study was the evaluation of the overall safety and preliminary 
efficacy of RZL-012 after subcutaneous injection. The primary endpoint for efficacy was a 
significant thermogenic effect, apparent at least 28 days after injection, at the injected site 
compared with the contra-lateral, non-injected site.  
The secondary objective was the determination of RZL-012 pharmacodynamics and 
pharmacokinetics. The secondary efficacy endpoints included the following: 
1. Duration of the thermogenic effect, defined as a net-delta ≥ 1.  
2. Local reduction in fat mass as determined by MRI. 


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3. Clinical laboratory changes from baseline 
4. Establishing the pharmacokinetic profile for RZL-012. 
5. Anthropometric changes from baseline 
6. Elucidation of the histological changes that may account for the thermogenic effect by biopsy 
of the injection site. 
7. Change from baseline in inflammatory markers and cytokines. 
The study was composed of 4 cohorts. Each cohort was designed to enroll 8 subjects (6 active 
and 2 control). In Cohort 3, 3 subjects were injected with control vehicle and not 2 as planned 
due to subject’s dropout. The overall number of subjects in the study was 33.  
Subjects received a single treatment at multiple sites (8-36) of injection diagonally (45°) to the 
skin surface at 5 cm lateral to the umbilicus lateral wall. The distance between injected sites was 
2 cm in cohorts 1-3 and 1cm in Cohort 4 as seen in Figure 2. 
Figure 2:  Injection Sites for Phase 2A Study 
 
 
RZL-012-P2aUS-001.4 Study Results: 
In the current study, in which significantly higher doses were tested (up to 180 mg), RZL-012 
was found to be safe in all cohorts. There were no clinically significant changes in vital signs, 
ECG and all blood laboratory parameter. The most commonly reported AEs for which there 
seems to be a causal relationship to active treatment, due to the higher incidence in the active 
treatment groups compared to the placebo groups, were injection site pain and injection site 
edema. Most AEs were transient. There was only a single case in the highest injected dose, 
Cohort 4, where erythema and edema were still observed up to Day 140. 
The only systemic effect found due to the subcutaneous injection of RZL-012, was elevation in 
d-dimer values at the highest injected dose, 180 mg. However, this increase was transient, up to 
3 days after injection, and non-clinically significant.  
Biopsies taken from two injection sites revealed no damage to the skin 56 days following RZL-
012 injection. Based on the histology results, the process that seemed to be dominant is fat 


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necrosis and infiltration of macrophages into the necrotic fat tissue that resulted in a replacement 
of the local fat tissue by fibrotic tissue.  
A decrease from baseline in SFM ratio (injected/non-injected side), as assessed by MRI, was 
noted in RZL-012 treated subjects of Cohorts 2-4 at all study time points. In addition, a dose 
dependent response was evident and statistically significant differences in SFM were found in 
RZL-012 treatment groups vs. Placebo. Among Cohort 4 subjects who were monitored until 
168 days post injection, a clear reduction in SFM was noticed (-14.32%). Cohort 4 subjects 
demonstrated the largest reduction in SFM at Day 56 (-18.10%). 
There were no major changes over time and no specific trend to suggest a dose correlation 
response in any of the parameters of lipid profile (TC, TG, LDL, HDL, and FFA) and fasting 
glucose.  
The PK profile of RZL-012 demonstrated dose proportionality. The maximal plasma 
concentration of RZL-012 was less than 0.5 µg/mL (500 ng/mL) in all subjects and Tmax was 
obtained at about 2 hours following injection. 
No significant decrease in BMI or in subjects’ weight values was evident in all cohorts, 
compared to vehicle injected subjects. There was no consistent pattern to suggest an association 
between inflammation markers and cytokines levels. Therefore, the inflammation reaction due to 
macrophage infiltration into the necrotic tissue seems to be local and without any systemic 
effect. 
Raziel concludes that the risk benefit profile of RZL-012 as seen in clinical trials to date, is in 
favor of RZL-012. RZL-012 may be useful in treating conditions in which removal of excess fat 
is desired such as excess in submental fat. 
1.2.4.1.3. Protocol No. RZL-012-FD-P2aUS-001.7 Status: ongoing 
An additional ongoing clinical trial is an open label Phase 2a study conducted under IND 135762 
to evaluate the safety and efficacy of RZL-012 for the treatment of women with lipedema 
involving substantial fat above the knee or of women and men with nodular Dercum’s disease 
(DD).   
The Primary objective is to evaluate the overall safety of RZL-012 following injection into the 
subcutaneous fat in patients with lipedema or DD.  
The secondary objective is to evaluate local fat reduction, its extent, duration and tissue 
associated changes, in response to RZL-012 treatment, utilizing minimal invasive means 
(ultrasound) following subcutaneous injection of RZL-012 into fatty tissue below the skin. 


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The study is composed of 2 cohorts where the 1st cohort is comprised of 6 subjects with 
Dercum's disease and the 2nd cohort is comprised of subjects with lipedema subjects having 
substantial fat above the knee.  
1st Cohort Dercum's disease:  
Several lipomas were injected per subject. Dosing was calculated according to the size of the 
nodule (diameter) reaching a maximal dose of 40mg per subject  
Subjects received a single treatment in multiple sites (2-8 cm lipoma size) of injection according 
to the design in Figure 3.  
Figure 3:  Injections Diagram According to Lipomas Size 
 
 
2nd cohort lipedema subjects with substantial fat above the knee: 
The first 3 subjects received 30 mg RZL-012 in 6 injections (0.1 mL each) in one leg followed 
by 30 mg RZL-012 (6 injections, 0.1 mL each) in the second leg adding up to 12 injections of 
60 mg RZL-012 (1/4th the NOAEL based on Human Equivalent Dose (HED) from GLP 
toxicology study).  
The last 3 subjects received 40 mg RZL-012 in 8 injections (0.1 mL each) in one leg followed by 
40 mg RZL-012 (8 injections, 0.1 mL each) in the second leg adding up to 16 injections of 
80 mg RZL-012 (1/3rd the NOAEL based on HED from GLP toxicology study), see Figure 4. 
Figure 4:  Injection Scheme Lipedema Subjects 
 


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RZL-012-FD-P2aUS-001.7 Interim Study results: 
As of April 2019, all 12 subjects from both cohorts were recruited and injected with study drug. 
Results for lipedema subjects are still pending. 
Below are the interim results of 5 subjects with Dercum’s disease. A total of 18 lipomas were 
injected with RZL-012 and followed up for 56 days for lipoma size changes and pain scores.  
Among the 5 subjects who completed the study, there were no clinically significant changes in 
vital signs, ECG and blood laboratory parameters. A total of 11 AEs was reported; 54% of the 
AEs were categorized as mild and 46% were categorized as moderate. No severe AEs were 
reported. Injection site pain constituted 27% of the AEs and were categorized as moderate and 
considered as definitely related to the study drug. The remaining AEs were considered as 
unrelated or unlikely to be related to the investigated study drug.  
Assessment of lipoma size change was performed using ultrasound measuring the height, width 
and length of each injected lipoma at Baseline, Day 28 and Day 56 visits. Lipoma dimension 
changes were best characterized by lipoma height. Out of 18 lipomas treated with RZL-012, 
8 lipomas were completely eliminated at Day 56. All the eliminated lipomas were without 
fibrotic tissue in their capsule. The other lipomas demonstrated a height reduction of up to ~60%. 
An overall reduction of 55% in lipomas height was measured at Day 56 visit vs. baseline. 
Based on the results described above it seems that RZL-012 is more effective in reducing 
lipomas that contain only fat tissue than those containing fibrotic tissue. 
Pain assessment per individual lipomas was performed using a Comparative Pain Scale with 
numerical limits of 0-10 where 0 is rated as ‘no pain’ and 10 is rated as ‘unimaginable pain’.  
Pain associated lipomas had an overall reduction of 74.6% at Day 56 vs. screening. Four (4) out 
of 5 subjects demonstrated significant pain reduction (from averaged pain score of 4.6 at 
screening vs. average of pain score of 0.5 at Day 56, according to comparative pain scale). Only 
one subject (subject 1001) did not demonstrate any change in pain at Day 56. 
Based on interim data, Raziel Therapeutics believes that RZL-012 can be beneficial for treating 
patients with fat disorders such Dercum's disease. 
Further details of clinical trials results are described in the IB. 


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2. 
PURPOSE AND STUDY OBJECTIVES 
2.1. 
PURPOSE 
A single blind, randomized, placebo-controlled, Phase 2a, 2-cohort study for the evaluation of 
safety and efficacy of RZL-012 for submental fat reduction in healthy volunteers. 
2.2. 
STUDY OBJECTIVES 
2.2.1. Primary  
To evaluate the safety of RZL-012 subcutaneous injections in the submental area, relative to 
placebo, as assessed by spontaneous adverse event reports and post injection evaluation of 
subjects by treating physician. 
2.2.2. Secondary 
The secondary objectives are to evaluate the efficacy of RZL-012 subcutaneous injections in the 
submental area, relative to placebo by: 
- 
Evaluation of treatment efficacy by using Physician’s global assessment questionnaire, 
on study Days 28, 56, and 84 
- 
Reduction from baseline in submental fat volume, as measured by MRI 
- 
Improvement in subject’s satisfaction rating score of the FACE-Q questionnaire on study 
Days 28, 56, and 84 vs. baseline 
3. 
STUDY DESIGN 
3.1. 
DESCRIPTION OF STUDY DESIGN 
This is a single blinded, randomized, placebo-controlled, 2-cohort, clinical study in healthy 
volunteers.  
Cohort 1 will be comprised of 8 active (RZL-012) and 4 placebo subjects.  Cohort 2 will be 
comprised of 16 subjects. That will be randomized to receive active or placebo treatment All 
subjects will receive a single dose of RZL-012 or vehicle into the submental fat, after which they 
will be monitored for safety and efficacy assessments across 84 days of follow-up. All subjects 
per cohort will be randomized to either active treatment or placebo at a ratio of 2:1 per cohort. 
Subjects will be blinded to study treatment while physicians will not be blinded. 
The study will be composed of 2 treatment cohorts, 12 subjects at cohort 1 and 16 subjects at 
cohort 2. 


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A total of 28 subjects will be treated in 2 clinical sites.  
At cohort 1, a total of 12 subjects will be randomized to receive active or placebo treatment (2:1) 
according to randomization program that will be prepared prior to study initiation. At cohort 2, 
16 subjects will be randomized to receive active or placebo treatment.  Each clinical site will 
have at least one active and one placebo treatment subject per each study cohort. In case of slow 
enrollment in one of the sites, other sites may complete the enrollment of subjects in each cohort. 
3.2. 
DOSE RATIONALE 
In all previous clinical trials, the maximal RZL-012 dose per injection site was 5 mg, and a 
distance of 2-3 cm or 1 cm between injection points was maintained. The total overall RZL-012 
dose tested to date was 180 mg, which is 75% of the NOAEL. No serious adverse events were 
associated with this dose per injection site, with the distance maintained between injection sites 
or with the maximal overall dose.  
Thus, for the current trial, the starting dose of a maximal 120 mg has been chosen based on a 
dose of 2.5 mg per injection site, a distance of 1 cm between injection columns and rows of the 
submental pattern and on an estimation of the dimensions of the submental area. A distance of 
1 cm will allow a good distribution RZL-012 into the submental area. 
To increase the potential to demonstrate efficacy, a higher RZL-012 dose of a maximal 240 mg 
will also be assessed, on condition that no serious safety concerns are raised within 28 days of 
follow-up post-dose of 12 subjects having received the starting dose. To achieve this maximal 
dose, the 5 mg dose per injection site will be used with the same pattern of submental fat grid 
(i.e., 1 cm between injection columns and 1 cm between injection rows). The number of 
injections will be determined by the physician based on the fullness of submental fat. Upon 
review of initial safety data in subjects receiving the lower dose, sponsor may or may not decide 
to increase the dose as planned for remaining subjects. 
3.3. 
DOSING 
3.3.1. Dosing Regimen 
All subjects will receive a single dose of RZL-012 or placebo in multiple injections, in 
accordance with the treatment cohorts as shown in Table 2 below. 


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Table 2:  Study Design 
 
N=28 
Cohort 1 
N=12 
Cohort 2 
N=16 
Number of RZL-012/Placebo 
8/4 
At least 4 placebo 
subjects 
Total Maximal Dose RZL-012 (mg)/vehicle (mL)  
Up to 120 mg/2.4 mL 
Up to 240 mg/4.8 mL 
Dose of RZL-012 (mg)/vehicle (mL) per single injection 
2.5 mg/0.05 mL 
5 mg/0.1 mL 
Maximal Number of Injections per subject 
48 
48 
 
Cohort 1 active subjects will receive a maximal dose of up to 120 mg RZL-012 in a series of up 
to 48 injections. Each injection point will be dosed with 2.5 mg RZL-012 (0.05 mL of RZL-012 
solution). Placebo (vehicle) subjects will be injected with 0.05 mL vehicle at each injection site, 
resulting in a total volume of up to 2.4 mL. 
Cohort 2 active subjects will receive a maximal dose of up to 240 mg RZL-012 in a series of up 
to 48 injections. Each injection point will be dosed with 5 mg RZL-012 (0.1 mL of RZL-012 
solution). Placebo (vehicle) subjects will be injected with 0.1 mL vehicle at each injection site, 
resulting in a total volume of up to 4.8 mL. 
The injection pattern in Cohort 1 and Cohort 2 will be based on a submental area shaped grid in 
which the distance between rows will be 1cm and distance between columns will also be 1 cm as 
seen in the figure below. Physician will choose two points at the edge of the 50-point pattern that 
will not be injected (up to 48 injections): 
Figure 5:  Scheme of Injection Pattern that will be used by the Physician to Inject into the 
Submental Fat Area in Both Study Cohorts 
 
Twelve (12) subjects from Cohort 1 that will be enrolled in 2 clinical sites (8 active and 
4 placebo) will be injected with a maximal dose of 120 mg/subject or with up to 2.4 mL of 
vehicle. If no serious safety concerns will be noted within 28 days of follow-up post-dose of 
subjects from Cohort 1, the study will proceed to the additional 16 subjects of Cohort 2. These 
subjects (that will be randomized to receive active or placebo treatment with at least 4 placebo 
subjects) will be injected with a maximal dose of 240 mg/subjector up to 4.8 mL vehicle . 


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Treatment of Cohort 2 will start following Cohort 1 Day 28 data. An independent Data Safety 
Monitoring Board (DSMB) will review the safety and tolerability data for Cohort 1 subjects, 
28 days after injection, and decide whether it is safe to increase the dose for next study cohort. 
The decision to proceed to the Cohort 2 will be made within 30 days (28 days +2) after injection 
of the last dosed subject of Cohort 1. 
The DSMB will be comprised of 2 independent MDs with expertise in the aesthetic area and in 
conduction of clinical trials. 
In case of serious safety concerns (e.g., prolonged severe swelling or severe pain following 
injection) among Cohort 1 subjects receiving the 120 mg dose, sponsor and DSMB may decide 
to reduce or stay with the 120 mg/subject dose level for Cohort 2 subjects.  
Subjects will be injected with RZL-012 or vehicle perpendicularly (90) to the skin. An ice pack 
will be placed on the injected area for pain relief immediately after injection. Subjects will have 
to remain seated in the injection position for an additional 10 minutes after dosing. 
3.3.2. Serious Adverse Events Considered Related to the Investigational Drug 
The adverse events (AEs) and serious adverse events (SAEs) will be monitored throughout the 
study. 
Study discontinuation is to be considered by the investigator in any case of SAEs and the actions 
taken are to be fully documented in source documents and Case Report Forms (CRFs).  
SAEs are considered to be possibly or probably related to the study drug. 
Subjects experiencing an SAEs will be followed for their skin condition. 
SAE should be reported within 24 hours to the medical monitor. 
The study may also be prematurely terminated in any of the following cases:  
• Recurring serious or severe Adverse Drug Reaction (ADR) clinically evaluated by PI as 
warranting study termination.  
• A decision made by Sponsor/medical monitor and/or IRBEC and/or local regulatory 
agency to terminate the study.  


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4. 
STUDY ENDPOINTS 
4.1. 
PRIMARY ENDPOINTS 
The main objective is to evaluate safety following injection of RZL-012 vs. placebo injection 
into submental fat. Skin irritancy and AEs related to injection procedure will be mainly evaluated 
for its frequency, severity and duration. Specifically, the assessment of the following AEs will be 
monitored: bruising, pain, induration erythema and swelling/edema.  
In cohort 1a total of 12 subjects will be randomized to receive active treatment or placebo (2:1) 
and in cohort 2 16 subjects will be randomized (at least 4 placebo subjects will be randomized) 
in the 2 clinical sites. Each clinical site will have at least one active and one placebo at each 
study cohort. 
Twelve (12) subjects from Cohort 1 (8 active and 4 placebo) will be injected with a maximal 
dose of 120mg/subject or with up to 2.4 mL of vehicle. If no serious safety concerns will be 
noted within 28 days of follow-up post-dose of subjects from Cohort 1 (e.g., prolonged severe 
pain or severe swelling following injection), the study will proceed to the additional 16 subjects 
of Cohort 2 that are designated to be injected with a maximal dose of 240 mg/subject for active 
treatment or up to 4.8 mL vehicle in 4 for at least 4 placebo subjects that will b randomized.   
In case of serious safety concerns among subjects receiving the 120 mg dose, sponsor and 
DSMB review may decide to reduce or remain with the 120 mg/subject dose level for remaining 
subjects. 
4.2. 
SECONDARY ENDPOINTS 
Following are the study's secondary endpoints that evaluate treatment efficacy of active 
treatment vs. placebo subjects:  
1. Improvement of Physician’ global assessment questionnaire for treatment efficacy in 
active vs. placebo treated subjects on Days 28, 56, and 84 follow up visits to evaluate 
treatment response, see definition in Section 6.1.15.2.1. 
2. Reduction from baseline in submental fat volume, as measured with MRI on Day 84 vs. 
screening, in RZL-012 treated subjects vs. placebo treated subjects, see definition in 
Section 6.1.15.2.2. 
3. Improvement from baseline in Subject’s satisfaction Rating by using validated FACE-Q 
questionnaire (Satisfaction of chin) on Days 28, 56, and 84 follow up visits to evaluate 
treatment response among RZL-012 treated subjects vs. placebo treated subjects, see 
definition in Section 6.1.15.2.3. 


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5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria will be eligible for study participation: 
1. Men and women 18-65 years old, all in good health.  
2. Subjects with Body Mass Index < 35 as determined at screening visit. 
3. Subjects must have submental skin fold thickness greater than 1.5 cm as measured with 
calipers. 
4. Males must be willing to be clean shaved for all study visits. 
5. Patient weight must be stable (no fluctuation of >15 pounds in the past year). 
6. Males or females in the age of fertility agree to use a double-barrier contraceptive device 
(e.g., condom and spermicide) for 4 weeks after treatment with RZL-012. 
7. Subjects must be able to adhere to the visit schedule and protocol requirements and be 
available to complete the study. 
8. Subjects must sign an IRB approved informed consent indicating 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. Unable to tolerate subcutaneous injection. 
2. Pregnant or lactating women.  
3. Subjects with dysfunctional gallbladder activity, e.g., underwent cholecystectomy or 
cholecystitis. 
4. Any uncontrolled systemic disease -a potential patient in whom therapy for a systemic 
disease is not yet stabilized will not be considered for entry into the study. 
5. Treatment with botulinum toxin injections in the neck or chin area within 6 months 
before screening. 
6. Excessive submental skin laxity. 
7. Any Scars, unshaven hair, tattoos or jewelry on or near the proposed treatment area. 
8. Significant history or current evidence of a medical, psychological or other disorder that, 
in the investigator's opinion, would preclude enrollment into the study. 


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9. An active dermatitis or open wound in the proposed treatment area. 
10. An active bacterial, fungal, or viral infection in the proposed treatment area. 
11. Pre-existing skin condition to the submental region that may confound evaluation or 
analysis, at investigator discretion. 
12. Previously treated with focused ultrasound, radiofrequency, cryolipolysis, liposuction, 
sodium deoxycholate to the submental region within the previous 6 months. 
13. Pre-existing neurological or gastrointestinal condition leading to dysphagia, dysphonia or 
facial nerve palsy. 
14. Pre-existing medical condition other than increased submental fat that may result in 
increased submental fullness such as but not limited to thyroid enlargement, goiter, 
cervical lymphadenopathy etc., at investigator discretion. 
15. Must not have a planned fat reduction procedure of any variety to the submental region 
for the duration of the study. 
16. Must not have planned significant alterations in diet or physical activity that may result in 
significant fluctuations in weight. 
17. Subjects with medication or history of coagulopathy. 
18. Allergic subjects to Benadryl. 
19. Subjects treated chronically at least 3 months prior to study entry with systemic steroids 
or immunosuppressive drugs.  
20. Subjects treated chronically at least one week prior to study entry with Non-Steroidal 
Anti-Inflammatory Drugs (NSAIDs). 
21. Current participation or participation within 3 months prior to the start of this study in a 
drug or other investigational research study. 
22. Claustrophobia or MRI incompatible device or implant. 
5.3. 
SUBJECT IDENTIFICATION 
At each site, 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 AEs and/or other trial related data. 


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5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF SUBJECTS 
FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE EFFECTS 
Subjects experiencing serious side effect will be withdrawn from the study, but followed until 
the event resolves or becomes stable. If a subject is withdrawn or removed from the study due to 
serious side effects, the subject will not be replaced. 
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 by the person who conducted the Informed Consent discussion.  
If a subject is unable to read, he may not participate in the study. 
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 International Conference on 
Harmonization Good Clinical Practice (ICH-GCP) guidelines, as described above. 
6.1.2. Medical History 
Subjects' medical history should be fully documented at Screening Day (45 through 1 day 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 


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to, past and present medical conditions, concomitant non-drug treatments and hypersensitivity to 
drugs. 
6.1.3. Concomitant Medication 
All concomitant medication given 1 month 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 and changes should be updated from medical records as well.  
6.1.4. Physical Examination 
The investigator (or medically qualified nominee) will conduct a complete physical examination, 
at Screening Day (performed 45 through 1 days prior to baseline). Additional examination that 
will be performed during screening will include height and weight measurements to determine 
BMI in order to ensure compliance with study criteria. A skin type score using Fitzpatrick Skin 
Type will be performed. Skin type will be assessed prior to injection in order to determine skin 
sensitivity to treatment. 
The Fitzpatrick scale is based on 6 categories of skins as described below:  
Type I 
Light, Pale white  
Always burns, never tans 
Type II 
White, fair 
Usually burns, tans with 
difficulty 
Type III 
Medium, white to olive 
Sometimes mild burn, 
gradually tans to olive 
Type IV 
Olive, moderate brown 
Rarely burns, tans with 
ease to a moderate brown 
Type V 
Brown, Dark brown  
Very rarely burns, tans 
very easy 
Type VI  
Black, very dark brown to 
black 
Never burns, tans very 
easily, deeply pigmented  
 


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6.1.5. Weight Measurement  
Weight measurement will be performed at screening visit to determine BMI value prior to 
injection. An additional weight measurement will be performed at Baseline visit and on study 
visits at Day 56 and 84 following injection to verify that there are no significant changes in 
weight throughout the assessment of submental fat changes during the study.   
6.1.6. Vital Signs Measurements 
Subjects' vital signs will be measured at Screening Day (performed 45 through 1 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, the following day (Day 1) after drug injection and on study visits 
7, 14, 28, and 56 days following injection.  
6.1.7. Draize Score 
Subjects' skin irritancy will be evaluated by Draize score at baseline visit prior to injection 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 
2 hours ± 30min following injection, on the following visits days: 1, 7,14, 28, 56, and 84. 
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 
 


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6.1.8. 2D Standardized Photography  
Standardized photography (2 dimensional) of the face (submental fat area) will be applied at 
baseline visit prior to treatment in order to establish a baseline to compare following drug 
injection. 
Additional photography will be conducted on Days: 7, 14, 28, 56, and 84 to evaluate qualitative 
changes in submental fat area at study follow ups and to assist physician and subjects to assess 
treatment efficacy and satisfaction by comparison of images taken at each study visit vs. 
screening visit.  
Photographs will be taken with digital camera according to photography standards in 
dermatology surgeries for the face/neck area (See Appendix II). 
Lateral and anterior images of the face will be taken.  
6.1.9. MRI 
The aim of the MRI exam is to evaluate fat reduction before and following treatment. MRI 
exams will be conducted in imaging centers close to selected clinical sites. 
MRI will be conducted to all subjects enrolled into the study, at Screening Day (performed 45 
through 1 day prior to baseline) in order to establish a baseline to compare at study endpoint, and 
at Day 84.  
MRI (performed during screening period) will be conducted after subject qualifies on all 
screening criteria within a window of 5 days from the visit in the clinic. Post-treatment period 
MRI will be completed 84 days (± 5 days) after the subject’s last treatment session. 
Quantitative measurements such as fat volume of the submental fat area will be used as an 
objective parameter for submental fat reduction before and following treatment.  
Sagittal 2D and 3D images of the head and neck (chin area) will be obtained using 1.5 Tesla 
machine (General Electric or Siemens or Phillips). For each MRI acquisition visit, the total 
imaging time is expected to be approximately 30 minutes.  
During the imaging, subjects will be positioned in Head first Supine recumbent. Images in the 
sagittal plane across the entire submental region will be collected using an appropriate MR 
sequence to minimize the effects of air cavities, dental implants, and amalgam on the resultant 
MR image. This imaging approach will generate a 2D and 3D image data set that allows for the 
quantification of the submental fat volume in several slices covering the treatment area. In the 
follow up MRI exam slices will be positioned as similar as possible to the first MRI exam. MRI 
will be performed according to a detailed written manual.  


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Images should be saved in a DICOM format with the information of date and subject's screening 
number to be transferred by the Sponsor's request for central analysis.   
Submental volume analysis will be performed by computer-assisted tools to delineate the tissue 
boundaries and limits of the submental region and calculation of submental volume will be done 
before and following RZL-012 injection. 
6.1.10. Subject’s Satisfaction Rating following Treatment 
Subject’s satisfaction questionnaire will be collected by use of FACE-Q questionnaire 
(Copyright©2013 Memorial Sloan-Kettering Cancer Center, New York, USA), at baseline visit 
prior to injection and at posttreatment follow up visits Day 28, 56, and 84. 
The questionnaire will be filled following a comparison of 2D images taken at each time point 
and comparison to the images taken at baseline visit, prior to injection of RZL-012  
The comparison of the images at each study visit vs. baseline will be done by displaying the 
images of the images of the visit day vs. baseline on the computer.  
The FACE-Q questionnaire includes a list of 10 questions related to the chin visibility and 
degree of subject’s satisfaction from his/her chin at each question. Some of the scores reflect a 
better outcome. A Conversion Table to convert the raw scale summed score into a score from 0 
(worst) to 100 (best). See Appendix III for conversion table of FACE-Q questionnaire. 
The list of the questions of Face-Q questionnaire is described below: 
 


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6.1.11. Physician’s Evaluation of Improvement 
Physician evaluation of improvement will be conducted by using physician’s global assessment 
of submental fat at posttreatment follow-up visits, Days 28, 56, and 84 following injections. 
The evaluation will be made by the physician and based on comparison of the submental fat area 
of the subject at each visit time point to the 2D images that were taken at baseline visit, prior to 
injection of RZL-012.  
The assessment will grade the improvement in submental fat condition at each follow up time 
point Day 28, 56 and 84 vs. Baseline: 
Grade 
Description 
0 
Completely clear 
No evidence of submental fat volume; 100% 
improvement 
1 
Almost clear 
Very significant clearance (≥90% to <100%); only 
trace remain 
2 
Marked 
improvement 
Significant improvement (≥75% to <90%); some 
evidence of submental fat remains 
3 
Moderate 
improvement 
Intermediate between slight and marked improvement 
(≥50% to <75%) 
4 
Slight 
improvement 
Some improvement (≥25% to <50%); significance 
evidence of submental fat remains 
5 
No change 
Submental fat has not changed from baseline condition 
(±25%) 
6 
Worse 
Submental fat is worse than at baseline evaluation by 
≥25% or more  
 
6.1.12. Pregnancy Test 
Pregnancy test will be performed by women in the age of fertility to eliminate pregnancy prior to 
dosing at Baseline visit. 
At screening visit women will be asked whether they are pregnant, as part of exclusion criteria. 
6.1.13. Submental Fat Thickness using Calipers 
Prior to study entry, at screening visit, caliper measurement will be made with the subject’s head 
maintained in a neutral position. The caliper will be positioned to pinch the skin at 15 mm on 
either side of the center point of the submental area. 
Only subjects with skin fold larger than 1.5 cm will be enrolled into the study. 


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6.1.14. Adverse Events  
The information obtained via subjects questioning through the study visits, review of subject’s 
compliance record, evaluation of skin irritancy, vital signs measurements, 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.  
Twelve (12) subjects from cohort 1 (8 active and 4 placebo) will be injected with a maximal dose 
of 120 mg/subject or with up to 2.4 mL of vehicle. If no serious safety concerns will be noted 
within 28 days of follow-up post-dose of subjects from cohort 1, the study will proceed to the 
additional 16 subjects of cohort 2 that are designated to be injected with a maximal dose of 
240mg/subject for active treatment or up to 4.8 mL vehicle in at least 4  placebo subjects that 
will be randomized. 
The AEs reported during the trial will be graded (see Section 9), documented, and assessed in 
light of their clinical significance and relation to investigational product. Specifically, the 
tolerability and assessment of the AEs related to skin condition and injection procedure will be 
monitored among RZL-012 vs. placebo treated subjects: bruising, pain, induration erythema, and 
swelling/edema. 
Erythema and Edema will be assessed according to Draize Score, as described in Section 6.1.7.   
Pain will be assessed by using Numeric Rating Scale (NRS). NRS is an 11-point scale for patient 
self-reporting of pain, where 0 is no pain, rate 1-3 is mild pain, rate 4-6 is moderate pain and rate 
of 7-10 is severe pain, where 10 is worst pain imaginable.  
 
Induration will be assessed by palpation of submental fat area.   
Bruising will be assessed by visual inspection. 
Individual 4-point grading scales were implemented to provide greater specificity in the 
characterization of bruising and induration (4). 
 


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Table 3:  Grading scales of bruising and induration  
Grade 
Bruising 
Induration 
0 
No Bruising 
No Induration 
1 
Bruising associated with 1–3 
needle insertion points 
Induration associated with at 
least approximately 30% of 
the treatment area 
2 
Bruising spreading beyond 4 
or more individual needle 
insertion points but contained 
within the treatment area 
Induration associated with 
greater than approximately 
30% to at least 60% of the 
treatment area 
3 
Bruising covering the entire 
treatment area but contained 
within it 
Induration covering the entire 
treatment area but contained 
within it 
4 
Bruising of the neck and face 
beyond the treatment area 
Induration of the neck and face 
beyond the treatment area 
 
In addition, the following information regarding AEs 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 serious adverse event 
(SAE) expectedness based on data included in the IB. AE monitoring will be conducted 
throughout subject’s participation up to 84 days after injection.   
6.1.15. Evaluation of Response 
Evaluation of response will be conducted on Days 28, 56, and 84 following injection. 
6.1.15.1. Evaluation of Primary Endpoints 
6.1.15.1.1. 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 related to skin condition and injection procedure, general AEs and 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. 
3. Subjects questioning - full medical history during screening, routine AE reporting. 


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6.1.15.2. Evaluation of Secondary Endpoints 
6.1.15.2.1. Physician evaluation of treatment  
Evaluation of treatment response by physician and obtaining a low score among RZL-012 treated 
subjects vs. placebo treated subjects, as measured by a 7 grade scale. This will be conducted on 
Days 28, 56, and 84 follow up visits. 
6.1.15.2.2. MRI to calculate volume changes of submental fat 
MRI will be conducted at Screening Visit and on Day 84 visits to quantitively assess a change or 
reduction from baseline in submental fat dimensions (volumetric measurement).  
MRI (performed during screening period) will be conducted after subject qualifies on all 
screening criteria within a window of 5 days from the visit in the clinic. Post-treatment period 
MRI will be completed 84 days (± 5 days) after the subject’s last treatment session. 
Lower volume is expected to be measured 84 days following treatment among RZL-012 treated 
subjects and no change or minor change in submental fat volume is expected in placebo treated 
subjects. This will be served as an objective parameter to asses treatment efficacy.  
6.1.15.2.3. Subject’s Satisfaction Questionnaire at earlier timepoints than study termination 
Evaluation of subject’s treatment satisfaction by using the Face-Q satisfaction questionnaire 
rating score at each of the follow ups visit compared to baseline. The evaluation will be 
conducted at baseline visit and on Day 28, 56, and 84 following injection. A higher grade 
following the use of conversion table of the questionnaire is expected among RZL-012 treated 
subjects compared placebo at follow ups visits vs. baseline.  
6.1.15.3. 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. 
6.1.15.4. 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). 


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6.1.15.5. 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. 
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 should be performed 45 days ahead and no later than 1 day prior to baseline visit 
for the two study cohorts.  
Study Screening Day 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 
• Weight Measurement – Section 6.1.5 
• Vital signs Measurement –Section 6.1.6 
• MRI – Section 6.1.9 
• Pregnancy elimination – Section 6.1.12 
• Caliper measurement of submental fat thickness – Section 6.1.13 
Subjects may be rescreened if they were screened and not dosed within 45 days.  The following 
procedures will be performed: vital signs, weight measurements. 
6.2.2. Study Randomization 
Subjects will be randomized to each study group, i.e., investigational therapy or control, 
according to a predefined randomization scheme in a ratio of 2:1 (active:placebo) among the 


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2 clinical sites and per each study cohort. 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. 
Assignment to study group will be disclosed only after subject eligibility is confirmed and 
immediately before treatment initiation. The investigator and clinical staff will be unmasked and 
will be responsible to fill the syringes for injection. The subject will be blinded and will not 
know whether he is injected with active or placebo treatment. 
6.2.3. Study Treatment 
6.2.3.1. 
Treatment with RZL-012 Investigational Drug to Submental Fat 
RZL-012 or placebo is an investigational product supplied as a single treatment in multiple sites 
of injections (48 injections).  
The injection dosing regimen and technique is crucial for the therapy safety.  
The following procedures prior to injection into the submental fat will be applied: 
1. The lower face and anterior neck will be cleaned with an appropriate topical antiseptic.  
2. Ice/cold pack or topical local anesthesia (i.e., lidocaine cream) may be used prior to RZL-
012 administration to enhance subject’s comfort.   
3.  The treatment area will be bounded superiorly by a line 1 cm inferior to the mandibular 
margin, laterally by the sternocleidomastoid muscles, and inferiorly by the hyoid bone. 
4. Injection grid pattern will be applied by pressing the grid firmly onto the clean dry skin, 
where the printed grid pattern facing the skin. The grid paper backing will be thoroughly 
wetted with a cotton pad soaked with sterile water. Following 15 seconds waiting, the 
grid cover will be peeled off.  
5. The number of injections and injection volume in each cohort will be determined 
following physician’s evaluation.  
6. Syringes will be filled with 0.5 mL (Cohort 1) or 1 mL (Cohort 2) RZL-012 or vehicle 
and the number of syringes will be compatible with the total volume of injection. Up to 
5 syringes for a total volume of 2.4 mL (each syringe having a volume of 0.5 mL) or up 
to 5 syringes (each syringe having a volume of 1 mL) for a total volume of 4.8 mL. See 
table below for details on injection of both cohorts: 


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Cohort 
Syringe 
volume 
Injection 
volume of 
RZL-
012/placebo 
No. of 
injections 
Total injected 
volume of 
RZL-012 or 
placebo 
Amount of 
injected RZL-012 
1 
0.5 ml 
0.05 ml 
Up to 48 
Up to 2.4 mL 
Up to 120 mg 
2 
1 ml 
0.1 ml 
Up to 48 
Up to 4.8 mL 
Up to 240 mg 
 
7. All injections will be administered diagonally in 90°, using a 0.5 mL syringe (Cohort 1) 
or 1 mL (Cohort 2) Luer-lock syringe and a 29/30 G x 1/2" needle, respectively. 
8. The hole of the needle should be pointing into the fat layer and the injection direction 
should be towards the earth. 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 viscous; therefore, a resistance is expected 
while injecting. 
9. Immediately following completion injection of the submental fat, an ice/cold pack will be 
applied for immediate pain relief. It will be held by the subject for at least 2 minutes. 
10. The physician will record the number of injections administrated for each subject, at each 
cohort.  
In Cohort 1, the first 8 subjects randomly assigned to the RZL-012 treatment group will initiate 
at the dose of 2.5 mg (0.05 mL volume of RZL-012 solution) RZL-012 in a single injection 
(resulting in a total of up to 120 mg) in a series of maximum 48 injections. Additional 4 subjects 
will be given placebo (vehicle) in a volume of 0.05 mL in a single injection, resulting in a 
maximal volume of 2.4 mL injected into the submental area. 
In Cohort 2, an additional 16 subjects randomly assigned to the RZL-012 treatment group will 
initiate at the dose of 5 mg (0.1 mL volume of RZL-012 solution) RZL-012 in a single injection 
(resulting in a total of up to 240 mg) in a series of maximum 48 injections, where at least 4 
subjects will be given placebo (vehicle) in a volume of 0.1 mL in a single injection, resulting in a 
maximal volume of 4.8 mL. 
The injection pattern that will be used in both cohorts will be based on existing grid in the shape 
of submental area, where distance between injection rows will be 1cm and distance between 
injection columns will be 1cm as seen in Figure 5, Section 3.3.1.  


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The amount of injections for each subject will be decided by the physician according to the 
fullness of submental fat. 
In cases where the physician will have to inject a total number of 48 injections, the physician will 
choose two points in the edge of the grid pattern that will not be injected (The grid contains 
50 injections points). 
If no serious safety concerns will be noted by DSMB within 28 days of follow-up post-dose of 
subjects from Cohort 1, the study will proceed to cohort 2 where an additional 16 subjects will 
receive active treatment where at least 4 out of the 16 subjects will be injected with vehicle. 
Each RZL-012 kit contains 1 vial (250 mg/5 mL) corresponding to the number of subjects 
receiving treatment in each cohort. 
RZL-012 will be injected on Day 0 study visit (baseline). 
Following completion of injections, an ice pack will be placed on the injected area for pain relief. 
Subject will have to remain seated in the injection position for an additional 10 minutes after 
dosing. Following completion of injection procedures, subjects will remain in the clinic for an 
additional 2 hours±30min for medical supervision and in order to follow adverse events 
following injection. During the stay in the clinic there are no restrictions in terms of activity or 
diet.   
6.2.4. Treatment with Placebo 
Four (4) subjects randomly assigned to the study in every cohort 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).  
6.2.5. 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 under supervision in the study center till 2 hours ± 30 minutes following drug 
injection. 
Screening information may be considered for baseline data if acquired within the adequate 
timeframe as described in Table 4. 


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Table 4:  Subject Information and Timeframes 
Information 
Timeframe 
Follow-up Timeframe 
Informed Consent Form 
Signed prior to any study 
dedicated procedure 
 
Medical History  
At Screening Day visit 
 
RZL-012 dosing 
At baseline 
 
Concomitant Medications 
At screening Day visit and at 
baseline, Day 1, 7, 14, 28, 56, 
and 84 
 
Physical examination  
At Screening Day visit 
 
Weight measurement 
At screening visit, baseline, day 
56 and 84 
 
Vital Signs  
At Screening Day visit and at 
Days 0, 1, 7, 14, 21, 28 and 56 
 
Pregnancy test (women only) 
Will be performed at Baseline 
 
Caliper measurement of submental thickness Will be performed at Screening 
day 
 
Subject’s satisfaction questionnaire (FACE-
Q) 
At baseline and at Days 28, 56 
Day 84 
Physician evaluation of treatment using 
Physician’s global assessment questionnaire 
At Day 28 and 56 
Day 84 
MRI 
At Screening  
Day 84 
Photography of submental fat 2D  
At  Baseline, Day 7,14,28 
On 56 and 84 
Draize Score at the Injected Site 
At Baseline visit (pre- and 
following injection) and on Day 
1, 7, 14, 28, 56 
Day 84 
AE Assessment for submental fat skin area 
(pain, bruising and induration grading) and 
general AEs 
At Days 0 (pre- and following 
injection), 1 7, 14, 28, 56 
Day 84 
 
6.2.6. Subject Site Visits 
Subject site visits will be performed ± 1 day from scheduled date (for study visits at Days 7, 14, 
28, 56, and 84).  
For site visit that results in study discontinuation, see termination visit in Section 6.2.7. 
6.2.7. 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:  


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AE reporting, evaluation of response and updating of subject contact information. An effort 
should be made to perform all activities conducted on visit Day 84. 
6.2.8. 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 at least 3 months prior to study entry:  
• Chronic treatment with systemic steroids or immunosuppressive drugs.  
• Any investigational product other than RZL-012.  
Subjects may not receive the following medications at least one week prior to study entry:  
• Chronic treatment with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).  
Before dosing, topical analgesic gels such as Lidocaine (e.g., Emla) or Pramoxine may be used 
to numb the injected site. An ice pack should be applied on the site of injection immediately 
following dosing to help reduce pain.   
At Day 1 following injection application of the antihistamine Benadryl Gel (Diphenhydramine 
hydrochloride 1% for topical use only) may be initiated prophylactically, according to drug 
instructions for use, to avoid itching at the injected area. Benadryl Gel should be applied for 
7 days or as needed.  
7.2. 
SAFETY MEASUREMENTS  
Safety measurements will be performed by monitoring the specific skin AEs: bruising, pain, 
induration, erythema and swelling/edema that have been identified as being associated with the 
use of RZL-012 investigational product. The AEs of RZL-012 vs. placebo will be evaluated for 
their frequency, severity and duration.  


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7.3. 
PREMATURE DISCONTINUATION FROM STUDY 
Study will be prematurely discontinued in any of the following cases:  
• Subject's request.  
• Any life-threatening AE may cause prematurely discontinuation.  
• Systemic hypersensitivity reaction may cause premature discontinuation.  
• Any serious or severe 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 AE 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 


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before they can be implemented. Accordingly, the Sponsor will not assume responsibility or 
liability for any unauthorized deviation from or change to the protocol. 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS 
8.1. 
DESCRIPTION OF RZL-012 
RZL-012 investigational drug is intended to be administered as a single dose via multiple 
injections into the subcutaneous fat. The injection dosing regimen and technique is crucial for the 
therapy efficacy and safety. 
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/5 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 5 mL of formulation F12. 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE  
The RZL-012 kit and vehicle will be stored in the site at monitored room temperature conditions 
(22 ± 7 ᵒC) protected from light. Storage space will be separate, designated and adequately 
labeled as containing investigational product.  
Drug product stability has successfully reached 3 years. 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 5. 
Table 5:  RZL-012 Storage Conditions  
Storage Conditions 
Maximal Storage Duration 
Individual vials:  
Room temperature (15-30 ᵒC) 
According to expiration date as will be 
provided by manufacturer. 
*  Drug product stability program has successfully reached 3 years. 
 


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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/5 mL. 
The vehicle is available in vials of 5 mL. 
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 syringe or 0.5mL syringe with RZL-012 solution should be filled with 30/29 G 
1/2" sterile needle as described below: 
• Cohort 1 – a maximal dose of 120 mg:  
A maximum of 48* 0.05 mL/ subject results in filling of up to 5 syringes in the volume of 
0.5mL, prior to injection.  
• Cohort 2 – a maximal dose of 240 mg:  
A maximum of 48* 0.1 mL/ subject results in filling of up to 5 syringes in the volume of 
1 mL, prior to injection.  
One vial will be used for dosing of one 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 were done by Nextar (Israel) and complies 
with cGMP requirements. 
The vehicle was manufactured and packed by Nextar (Israel) 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. 


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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.  
9. 
ADVERSE EVENTS 
9.1. 
ADVERSE EVENT DEFINITIONS 
9.1.1. Definition of 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. 


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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 ADRs. 
9.2. 
ADVERSE EVENT GRADING 
AE will be documented in each study visit.  
AEs severity 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  
All AEs will be evaluated by the investigator and assigned an estimated relationship to the 
RZL-012 investigational product. The terms "related” or "unrelated" refer to the association with 
the use of the investigational product, as defined below in Table 6.  
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 6). 


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Table 6:  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.) 
 
 
 
▪  
 
 
▪  
 
 
▪  
Related 
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with high degree 
of certainty to be related to the 
study procedures/investigational 
product. 
An AE may be considered 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. 
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). 
9.5. 
ADVERSE EVENT REPORTING AND MONITORING REQUIREMENTS 
9.5.1. General 
All AEs, serious and non-serious, will be fully documented in both source documents and CRFs 
as described in Section 6.1.14, and each AE will be assessed in light of its clinical significance.  
For each AE, 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 AE page of the CRF. All AEs 
occurring until subject is terminated from the study (84 days after the injection of RZL-012), 
should be captured in the CRF. AEs should be recorded in the CRF using the medical 


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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 serious or severe ADR must warrant clinical evaluation by the treating 
investigator and reported to the Sponsor/medical monitor within 24 hours.  
ADRs 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:  
Dr. Sarina Tanimoto, RazielSafety@pacificlinkconsulting.com or fax: 858-769-0288. 
An initial report must be faxed or emailed to RazielSafety@pacificlinkconsulting.com  fax: 858-
769-0288 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.  
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 AEs 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 


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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.  
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 
This study is planned as a single blind, randomized, placebo-controlled, Phase 2a, 2-cohort study 
for the treatment of submental fat. Eligible subjects will be randomized to receive either RZL-
012 or placebo (vehicle) in each study cohort and will be monitored for safety and efficacy 
during 84 days of follow up. 
Primary objective:   
The main objective is to evaluate safety following injection of RZL-012 vs. placebo into 
submental fat. Skin irritancy and AEs related to the injection procedure will be evaluated for 
frequency, severity and duration. Specifically, tolerability and assessment of the following AEs 
will be monitored: bruising, pain, induration erythema and swelling/edema.  
Secondary Endpoints: 
Secondary endpoints will test the efficacy of RZL-012 vs. placebo according to the following 
measures: 
1. Improvement of Physician’s global assessment questionnaire for treatment efficacy in 
active vs. placebo treated subjects at Day 28, 56 and 84 following injection. 
2. Reduction from baseline in submental fat volume as measured by MRI, in RZL-012 treated 
subjects vs. placebo treated subjects at Day 84 following injection. 
3. Improvement from baseline in the self-assessment of submental fat using the Face-Q 
satisfaction questionnaire rating score in RZL-012 treated subjects vs. placebo treated 
subjects on Days 28, 56 and 84.  


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10.2. STUDY ENDPOINTS 
10.2.1. Primary Safety Endpoints 
Skin AEs will be evaluated for their frequency, severity and duration. Specifically, the 
assessment of the following AEs will be monitored among RZL-012 vs. placebo treated subjects: 
bruising, pain, induration, erythema, and swelling/edema. 
10.2.2. Secondary Efficacy Endpoints 
Secondary efficacy endpoints include testing of RZL-012 vs. placebo according to the following 
measures: 
• Improvement in Physician’s global assessment questionnaire for treatment efficacy 
assessment at Day 28, 56, and 84 following injection. 
• Improvement from baseline in a quantitative measure of submental volume as measured 
by MRI, before and 3 months after injection. 
Improvement from baseline in score of FACE-Q questionnaire rating subject’s 
satisfaction on Day 28, 56, and 84 follow up visits. 
10.2.3. Safety and Tolerability Endpoints 
Safety endpoints include: 
• Incidence of AEs and SAEs, by severity and relation to study treatment of RZL-012 vs. 
placebo treated subjects. AEs will be coded using MedDRA version 22 (or higher).  
• Specific AEs will be closely monitored: bruising, pain, induration and swelling/ Edema 
and Erythema (Draize Score).  
• Vital signs  
10.3. SAMPLE SIZE JUSTIFICATION 
A maximum of 28 evaluable subjects will be included in the study (12 cohort 1 and 16 in cohort 
2) and followed for as long as 3 months. 
This study is planned as a dose escalation study following randomization of 8 subjects per active 
dose group paradigm with the addition of a 4 subjects vehicle control group at cohort 1 
(active/placebo ration of 2:1). At cohort 2, out of the 16 subjects that will be randomized, at least 
4 subjects will receive placebo treatment.   


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Selection of sample size of 12/16 at each cohort was based on discussions with physicians and is 
similar in numbers to that encountered in the literature for treatments at this stage of 
development.  
10.4. ANALYSIS SETS 
10.4.1. Safety Analysis Set (SA) 
The SA will consist of all enrolled subjects who received the study treatment, (exposed 
population), including subjects prematurely withdrawn. 
All enrolled subjects receiving the study drug injection are considered evaluable for the SA set. 
10.4.2. Efficacy Analysis Set (EF) 
The 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. 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. 
10.5. STATISTICAL ANALYSIS 
10.5.1. General  
Statistical analyses will be mainly descriptive in nature where study data will be tabulated and 
summarized using the mean, standard deviation or standard error. The results will be presented 
overall per cohort and per treatment.  
AEs related to injection and Draize scores will be presented in tabular format by visit, cohort and 
treatment. 
Improvement in Global physician’s scale score pf RZL-012 treated subjects vs. placebo treated 
subjects by cohort and overall. 
The average change from baseline in submental volume as analyzed from MRI images will be 
presented in a tabular form by treatment received (RZL-012 / placebo) by cohort and overall. 


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The average change in Face Q questionnaires score from baseline will be presented in a tabular 
form by treatment received (RZL-012 / placebo) by cohort and overall. 
Any statistical tests will be two-sided. The required significance level (p value) of findings will 
be equal to or lower than 5%.   
10.5.2. Subject Disposition 
A detailed description of subject accountability including count of subjects included, exposed, 
completed (i.e., subjects who complete the study treatment) and discontinued along with the 
main reason for discontinuation will be generated for each treatment group 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 4.5 months, with efficacy 
analyses being conducted at Day 28, 56, and 84 visits. 
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. 
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 SAEs considered related to treatment will be presented overall and by study 
cohort. 
10.5.5. Efficacy Analysis 
The change from baseline of submental fat volume will be presented in tabular form by treatment 
and dose. 
The changes from baseline in FACE-Q score as a function of treatment group will be presented 
in tabular form per treatment group and dosing group.  
10.5.6. Safety and Tolerability 
Safety analyses will be descriptive in nature.  


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All reported AEs will be coded to a standard set of terms using MedDRA coding dictionary 
(V.22 or higher) treatment.  
AEs and tolerability data will be presented descriptively by study cohort. AEs will be tabulated 
by body system, preferred term, seriousness, severity and relation to study drug by cohort. 
10.6. HANDLING OF MISSING DATA 
No imputation of missing data will be performed. 
10.7. INTERIM ANALYSIS 
No interim analysis is planned. 
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.  
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, ICFs, safety reports, subjects' CRF, and any other pertinent data. All records are to be 
retained by the investigator for a period of seven 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' 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 to 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 a Clinical Research 
Organization (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, at each site. 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 IB, 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 CRFs 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.  


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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 
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-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. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, randomized, double-
blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat 
reduction. Dermatol Surg. 2016;42:38–49. 
2. Duncan D, Rotunda AM. Injectable therapies for localized fat loss: state of the art, clinics in 
plastic surgery. Clin Plast Surg. 2011;38:489–501.  
3. Humphrey et al, ATX-101 for reduction of submental fat:A phase III randomized controlled 
trial,  J AM ACAD DERMATOL Volume 75, Number 4 (2016), PP 788-797. 
4. Dover et al, Management of Patient Experience With ATX-101 (Deoxycholic Acid Injection)  
    for Reduction of Submental Fat, American Society for Dermatologic Surgery, 
    42:11S:NOVEMBER SUPPLEMENT 2016 
 
 


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APPENDIX I:  TRIAL SCHEDULE OF EVENTS 
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
b. 
Including Fitzpatrick skin type, height, BMI 
c. 
At screening visit women will be asked whether they are pregnant, test will be performed at baseline visit before dosing 
d. 
MRI (performed during screening period) will be conducted after subject qualifies on all screening criteria within a window 
of 5 days from the visit in the clinic. Post-treatment period MRI will be completed 84 days (± 5 days) after the subject’s last 
treatment session. 
e. 
Pre/post – refers to before/after injection, respectively 
 
Study Procedure 
Screening Day  
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Study Daya 
Day (-45) 
through Day (-
1) 
Day a 0 
Day 
1 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
Day 
84 
Signed informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical Examb 
X 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy kit test (women)c 
 
X 
 
 
 
 
 
 
Caliper measurement of 
submental fat 
X 
 
 
 
 
 
 
 
Weight measurements 
X 
X 
 
 
 
 
X 
X 
Vital signs  
X 
Pred X post d 
X 
X 
X 
X 
X 
 
Injection of RZL-012 
 
X 
 
 
 
 
 
 
Physician’s global assessment 
questionnaire 
 
 
 
 
 
X 
X 
X 
Subject’s satisfaction 
questionnaire ( FACE-Q ) 
 
X 
 
 
 
X 
X 
X 
2D Standardized photography 
 
X 
 
X 
X 
X 
X 
X 
MRI 
Xd 
 
 
 
 
 
 
X 
Draize Score  
 
Pre e X post e 
X 
X 
X 
X 
X 
X 
AEs (including  pain bruising 
and induration grading  ) 
assessment 
 
X 
X 
X 
X 
X 
X 
X 


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APPENDIX II:  PHOTOGRAPHIC STANDARDS OF THE FACE AREA 
 
 
 
 
 


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APPENDIX III:  CONVERSION TABLE FACE-Q QUESTIONNAIRE SUMMED 
SCORE A SCORE FROM 0 (WORST) TO 100 (BEST)