Clinical trial NCT04867434
Conditions: Submental Fat
Sponsor: Raziel Therapeutics Ltd.
Start date: 2021-06-15; Completion date: 2022-05-31
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A total of 135 eligible male or female subjects will be randomized according to a predetermined randomization scheme (1:1:1 ratio) to receive a single multi-injection treatment of high dose RZL-012, low dose RZL-012, or placebo on Day 0. They will be monitored for safety and efficacy over 84 days.

Detailed description:
Each subject will be randomized to either active treatment (high or low dose RZL-012) or placebo at a ratio of 1:1:1 per group and receive one of the following:

* low dose (concentration of injected solution 34 mg/mL RZL-012) of 5.1 mg/0.15 mL/injection point that results in a dose/volume of 163.2±20.4 mg/4.8±0.6 mL RZL-012,
* high dose (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 mL/injection point that results in a maximum total dose/volume of 240±30 mg/4.8±0.6 mL RZL-012,
* placebo of 0.15 mL/injection point that results in a total maximum volume of 4.8±0.6 mL.

Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. The maximal number of injections will be 36 with maximal doses of 183.6 mg and 270 mg for the low and high doses, respectively. Each injection point will be dosed with 5.1 mg RZL-012 for the low dose or 7.5 mg for the high dose in a volume of 0.15 mL/injection site. Placebo (vehicle) subjects will be injected with a 0.15 mL vehicle per each injection site. The maximal injection volume for all groups will be up to 5.4 mL.

Arms: arm 1: Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. The maximal number of injections will be 36 with maximal doses 270 mg for the high doses. Each injection point will be dosed with 7.5 mg for the high dose in a volume of 0.15 mL/injection site. arm 2: Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. The maximal number of injections will be 36 with maximal doses of 183.6 mg for the low dose. Each injection point will be dosed with 5.1 mg RZL-012 for the low dose in a volume of 0.15 mL/injection site. arm 3: Placebo (vehicle) subjects will be injected with a 0.15 mL vehicle per each injection site. The maximal injection volume for all groups will be up to 5.4 mL.
Interventions: intervention 1: RZL-012 intervention 2: Placebo
Intervention descriptions: intervention 1: small synthetic molecule for submental fat reduction intervention 2: Placebo

Protocol documents:
SAP_002.pdf: 
A DOUBLE BLIND, RANDOMIZED, THREE-ARM, PLACEBO-CONTROLLED 
PHASE 2b STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RZL-012 
IN SUBJECTS SEEKING SUBMENTAL FAT REDUCTION 
 
A DOUBLE BLIND, RANDOMIZED, THREE-ARM, PLACEBO-CONTROLLED 
PHASE 2b STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RZL-012 
IN SUBJECTS SEEKING SUBMENTAL FAT REDUCTION 
 
 
 
 
NCT04867434 
 
08 March 2022 
 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 1 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
  
Revision History 
 
Revision 
Revision Date 
Reason for Revision/Change Request 
Revised By 
1.0 
08/03/2022 
Original Release 
Alexandra Perez-Alterman , 
Senior Biostatistician 
 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 2 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
 
 
Statistical Analysis Plan 
                                  Study Title:  
 
A double blind, randomized, three-arm, placebo-controlled Phase 2b study to evaluate the 
efficacy and safety of RZL-012 in subjects seeking submental fat reduction 
Study RZL-012-SMF-P2bUS-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 3 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
TABLE OF CONTENTS 
 
SIGNATURES PAGE .................................................................................................................... 4 
1. 
DEFINITIONS AND/OR ABBREVIATIONS ...................................................................... 5 
2. 
PURPOSE ............................................................................................................................... 7 
3. 
SCOPE .................................................................................................................................... 7 
4. 
RESPONSIBILITies ............................................................................................................... 7 
5. 
PROCEDURE ......................................................................................................................... 8 
6. 
Statistical Analysis ................................................................................................................ 13 
7. 
RELATED DOCUMENTS (optional) .................................................................................. 15 
8. 
RELATED FORMS (optional) ............................................................................................. 15 
9. 
REFERENCES ..................................................................................................................... 16 
10. 
Appendices ......................................................................................................................... 16 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 4 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
SIGNATURES PAGE 
Author : Alexandra Perez-Alterman  
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 28/04/2022 
 
Reviewer: David Israel 
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 28/04/2022 
 
 
Approved by: Racheli Gueta 
Raziel Therapy Ltd.                                                                         Date: 28/04/22 
 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 5 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
1. DEFINITIONS AND/OR ABBREVIATIONS  
ADR 
Adverse drug reaction 
AE 
Adverse event 
BMI 
Body Mass Index 
C-CAT 
Clinical Chin Assessment Tool 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence Interval 
CRF 
Case Report Form 
ECG 
Electrocardiograms 
GAIS 
Global Aesthetics Improvement Scale 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical Practice 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No observed adverse effect level 
PI 
Principal Investigator 
PP 
Per-Protocol 
QA 
Quality Assurance 
QOL 
Quality of life 
S-CAT 
Subject  Self-Chin Assessment Tool 
SAE 
Serious adverse event 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 6 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SMF 
Submental fat 
TEAE 
Treatment emergent adverse event(s) 
US/USA 
United States/United States of America 
WHO 
World health organization 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 7 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
2. PURPOSE 
The purpose of this statistical analysis plan (SAP) is to describe in detail the statistical analyses 
to be conducted by Medistat Ltd on data generated from the clinical trial sponsored by Raziel 
Therapeutics Ltd. (clinical trial RZL-012-SMF-P2bUS-001).  
This SAP aims to provide details on: sample size calculation, efficacy analyses and safety 
analyses. 
3. SCOPE 
This document applies to all members of the statistical & data management units in Medistat Ltd.  
This document includes the main study trial analyses. 
4. RESPONSIBILITIES 
Medistat Ltd. Responsibilities  
The following personnel are responsible for these activities: 
Activities 
Responsible and 
accountable 
Title 
Statistical Analysis Plan 
(SAP) 
Alexandra Perez-Alterman 
Senior Biostatistician 
& SAS Programmer 
Statistical Report and listing  
Alexandra Perez-Alterman 
Senior Biostatistician 
& SAS Programmer 
Quality Assurance (QA)  of 
SAP and programs 
David Israel 
Senior Biostatistician 
& SAS Programmer 
Quality Assurance (QA)  of 
final report 
David Israel 
Quality & Data 
Assurance Manager 
 
 
Raziel Therapeutics’s Responsibilities 
To review and approve the SAP and related documents prior to database lock 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 8 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
5. PROCEDURE  
• Introduction 
This Statistical Analysis Plan (SAP) is based on RZL-012-SMF-P2bUS-001study protocol 
version 1.6, dated 08 March 2022 
This Statistical Analysis Plan (SAP) contains details of the statistical analyses that will be 
performed, providing a more detailed description of the approach defined in the study protocol. 
Definitions of variables and populations used for the analyses are also included. The SAP will be 
finalized and signed prior to hard lock of the database. 
General output specifications are provided; examples are given of calculations of derived 
variables. 
• Study Objectives and Endpoints 
 
Primary Objective 
To determine the efficacy of RZL-012 versus placebo on submental fat (SMF) reduction 
measured on Day 84 versus baseline using the Clinician Assessment Tool (C-CAT).  
 
Secondary Objectives 
To determine the efficacy of RZL-012 versus placebo on SMF reduction measured on Day 84 
versus baseline using both the Subject Self-Chin Assessment Tool (S-CAT) and the Clinician 
Assessment Tool (C-CAT).;  
To assess the reduction in SMF on Day 84 versus baseline using the caliper measured submental 
thickness and magnetic resonance imaging (MRI); 
To assess the safety of RZL-012 in the treatment of SMF reduction. 
 
Primary Endpoint 
Comparison of the proportion of subjects who have at least a 1-grade improvement in the C-CAT 
on Day 84 versus baseline between the RZL-012 high dose (270 mg/5.4 mL) group and the 
placebo group. 
Secondary Endpoints: 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 9 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
- 
Proportion of subjects who have at least a 1-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
- 
Proportion of subjects who have at least a 2-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
- 
Reduction in SMF volume by MRI (Day 84 versus screening) in the RZL-012 groups 
versus placebo group. 
- 
Reduction in SMF thickness measured with caliper (Day 84 versus baseline) in the RZL-
012 groups versus placebo group.Safety assessment of RZL-012 in the treatment of SMF 
reduction. 
- 
safety of RZL-012 in the treatment of SMF reduction. 
 
Exploratory endpoints: 
- 
Physicians Global Assessment 
- 
SMF improvement using the Global Aesthetic Improvement Scale (GAIS). 
- 
Subject Global Self-Assessment 
- 
SMF improvement using the Subject Global Assessment of Change Scale. 
- 
SMF improvement using the subject’s satisfaction questionnaires. 
- 
SMF improvement using Subject’s impact questionnaire. 
 
• Study Design 
This is a Phase 2b, double-blind, randomized, three-arm, placebo-controlled study that consists 
of a screening period, baseline period, and a randomized treatment period.  Subjects receive a 
single treatment session that consists of multiple injections of RZL-012 or placebo into the 
submental area under the chin, after which they are monitored for safety and efficacy over 84 
days. 
Following the completion of  Day 84 visit of the last subject, subjects from three (3) chosen 
clinical sites are followed up to a 1 year after injection to evaluate the long term safety and 
efficacy. The additional follow up visits are conducted at 6 and 12 months after injection. 
Study participants are adult volunteers (135 subjects - 45 subjects per group) of 18 to 65 years of 
age who have consented to participate in this study. Each subject is randomized to either active 
treatment (high or low dose RZL-012) or placebo at a ratio of 1:1:1 per group and receives one 
of the following: 
- 
low dose (concentration of injected solution 34 mg/mL RZL-012) of 5.1 mg/0.15 
mL/injection point (32±4 injection points) that results in an average total injected 
dose/volume of 163.2±20.4mg/4.8±0.6 mL RZL-012. 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 10 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
- 
high dose (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 
mL/injection point (32±4 injection points) that results in an average total injected 
dose/volume of 240±30mg/4.8±0.6mL RZL-012. 
- 
placebo of 0.15 mL/injection point (32±4 injection points) that results in an average total 
injected volume of 4.8±0.6mL. 
 
• Schedule of Assessments 
Study Procedure 
Screening 
Day  
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Additional follow up of RZL-
012 treated subjects (6 and 12 
months after injection) 
Study Daya 
Day (-28) 
through 
Day (-1) 
Day a 0 
Day 
1 
Day 7 
Day 28 
Day 56 
Day 84 
6 months 
12 months 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical Examb 
X 
 
 
 
 
 
X 
Xh 
Xh 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy ß-hCG 
X 
 
 
 
 
 
 
 
 
Pregnancy urine test 
(women)c 
 
X 
 
 
 
 
 
 
 
Caliper 
measurement of 
submental fat 
X 
 
 
 
X 
X 
X 
 
 
Weight 
measurements  
X 
X 
 
 
 
X 
X 
 
 
Hematology and 
Chemistryd 
X 
 
X 
X 
X 
 
X 
 
 
ECG 
X 
 
 
X 
 
 
X 
 
 
Vital signs  
X 
Pree X poste 
X 
X 
X 
X 
 
 
 
Injection of RZL-
012 
 
X 
 
 
 
 
 
 
 
Clinician Chin 
Assessment Tool 
(C-CAT) 
X 
X 
 
 
X 
X 
X 
X 
X 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 11 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
b. 
Including Fitzpatrick skin type, height, BMI 
c. A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at screening and a urine pregnancy test 
will be administered at baseline prior to dosing  
d. In case of clinically significant values at any visit, an unscheduled visit will be added 
e. Pre/post – refers to before/after injection, respectively 
f. MRI (performed during screening period) will be conducted after subject qualifies on all screening criteria within a window of 10 
days from the visit in the clinic. Post-treatment period MRI will be completed 84 days (± 7 days) after the subject’s last treatment 
session. 
g. Subjects will be asked on their neck appearance satisfaction at screening visit 
h. Physical exam will be done only to the treated area 
 
 
 
Study Procedure 
Screening 
Day  
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Additional follow up of RZL-
012 treated subjects (6 and 12 
months after injection) 
Study Daya 
Day (-28) 
through 
Day (-1) 
Day a 0 
Day 
1 
Day 7 
Day 28 
Day 56 
Day 84 
6 months 
12 months 
Subject- Self-Chin 
Assessment Tool 
(S-CAT) 
X 
X 
 
 
X 
X 
X 
X 
X 
Physician Global 
Assessment 
Improvement Scale 
(GAIS) and 
physician global 
assessment 
X 
 
 
 
X 
X 
X 
 
 
Subject’s 
Satisfaction 
questionnaire for 
SMF appearance 
Xg 
 
 
 
X 
X 
X 
 
 
Subject’s impact 
questionnaire 
X 
 
 
 
X 
X 
X 
 
 
Subject Global 
Assessment of 
Change and subject 
self assessment 
X 
 
 
 
X 
X 
X 
 
 
2D Standardized 
photography 
X 
 
X 
X 
X 
X 
X 
X 
X 
MRI 
Xf 
 
 
 
 
 
X 
 
 
AEs  
 
X 
X 
X 
X 
X 
X 
X 
X 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 12 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
• Rationale Sample Size Calculation 
For the primary endpoint (proportion of high dose group subjects who have at least a 1-grade 
improvement from baseline to Day 84 on the C-CAT scale), the assumed true rates are 70% in 
the RZL-012 high dose group and 35% in the placebo group (a difference of 35 percentage 
points). Based on the use of a two-sided test of equality of binomial proportions at the 
alpha=0.05 level of significance, 41 subjects per group are required at 90% power. In order to 
account for a dropout rate of up to ~9%, the planned sample size is 45 subjects per group, for a 
total sample size of 135 subjects. 
 
• Statistical Analysis Software and Data Management 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed using SAS® version 9.4 or higher for Windows. If 
the use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
• Data Management 
Data management for the study is performed by Medistat. 
 
• Medical Coding 
Concomitant medications entered into the database  are coded using the WHO (World Health 
Organization) Drug Public Website Dictionary named WHOCC-ATC/DDD index, which 
employs the Anatomical Therapeutic Chemical classification system.  
Adverse events are coded using the most updated version of Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. 
Medical history events are coded using the most updated version of Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. 
• Handling of Missing data 
Every effort will be made to obtain all data from all subjects who have been enrolled, to 
minimize missing data.  
A subject with missing primary endpoint data will be imputed as treatment failure. 
• Subject Population for analyses 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 13 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
The Intent-to-treat population  (ITT) will consist of all enrolled subjects who received the study 
treatment, (exposed population), including subjects prematurely withdrawn. The ITT population 
will serve as the principal data analysis set for analyses of efficacy and safety endpoints. Subjects 
will be analyzed according to the treatment received 
The Per-Protocol population (PP) will consist of all subject included in the ITT population who 
were rated for both S-CAT and C-CAT on both baseline and day 84 visits. The PP population 
will serve as a sensitivity analysis of the efficacy endpoints. 
 
6. STATISTICAL ANALYSIS 
• General 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics.  
For categorical variables, summary tables will be provided giving sample size, absolute and 
relative frequency and 95% CI (Confidence Interval) for proportions by study group. 
For continuous variables, summary tables will be provided giving sample size, arithmetic mean, 
standard deviation, coefficient of variation (CV%), median, minimum and maximum and 95% 
CI (Confidence Interval) for means of variables by study group.  
All tests will be two-tailed, and a p value of 5% or less will be considered statistically 
significant. 
The data will be analyzed using the SAS ® version 9.4 (SAS Institute, Cary North Carolina). 
Statistical methods presented in the SAP may be slightly different from those that are presented 
in the protocol. Differences are clearly stated and the SAP supersedes the protocol only with 
regard to the way data will be handled and analysed. 
• 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. 
Demographic and Baseline Characteristics 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 14 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
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. 
• Analysis of Efficacy for Primary Endpoint 
The proportion of subjects who have at least a 1-grade improvement in the C-CAT on Day 84 
versus baseline will be calculated for the placebo group and the RZL-012 high-dose group along 
with 95% Confidence interval for proportion. 
The Chi-Square test will be applied to test the statistical difference between the placebo group 
and the RZL-012 high-dose group in responder rate at Day 84. Responder rate is defined as the 
percentage of subject achieving at least a 1-grade improvement from baseline in C-CAT.  
• Analysis of secondary Endpoints 
 
Secondary endpoints (improvement in 1 point in S-CAT and C-CAT, improvement in 2 points in 
both S-CAT and C-CAT) will be tested using a two-sided test of equality of binomial 
proportions  at the alpha=0.05 level of significance.  
All other secondary endpoints will be tested using a two-sided test at the alpha=0.05 level of 
significance. 
 
- 
The Chi-Square test will be applied to test the statistical difference between the placebo 
group and each of the RZL-012 dose groups in the responder rate at Day 84 where 
responder rate is defined as the percentage of subject achievieng at least a 1-grade 
improvement from baseline in both S-CAT and C-CAT.  
 
 
- 
The change and percentage of change from baseline at Day 84 in SMF thickness 
measured with caliper and in SMF volume by MRI will be calculated along with 95% 
Confidence intervals. 
The Paired T-test for two means (paired observations) will be applied for testing the statistical 
significance of the change and percentage of change from baseline at Day 84 in SMF thickness 
measured with caliper and in SMF volume by MRI within each study group. 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 15 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
The two-sample T-test for independent samples will be applied for testing the statistical 
significance of the change and percentage of change from baseline at Day 84 in SMF thickness 
measured with caliper and in SMF volume by MRI between each of the RZL-012 dose groups 
and the placebo group. 
 
 
• Analysis of Exploratory endpoint 
 
- 
SMF improvement 
The SMF improvement using the Global Aesthetic Improvement Scale (GAIS) , the physician 
Global Assessment of Change Scale, Subjects Global Self-Assessment of Change Scale, Subject 
Global Assessment of Change Scale, the subject’s satisfaction questionnaires, and the subjects's 
impact questionnaire will be summarized at each timepoint and by treatment group. 
• Analysis of Safety  
Safety data from the study will be summarized descriptively by treatment.  The incidence of AEs 
will be presented by treatment.  
Descriptive statistics will be calculated for quantitative data and frequency counts and 
percentages will be provided for categorical data.  The nature, frequency, seriousness, severity 
and relation of AEs to study treatment will be tabulated for all subjects combined and by 
treatment.   
Change-from-baseline values for vital signs, clinical laboratory and ECG will be summarized.  
Serious adverse events (SAEs) will be described in narratives as part of the study report. 
 
7. RELATED DOCUMENTS (OPTIONAL) 
Raziel Protocol_RZL-012-SMF-P2BUS-001.6 , March 08 2022.  
 
8. RELATED FORMS (OPTIONAL) 
Not Applicable 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 16 of 16 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMF-P2bUS-001 
EFFECTIVE DATE : 08/03/2022  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
9. REFERENCES 
Not Applicable 
 
10. APPENDICES 
Not Applicable 
 

Prot_001.pdf: 
 
 
A DOUBLE BLIND, RANDOMIZED, THREE-ARM, PLACEBO-CONTROLLED 
PHASE 2b STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RZL-012 
IN SUBJECTS SEEKING SUBMENTAL FAT REDUCTION 
A DOUBLE BLIND, RANDOMIZED, THREE-ARM, PLACEBO-CONTROLLED 
PHASE 2b STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RZL-012 
IN SUBJECTS SEEKING SUBMENTAL FAT REDUCTION 
 
 
NCT04867434 
 
08 March 2022 
 
 


 
 
 
RAZIEL THERAPEUTICS LTD. 
 
INVESTIGATIONAL NEW DRUG PROTOCOL 
 
RZL-012 
PROTOCOL NUMBER RZL-012-SMF-P2BUS-001 
VERSION 1.6 
08 MARCH 2022 
 
A DOUBLE BLIND, RANDOMIZED, THREE-ARM, PLACEBO-CONTROLLED 
PHASE 2b STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RZL-012 
IN SUBJECTS SEEKING SUBMENTAL FAT REDUCTION 
SPONSOR: 
Raziel Therapeutics, Ltd. 
10 Plaut Str. 
Rehovot, Israel 7610000 
CONFIDENTIAL  
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. 
Version 1.0:  01 February 2021 
 
 
 
 
    Version 1.1:  22 April 2021 
    Version 1.2 : 14 June 2021 
Version 1.3: 25 October 2021 
Version 1.4: 24 November 2021 
Version 1.5: 09 December 2021 


 
 
Version 1.6: 08 March 2022


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 3 of 87 
CONFIDENTIAL 
 
KEY CONTACTS FOR THE STUDY 
SPONSOR’S  
REPRESENTATIVES: 
 
Sponsor Contact 
Richard E. Lowenthal, MSc, MBA 
Program Manager 
Pacific-Link Research Inc. 
Cell: +1-858-335-1300 
Tel: +1-858-227-3008 
E-mail: richard@pacificlinkconsulting.com 
 
Study Director 
Robert Hasson 
Project Manager, PLC 
Pacific-Link Research Inc. 
Cell:  +1-619-540-6253 
Tel: +1-858-368-9925 
E-mail: 
rhasson@pacificlinkconsulting.com 
 
Study Medical Monitor 
Patricia Walker MD, PhD, MD, PhD 
Chief Medical Officer,  
Raziel Therapeutics 
Cell: +1-805-705-5853 
E-mail: dr.patricia.walker@gmail.com 
 
Serious Adverse Event Reporting 
 
 
 
 
 
 
 
Fax:+1-858-769-0288 
Email: 
RazielSafety@pacificlinkconsulting.com 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 4 of 87 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
KEY CONTACTS FOR THE STUDY .......................................................................................... 3 
LIST OF TABLES .......................................................................................................................... 8 
LIST OF FIGURES ........................................................................................................................ 8 
LIST OF APPENDICES ................................................................................................................. 8 
STATEMENT OF COMPLIANCE .............................................................................................. 12 
INVESTIGATOR STATEMENT ................................................................................................ 13 
PROTOCOL SYNOPSIS ............................................................................................................. 15 
1.0 
INTRODUCTION ............................................................................................................. 22 
1.1. 
BACKGROUND ............................................................................................................... 22 
1.1.1. 
Scientific Background and Clinical Rationale ................................................................. 22 
1.1.2. 
RZL-012 Formulation Development ............................................................................... 23 
1.2. 
NONCLINICAL ASSESSMENTS ................................................................................... 24 
1.2.1. 
Pharmacology .................................................................................................................. 24 
1.2.2. 
Toxicology ....................................................................................................................... 25 
1.2.3. 
Additional Nonclinical Studies ........................................................................................ 26 
1.2.4. 
Clinical Studies ................................................................................................................ 27 
2.0 
STUDY OBJECTIVES ...................................................................................................... 37 
2.1 
Study Objectives ................................................................................................................ 37 
2.1.1 Primary Objective .............................................................................................................. 38 
2.1.2 Secondary Objectives......................................................................................................... 38 
2.2 
Description of Study Design .............................................................................................. 38 
2.3 
Study Endpoints ................................................................................................................. 39 
2.3.1 Primary Endpoint ............................................................................................................... 39 
2.3.2 Secondary Endpoints ......................................................................................................... 40 
2.3.3 Exploratory Endpoints ....................................................................................................... 40 
2.3.4 Randomization/Assignment to Study Drug ....................................................................... 40 
2.4 
Study Drugs ....................................................................................................................... 40 
2.4.1 Test Product and Dosing .................................................................................................... 40 
2.4.2 Dose Rationale ................................................................................................................... 42 
2.4.3 Serious Adverse Events Considered Related to the Investigational Drug ......................... 42 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 5 of 87 
CONFIDENTIAL 
 
2.5 
Concomitant Medications .................................................................................................. 43 
2.5.1 Prior and Concomitant Medications .................................................................................. 43 
3.0 
STUDY POPULATION .................................................................................................... 43 
3.1 
Inclusion Criteria ............................................................................................................... 43 
3.2 
Exclusion Criteria .............................................................................................................. 44 
3.3 
Subject Identification ......................................................................................................... 46 
3.4 
Removal, Replacement or Early Withdrawal of Subjects from the Assessment Not Due to 
Intolerable Side Effects ................................................................................................................. 47 
4.0 
STUDY PROCEDURES AND ASSESSMENTS ............................................................. 47 
4.1 
Informed Consent............................................................................................................... 47 
4.2 
Complete physical examination ......................................................................................... 47 
4.3 
Medical History ................................................................................................................. 48 
4.4 
Vital Signs .......................................................................................................................... 48 
4.5 
ECG.................................................................................................................................... 48 
4.6 
Height and Weight ............................................................................................................. 48 
4.7 
Clinical Laboratory Evaluations – Hematology and Serum Chemistry............................. 49 
4.7.1 Hematology ........................................................................................................................ 49 
4.7.2 Serum Chemistry ............................................................................................................... 49 
4.7.3 Pregnancy Tests ................................................................................................................. 49 
4.8 
Submental Fat Thickness using Calipers ........................................................................... 49 
4.9 
2-D Standardized Photography .......................................................................................... 50 
4.10 Magnetic Resonance Imaging (MRI) ................................................................................. 50 
4.11 Clinician-Chin Assessment Tool (C-CAT) ........................................................................ 51 
4.12 Subject – Self-Chin Assessment Tool (S-CAT) ................................................................ 52 
4.13 Subject’s Satisfaction Questionnaire for SMF Appearance............................................... 53 
*subjects will be asked this question only at study visits on Days 28, 56, and 84 ....................... 55 
4.14 Subject’s Impact Questionnaires .................................................................................... 55 
4.15 Physician Global Assessment Improvement Scale (GAIS) and physician assessment
 
57 
4.16 Subject Global Assessment of Change  and subject self-assessment ........................... 58 
4.17 Evaluation of Response.................................................................................................... 59 
4.18 Compliance Monitoring................................................................................................... 59 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 6 of 87 
CONFIDENTIAL 
 
5.0 
SAFETY ASSESSMENTS ................................................................................................ 59 
5.1 
Collection of Adverse Events Data .................................................................................... 59 
5.2 
Complete or Targeted Physical Examination .................................................................... 60 
5.3 
Vital Signs .......................................................................................................................... 60 
6.0 
PHARMACOKINETICS ................................................................................................... 60 
7.0 
EFFICACY ........................................................................................................................ 60 
8.0 
STUDY VISITS AND PROCEDURES ............................................................................ 60 
8.1 
Screening (Days -28 to -1) ................................................................................................. 61 
8.2 
Baseline Evaluations (Day 0) ............................................................................................. 62 
8.3 
Study Randomization ......................................................................................................... 62 
8.4 
Pre-dose Evaluation (Day 0) .............................................................................................. 62 
8.5 
Drug Administration .......................................................................................................... 63 
8.6 
Post-dose Evaluations (Day 0) ........................................................................................... 64 
8.7 
Study Visits (Days 1, 7, 28, and 56) .................................................................................. 64 
8.8 
Final Visit (Day 84) .......................................................................................................... 66 
8.9 
Additional follow up of subjects: .................................................................................... 66 
9.0 
PREMATURE DISCONTINUATION FROM STUDY ................................................... 67 
10.0 PRODUCT SPECIFICATIONS ........................................................................................ 67 
10.1 Description ......................................................................................................................... 67 
10.2 Formulation, Packaging, and Labeling .............................................................................. 67 
10.3 Receipt, Storage and Stability of RZL-012........................................................................ 68 
10.4 Study Drug Administration ............................................................................................ 68 
10.5 Ordering and Distribution of Study Drug .......................................................................... 68 
10.6 Accountability of Study Drugs .......................................................................................... 69 
11.0 SAFETY MONITORING AND ADVERSE EVENTS .................................................... 69 
11.1 Adverse Events .................................................................................................................. 69 
11.2 Serious Adverse Events ..................................................................................................... 72 
11.2.1 Reporting Requirements for Serious Adverse Events ....................................................... 72 
11.2.2 Reporting pregnancy .......................................................................................................... 73 
11.2.3 Recording of Serious Adverse Events ............................................................................... 73 
11.2.4 Internal Safety Committee ................................................................................................. 73 
12.0 STATISTICAL CONSIDERATIONS............................................................................... 74 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 7 of 87 
CONFIDENTIAL 
 
12.1 Sample Size Determination................................................................................................ 74 
12.2 Analysis Data Sets ............................................................................................................. 74 
12.3 Endpoints Analyses ............................................................................................................ 74 
12.4 Safety ................................................................................................................................. 75 
13.0 DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ............ 76 
13.1 Data Collection and Reporting........................................................................................... 76 
13.2 Study Monitoring ............................................................................................................... 76 
13.3 Audit and Inspection .......................................................................................................... 76 
13.4 Deviation from Clinical Trial Protocol .............................................................................. 76 
13.5 Retention of Records.......................................................................................................... 77 
13.6 Data Disclosure and Subject Confidentiality ..................................................................... 77 
14.0 PROTECTION OF HUMAN SUBJECTS ........................................................................ 78 
14.1 Basic Principles .................................................................................................................. 78 
14.2 Institutional Review Board/Ethics Committee .................................................................. 78 
14.3 Informed Consent............................................................................................................... 78 
14.4 Subject Health Injury and Insurance .................................................................................. 79 
14.5 Completion of the Study .................................................................................................... 79 
15.0 REFERENCE LIST ........................................................................................................... 80 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 8 of 87 
CONFIDENTIAL 
 
LIST OF TABLES 
Table 1:  Composition of RZL-012 .............................................................................................. 23 
Table 2:  Overview of Ongoing and Completed Clinical Studies ................................................ 27 
Table 3: Dosages According to Lipomas Size .............................................................................. 37 
Table 4:  Dosing Regimen ............................................................................................................ 41 
Table 5:  Severity Assessment Terminology for Reporting Adverse Events (CTCAE v 5.0) ...... 71 
Table 6:  Contact Information for SAE Reporting ........................................................................ 72 
 
LIST OF FIGURES 
Figure 1:  Structural Formula of RZL-012 ................................................................................... 23 
Figure 2:  Injection Sites for Phase 0 Study .................................................................................. 29 
Figure 3:  Injection Sites for Phase 2A Study ............................................................................... 31 
Figure 4:  Injections Diagram According to Lipomas Size .......................................................... 33 
Figure 5:  Injection Scheme Lipedema Subjects........................................................................... 33 
Figure 6:  Diagram of Injection Pattern ........................................................................................ 35 
Figure 7:  Scheme of Injection Pattern Grid ................................................................................. 41 
 
LIST OF APPENDICES 
Appendix A:  Schedule of Study Procedures ............................................................................ 81 
Appendix B:  Photographic Standards of the Face Area ............................................................. 85 
Appendix C:  Clinician Chin Assessment Tool ........................................................................ 86 
Appendix D:   Subject Chin Assessment Tool .......................................................................... 87 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 9 of 87 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase  
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
C-CAT 
Clinician Chin assessment Tool 
CBC 
Complete blood count 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence interval 
cm 
Centimeter 
CNS 
Central nervous system 
CRF 
Case report form 
CV 
Coefficient of variable 
DD 
Dercum’s disease 
ECG 
Electrocardiograms 
FDA 
Food and Drug Administration 
FOB 
Functional Observational Battery 
FSH 
Follicle-Stimulating Hormone 
GAIS 
Global Aesthetics Improvement Scale 
GGT 
Gamma-glutamic transferase  
GLP 
Good Laboratory Practice 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 10 of 87 
CONFIDENTIAL 
 
ABBREVIATION 
DEFINITION 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical Practice 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB/EC 
Institutional Review Board/Ethics Committee  
kg 
Kilogram 
LDH 
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter  
MOA 
Mechanism of action 
MRI 
Magnetic resonance imaging 
N 
Number of subjects 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drugs 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QOL 
Quality of life 
RBC 
Red blood count 
S-CAT 
Subject  Self-Chin Assessment Tool 
SAE 
Serious adverse event 
SFM 
Subcutaneous Fat Mass 
SMF 
Submental fat 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 11 of 87 
CONFIDENTIAL 
 
ABBREVIATION 
DEFINITION 
SOP 
Standard operating procedure 
TEAE 
Treatment emergent adverse event(s) 
US/USA 
United States of America 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 12 of 87 
CONFIDENTIAL 
 
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. 
 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 13 of 87 
CONFIDENTIAL 
 
INVESTIGATOR STATEMENT 
I have read and understand 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 maintain accurate source documents from which data are transcribed onto case report 
forms and accurate drug accountability records that show the receipt and disposition of all study 
drugs. 
I will provide adequate protocol training to my associates, colleagues, and employees assisting in 
the conduct of the study. 
I will obtain Institutional Review Board/Ethics Committee (IRB/EC) approval of the protocol 
and Informed Consent Form (ICF) prior to enrollment of subjects in the study. I understand that 
any modifications to the protocol made during the course of the study must first be approved by 
the IRB/EC prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
I will ensure that a fully executed IRB-approved 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, regardless of relationship to study drug, 
or pregnancy that occurs during the course of the study, in accordance with the procedures 
described in Section 11.0 of the protocol. I will notify the Sponsor if I become aware that a 
partner of a study subject becomes pregnant while the subject was receiving this study drug. 
I will submit all protocol inclusion/exclusion violations to the Medical Monitor for approval 
prior to enrollment of the subject in the study. 
I will allow the Sponsor, Raziel Therapeutics Ltd. (Raziel) and its agents, as well as the United 
States (U.S.) 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). 
This protocol contains information that is proprietary to Raziel.  The information contained 
herein is provided for the purpose of conducting a clinical trial for Raziel. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 14 of 87 
CONFIDENTIAL 
 
The contents of this protocol may be disclosed to study personnel under your supervision and to 
your IRB/EC. The contents of this protocol may not be disclosed to any other parties (unless 
such disclosure is required by government regulations or laws) without the prior written approval 
of Raziel. 
 
 
 
______________________     ______________________________       
________________ 
Investigator’s Name                Investigator’s Signature 
 
 
Date 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 15 of 87 
CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
Study Title 
A double blind, randomized, three-arm, placebo-controlled Phase 2b study to evaluate the 
efficacy and safety of RZL-012 in subjects seeking submental fat reduction (RZL-012-SMF-
P2bUS-001) 
Phase 
Phase 2b 
Study Drug 
RZL-012 
Study Objectives 
and Endpoints 
• 
Primary Objective:  
• 
to determine the efficacy of RZL-012 versus placebo on submental fat (SMF) reduction 
measured on Day 84 versus baseline using the Clinician Assessment Tool (C-CAT).  
• 
Secondary Objectives: 
• 
to determine the efficacy of RZL-012 versus placebo on SMF reduction measured on 
Day 84 versus baseline using both Subject Self-Chin Assessment Tool (S-CAT) and the 
Clinician Assessment Tool (C-CAT); 
• 
;  
• 
to assess the reduction in SMF on Day 84 versus baseline using the caliper measured 
submental thickness and magnetic resonance imaging (MRI); 
• 
to assess the safety of RZL-012 in the treatment of SMF reduction. 
 
• 
Primary Endpoint: 
• 
comparison of the proportion of subjects who have at least a 1-grade improvement in the 
C-CAT on Day 84 versus baseline between the RZL-012 high dose (270 mg/5.4 mL) 
group and the placebo group. 
• 
Secondary Endpoints: 
• 
proportion of subjects who have at least a 1-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
• 
proportion of subjects who have at least a 2-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
• 
reduction in SMF volume by MRI (Day 84 versus screening) in the RZL-012 groups 
versus placebo group. 
• 
 
• 
reduction in SMF thickness measured with caliper (Day 84 versus baseline) in the RZL-
012 groups versus placebo group. 
• 
safety of RZL-012 in the treatment of SMF reduction. 
• 
Exploratory endpoints: 
• 
Physicians Global Assessment 
• 
SMF improvement using the Global Aesthetic Improvement Scale (GAIS). 
• 
Subject Global Self-Assessment 
• 
SMF improvement using the Subject Global Assessment of Change Scale. 
• 
SMF improvement using the subject’s satisfaction questionnaires. 
• 
SMF improvement using Subject’s impact questionnaire. 
Study Design 
This is a Phase 2b, double-blind, randomized, three-arm, placebo-controlled study that will 
consist of a screening period, baseline period, and a randomized treatment period.  Subjects 
will receive a single treatment session that consists of multiple injections of RZL-012 or 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 16 of 87 
CONFIDENTIAL 
 
placebo into the submental area under the chin, after which they will be monitored for safety 
and efficacy over 84 days. 
Following the completion of  Day 84 visit of the last subject, subjects from three (3) chosen 
clinical sites will be followed up further twice up to a 1 year after injection to evaluate the 
long term safety and efficacy. The additional follow up visits will be at 6 and 12 months 
after injection. 
For subjects from all sites  that their adverse events were not resolved by Day 84, an 
unscheduled visit will be set 6-8 weeks after Day 84 to verify the resolution of the AE. On 
that visit, follow up of efficacy using C-CAT and S-CAT will also be conducted.  
 
Each subject will be randomized to either active treatment (high or low dose RZL-012) or 
placebo at a ratio of 1:1:1 per group and receive one of the following: 
• 
low dose (concentration of injected solution 34 mg/mL RZL-012) of 5.1 mg/0.15 
mL/injection point that results in a dose/volume of 183.6mg/5.4 mL RZL-012, 
• 
high dose (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 
mL/injection point that results in a maximum total dose/volume of 270 mg/5.4 mL 
RZL-012, 
• 
placebo of 0.15 mL/injection point that results in a total maximum volume of 
4.8±0.6 mL. 
Screening Period:  Subjects will undergo screening within 28 days prior to entering into the 
study. Screening period will contain 2 visits, pre-screening visit to verify that subject 
qualifies the study based on S-CAT , C-CAT and 2D photography and another visit that will 
include an assessment of eligibility by measurement of SMF thickness using calipers, skin 
type by Fitzpatrick scale,  subject’s satisfaction scale related to appearance of SMF, subject 
impact questionnaire,  and MRI. MRI will be conducted prior to the baseline visit. ECG and 
blood samples will also be conducted during the second screening visit. 
Baseline Treatment Period:  A total of 135 eligible male or female subjects will be 
randomized according to a predetermined randomization scheme (1:1:1 ratio) to receive a 
single multi-injection treatment of high dose RZL-012, low dose RZL-012, or placebo on 
Day 0. Subjects will be monitored for adverse events (AEs) and treatment area evaluation 
for 30 minutes post dose prior to discharge from the clinical trial site. Subjects will return to 
the site for study visits on Days 1, 7, 28, and 56 and for a final study visit on Day 84 for 
efficacy and safety assessments. 
Subjects will be advised to continue their regular diet and physical activity during the study. 
Blood samples will be collected at Day 1, 7, 28 and Day 84 study visits for assessment of 
hematology and serum chemistry. If there are clinically significant alerts obtained at  any 
visit, an unscheduled visit will be added for an additional blood sampling 
Safety assessments will be performed at each study visit and subjects can be released after 
blood sampling and study assessments are completed. 
Safety assessments include vital signs, blood samples, ECG, AE assessment, and treatment 
area evaluation. Treatment area evaluations including, but not limited to evaluation of 
edema, bruising, dysphasia, dysphonia, erythema, dyspigmentation, induration, numbness, 
pain, paresthesia , pruritus, skin ulceration and necrosis, injury to the marginal mandibular 
nerve, vascular and nerve injury and tissue damage to nearby vulnerable anatomic 
structures. Concomitant medications will be recorded. An internal safety review committee 
will review the safety data collected during the study in a blinded manner. The committee 
members will include study medical monitor, Raziel’s CMO and clinical director. The 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 17 of 87 
CONFIDENTIAL 
 
meeting will be held for every enrolled 40 subjects. Following completion of enrollment 
period, the committee will meet quarterly during the follow up period.  
The study enrollment will be suspended if either of the following occur: 
• 
Greater than 20% of subjects report a drug related grade 3 (severe) adverse event 
for a period duration of more than 28 days after injection. Of note severe swelling 
is expected and may be  present for the first 24-96 hours after injection. 
• 
>1 subject with a drug related CTCAE Grade of 4 or 5 
In the event of the above, the enrollment and treatment will be suspended, the safety 
committee will review all data to examine potential safety issue. Additional experts may be 
brought in to review safety data if deemed necessary by the safety committee. A safety 
report will be issued with the conclusions of the meeting. The recommendation of the safety 
committee will be documented. Potential outcomes are reinitiating enrollment with current 
safety practices, reinitiating study enrollment with caveats (e.g. additional 
precautions/limitations or safety training), stop enrollment.   
Sample Size 
135 subjects (45 subjects per group): 
1. RZL low dose – dose of 163.2±20.4 mg/subject spreads over 32±4 injection points  
2. RZL high dose – dose of 240±30mg/subject spread over 32±4 injection points 
3. Placebo – volume of 4.8±0.6ml vehicle/subject spread over 32±4 injection points 
Study 
Population 
Adult volunteers age 18 to 65 years who have consented to participate in this study. 
Main Inclusion 
Criteria 
For a subject to be eligible for this study, he or she must meet all of the following criteria: 
1. Is a male or female subject between the ages of 18 and 65 years, inclusive. 
2. Has body mass index (BMI) between >22 and <40. 
3. Has SMF  bulge that is contiguous and fits to 32±4 injections sites according to a grid 
with 1 centimeter (cm) distance between injection points. 
4. Has grade 3 to 4 of SMF as rated by the C-CAT. 
5. Has a visible or large pocket of submental fat- according to physician global 
assessment. 
6. Has grade 3 to 4 of SMF as rated by the S-CAT. 
7. Has stable weight, with no fluctuation of >5 kg in the past 12 months. 
8. If female, is not pregnant or breastfeeding based on the following: 
a. 
agree to the use of highly effective contraceptive methods for at least 2 weeks 
before baseline until 4 weeks after the last day of study drug and a negative 
serum pregnancy test (ß-hCG) at screening and negative urine pregnancy test at 
baseline; or  
b. is of nonchildbearing potential defined as clinically infertile as the result of 
surgical sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral 
oophorectomy); or  
c. 
is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 
12 consecutive months without another cause and documented serum follicle-
stimulating hormone (FSH) level > 40 mIU/mL or another documented medical 
condition (e.g., was born without a uterus)) 
NOTE: The following are considered highly effective contraceptive methods: 
hormonal oral contraceptives, injectables, and patches; intrauterine devices; 
double-barrier methods (synthetic condom, diaphragm, or cervical cap used with 
spermicidal foam, cream, or gel); and male partner sterilization. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 18 of 87 
CONFIDENTIAL 
 
9. If male (with or without vasectomy), agree to the use of highly effective contraceptive 
methods as listed above in criteria 7 as well as to use a barrier method, e.g. condom , 
from study check-in until 7 days after the last day of study drug. 
10. Is willing to avoid strenuous exercise for seven (7) days post treatment. 
11. Is able to adhere to the visit schedule and protocol requirements and be available to 
complete the study. 
12. Is willing and able to sign an Institutional Review Board (IRB) approved informed 
consent form (ICF) indicating that they are aware of the investigational nature of the 
study. 
Main Exclusion 
Criteria  
Subjects must NOT meet any of the following Exclusion criteria to be eligible for 
enrollment: 
1. Is unable to tolerate subcutaneous injections. 
2. Has dysfunctional gallbladder activity (e.g., underwent cholecystectomy or 
cholecystitis). 
3. Has any uncontrolled systemic disease that is not stabilized (i.e., cardiovascular disease, 
mental illness). 
4. Has had treatment with botulinum toxin injections in the neck or chin area within nine 
(9) months prior to screening. 
5. Has used anticoagulation therapies that may increase bleeding or bruising (i.e., aspirin, 
ibuprofen, vitamins, and herbal preparations) for seven (7) days prior to treatment. 
6. Has skin laxity (i.e., elastosis, skin crepiness, skin redundancy, skin draping, vertical 
and/or horizontal skin bands and folds, blunting of cervical mental angle, loss of 
opposition of skin to underlying neck structures due to skin laxity) that could obscure 
the evaluation and treatment of SMF. 
7. Has any scars, unshaven hair, tattoos, facial hair or jewelry on or near the proposed 
treatment area. 
8. Has presence of structures or confounding factors that may interfere with assessing 
SMF such as but not limited to enlarged submandibular salivary and/or parotid glands, 
micrognanthia, chin implant, soft tissue volume augmentation of chin and/or jawline, 
pronounced platysmal bands and deep necklace lines or presence of facial jowls that 
could obscure the evaluation of SMF.  
9. Has a fat bulge under the chin that is too large to be adequately treated by 32+/-4 
contiguous injections on a 1cm grid . 
10. Has a fat bulge under the chin that is of an insufficient volume to allow 28 injections 
within a contiguous 1 cm grid.  
11. Has significant history or current evidence of a medical, psychological or other disorder 
that, in the Investigator’s opinion, would preclude enrollment in the study. 
12. Has an active dermatitis or open wound in the proposed treatment area. 
13. Abnormal coagulation profile including: activated partial thromboplastin time (aPTT) > 
ULN, international normalized ratio (INR) > ULN reference range (> 1.3), prothrombin 
time (PT) > ULN 
14. Has D-dimer value >0.64mg/L in screening visit 
15. Has an active bacterial, fungal, or viral infection in the proposed treatment area. 
16. Has a pre-existing skin condition in the submental region that, at the Investigator’s 
discretion, may confound evaluation or analysis. 
17. Has previously had treatments or surgery in the submentum, such as but not limited to, 
focused ultrasound, radiofrequency, cryolipolysis, liposuction, sodium deoxycholate, or 
neck lift. 
18. Has pre-existing neurological or gastrointestinal condition leading to dysphagia, 
dysphonia, or facial nerve palsy. 
19. Has Dercum’s Disease. 
20. Has allergic reactions to injectables. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 19 of 87 
CONFIDENTIAL 
 
21. Has any pre-existing medical condition other than increased SMF that, at the 
Investigator’s discretion, may result in increased submental fullness, such as but not 
limited to, thyroid enlargement, goiter, cervical lymphadenopathy, etc. 
22. Has a planned fat reduction procedure of any variety to the submental region for the 
duration of the study. 
23. Has medication or a history of coagulopathy. 
24. Has a history or family history of venous thrombotic disease. 
25. Has been treated chronically at least three (3) months prior to study entry with systemic 
steroids or immunosuppressive drugs. 
26. Has been treated chronically at least one (1) week prior to study entry with non-
steroidal anti-inflammatory drugs (NSAIDs). 
27. Current participation or participation within three (3) months prior to the start of this 
study in a drug or other investigational research study. 
28. Has claustrophobia or an MRI incompatible device or implant.  
Dosage and 
Administration 
of Study Drug 
All subjects will receive a single multi-injection session of RZL-012 or placebo in 
accordance with the table below:  
 
 
Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. 
The maximal number of injections will be 36 with maximal doses of 183.6 mg and 270 mg 
for the low and high doses, respectively. Each injection point will be dosed with 5.1 mg 
RZL-012 for the low dose or 7.5 mg for the high dose in a volume of 0.15 mL/injection site. 
Placebo (vehicle) subjects will be injected with a 0.15 mL vehicle per each injection site. 
The maximal injection volume for all groups will be up to 5.4 mL. 
Subjects will be injected with RZL-012 or placebo perpendicularly (90°) to the skin. An ice 
pack will be placed on the injected area for pain relief immediately after injection. Subjects 
will remain seated in the injection position for an additional 10 minutes after dosing. 
The injection pattern will be based on a submental area shaped grid in which the distance 
between rows and columns will be 1 cm, as seen in the figure below. The Investigator will 
choose 32±4 sequential points on the grid that will mark the injected area according to SMF 
fullness and convexity. The 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. 
 
N=135 
 
RZL-012 High dose 
(50mg/mL) 
RZL-012 Low dose 
(34mg/mL) 
Placebo 
Number of subjects (N) 
45 
45 
45 
Maximum RZL-012 
dose (mg)/volume (mL) 
270mg/5.4 mL 
183.6 mg/5.4 mL 
0mg/5.4±0.6mL 
RZL-012 Dose 
(mg)/volume (mL) per 
single injection 
7.5mg/0.15mL 
5.1mg/0.15mL 
0mg/0.15mL 
Number of Injections 
per subject 
32±4, maximum of 36 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 20 of 87 
CONFIDENTIAL 
 
 
 
Safety Analysis 
AEs will be collected and reviewed to evaluate the safety and tolerability of RZL-012. AE 
collection will begin after dosing and will end at discharge assessments on Day 84. AEs 
may be either spontaneously reported or elicited during questioning and examination of a 
subject.  AE information will be elicited at appropriate intervals by indirect questioning 
using a non-leading question. 
Other safety measures will include vital sign measurements, ECG, blood samples, and 
treatment area evaluation. Treatment area evaluations including, but not limited to 
evaluation of edema, bruising, dysphasia, dysphonia, erythema, dyspigmentation, 
induration, numbness, pain, paresthesia, , pruritus, skin ulceration and necrosis, injury to the 
marginal mandibular nerve, vascular and nerve injury and tissue damage to nearby 
vulnerable anatomic structures.  Concomitant medications will be recorded. An internal 
safety review committee will review the safety data collected during the study in a blinded 
manner. The meeting will be held for every enrolled 40 subjects. Following completion of 
enrollment period, the committee will meet quarterly during the follow up period.  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 21 of 87 
CONFIDENTIAL 
 
Statistical 
Analysis 
A sample size of 135 subjects will be included in the study, divided into three (3) groups: 
RZL-012 low dose (up to 183.6 mg/5.4 mL), RZL-012 high dose (up to 270 mg/5.4 mL) 
and placebo (up to 5.4 mL), with 45 subjects in each group. 
For the primary endpoint (proportion of high-dose group subjects who have at least a 1-
grade improvement from baseline to day 84 on the C-CAT scale), the assumed true rates are 
70% in the RZL-012 high dose group and 35% in the placebo group (a difference of 35 
percentage points). Based on the use of a two-sided test of equality of binomial proportions 
at the alpha=0.05 level of significance, 41 subjects per group are required at 90% power. In 
order to account for a dropout rate of up to ~9%, the planned sample size is 45 subjects per 
group, for a total sample size of 135 subjects. 
Secondary endpoints (improvement in 1 point in S-CAT and C-CAT, improvement in 2 
points in both S-CAT and C-CAT) will be tested using a two-sided test of equality of 
binomial proportions at the alpha=0.05 level of significance. If the primary analysis is not 
statistically significant, then the results of the secondary analysis will be exploratory rather 
than confirmatory.  All secondary endpoints will be tested using a two-sided test at the 
alpha=0.05 level of significance. 
All other secondary endpoints will be tested using a two-sided test at the alpha=0.05 level of 
significance. 
All measured variables and derived parameters will be listed individually and, if 
appropriate, tabulated by descriptive statistics. 
For categorical variables, summary tables will be provided giving sample size, absolute and 
relative frequency, and 95% confidence interval (CI) for proportions by study arm. 
For continuous variables, summary tables will be provided giving sample size, arithmetic 
mean, standard deviation, coefficient of variations (CV%), median, minimum and 
maximum, and 95% CI for means of variables by study arm. 
The data will be analyzed using the SAS version 9.4 (SAS Institute, Cary North Carolina). 
For the primary endpoint analysis, Pearson’s chi-square test will test the statistical 
significance of the difference in the proportion of responding subjects between the high dose 
RZL-012 group and the placebo group. A responder is defined as a subject who has at least 
a 1-grade improvement between Day 84 and baseline on the C-CAT. 
 
Study Duration 
It is planned that each subject will participate in the study for four (4) months, which 
comprises a screening period, baseline/treatment period, and follow up period. In 3 chosen 
clinical sites, there will be additional follow up of subjects for  maximum 1 year period.  
Study Centers 
Up to twelve (12) centers  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 22 of 87 
CONFIDENTIAL 
 
1.0 INTRODUCTION 
1.1. 
BACKGROUND 
1.1.1. Scientific Background and Clinical Rationale 
Submental fat (SMF) can represents an aesthetic problem in males and females. Although 
localized fat deposits are present in many parts of the body, SMF is particularly noticeable due to 
its location. Until recently, treatments of SMF 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, was approved as an injectable treatment for SMF. However, due to repeated 
treatments (up to 6 treatments) and adverse events (AEs) such as swelling and bruising after 
every treatment, physicians and patients are still searching for additional alternatives for SMF 
reduction. 
Raziel Therapeutics, Ltd. (Raziel) has discovered that a novel synthetic molecule (termed RZL-
012) can help reduce fat content in humans and pigs following its injection into the subcutaneous 
fat.  The suggested 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, most likely due to a local inflammatory response. 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 followed a different pattern 
compared with liponecrosis and inflammation as 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. 
To date, Raziel has conducted several clinical studies under INDs to evaluate the safety and 
efficacy of RZL-012 for local fat reductions, including obesity (INDs 11941, 133324) and 
lipomas of Dercum’s Disease subjects (IND 135762). Based on the results of these studies, 
Raziel concluded that the safety profile of RZL-012 is good and acceptable and the compound 
demonstrated efficacy in long-term reduction of local subcutaneous fat mass. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 23 of 87 
CONFIDENTIAL 
 
Based on the clinical study results received to date, Raziel continues to investigate the efficacy 
and safety of RZL-012 for the treatment of SMF in a larger clinical population and conducted in 
a more controlled manner. 
Chemically, RZL-012 is 5-(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium 
chloride. RZL-012 is generated by a single step reaction and the final product is >97% pure. 
The molecular weight is 488 gr/mole and its structural formula, C20H25Br2CIN2, is illustrated in 
Figure 1 below. 
Figure 1:  Structural Formula of RZL-012 
 
C20H25Br2CIN2 
1.1.2. RZL-012 Formulation Development 
The active ingredient RZL-012 drug substance was manufactured by Cambrex,  NC, USA.  
RZL-012 drug product was manufactured in Patheon (Italy) and packed and labeled at 
ThermoFischer, USA. The drug product is provided in vials of 240 mg/4.8 mL (50 mg/mL) and 
163mg/4.8 mL (34 mg/ml). 
The active ingredient and formulation manufacturing and packing were in accordance with 
current Good Manufacturing Practices (cGMPs).  
RZL-012 is provided as a sterile liquid solution suitable for injection. The quantitative 
composition of RZL-012 is listed in Table 1 below. 
Table 1:  Composition of RZL-012 
Component 
Concentration (mg/ml) 
RZL-012 
50 and 34 
Tween-80 
100 
Propylene glycol 
570 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 24 of 87 
CONFIDENTIAL 
 
 
 
1.2. NONCLINICAL 
ASSESSMENTS 
1.2.1. Pharmacology 
Pig studies concluded that the RZL-012 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. 
1.2.1.1. 
In-vivo Efficacy Studies 
The effect of RZL-012 injection Several nonclinical studies in pigs, in which the subcutaneous 
fat tissues 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 injections 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 
Component 
Concentration (mg/ml) 
Benzyl alcohol 
30 
Water 
250 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 25 of 87 
CONFIDENTIAL 
 
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 art the 
injected areas causing shrinkage of treated tissues. 
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 hours 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. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 26 of 87 
CONFIDENTIAL 
 
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 hematological 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. 
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) 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 27 of 87 
CONFIDENTIAL 
 
• Absorption studies in rats and pigs 
• MOA – in vitro studies 
Methods and results from these safety studies are described in the IB. 
1.2.4. Clinical Studies 
RZL-012 has been tested in several clinical trials. A total of 92 subjects were exposed to RZL-
012 at single doses of up to 240 mg. The currently planned clinical trial is the second trial to 
assess the potential efficacy of RZL-012 in reducing SMF volume. 
Five studies have been completed and efficacy analysis was completed to 4 out of the 5 studies. 
Safety analysis of all studies demonstrated that 91/92 subjects has adverse events (AEs). None of 
the studies was reported with serious AEs. Most of AEs were mild to moderate and were 
associated with local injection site reactions. Only 10 subjects were reported with severe AEs 
(7% of the reported events). 
 
Table 2:  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 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 28 of 87 
CONFIDENTIAL 
 
Study ID 
STATUS 
Phase Country Study Title 
Study Design 
Dosing 
Regimen 
Study Population 
RZL-012-FD-
P2aUS-001.7 
 
COMPLETED 
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  
received up to 
40 mg RZL-
012 
Cohort 2 
Lipedema: 
Each 3 
subjects 
received 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 Dercum’s 
disease 
RZL-012-
SMF-P2aUS-
001.2 
COMPLETED 
2a 
USA 
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 
A single blind, 2-
cohorts clinical 
study to test 
safety and efficacy 
in healthy subjects 
Cohort 1:  
8 active (RZL-
012) and 4 
placebo 
subjects were 
injected with 
up to 
120mg/2.4mL
, based on 
SMF fullness. 
Cohort 2: 
 10 active and 
6 placebo 
subjects were 
injected with 
up to 
240mg/4.8mL
, based on 
SMF fullness.  
Men and women 18-
65 years old 
RZL-012-DD-
P2bUS-001.4 
 
COMPLETED. 
Pending 
efficacy 
analysis. 
2b 
USA 
A Double Blind, 
Randomized, Multi-Center, 
Placebo-Controlled Phase 
2B Clinical Trial for the 
Evaluation of Efficacy and 
Safety of RZL-012 in 
Subjects having Dercum’s 
Disease (DD) Lipomas 
A double blind 
clinical study to 
test efficacy and 
safety in DD 
subjects with 
painful lipomas 
At least 4 
lipomas/nodu
les, preferably 
6, and no 
more than 8, 
are injected 
per subject. 
Dosing is 
according to 
lipoma size, 
where the 
total injected 
dose does not 
exceed 
240 mg per 
patient (48 
injections of 
5mg/injection
). 
Women and men, 18- 
70 years old, 
diagnosed with DD 
having lipomas 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 29 of 87 
CONFIDENTIAL 
 
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 from the baseline visit (Day 0) through Day 1. 
The primary objective of the study was to evaluate the overall safety of RZL-012 after 
subcutaneous injection and the existence of a thermogenic effect. A thermogenic effect was 
defined as 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, with 8 subjects per cohort. Each subject was injected with 
either RZL-012 (6 subjects) or vehicle (2 subjects). This was a dose escalation study; therefore, 
RZL-012 was injected at doses of 5, 10, and 20 mg/subject at cohorts 1, 2, and 3, respectively. 
Subjects received a single treatment in multiple sites (1 - 4) of injection diagonally (45°) to the 
skin surface at 3 centimeter (cm) lateral to the umbilicus lateral wall. The distance between 
injected sites was 1 cm (see Figure 2).  
Figure 2:  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 
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). 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 30 of 87 
CONFIDENTIAL 
 
One systemic clinically significant AE involved a severe elevation of alanine transaminase 
(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. 
MRI results demonstrated a decrease over time in Subcutaneous Fat Mass (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. 
3. Clinical laboratory changes from baseline. 
4. Establishing the PK profile for RZL-012. 
5. Anthropometric changes from baseline. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 31 of 87 
CONFIDENTIAL 
 
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 1 cm in Cohort 4 as seen in Figure 3.  
Figure 3:  Injection Sites for Phase 2A Study 
 
 
 
 
RZL-012-P2aUS-001.4 Study Results: 
In this 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 seemed 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 due to the subcutaneous injection of RZL-012 was elevation in d-dimer 
values at the highest injected dose of 180 mg. However, this increase was transient, up to 3 days 
after injection, and non-clinically significant. Further review of coagulation parameters revealed 
there was no clinically significant activation of the coagulation system nor any presence of 
Disseminated Intravascular Coagulation (DIC). The absence of any clinical symptoms related to 
elevation of D-dimer supports a direct link between RZL-012 induced inflammation and elevated D-
dimer levels, unrelated to venous thromboembolic disease 
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 
necrosis and infiltration of macrophages into the necrotic fat tissue that resulted in a replacement 
of the local fat tissue by fibrotic tissue. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 32 of 87 
CONFIDENTIAL 
 
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 versus placebo. Among Cohorts 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 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 concluded that the risk benefit profile of RZL-012 as seen in the 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 (i.e., excess in SMF). 
1.2.4.1.3. Protocol No. RZL-012-FD-P2aUS-001.7 Status: Completed 
An additional clinical trial was 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 was to evaluate the overall safety of RZL-012 following injection into the 
subcutaneous fat in patients with lipedema or DD. 
The secondary objective was 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. 
The study was composed of 2 cohorts. Cohort 1 was comprised of 6 subjects with DD and 
Cohort 2 was comprised of lipedema subjects having substantial fat above the knee. 
Cohort 1 (Subjects with DD): 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 33 of 87 
CONFIDENTIAL 
 
Several lipomas were injected per subject. Dosing was calculated according to the size of the 
nodule (diameter), reaching a maximal dose of 40 mg per subject.  
Subjects received a single treatment in multiple sites (2 - 8 cm lipoma size) of injection 
according to the design in Figure 4. 
Figure 4:  Injections Diagram According to Lipomas Size 
 
 
 
 
Cohort 2 (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, for a total of 12 injections of 60 
mg RZL-012 (see Figure 5 for injection scheme). 
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, for a total of 16 injections of 80 
mg RZL-012 (Figure 5).  
Figure 5:  Injection Scheme Lipedema Subjects 
 
 
 
 
 
RZL-012-FD-P2aUS-001.7 Results: 
Overall, 11 out of 12 subjects reported at least 1 AE, with a total of 42 reported AEs. One 
lipedema subject reported no AEs. Most AEs were mild or moderate in intensity. 
The AEs with the highest incidence were injection site pain and headache, each of which was 
reported by 3 of 12 subjects (25%). Pain, contusion, sleep disorders/insomnia, and muscle 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 34 of 87 
CONFIDENTIAL 
 
spasms were each reported by 2 of 12 subjects (16.7%). All remaining AEs were reported by 
single subjects only. 
There were 6 AEs with severe intensity, all of which were reported by a single DD subject, and 
included swelling (injection site, joint swelling, peripheral swelling) and pain. Following an 
investigation by the Principal Investigator, it was found that the subject had a tendency to scratch 
or rub painful lipomas and, therefore, following compound injection, lipoma scratching led to 
swelling and pain in the injected lipomas as well as in the surrounding areas. Most severe AEs 
resolved within 14 days after injection and the AE of pain resolved at 35 days. No medical 
intervention was required. 
Measurements of lipoma size in 6 DD subjects included ultrasound measurements of height, 
width and length for 21 injected lipomas. Lipoma surface area was calculated by multiplying 
lipoma width by its length. Lipoma height was the dominant parameter when referring to its 
dimensions as it included aesthetic considerations and pressure application on nerves. The mean 
reduction in lipoma height on day 56 after injection versus baseline was -47.9±44.1% (P<0.001). 
The mean change in surface area versus baseline was 30.4±82.5% (NS). 
Lipoma pain was measured by the comparative pain scale in 19 of 21 injected lipomas in 6 DD 
subjects (specific pain assessment per each lipoma). The mean reduction in lipoma pain on day 
56 after injection versus baseline was 70±36.9% (P<0.0001). Sixteen (16) lipomas reported 
having lower pain scores compared to baseline and only 3 remained without change. 
Fat thickness in 6 lipedema subjects was evaluated by averaging ultrasound measurements of fat 
thickness at 84 injection points (6 - 8 injection points per leg per subject). The mean reduction in 
fat thickness on day 56 after injection as compared to baseline was approximately 7% (NS). No 
improvement was noted in quality of life (QOL) measurements. 
Based on the study results, Raziel concluded that RZL-012 could be beneficial in treating 
patients with fat disorders such as DD.  
1.2.4.1.4. Protocol No. RZL-012-SMF-P2aUS-001.2 Status: Completed 
An additional study was of a single blind, randomized, placebo-controlled, phase 2a, 2-cohort 
study for the evaluation of safety and efficacy of RZL-012 for SMF reduction in healthy 
volunteers was conducted under IND 135762. 
The primary objective was to evaluate safety following injection of RZL-012 vs. placebo 
injection into SMF. Skin irritancy and AEs related to injection procedure were mainly evaluated 
for its frequency, severity and duration. Specifically, the assessment of the following AEs was 
monitored: bruising, pain, induration erythema and swelling/edema. 
The following secondary endpoints evaluated treatment efficacy of active treatment versus 
placebo subjects: 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 35 of 87 
CONFIDENTIAL 
 
1. Reduction from baseline in SMF volume, as measured with MRI on Day 84 as compared 
to screening, in RZL-012 treated subjects versus placebo treated subjects. 
2. Improvement of Physician’ global assessment questionnaire for treatment efficacy in 
active versus placebo treated subjects on Day 84 visit to evaluate treatment response. 
3. Improvement from baseline in subject’s satisfaction rating by using validated FACE-Q 
questionnaire (Satisfaction of chin) on Day 84 visit to evaluate treatment response among 
RZL-012 treated subjects versus placebo treated subjects. 
Twenty-Eight (28) subjects (12 for cohort 1 and 16 for cohort 2) were included in the study. 
Subjects in each cohort were injected with a different dose.  Subjects in each cohort were 
randomized in a ratio of 2:1 of active versus placebo. A total of 28 subjects were enrolled in 
2 clinical sites. Subjects were blinded to study treatment while physicians were not blinded. 
Cohort 1 (N=12) – Each subject was dosed with up to 120 mg RZL-012 (depending on SMF 
area) or up to 2.4 mL of vehicle. Averaged injected dose was 80 mg. 
Cohort 2 (N=16) – Each subject was dosed with up to 240 mg RZL-012 (depending on SMF 
area) or up to 4.8 mL of vehicle. Averaged injected dose was 158.5 mg. 
The injection pattern in both cohorts was based on a submental area shaped grid in which the 
distance between rows was 1cm and distance between columns was also was 1 cm as seen in the 
figure below. Physicians chose two points at the edge of the 50-point pattern that were not 
injected (up to 48 injections) as seen in Figure 6 below: 
 
Figure 6:  Diagram of Injection Pattern 
 
 
 
 
 
Subjects were injected with RZL-012 or vehicle perpendicularly (90) to the skin. An ice pack 
was placed on the injected area for pain relief immediately after injection. Subjects had to remain 
seated in the injection position for an additional 10 minutes after dosing. 
RZL-012-SMF-P2a-US-001 Results: 
AEs were closely followed up throughout the study to determine the safety profile of RZL-012. 
Different scales were used to grade the severity degree of edema and erythema, pain, bruising 
and induration. Most of AEs were treatment related. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 36 of 87 
CONFIDENTIAL 
 
The most commonly reported AEs were bruising, induration, edema, pain and erythema all of 
which were reported with a similar incidence in the RZL-012 and placebo treatment groups. A 
difference was evident in the severity of some of the AEs in the RZL-012 high-dose treatment 
group vs. placebo with 3 reports by 3 subjects of severe edema and 2 reports by 2 subjects of 
severe induration in the high dose group. However, these AEs were characterized as such only 
within the first 24 hours of administration. The intensity then went from moderate to mild in the 
days following the RZL-012 injection and were completely resolved by 56 days after injection 
without any specific treatment or medication. Erythema, and bruising were not dose related and 
were mostly resolved at 14 days after injection. There were no clinically significant changes in 
vital signs, no deaths and no SAEs in any subjects. 
Based on the objective MRI, it can be concluded that the efficacy of RZL-012 in reducing SMF 
in this Phase 2a study was demonstrated. This is evident by both the change in the submental 
depth (thickness) as well as volume.  The robustness of these results is supported by the dose 
response that shows larger effects for the higher dose of RZL, i.e., a volume reduction of -
22.2%±14.9 vs. Volume reduction of -10.6%±14.5 and -0.4%±13.9 for RZL-012 low dose and 
placebo, respectively. 
The objective MRI assessments were supported by the Physician Impression scale. This scale 
which shows a more pronounced improvement at days 56 and 84 compared to day 28 may 
indicate that the effects of RZL-012 on SMF progress and cumulate in the weeks following the 
administration of the product. All besides 1 of the 18 RZL-012-treated subjects demonstrated 
improvement in SMF at 84 days after treatment.  On the other hand, at Day 84, none of the 
placebo subjects demonstrated any change in their SMF. 
Subjects were clearly satisfied by RZL-012 effect as indicated by the improvement of score 
according to Subject Face-Q Questionnaire. Subjects that were treated with RZL-012 low dose 
showed a 2.4-fold increase in the mean subject satisfaction. Subjects that were treated with RZL-
012 high dose showed a 2.5- fold increase in the mean subject satisfaction. Placebo subjects did 
not demonstrate a satisfaction on Day 84 vs. baseline. 
1.2.4.1.5. Protocol No. RZL-012-DD-P2bUS-001.4 Status: On-going 
Another study for DD patients, a double blind, randomized, multi-center, placebo-controlled 
phase 2b clinical trial for the evaluation of efficacy and safety of RZL-012 in subjects having 
DD, is being conducted under IND 135762. 
The primary objective is to evaluate of the efficacy of RZL-012 following injection into 
lipomas/nodules of DD subjects. Efficacy is determined by ultrasound assessment of the 
lipoma/nodule dimensions after treatment as compared to baseline assessments. 
The key secondary objective is the assessment of lipoma/nodule associated pain using the 
Comparative Pain Scale. Safety is assessed by the frequency of AEs and by change-from-
baseline values for vital signs, clinical laboratory and ECG. An exploratory objective is to follow 
improvement in Quality of Life by using QOL questionnaire. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 37 of 87 
CONFIDENTIAL 
 
A total of 38 subjects have been enrolled into the study. Subjects were randomized in a 1:1 ratio 
into either the RZL-012 or the placebo arm. 
At least 4 lipomas/nodules, preferably 6, and no more than 8, were injected per subject. Dosing 
was determined according to lipoma size, where the total injected dose did exceed 240 mg per 
patient (48 injections of 5mg/injection). Table 3 describes the dosages according to lipoma size. 
Table 3: Dosages According to Lipomas Size 
 
 
 
 
 
 
 
The injections are spread randomly on the lipoma surface with a distance between injections of 
at least 1 cm. Injections are given at 90° to the injected skin surface. 
Once the study ends and codes are opened, 84 days after dosing, placebo-treated subjects will be 
offered the option of receiving treatment with RZL-012. Subjects who choose to receive 
treatment with RZL-012 will be followed for an additional 84 days. 
RZL-012-DD-P2b-US-001.4 Results: 
All 38 subjects were enrolled and treated in accordance with the treatment arm to which they 
were randomized. Study results are pending. 
Safety results to date have demonstrated a tolerable and good safety profile. There were no 
systemic or serious AEs were reported. 
2.0 STUDY OBJECTIVES 
2.1 
Study Objectives 
Raziel continues to investigate the efficacy and safety of RZL-012 for the treatment of SMF in a 
larger clinical population and conducted in a more controlled manner. 
Number of Subjects – 
Active/Placebo 
20/18 
Lipoma/Nodule size – 
diameter (cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Total Dose of RZL-012 
in the RZL group (mg) 
10 
20 
40 
50 
60 
Number of Injections  
2 
4 
8 
10 
12 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 38 of 87 
CONFIDENTIAL 
 
2.1.1 
Primary Objective 
The primary objective of this study is as follows: 
• 
to determine the efficacy of RZL-012 versus placebo on SMF reduction measured on Day 
84 versus baseline using the Clinician Chin Assessment Tool (C-CAT). 
2.1.2 
Secondary Objectives 
The secondary objectives of this study are as follows: 
 
• to determine the efficacy of RZL-012 versus placebo on SMF reduction measured on Day 
84 versus baseline using both Subject Self-Chin Assessment Tool (S-CAT) and the 
Clinician Assessment Tool (C-CAT); 
• to assess the reduction in SMF on Day 84 versus baseline using the caliper measured 
submental thickness and magnetic resonance imaging (MRI);  
• to assess the safety of RZL-012 in the treatment of SMF reduction. 
2.2 
Description of Study Design 
This is a Phase 2b, double-blind, randomized, three-arm, placebo-controlled study that will 
consist of a screening period, baseline period, and a randomized treatment period. 
Subjects will receive a single treatment session that consists of multiple injections of RZL-012 or 
placebo (tween-80, propylene glycol, benzyl alcohol, and water) into the submental area under 
the chin, after which they will be monitored for safety and efficacy over 84 days. 
Following the Day 84 visit of the last subject, subjects from three (3) chosen clinical sites will be 
followed up further twice up to a 1 year after injection to evaluate the long term safety and 
efficacy. The additional follow up visits will be at 6 and 12 months after injection. 
For subjects from all sites  that their adverse events were not resolved by Day 84, an unscheduled 
visit will be set 6-8 weeks after Day 84 to verify the resolution of the AE. On that visit, follow up 
of efficacy using C-CAT and S-CAT will also be conducted.  
 
Each subject will be randomized to either active treatment (high or low dose RZL-012) or 
placebo at a ratio of 1:1:1 per group and receive one of the following: 
• low dose (concentration of injected solution 34 mg/mL RZL-012) of 5.1 mg/0.15 
mL/injection point that results in a dose/volume of 163.2±20.4 mg/4.8±0.6 mL RZL-012, 
• high dose (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 
mL/injection point that results in a maximum total dose/volume of 240±30 mg/4.8±0.6 
mL RZL-012, 
• placebo of 0.15 mL/injection point that results in a total maximum volume of 4.8±0.6 
mL. 
Screening period: Subjects will undergo screening within 28 days prior to entering into the 
study.  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 39 of 87 
CONFIDENTIAL 
 
Screening period will contain 2 visits, pre-screening visit to verify that subject qualifies the study 
based on S-CAT , C-CAT and 2D photography and another visit that will include an assessment 
of eligibility by measurement of SMF thickness using calipers, skin type by Fitzpatrick scale,  
subject’s satisfaction scale related to appearance of SMF, subject impact questionnaire,  and 
MRI. MRI will be conducted prior to the baseline visit. ECG and blood samples will also be 
conducted during the second screening visit. 
Baseline treatment period: A total of 135 eligible male or female subjects will be randomized 
according to a predetermined randomization scheme (1:1:1 ratio) to receive a single multi-
injection treatment of high dose RZL-012, low dose RZL-012, or placebo on Day 0. Subjects 
will be monitored for AEs and treatment area evaluation for 30 minutes post dose prior to 
discharge from the clinical trial site. Subjects will return to the site for study visits on Days 1, 7, 
28, and 56 and for a final study visit on Day 84 for efficacy and safety assessments. 
Subjects will be advised to continue their regular diet and physical activity during the study. 
Blood samples will be collected at Day 1, 7, 28 and Day 84 study visits for assessment of 
hematology and serum chemistry. If there are clinically significant alerts obtained at any visit, , 
an unscheduled visit will be added foradditional blood sampling. 
Safety assessments will be performed at each study visit and subjects can be released after blood 
sampling and study assessments are completed. 
Safety assessments include vital signs, ECG, blood samples, AE assessment, and treatment area 
evaluation. Treatment area evaluations including, but not limited to evaluation of edema, 
bruising, dysphasia, dysphonia, erythema, dyspigmentation, induration, numbness, pain, 
paresthesia , pruritus, skin ulceration and necrosis, injury to the marginal mandibular nerve, 
vascular and nerve injury and tissue damage to nearby vulnerable anatomic structures .. 
Concomitant medications will be recorded. An internal safety review committee will review the 
safety data collected during the study in a blinded manner. The committee members will include 
study medical monitor, Raziel’s CMO and clinical director. The meeting will be held for every 
40 subjects enrolled. Following completion of enrollment period, the committee will meet 
quarterly during the follow up period. 
2.3 
Study Endpoints 
2.3.1 
Primary Endpoint 
The primary endpoint of this study is as follows: 
• 
comparison of the proportion of subjects who have at least a 1-grade improvement in the C-
CAT on Day 84 versus baseline between the RZL-012 high dose (270 mg/5.4 mL) group 
and the placebo group. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 40 of 87 
CONFIDENTIAL 
 
2.3.2 
Secondary Endpoints 
The secondary endpoints of this study are as follows: 
• Proportion of subjects who have at least a 1-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
• Proportion of subjects who have at least a 2-grade improvement in both the C-CAT and 
S-CAT (Day 84 versus baseline) in the RZL-012 groups versus placebo group. 
• Reduction in SMF volume by MRI (Day 84 versus screening) in the RZL-012 groups 
versus placebo group. 
• Reduction in SMF thickness measured with caliper (Day 84 versus baseline) in the RZL-
012 groups versus placebo group.Safety assessment of RZL-012 in the treatment of SMF 
reduction. 
• safety of RZL-012 in the treatment of SMF reduction. 
2.3.3 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
• SMF improvement using the Global Aesthetic Improvement Scale (GAIS). 
• SMF improvement using the physician Global Assessment of Change Scale. 
• SMF improvement using the Subjects Global Self-Assessment of Change Scale 
• SMF improvement using the Subject Global Assessment of Change Scale. 
• SMF improvement using the subject’s satisfaction questionnaires. 
• SMF improvement using Subject’s impact questionnaire. 
2.3.4 
Randomization/Assignment to Study Drug 
A total of 135 eligible male or female subjects (45 subjects per group) will be randomized 
according to a predetermined randomization scheme (1:1:1 ratio) to receive a single multi-
injection treatment of high dose RZL-012, low dose RZL-012, or placebo. Each subject will be 
randomized to receive one of the following: 
1. RZL low dose – dose of 163.2±20.4 mg/subject spreads over 32±4 injection points. 
2. RZL high dose – dose of 240±30mg/subject spread over 32±4 injection points. 
3. Placebo – volume of 4.8±0.6ml vehicle/subject spread over 32±4 injection points. 
2.4 
Study Drugs 
2.4.1 
Test Product and Dosing 
RZL-012 is a novel synthetic molecule provided as a sterile liquid solution suitable for injection. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 41 of 87 
CONFIDENTIAL 
 
All subjects will receive a single treatment of RZL-012 or placebo in multiple injections in 
accordance with the treatment cohort schedule as shown in Table 4 below: 
Table 4:  Dosing Regimen 
 
 
 
 
 
 
 
 
Subjects treated with RZL-012 will undergo a single treatment session with 32±4 injections. The 
maximal number of injections will be 36 with maximal doses of 183.6 mg and 270 mg for the 
low and high doses, respectively. Each injection point will be dosed with 5.1 mg RZL-012 for 
the low dose or 7.5 mg for the high dose in a volume of 0.15 mL/injection site. Placebo subjects 
will be injected with a 0.15 mL placebo per each injection site. The maximal injection volume 
for all groups will be up to 5.4 mL. 
Subjects will be injected with RZL-012 or placebo perpendicularly (90°) to the skin. An ice pack 
will be placed on the injected area for pain relief immediately after injection. Subjects will 
remain seated in the injection position for an additional 10 minutes after dosing. 
The injection pattern will be based on a submental area shaped grid in which the distance 
between rows and columns will be 1 cm, as seen in Figure 7 below. The Investigator will choose 
32±4 sequential points on the grid that will mark the injected area according to SMF fullness and 
convexity. The 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. 
Figure 7:  Scheme of Injection Pattern Grid 
 
N=135 
 
RZL-012 High 
dose (50mg/mL) 
RZL-012 Low dose 
(34mg/mL) 
Placebo 
Number of subjects (N) 
45 
45 
45 
Maximum RZL-012 dose 
(mg)/volume (mL) 
270mg/5.4 mL 
183.6 mg/5.4 mL 
0mg/5.4±0.6mL 
RZL-012 Dose (mg)/volume 
(mL) per single injection 
7.5mg/0.15mL 
5.1mg/0.15mL 
0mg/0.15mL 
Number of Injections per 
subject 
32±4, maximum of 36 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 42 of 87 
CONFIDENTIAL 
 
 
 
 
 
 
An internal safety review committee will review the safety data collected during the study in a 
blinded manner. The committee members will include study medical monitor, Raziel’s CMO and 
clinical director. The meeting will be held for every enrolled 40 subjects. Following completion 
of enrollment period, the committee will meet every quarterly during the follow up period. 
2.4.2 
Dose Rationale 
The maximal RZL-012 dose tested in the SMF phase 2a study was 210 mg, which is 87.5% of 
the NOAEL. No serious AEs were associated with this dose per injection site (5mg, 0.1mL), 
with the distance maintained between injection sites (1cm) or with the maximal overall dose. A 
distance of 1 cm will allow a good distribution RZL-012 into the submental area. 
The averaged doses that were injected during phase 2a study were based on injection of 32 
injections points on the grid that were spread with a distance of 1cm between injection columns 
and rows of the SMF pattern. Therefore, in the current phase 2b study, an area which includes 
32±4 injection points on the submental pattern grid was chosen. 
For this study, two (2) doses have been chosen where the local injection volume is increased to 
0.15 mL per injection site with a dose of 5.1 mg per injection site for RZL-012 low dose. 
Therefore, a maximal injection volume and dose will result in a maximal dose of 183.6 mg/5.4 
mL into SMF area. 
To increase the potential to demonstrate efficacy, a higher RZL-012 dose of RZL will also be 
assessed with a dose of 7.5 mg per injection site. Therefore, a maximal injection volume and 
dose for RZL-012 high dose will result in a maximal dose of 270 mg/5.4 mL into SMF area. 
An increase from 240 mg which was determined as the NOAEL is justified based on available 
preclinical and clinical safety data of RZL-012. 
Based on Kyebella’s studies, injections up to 10 mL into the SMF area are acceptable. 
2.4.3 
Serious Adverse Events Considered Related to the Investigational Drug 
AEs and serious adverse events (SAEs) will be monitored throughout the study. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 43 of 87 
CONFIDENTIAL 
 
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 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 
2.5 
Concomitant Medications 
2.5.1 
Prior and Concomitant Medications 
Prior medications are defined as medications that were taken within 30 days prior to initial 
dosing with study drug. 
Concomitant medications are defined as medications taken any time after the start of dosing until 
discharge assessments. All concomitant medication, 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. 
3.0 STUDY POPULATION 
The study population will be male or female adult healthy volunteers age 18 to 65 years who 
have consented to participate in this study. 
3.1 
Inclusion Criteria 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 44 of 87 
CONFIDENTIAL 
 
1. For a subject to be eligible for this study, he or she must meet all of the following 
criteria: Is a male or female subject between the ages of 18 and 65 years, inclusive. 
2. Has body mass index (BMI) between >22 and <40. 
3. Has SMF  bulge that is contiguous and fits to 32±4 injections sites according to a grid 
with 1 centimeter (cm) distance between injection points. 
4. Has grade 3 to 4 of SMF as rated by the C-CAT. 
5. Has a visible or large pocket of submental fat- according to physician global assessment. 
6. Has grade 3 to 4 of SMF as rated by the S-CAT. 
7. Has stable weight, with no fluctuation of >5 kg in the past 12 months. 
8. If female, is not pregnant or breastfeeding based on the following: 
a. agree to the use of highly effective contraceptive methods for at least 2 weeks 
before baseline until 4 weeks after the last day of study drug and a negative serum 
pregnancy test (ß-hCG) at screening and negative urine pregnancy test at baseline; 
or  
b. is of nonchildbearing potential defined as clinically infertile as the result of surgical 
sterilization (hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy); 
or  
c. is confirmed postmenopausal status (defined as either having amenorrhea for ≥ 12 
consecutive months without another cause and documented serum follicle-
stimulating hormone (FSH) level > 40 mIU/mL or another documented medical 
condition (e.g., was born without a uterus)) 
NOTE: The following are considered highly effective contraceptive methods: hormonal 
oral contraceptives, injectables, and patches; intrauterine devices; double-barrier methods 
(synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or 
gel); and male partner sterilization. 
 
9. If male (with or without vasectomy), agree to the use of highly effective contraceptive 
methods e.g., condom , from study check-in until 7 days after the last day of study drug. 
10. Is willing to avoid strenuous exercise for seven (7) days post treatment. 
11. Is able to adhere to the visit schedule and protocol requirements and be available to 
complete the study. 
12. Is willing and able to sign an Institutional Review Board (IRB) approved informed 
consent form (ICF) indicating that they are aware of the investigational nature of the 
study. 
3.2 
Exclusion Criteria 
Subjects must NOT meet any of the following Exclusion criteria to be eligible for enrollment: 
1. Is unable to tolerate subcutaneous injections. 
2. Has dysfunctional gallbladder activity (e.g., underwent cholecystectomy or 
cholecystitis). 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 45 of 87 
CONFIDENTIAL 
 
3. Has any uncontrolled systemic disease that is not stabilized (i.e., cardiovascular disease, 
mental illness). 
4. Has had treatment with botulinum toxin injections in the neck or chin area within nine 
(9) months prior to screening. 
5. Has used anticoagulation therapies that may increase bleeding or bruising (i.e., aspirin, 
ibuprofen, vitamins, and herbal preparations) for seven (7) days prior to treatment. 
6. Has skin laxity (i.e., elastosis, skin crepiness, skin redundancy, skin draping, vertical 
and/or horizontal skin bands and folds, blunting of cervical mental angle, loss of 
opposition of skin to underlying neck structures due to skin laxity) that could obscure 
the evaluation and treatment of SMF. 
7. Has any scars, unshaven hair, tattoos, facial hair or jewelry on or near the proposed 
treatment area. 
8. Has presence of structures or confounding factors that may interfere with assessing SMF 
such as but not limited to enlarged submandibular salivary and/or parotid glands, 
micrognanthia, chin implant, soft tissue volume augmentation of chin and/or jawline, 
pronounced platysmal bands and deep necklace lines or presence of facial jowls that 
could obscure the evaluation of SMF.  
9. Has a fat bulge under the chin that is too large to be adequately treated by 32+/-4 
contiguous injections on a 1cm grid . 
10. Has a fat bulge under the chin that is of an insufficient volume to allow 28 injections 
within a contiguous 1 cm grid.  
11. Has significant history or current evidence of a medical, psychological or other disorder 
that, in the Investigator’s opinion, would preclude enrollment in the study. 
12. Has an active dermatitis or open wound in the proposed treatment area. 
13. Has abnormal coagulation tests (PT, PTT) 
14. Has D-dimer value >0.64mg/L in screening visit 
15. Has an active bacterial, fungal, or viral infection in the proposed treatment area.   
16. Has a pre-existing skin condition in the submental region that, at the Investigator’s 
discretion, may confound evaluation or analysis. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 46 of 87 
CONFIDENTIAL 
 
17. Has previously had treatments or surgery in the submentum, such as but not limited to, 
focused ultrasound, radiofrequency, cryolipolysis, liposuction, sodium deoxycholate, or 
neck lift. 
18. Has pre-existing neurological or gastrointestinal condition leading to dysphagia, 
dysphonia, or facial nerve palsy. 
19. Has Dercum’s Disease 
20. Has allergic reactions to injectables. 
21. Has any pre-existing medical condition other than increased SMF that, at the 
Investigator’s discretion, may result in increased submental fullness, such as but not 
limited to, thyroid enlargement, goiter, cervical lymphadenopathy, etc. 
22. Has a planned fat reduction procedure of any variety to the submental region for the 
duration of the study. 
23. Has medication or a history of coagulopathy. 
24. Has a history or family history of venous thrombotic disease. 
25. Has been treated chronically at least three (3) months prior to study entry with systemic 
steroids or immunosuppressive drugs. 
26. Has been treated chronically at least one (1) week prior to study entry with non-steroidal 
anti-inflammatory drugs (NSAIDs). 
27. Current participation or participation within three (3) months prior to the start of this 
study in a drug or other investigational research study. 
28. Has claustrophobia or an MRI incompatible device or implant. 
3.3 
Subject Identification 
At each site, a unique code numbers will be assigned by the Investigator to the trial subject rather 
than the subjects’ name, 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 AE and/or other trial related data. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 47 of 87 
CONFIDENTIAL 
 
3.4 
Removal, Replacement or Early Withdrawal of Subjects from the Assessment Not 
Due to Intolerable Side Effects 
Subjects experiencing serious side effects will be withdrawn from the study, but will be 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. 
4.0 STUDY PROCEDURES AND ASSESSMENTS 
4.1 
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. The 
Investigator or his/her approved designee must explain the nature of the study protocol and 
associated risks to the potential study participant. The potential participant must be allowed to 
review the study information and to ask questions before being asked to sign the Informed 
Consent Form (ICF). Written informed consent must be provided by the potential study 
participant prior to initiation of any screening evaluations or other study-related procedures. The 
signature date and the name of the individual at the site who obtained the informed consent will 
be recorded in the subject’s medical record. 
The ICF approved by the IRB/EC will contain a description of the study’s purpose, purpose, 
procedures, inconveniences and potential risks, and anticipated benefits. 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 ICF provided to the subjects. 
After written informed consent is obtained, the subject will be assigned a screening number and 
will undergo the designated screening procedures listed in Appendix A. The Investigator, sub-
investigator or delegate will assess the results of these screening evaluations to determine 
eligibility for entry into the study according to the inclusion/exclusion criteria listed in Section 
3.0. 
4.2 
Complete physical examination 
The Investigator (or medically qualified nominee) will perform a complete physical exam at 
screening and on Day 84. Additional examinations that will be performed during the screening 
include height and weight to determine BMI to confirm eligibility. 
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 
six (6) categories of skin as described below: 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 48 of 87 
CONFIDENTIAL 
 
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 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 
 
4.3 
Medical History 
A medical history will be obtained at screening.  Subject’s medical history should be fully 
documented to confirm eligibility. Medical history must include, but not limited to, past and 
present medical conditions, concomitant non-drug treatments, and hypersensitivity to drugs. 
4.4 
Vital Signs 
Vital signs (systolic and diastolic sitting position blood pressure, pulse rate, respiratory rate, and 
body oral temperature) are to be obtained at screening to ensure compliance. 
Additional vital sign measurements to assess subject’s safety will be performed at baseline (Day 
0) prior to treatment and after treatment, Day 1, and during study visits on Days 7, 28, and 56. 
4.5 
ECG 
ECG test is to be obtained at screening to ensure compliance. ECG will be done in triplicates. 
Additional ECG will be performed on Day 7 and Day 84 visit. 
 
4.6 
Height and Weight 
Height will be reported in centimeters at screening.  Body weight will be reported in kilograms 
(kg) at screening.  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 49 of 87 
CONFIDENTIAL 
 
Weight measurement will be performed at screening to determine the BMI value. An additional 
weight measurement will be performed at baseline and at study visits on Days 56 and 84 to 
verify no significant changes in weight throughout the assessment of SMF changes during the 
study. 
4.7 
Clinical Laboratory Evaluations – Hematology and Serum Chemistry 
Screening blood samples and urine specimens for laboratory evaluation will be collected at 
screening to confirm eligibility. Additional blood samples will be collected at Day 1, 7, 28 and 
Day 84 study visits for an assessment of hematology and serum chemistry. 
If there are clinically significant alerts obtained at any visit, an unscheduled visit will be added 
for additional blood sampling. 
4.7.1 
Hematology 
Complete blood cell count (CBC) will include a standard red blood cell (RBC), white blood cell 
(WBC) with differential, hemoglobin, hematocrit, platelets, D-dimer, Fibrinogen and coagulation 
(International normalized ratio [INR], partial thromboplastin time [PTT] and prothrombin time 
[PT]). 
4.7.2 
Serum Chemistry 
Comprehensive metabolic panel will include serum alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), glucose, calcium, globulin 
(calculated), phosphorus, chloride, sodium, potassium, blood urea nitrogen (BUN)/creatinine 
ratio (calculated), creatinine with GFR estimated,  total bilirubin, albumin, albumin/globulin 
ratio (calculated), total protein, amylase, bicarbonate/carbon dioxide (CO2), uric acid, gamma-
glutamyl transferase (GGT), and lactate dehydrogenase (LDH).  
4.7.3 
Pregnancy Tests 
A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at 
screening and a urine pregnancy test will be administered at baseline prior to dosing. Additional 
serum pregnancy tests will be done at any time during the study (up to 84 days), if pregnancy is 
suspected. 
4.8 
Submental Fat Thickness using Calipers 
The aim of caliper measurement is to evaluate fat reduction before and after treatment. At 
screening, 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.  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 50 of 87 
CONFIDENTIAL 
 
Additional measurement to assess efficacy will be conducted at study visits at Days 28, 56, and 
84.  
4.9 
2-D Standardized Photography 
Standardized photography (2-dimensional) of the face (SMF area) will be conducted at screening 
in order to establish a baseline value for assessment of treatment efficacy.  
Additional photography will be conducted on Days 1, 7, 28, 56, and 84 to evaluate qualitative 
changes in SMF area at study visits.  
Photographs will be taken with a digital camera according to photography standards in 
dermatology surgeries for the face/neck area (see Appendix B). 
4.10 
Magnetic Resonance Imaging (MRI) 
The purpose of the MRI exam is to evaluate fat reduction following treatment. MRI exams will 
be conducted in imaging centers close to selected clinical sites. 
MRI will be conducted at screening in order to establish a baseline value for assessment of 
treatment efficacy. Post-treatment period MRI will be completed within 84 days (± 14 days) after 
the treatment session. 
Quantitative measurements such as fat volume of the SMF area will be used as an objective 
parameter for measurement of SMF reduction following treatment. 
Sagittal 2D and 3D images of the head and neck (chin area) will be obtained using 1.5 Tesla 
machine (General Electric, Siemens, Phillips or other). For each MRI visit, the total imaging 
time is expected to be approximately thirty (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 SMF 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. 
Images should be saved in a DICOM format and include the date completed and subject’s 
screening number to be transferred home the Sponsor’s request for central analysis. 
Submental volume analysis will be performed by computer-assisted tools and calculation of 
submental volume will be completed prior to dosing and after treatment. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 51 of 87 
CONFIDENTIAL 
 
4.11 
Clinician-Chin Assessment Tool (C-CAT) 
SMF ratings using the C-CAT will be conducted by the Investigator at screening and baseline 
and at study visits on Days 28, 56, and 84 to assess the change in SMF severity before and 
following treatment. 
The C-CAT score will be based on the Investigator’s clinical evaluation of the subject in the 
Frankfurt horizontal plane. Clinical evaluation will include palpation of the chin and neck area, 
anterior, oblique and profile views of the chin and neck, and observation of pronation, 
supination, and lateral movement of the head. The score will be determined using the rating scale 
definitions. The score will be recorded as a whole number. At screening, the score will be used in 
conjunction with inclusion criteria. 
The C-CAT is defined below. The scale is A 5-point scale (scored 0-4). 
The grading system categorizes 3 aspects of submental chin fat: bulge, (size of the submental fat 
bulge) neck (extension of the bulge into the neck, downward and lateral) and  jawline (the 
appearance of the jawline, presence of fat and definition of the jawline). 
Each grade contains a description and a line drawing. Each grade is distinct and non-overlapping. 
 
 
 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 52 of 87 
CONFIDENTIAL 
 
 
 
 
 
 
A comprehensive training guide with representative photographic examples and line drawing to 
each grade will be provided to the study center sites for training and visual comparison. The 
clinician training materials are attached in Appendix C. 
4.12 
Subject – Self-Chin Assessment Tool (S-CAT) 
SMF ratings using the S-CAT will be conducted by the subject at screening and baseline and at 
study visits on Days 28, 56, and 84 to assess the change in SMF area following treatment. 
The scale has 5 grades from 0 to 4. Each grade utilizing line-drawings and descriptors to identify 
5 unique and non-overlapping grades. 
The chin fat is categorized by the following features: bulge (size of the fat bulge) neck ( 
extension of the bulge downward and laterally into the neck) and jawline (presence of fat and 
definition of the jawline). 
 
 
 
 
 
 
 
 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 53 of 87 
CONFIDENTIAL 
 
Self evaluations should be made sitting in an upright position with the chin at a right angle (as 
illustrated in the line drawings). Mirrors will be used to see the chin, neck and jawline from both 
front and side views. 
A comprehensive training guide with representative photographic examples and line drawing to 
each grade will be provided to the subjects. 
The subject self -assessment training material are attached in Appendix D. 
4.13 
Subject’s Satisfaction Questionnaire for SMF Appearance 
SMF satisfaction questionnaire will be conducted by the subjects at in screening visit and study 
visits on Days 28, 56, and 84 to assess the subject’s satisfaction with their SMF after treatment. 
Subjects will be asked the following questions and will score their satisfaction based on the 
grades below: 
How satisfied are you currently with the appearance of your chin, neck and jawline area? 
Score 
Grade 
0 
Extremely Satisfied  
1 
Satisfied 
2 
Somewhat satisfied 
3 
 Neither Satisfied nor Dissatisfied 
4 
Somewhat Dissatisfied 
5 
Dissatisfied 
6 
Extremely Dissatisfied 
 
How happy are you with the appearance of your neck as it relates to your chin fat? 
Score 
Grade 
0 
Extremely Satisfied  
1 
Satisfied 
2 
Somewhat satisfied 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 54 of 87 
CONFIDENTIAL 
 
3 
 Neither Satisfied nor Dissatisfied 
4 
Somewhat Dissatisfied 
5 
Dissatisfied 
6 
Extremely Dissatisfied 
 
How satisfied are you with the result of your treatment*? 
Score 
Grade 
0 
Very dissatisfied  
1 
Dissatisfied  
2 
Somewhat dissatisfied  
3 
Somewhat satisfied 
4 
Satisfied 
5 
Very satisfied 
How likely would you be to recommend this procedure to friends and family*? 
Score 
Grade 
0 
Not at all likely 
1 
A little likely 
2  
Somewhat likely 
3 
Very likely 
4  
Extremely likely 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 55 of 87 
CONFIDENTIAL 
 
*subjects will be asked this question only at study visits on Days 28, 56, and 84 
4.14 
Subject’s Impact Questionnaires  
A  set of questions will be asked to assess subject’s impact based on their SMF appearance. This 
will be conducted by at screening and at study visits on Days 28, 56, and 84 to assess the change 
in SMF area following treatment. 
A. How self-conscious are you about your appearance as it relates to your chin fat? 
0-Not at all self-conscious 
1-A little self-conscious 
2-Moderately self-conscious 
3-Very self-conscious 
4-Extremely self-conscious 
 
B. How bothered are you by the appearance of your chin fat?  
0-Not at all bothered 
1-A little bothered 
2-Moderately bothered 
3-Very bothered 
4-Extremely bothered 
 
C. How much do you think that the appearance of your chin fat effects your career or work 
life? 
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
D. How much does the appearance of your chin fat effect your relationships? 
0-Not at all  
1-A little bit 
2-A Moderate amount  
3-A great deal 
4-An extreme amount 
 
E. How much does the appearance of your chin fat effect your self-confidence?  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 56 of 87 
CONFIDENTIAL 
 
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
F. Do you feel self-conscious about the appearance of your chin fat when you look at 
photographs?  
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
G. Do you try to hide or camouflage your chin fat?  For example, make-up and hair styles, 
beard hair, clothing or neck/head position?  
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
H. Do you feel self-conscious when you look at your chin fat in the mirror? 
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
I. How do you think the appearance of your neck effects your relationships? 
0-Not at all  
1-A little bit 
2- A moderate amount  
3-A great deal 
4-An extreme amount 
 
J. How heavy or thin do you think your chin fat makes you look?  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 57 of 87 
CONFIDENTIAL 
 
0 - I look more than 10 pounds thinner than I am 
1 - I look 10 pounds thinner 
2 - I look 5 pounds thinner 
3 - I look my weight 
4 - I look 5 pounds heavier 
5 - I look 10 pounds heavier 
6 - I look more than 10 pounds heavier  
 
4.15 
Physician Global Assessment Improvement Scale (GAIS) and physician assessment  
Investigators will assess the improvement in SMF following treatment by comparing the 
photographs of the subject taken at screening versus the photographs taken at study visits on 
Days 28, 56, and 84. 
At each study visit, the Investigator will assess the improvement degree based on the following 
scale: 
Global Aesthetic Improvement Scale (GAIS) 
Grade 
Degree 
Description 
1 
Very much improved 
Optimal cosmetic result 
2 
Very improved 
Marked improvement in appearance from the initial 
condition, but not completely optimal 
3 
Improved 
Obvious improvement in appearance from the 
initial condition 
4 
No change  
The appearance is essentially the same as the 
original condition 
5 
Worsened 
The appearance is worse than the original condition 
 
Clinicians will be asked which word best describes the amount of submental fat the subject has*:  
o No fat 
o Barely visible pocket of fat 
o Small but visible pocket of fat 
o Visible pocket of fat amount 
o Large pocket of fat 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 58 of 87 
CONFIDENTIAL 
 
*The question will be asked at screening and on study visits 28, 56 and 84 Days. 
 
4.16 
Subject Global Assessment of Change  and subject self-assessment 
Subjects will be asked to self-assess their SMF appearance and change.  
At each study visit, the subject will be asked to assess their improvement degree based on the 
following questions: 
A. Looking in a mirror today, how would you rate the amount of your submental (under the 
chin) fat from 1 (not fat) to 10 (extreme fat) using the numerical rating scale? * 
1       2       3       4       5       6       7       8       9       10 
No fat 
 
 
 
 
 
        extreme fat  
 
 
 
 
 
B. Subjects Global Self-Assessment of under the chin fat: Which word best describes the 
amount of your submental (under the chin) fat? * 
o No fat 
o Barely visible pocket of fat 
o Small but visible pocket of fat 
o Visible pocket of fat amount 
o Large pocket of fat 
 
* questions will be asked at screening visit and on Days 28,56 and 84  
 
At each study visit (Day 28,56 and 84), the subject will be asked to assess their improvement 
degree based on the following scale: 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 59 of 87 
CONFIDENTIAL 
 
 
 
Score 
Grade 
0 
Extremely improved 
1 
Very much improved 
2 
Improved 
3 
No Change  
4  
Worse 
5 
Very much worsened 
6 
Extremely worsened 
  
4.17 
Evaluation of Response 
Evaluation of response will be conducted on Days 28, 56, and 84 following injection of RZL-012 
or placebo. 
4.18 
Compliance Monitoring 
Compliance monitoring will include compliance assessment by site coordinator at the study 
visits, including but not limited to subject questioning. 
5.0 SAFETY ASSESSMENTS 
5.1 
Collection of Adverse Events Data 
Data regarding treatment-emergent AEs (TEAEs) will be collected in this study.  TEAEs are 
events that are not present at baseline, or if present at baseline, have worsened in severity. AEs 
will be assessed while the subjects are in the study. AEs assessed by the Investigator as related to 
study drug and “ongoing” at discharge will be monitored by the Investigator until resolved or 
until the subject is deemed “lost to follow-up”. 
Any AEs reported by the subject or noted by the Investigator or his/her designee will be recorded 
on the eCRF regardless of the Investigator opinion of causality. The following information will 
be recorded for each AE: description of the event, date and time of onset, date and time of 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 60 of 87 
CONFIDENTIAL 
 
resolution, severity, causal relationship to study drug, outcome, action taken with the study drug 
and any treatment given. 
The AEs reported during the trial will be graded, documented, and assessed in regards to their 
clinical significance and relation to study drug. Treatment area evaluations including, but not 
limited to evaluation of edema, bruising, dysphasia, dysphonia, erythema, dyspigmentation, 
induration, numbness, pain, paresthesia, pruritus, skin ulceration and necrosis, injury to the 
marginal mandibular nerve, vascular and nerve injury and tissue damage to nearby vulnerable 
anatomic structures.. 
All abnormal changes from baseline will be collected, graded with regards to severity or clinical 
significance, assessed for causal relationship and recorded on the eCRF. 
5.2 
Complete or Targeted Physical Examination  
The Investigator will perform a complete PE at screening and on Day 84 visit. 
5.3 
Vital Signs 
Vital signs (systolic and diastolic sitting position blood pressure, pulse rate, respiratory rate, and 
body oral temperature) are to be obtained at screening to ensure compliance. 
Additional vital sign measurements to assess subject’s safety will be performed at baseline (Day 
0) prior to treatment and after treatment, Day 1, and during study visits on Days 7, 28, and 56. 
6.0 PHARMACOKINETICS 
No PK measures will be assessed during this study.  
7.0 EFFICACY 
Efficacy measures include the following: 
• Efficacy of RZL-012 versus placebo on SMF reduction measured on Day 84 versus 
baseline using the C-CAT. 
• Assessment of the reduction in SMF on Day 84 as compared to baseline using the caliper 
measured submental thickness, MRI measured SMF volume, and the S-CAT.  
• Assessment of SMF improvement using the Physician global SMF assessment, GAIS, 
Subject Global Assessment of Change Scale, Subject Global Self-Assessment and subject 
satisfaction questionnaire, subject’s impact questionnaire.  
8.0 STUDY VISITS AND PROCEDURES 
Refer to Appendix A for the Schedule of Study Procedures. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 61 of 87 
CONFIDENTIAL 
 
8.1 
Screening (Days -28 to -1) 
The Investigator or his/her approved designee must explain the nature of the study protocol and 
associated risks to the potential study participant. The potential participant must be allowed to 
review the study information and to ask questions before being asked to sign the Informed 
Consent Form (ICF). Written informed consent must be provided by the potential study 
participant prior to initiation of any screening evaluations or other study-related procedures. The 
signature date and the name of the individual at the site who obtained the informed consent will 
be recorded in the subject’s medical record. 
After written informed consent is obtained, the subject will be assigned a screening number and 
will undergo the designated screening procedures listed in Appendix A. The Investigator, sub-
investigator or delegate will assess the results of these screening evaluations to determine 
eligibility for entry into the study according to the inclusion/exclusion criteria listed in Section 
3.0. 
Screening evaluations may be performed up to 28 days in advance of dosing but must be 
completed at least 1 day prior to Day 0. 
The following study evaluations and procedures are required to determine eligibility at pre-
screening visit: 
• C-CAT 
• S-CAT 
• 2D photography 
 
The following study evaluations and procedures are required to determine eligibility in the second 
part of the screening visit: 
• Obtain and record a medical history, including demographics, prior medications, and 
concomitant medications. 
• Complete physical examination 
• Vital signs  
• ECG 
• Height and weight measurements 
• Blood and serum samples for the following laboratory evaluations: 
o Hematology 
o Serum chemistry 
o Coagulation  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 62 of 87 
CONFIDENTIAL 
 
o Pregnancy (if applicable) 
• Caliper measurement of SMF thickness 
• MRI 
• Physicians Global Assessment Question 
• Subject’s satisfaction questionnaire (appearance of submental area) 
• Subject Global Assessment questions 
• Subject’s impact questionnaire 
Subjects may be re-screened if they were screened and not dosed within 28 days. The following 
procedures will be performed: vital signs and weight measurements.  
8.2 
Baseline Evaluations (Day 0) 
Following the screening visit, subjects determined to be eligible for participation in the study 
will undergo baseline assessments. Baseline evaluations will be performed upon admission to the 
clinical research unit on Day 0. 
Baseline assessments include the following: 
• Confirm eligibility  
• Vital signs  
• Weight measurement 
• Concomitant medications  
• Urine pregnancy test (if applicable) 
• S-CAT 
• C-CAT 
Once subjects are confirmed to be eligible, they will be randomized to one of the treatment 
groups based on the randomization schedule. 
8.3 
Study Randomization 
Subjects will be randomized to each treatment group according to a predefined randomization 
scheme in a ratio of 1:1:1 among eight (8) to twelve (12) clinical sites. Assignment to treatment 
group will be disclosed only after subject eligibility is confirmed and immediately prior to 
injection treatment. The Investigator, clinical staff and the subjects will be blinded to treatment 
group.  
8.4 
Pre-dose Evaluation (Day 0) 
Pre-dose assessments on Day 0 include the following: 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 63 of 87 
CONFIDENTIAL 
 
• Vital signs  
• AE assessment  
8.5 
Drug Administration 
RZL-012 or placebo will be supplied as a single treatment in multiple sites of injection (32±4 
injections). The injection dosing regimen and technique is crucial for the therapy safety. 
The following procedures prior to injection into the SMF 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 drug 
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, 
with the printed grid pattern facing the skin. The grid paper backing will be thoroughly 
wetted with a cotton pad soaked with sterile water. After 15 seconds, the grid cover will 
be peeled off. 
5. An area of 32±4 adjacent injection points will be determined following the Investigator’s 
evaluation. 
6. Syringes will be filled with 1 mL RZL-012 high dose or low dose or placebo and the 
number of syringes will be compatible with the total volume of injection. Up to six (6) 
syringes for a total volume of 5.4 mL will be used. 
7. All injections will be administered perpendicularly in 90 degrees, using a 1 mL Luer-lock 
syringe and a 29G 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 prior to 
injecting to ensure no blood is coming out. If so, the plunger should be pushed down to 
inject 0.15 ml the medicine. The formulation is viscous; therefore, resistance is expected 
during injection. 
9. Immediately following completion of the injections, an ice/cold pack will be applied for 
immediate pain relief. It will be held by the subject for at least two (2) minutes. 
10. The Investigator will record the number of injections administered for each subject. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 64 of 87 
CONFIDENTIAL 
 
The injection pattern used will be based on an existing grid in the shape of the submental area, 
where distance between injection rows will be 1 cm and distance between the injection columns 
will be 1 cm.   
The number of injections for each subject will be determined by the Investigator according to 
fullness of SMF but will not be lower than 28 injections or higher than 36 injections.  
Each RZL-012 kit contains 2 vials that will be assigned to each subject: 
• RZL-012 low dose will be provided in vials of 163 mg/4.8 mL (34 mg/mL) 
• RZL-012 high dose will be provided in vials of 240 mg/4.8 mL (50 mg/mL) 
 
Treatment with placebo will be conducted in the same manner as above. 
 
The calendar date and 24-hour clock time of all doses will be recorded on the CRF. 
8.6 
Post-dose Evaluations (Day 0)  
Post-dose assessments on Day 0 include the following: 
• Vital signs 
• Concomitant medication 
• AEs 
Following completion of injection treatment, an ice/cold pack will be placed on the injected area 
for pain relief. Subjects will remain seated in the injection position for an additional ten (10) 
minutes after injections. Subjects will remain in the clinic up to 30 minutes (15-30 minutes) post 
dosing for medical supervision and AE assessments. During the confinement period, there are no 
restrictions in terms of activity or diet. 
8.7 
Study Visits (Days 1, 7, 28, and 56) 
Subjects will return to the clinical site for study visits on Days 1, 7, 28, and 56. Study visit 
assessments include the following: 
• Vital signs 
• Concomitant medication 
• AEs 
• Weight measurement (Day 56) 
• Clinical laboratory tests (Days 1, 7, 28) 
• Serum pregnancy test (in case pregnancy is suspected) 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 65 of 87 
CONFIDENTIAL 
 
• ECG (Day 7) 
• Caliper measurement of submental thickness (Days 28 and 56) 
• S-CAT (Days 28 and 56) 
• C-CAT (Days 28 and 56) 
• 2D Photography (Days 1, 7, 28, and 56) 
• Subject Global Assessment of Change (Days 28 and 56) 
• Subject’s satisfaction questionnaire (Day 28 and 56) 
• Physician GAIS (Days 28 and 56) 
• Subject impact questionnaire (Day 28 and 56) 
 
In the case of clinically significant laboratory values at any visit, the subject will return for an 
unscheduled visit and a repeat of hematology and serum chemistry. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 66 of 87 
CONFIDENTIAL 
 
8.8 
Final Visit (Day 84) 
Final study visit assessments include the following: 
• ECG 
• Physical Exam 
• Concomitant medication 
• AEs 
• Clinical laboratory tests (including serum pregnancy test, in case pregnancy is suspected) 
• Weight measurement  
• Caliper measurement of submental thickness 
• S-CAT 
• C-CAT 
• MRI 
• 2D Photography  
• Physician GAIS and physician assessment 
• Subject Global Assessment of Change and self-assessment 
• Subject’s satisfaction questionnaires 
• Subject impact questionnaires 
8.9 
Additional follow up of subjects: 
Following the completion of  Day 84 visit of the last subject, subjects from three (3) chosen 
clinical sites will be followed up further twice up to a 1 year after injection to assess long term 
safety and duration of efficacy. The additional follow up visits will be at 6 and 12 months after 
injection. 
These visits will include the following procedures: 
• 2D Photography  
• Physical exam of the treated area 
• S-CAT 
• C-CAT 
• AEs 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 67 of 87 
CONFIDENTIAL 
 
 
9.0 PREMATURE DISCONTINUATION FROM STUDY 
A premature discontinuation from study will occur when a subject who signed informed consent 
ceases participation in this study, regardless of circumstances, prior to completion of the 
protocol. Subjects can be prematurely discontinued from the study for one of the following 
reasons:  
• Failure to meet inclusion/exclusion criteria before receiving first dose of study drug has 
been administered 
• Death 
• Significant safety event that in the opinion of the Investigator warrants discontinuation. 
Raziel will attempt to follow up all subjects for safety. 
• Lost to follow-up after every attempt has been made to contact the subject, including 
sending a registered letter 
• Subject withdraws consent 
The Principal Investigator and the Institutional Review Board/Ethics Committee (IRB/EC) 
reserve the right to prematurely terminate the study in the interest of subject safety and welfare. 
The Sponsor reserves the right to prematurely terminate the study at any time for administrative 
reasons. 
10.0 
PRODUCT SPECIFICATIONS 
10.1 
Description 
RZL-012, illustrated in Figure 1, is a novel synthetic molecule (termed RZL-012) that can help 
reduce fat content following its injection into the subcutaneous fat. Chemically, RZL-012 is 5-
(3,6-dibromo-9H-carbazol-9-yl)-N,N,N-trimethylpentan-1-aminium chloride. RZL-012 is 
generated by a single step reaction and the final product is >97% pure. 
RZL-012 is provided as a sterile liquid solution suitable for injection. RZL-012 investigational 
drug is intended to be administered as a single dose via multiple injections into the subcutaneous 
fat. 
Placebo will be supplied as a vehicle control of tween-80, propylene glycol, benzyl alcohol and 
water. 
10.2 
Formulation, Packaging, and Labeling 
The active ingredient RZL-012 drug substance was manufactured by Cambrex, NC, USA. RZL-
012 drug product was manufactured in Patheon (Italy) and packed and labeled at ThermoFischer, 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 68 of 87 
CONFIDENTIAL 
 
USA. The drug product is provided in vials of 240 mg/4.8 mL (50 mg/mL) and 163mg/4.8 mL 
(34 mg/ml).  
The active ingredient and formulation manufacturing and packing were in accordance with 
cGMPs. 
RZL-012 will be provided in 2 strengths of 240 mg/4.8 mL (50 mg/mL) and 163 mg/4.8 mL (34 
mg/mL). 
The placebo is a ready to use liquid to be injected into the subcutaneous fat, supplied in a 1 vial 
kit. Each vehicle vial contains 4.8 mL solution volume. 
10.3 
Receipt, Storage and Stability of RZL-012 
The RZL-012 kit and placebo vehicle will be stored in the site at monitored room temperature 
conditions (15 - 30 degrees Celsius) protected from light. 
Drug product stability has successfully reached three (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 First In First Out (FIFO) principals. 
10.4 
Study Drug Administration 
Each kit containing 2 vials must be kept and handled at room temperature. The vials should be 
manually shaken prior to injection. 
1 mL Luer-lock syringes with RZL-012 solution should be filled with 29 G ½”  sterile needle for 
a maximal low dose of 183.6 mg and a maximal high dose of 270 mg. Two vials will be used for 
each subject. Breached vials will not be used for another subject. Each vial must be placed back 
into the container. All open vials will be kept until the end of study when the Sponsor will 
determine if study drug should be returned or destroyed. 
10.5 
Ordering and Distribution of Study Drug 
RZL-012 drug product was manufactured in Patheon (Italy) and packed and labeled at 
ThermoFischer, USA. The drug product is provided in vials of 240 mg/4.8 mL (50 mg/mL) and 
163mg/4.8 mL (34 mg/ml). 
RZL-012 will be dispensed to the sites under monitored conditions by ThermoFischer USA. 
The active ingredient and formulation manufacturing and packing were in accordance with 
current Good Manufacturing Practices (cGMPs). 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 69 of 87 
CONFIDENTIAL 
 
10.6 
Accountability of Study Drugs 
All study drugs received, dispensed, and returned must be accounted for in the study drug 
Dispensing Log, including: 
• Subject number and initials 
• Date study drug was dispensed 
• Quantity dispensed 
• Quantity returned 
• Quantity wasted, as applicable 
All study drug received and dispensed by the Investigator will be inventoried and accounted for 
throughout the study. The study drug must be stored in a restricted area with limited access. 
Contents of the study drug containers must not be combined. Used sprayers will be accounted for 
and disposed appropriately. 
The Investigator must maintain an accurate, up to date Dispensing Log for all study drugs 
supplied by the Sponsor. Study drug dispensed for all subjects must be recorded on the Drug 
Accountability Form. The study drug Dispensing Log and remaining drug inventory will be 
reviewed at each monitoring visit by the Sponsor-designated clinical monitor. 
The study drug supplied for this study is for use only in subjects properly consented and enrolled 
into this protocol. Study drugs must be kept in a secure location physically separated from 
standard clinic or office drug supplies. 
11.0 
SAFETY MONITORING AND ADVERSE EVENTS 
11.1 
Adverse Events 
Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at 
baseline, or if present at baseline, have worsened in severity. 
AEs reported during the trial will be graded, documented, and assessed for relationship to study 
drug. Specifically, assessment of AEs related to skin condition and injection procedure will be 
closely monitored, including edema, bruising, dysphasia, dysphonia, erythema, dyspigmentation, 
induration, numbness, pain, paresthesia, pruritus, skin ulceration and necrosis, injury to the 
marginal mandibular nerve, vascular and nerve injury and tissue damage to nearby vulnerable 
anatomic structures.. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 70 of 87 
CONFIDENTIAL 
 
Definition of Adverse Events and Adverse Drug Reactions: 
AEs in the eCRF will be classified according to the most recent FDA definitions and in a manner 
consistent with International Conference on Harmonization (ICH) guidelines. As such the 
following definitions will be used: 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational (medicinal) product (IP) or other protocol-imposed intervention, 
regardless of attribution.  An AE may include intercurrent illnesses or injuries that represent an 
exacerbation (increase in frequency, severity, or specificity) of pre-existing conditions (e.g., 
worsening of asthma).  A laboratory abnormality will be reported on the “Adverse Event” case 
report forms only if it is associated with clinical sequelae or requires therapeutic intervention.  
Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of 
symptoms relating to a diagnosis.  AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v 5.0 (Table 5). 
The reporting period for AEs starts after dosing of study drug and will end at final study visit on 
Day 84. At study completion, after the Day 84 visit of the last subject, subjects at 3 chosen 
clinical sites will be followed up at 6 and 12 months after injection to follow safety and duration 
of efficacy. 
If an AE remains unresolved at discharge, subject will be scheduled for a visit that will be held  
6-8 weeks after study termination to verify the resolution of AE. On that visit, follow up of 
efficacy using C-CAT and S-CAT will also be conducted. In case the AE will not resolved 
following that visit,  the subject will be followed, at the Investigator’s discretion, until resolution 
of the event or until the subject is deemed “lost to follow-up”.  AEs assessed by the Investigator 
as related to study drug and “ongoing” at discharge will be monitored by the Investigator until 
resolved or until the subject is deemed “lost to follow-up”.  SAEs must be followed until 
resolution by the PI, even if this extends beyond the study-reporting period.  Resolution is 
defined as the return to baseline status or stabilization of the condition with the expectation that it 
will remain chronic. 
The Investigator will assess AEs for severity, relationship to IP, and as to whether the event 
meets one or more of the definitions of an SAE.  The assessments will be recorded on the source 
documents and AE CRF, using the categories defined below.  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 71 of 87 
CONFIDENTIAL 
 
Causality 
Category 
Description 
Un-related 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. For the purpose of 
this protocol, the term unlikely will be considered not related to study 
medication and an “Adverse Event”. 
Related 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
For the purpose of this protocol, an event that has possible or probable 
relationship to study medication will be defined as a “Suspected 
Adverse Drug Reaction”.   
In order to classify AEs and diseases, preferred terms will be assigned by the sponsor or its 
designee to the original terms entered on the CRF, using MedDRA. 
For those AEs that are not described on the CTCAE v 5.0, such AEs will be graded on a 5-point 
scale (mild, moderate, severe) and reported as indicated on the CRF. Intensity of such an AE is 
defined as follows: 
Table 5:  Severity Assessment Terminology for Reporting Adverse Events (CTCAE v 5.0) 
CTCAE 
Grade 
Common 
Term 
Description 
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental Assisted 
Daily Living (ADL). 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL. 
4 
Life-
Threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Death 
Death related to AE  


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 72 of 87 
CONFIDENTIAL 
 
11.2 
Serious Adverse Events 
According to the ICH Guidelines for Good Clinical Practice (E6), an SAE is any untoward 
medical occurrence during the course of a clinical investigation that is characterized by one or 
more of the following: 
• Results in death 
• Is life-threatening 
• Requires in-subject hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical events 
Although not an SAE, exposure to study drug during pregnancy, even if no AE is reported in the 
mother, should be reported within 24 hours. 
11.2.1 
Reporting Requirements for Serious Adverse Events 
All SAEs must be reported to the Sponsor by the Investigator, study coordinator, other 
designated study personnel, or clinical research associate within 24 hours of notification of the 
SAE. To report such events, an SAE form must be completed by the Investigator and sent within 
24 hours by email or fax with relevant information. 
Within the 48 hours following the initial report, the Investigator must provide further information 
on the SAE if available. This should include a copy of the completed SAE form, and any other 
information that will assist the understanding of the event. Significant new information on 
ongoing SAEs should be provided promptly as a follow-up. 
The Investigator also must report all SAEs promptly to the appropriate IRB/EC as required by 
the institution within 24 hours or 48 hours if on weekend/holiday. 
Report SAEs by fax or email to: 
Fax:  +1-858-436-1401 
Email:  RazielSafety@pacificlinkconsulting.com/ dr.patricia.walker@gmail.com 
Table 6:  Contact Information for SAE Reporting 
Primary Contact 
Sponsor Contact 
Medical Monitor  
Study Director: 
Patricia Walker, MD, PhD 
Robert Hasson 
Mobile: 
1-805-705-5853 
Mobile: 
1-619-540-6253 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 73 of 87 
CONFIDENTIAL 
 
Email: 
dr.patricia.walker@gmail.com  
Office: 
1-858-368-9925 
 
 
Fax: 
1-858-436-1401 
 
 
Email: 
rhasson@pacificlinkconsulting.com 
11.2.2 
Reporting pregnancy 
Pregnancy testing must be preformed on all women of childbearing potential prior to dosing, and 
all the results of all pregnancy tests are to be recorded in the eCRF’s. All women must have a 
negative pregnancy test to be enrolled into the study. If a pregnancy test turns positive after study 
drug treatment, the patient will be discontinued and protocol-required procedures for study 
discontinuation and follow-up must be preformed. The subject will be followed to determine the 
outcome of the pregnancy.  All women of childbearing potential should be instructed to contact 
the investigator if they suspect they might be pregnant (e.g. missed or late menstrual period) at 
any time during the study.  
The investigator must notify the sponsor of any pregnancies in accordance with the SAE 
reporting procedures described in section 11.2.1.  Note, while the pregnancy is not considered an 
AE or an SAE, any pregnancy complication or newborn complication will be reported as an AE 
or SAE if it meets the criteria.  Follow-up information regarding the course of pregnancy, 
including perinatal and neonatal outcomes and, where applicable, offspring information must be 
reported on the Pregnancy Outcome eCRF.   
 
11.2.3 
Recording of Serious Adverse Events 
All SAE information must be recorded on the SAE form provided by the Sponsor. Additional 
follow-up information (e.g., test results, autopsy, and discharge summary) must be obtained to 
supplement the SAE report form. A copy of all initial and follow-up reports must be filed with 
the subject’s eCRF. 
11.2.4 
Internal Safety Committee 
An internal safety review committee will review the safety data collected during the study in a 
blinded manner. The committee members will include study medical monitor, Raziel’s CMO and 
clinical director.  
The meeting will be held when every enrolled 40 subjects completed Day 7.  Summary of the 
safety including all subjects up to that point may be reviewed as well.  Following completion of 
enrollment of all subjects, the committee will meet quarterly during the follow up period. 
The study enrollment will be suspended if either of the following occur: 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 74 of 87 
CONFIDENTIAL 
 
• Greater than 20% of subjects report a drug related grade 3 (severe) adverse event for a 
period duration of more than 28 days after injection. Of note severe swelling is may be 
during the first 24 – 96 hours after injection. 
• >1 subject with a drug related CTCAE Grade of 4 or 5 
In the event of the above, the enrollment and treatment will be suspended, the safety committee 
will review all data to examine potential safety issue. Additional experts may be brought in to 
review safety data if deemed necessary by the safety committee. A safety report will be issued 
with the conclusions of the meeting. The recommendation of the safety committee will be 
documented. Potential outcomes are reinitiating enrollment with current safety practices, 
reinitiating study with caveats (e.g. additional precautions/limitations or safety training), stop 
enrollment..  For each internal safety committee meeting, report will be prepared by the medical 
monitor that include data about enrollment, list of SAEs, summary of AEs.   
 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Sample Size Determination 
A total of 135 subjects will be included in the study, divided into three (3) groups: RZL-012 low 
dose (up to 183.6 mg/5.4 mL), RZL-012 high dose (up to 270 mg/5.4 mL) and placebo (up to 5.4 
mL) with 45 subjects in each group.  
For the primary endpoint (proportion of high dose group subjects who have at least a 1-grade 
improvement from baseline to Day 84 on the C-CAT scale), the assumed true rates are 70% in 
the RZL-012 high dose group and 35% in the placebo group (a difference of 35 percentage 
points). Based on the use of a two-sided test of equality of binomial proportions at the 
alpha=0.05 level of significance, 41 subjects per group are required at 90% power. In order to 
account for a dropout rate of up to ~9%, the planned sample size is 45 subjects per group, for a 
total sample size of 135 subjects. 
. 
12.2 
Analysis Data Sets 
Subjects who receive study treatment will be included in the safety analyses.  
12.3 
Endpoints Analyses 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. 
For categorical variables, summary tables will be provided giving sample size, absolute and 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 75 of 87 
CONFIDENTIAL 
 
relative frequency, and 95% confidence interval (CI) for proportions by study arm. 
For continuous variables, summary tables will be provided giving sample size, arithmetic mean, 
standard deviation, coefficient of variations (CV%), median, minimum and maximum, and 95% 
CI for means of variables by study arm. 
The data will be analyzed using the SAS version 9.4 (SAS Institute, Cary North Carolina). 
For the primary endpoint analysis, Pearson’s chi-square test will test the statistical significance 
of the difference in the proportion of responding subjects between the high dose RZL-012 group 
and the placebo group. A responder is defined as a subject who has at least a 1-grade 
improvement between Day 84 and baseline on the C-CAT. 
Secondary endpoints (improvement in 1 point in S-CAT and C-CAT, improvement in 2 points in 
both S-CAT and C-CAT) will be tested using a two-sided test of equality of binomial 
proportions at the alpha=0.05 level of significance. If the primary analysis is not statistically 
significant, then the results of the secondary analysis will be exploratory rather than 
confirmatory. 
All other secondary endpoints will be tested using a two-sided test at the alpha=0.05 level of 
significance. 
 
12.4 
Safety 
Safety data will be summarized by dose group and based on their initial dose level or treatment 
group (i.e., if a dose reduction occurs, they will be considered in their initial group). Descriptive 
statistics will be provided for actual values and change from baseline values for vital signs, 
weight, blood parameters, ECG (QT). 
AE assessment and treatment area evaluation including, but not limited to evaluation of edema, 
bruising, dysphasia, dysphonia, erythema, dyspigmentation, induration, numbness, pain, 
paresthesia, and pruritus. 
The incidence and severity of AEs reported during the study and their relationship to study drug 
will be tabulated. AEs will be coded using MedDRA™ and will be presented by body system. 
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0 (Table 5).  
The World Health Organization Drug Dictionary (WHODD) will be used to classify prior and 
concomitant medications by therapeutic class and preferred term. Prior and concomitant 
medication usage will be summarized by the number and percentage of subjects receiving each 
medication within each therapeutic class by dose cohort. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 76 of 87 
CONFIDENTIAL 
 
13.0 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
13.1 
Data Collection and Reporting 
An eCRF will be completed for each subject who receives at least one dose of study drug. All 
entries on the eCRF must be supported by original source documentation (e.g., laboratory 
reports, medical records) maintained at the investigational site. 
The Investigator will make all safety assessments (AEs and vital signs) on an ongoing basis. The 
Investigator is required to review all entries on the eCRF and sign at appropriate time intervals. 
13.2 
Study Monitoring 
All aspects of the study will be monitored carefully by the Sponsor’s designees with respect to 
current Good Clinical Practice (GCP) and Standard Operating Procedures (SOP) for compliance 
with applicable government regulations. It is the responsibility of the Investigator to provide all 
study records, including eCRFs, source documents, etc., for review and source document 
verification by the clinical monitor. 
All eCRFs will be 100% source verified against corresponding source documentation (e.g., 
office and clinical laboratory records) for each subject. Clinical monitors will evaluate 
periodically the progress of the study, including the verification of appropriate consent form 
procedures, review of drug accountability and preparation procedures, adherence to dosing 
procedures, and the verification of the accuracy and completeness of eCRFs. Clinical monitors 
will also ensure that all protocol requirements, applicable FDA regulations, other requirements, 
and Investigator’s obligations are being fulfilled. 
13.3 
Audit and Inspection 
The sponsor or representative may conduct audits at the trial site(s). Audits will include, but are 
not limited to protocol compliance, drug supply, presence of required documents, the informed 
consent process, and comparison of eCRFs with source documents. The investigator agrees to 
participate with audits conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may inspect the trial site during or after the trial. The 
investigator should contact the sponsor immediately if this occurs and must fully cooperate with 
the inspections conducted at a reasonable time in a reasonable manner.  
13.4 
Deviation from Clinical Trial Protocol 
Deviations from the protocol are to be avoided. If a deviation occurs, the Investigator must 
promptly report the deviation to the study monitor. 
The Investigator (or designee) will record any failure to follow the protocol because of any other 
medical unavoidable reason to avoid the subject's urgent risk, and record a document as soon as 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 77 of 87 
CONFIDENTIAL 
 
possible stating this and the reason. It must be submitted to the sponsor and the director of the 
study site. 
13.5 
Retention of Records 
The Investigator must retain all study records required by Raziel and by the applicable 
regulations in a secure and safe facility. The Investigator must notify Raziel of any change in the 
location, disposition or custody of the study files. The Investigator /institution must take 
measures to prevent accidental or premature destruction of essential documents, that is, 
documents that permit evaluation of the conduct of a study and the quality of the data produced, 
including paper copies of study records (e.g., subject charts) as well as any original source 
documents that are electronic as required by applicable regulatory requirements. 
All study records must be retained until whichever is the later day in the following: (1) At least 
the date of approval for the drug or (2) the date when 3 years have passed since the 
discontinuation or completion of the study. No records relating to this study should be disposed 
of without the written approval of Raziel. It is the responsibility of Raziel to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
13.6 
Data Disclosure and Subject Confidentiality 
Subject medical information and video recordings obtained as a result of this study is considered 
confidential and used only for study evaluation purposes. Disclosure to third parties other than 
those noted below is prohibited. All reports and communications relating to subjects in this study 
will identify each subject only by number. Medical information resulting from a subject’s 
participation in this study may be given to the subject’s personal physician or to the appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of this study 
are to be available for inspection on request by FDA or other government regulatory agency 
auditors, the Sponsor clinical monitor (or designee), and the IRB/EC. 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by a coded number to maintain subject confidentiality. All records will be kept in a 
locked and secured area. All computer entry and networking programs will be identifiable only 
by coded numbers. Clinical information will not be released without written permission from the 
subject, except as necessary for monitoring by the IRB, the FDA, or the study Sponsor. 
Any information, inventions, or discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports, made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole property of 
the Sponsor. The Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to 
execute such documents and to take such other actions, as the Sponsor deems necessary or 
appropriate, to obtain patents in the Sponsor’s name covering any of the foregoing. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 78 of 87 
CONFIDENTIAL 
 
The results of this study will be published under the direction of the Sponsor. Results will not be 
published without prior review and approval by the Sponsor and Study Investigator. 
14.0 
PROTECTION OF HUMAN SUBJECTS 
14.1 
Basic Principles 
The study will be conducted in accordance with the relevant regulatory requirements, this 
protocol, and ethical principles that are consisted with the GCP guideline developed by the 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). This clinical trial will also be conducted in compliance 
with Declaration of Helsinki, protocol, Standard specified in the relevant local regulations. Prior 
to initiation of the study, the investigator and the sponsor should obtain approval from the 
IRB/IEC on this protocol and any further amendments, and the subject information and informed 
consent form. 
Any suspected serious breaches must be immediately reported to the sponsor. A serious breach is 
a breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety of the subjects or the scientific value 
of the study. 
Personnel involved in the study will be qualified by education, training, and experience to 
perform their respective tasks. 
14.2 
Institutional Review Board/Ethics Committee 
The Investigator or designee agrees to provide the IRB/EC with all appropriate material, 
including a copy of the ICF. The study will not be initiated until the Investigator obtains written 
approval of the research plan and the ICF from the appropriate IRB/EC and copies of these 
documents are received by the Sponsor. Appropriate reports on the progress of this study will be 
made by the Investigator to the IRB/EC and Sponsor in accordance with applicable government 
regulations and in agreement with the policies established by the Sponsor. The Sponsor ensures 
that the IRB/EC complies with the requirements set forth in 21 CFR Part 56 (Code of Federal 
Regulations). 
14.3 
Informed Consent 
The investigator is responsible for: 
• Explain the subject of the study, the risks and benefits expected from participating in the study, 
and that the participation is voluntary so that the subject can understand. 
• Obtain informed consent to participate in the trial from the subject by signing or signing the 
consent form and entering the date before starting the study procedure and study drugs. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 79 of 87 
CONFIDENTIAL 
 
• Properly answer questions from subjects at any time during the trial and if new information that 
can affect the subject's intention to continue the trial is obtained while the subject is participating 
in the trial, the information is promptly communicated to the subject. 
• Give a copy of the written consent form to the study participants and keep one copy at the 
study site. 
14.4 
Subject Health Injury and Insurance 
In general, if a subject is health-injured as a direct result of the investigational products, the 
sponsor or its contracted insurance company will pay for reasonable and necessary medical 
treatment for the health-injury. If laws or regulations of the locality in which the study is taking 
place require additional payment of expenses, the sponsor should comply with such laws or 
regulations. Where applicable, the sponsor will arrange for specific insurance coverage. If health 
damage occurred in subject participating the clinical trial due to the willful or gross negligence 
of investigator’s site, indemnification will be discussed based on the contract with the site. The 
indemnification for the health damage and the payment to subjects will be described in the ICF. 
14.5 
Completion of the Study 
If the clinical trial is completed at the study site, the investigator will notify the director of the 
study site that the trial has been completed and provide an approximate summary in writing.  The 
director of the study site will promptly notify the IRB/EC and the Sponsor in writing about the 
completion. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 80 of 87 
CONFIDENTIAL 
 
15.0 
REFERENCE LIST 
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 
5. Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, et al. Nanoghosts as a Novel Natural 
Nonviral Gene Delivery Platform Safely Targeting Multiple Cancers. Nano Lett 2016 Mar 
9;16(3):1574-82.  
6. Oieni J, Levy L, Letko Khait N, Yosef L, et al. Nano-Ghosts: Biomimetic 
MembranalVesicles, Technology and Characterization. Methods. 2020 May 1;177:126-134. 
 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
 
08 March   2022 
Page 81 of 87 
CONFIDENTIAL 
 
 
Appendix A:  Schedule of Study Procedures 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version: 1.6 
08 March 2022 
Page 82 of 87 
CONFIDENTIAL 
Table 1: Schedule of Study Procedures 
Study Procedure 
Screening Day 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Additional follow up of RZL-012 
treated subjects (6 and 12 months 
after injection) 
Study Daya 
Day (-28) 
through 
Day (-1) 
Day a 0 
Day 1 
Day 7 
Day 28 
Day 56 
Day 84 
6 months 
12 months 
Signed informed 
consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical Examb 
X 
 
 
 
 
 
X 
Xh 
Xh 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy ß-hCG 
X 
 
 
 
 
 
 
 
 
Pregnancy urine test 
(women)c 
 
X 
 
 
 
 
 
 
 
Caliper measurement of 
submental fat 
X 
 
 
 
X 
X 
X 
 
 
Weight measurements  
X 
X 
 
 
 
X 
X 
 
 
Hematology and 
Chemistryd 
X 
 
X 
X 
X 
 
X 
 
 
ECG 
X 
 
 
X 
 
 
X 
 
 
Vital signs  
X 
Pree X poste 
X 
X 
X 
X 
 
 
 
Injection of RZL-012 
 
X 
 
 
 
 
 
 
 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version:1.6 
08 March 2022                                                     Page 83 of 87                                              CONFIDENTIAL 
                             
Study Procedure 
Screening Day 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Additional follow up of RZL-012 
treated subjects (6 and 12 months 
after injection) 
Study Daya 
Day (-28) 
through 
Day (-1) 
Day a 0 
Day 1 
Day 7 
Day 28 
Day 56 
Day 84 
6 months 
12 months 
Clinician Chin 
Assessment Tool (C-
CAT) 
X 
X 
 
 
X 
X 
X 
X 
X 
Subject- Self-Chin 
Assessment Tool (S-
CAT) 
X 
X 
 
 
X 
X 
X 
X 
X 
Physician Global 
Assessment 
Improvement Scale 
(GAIS) and physician 
global assessment 
X 
 
 
 
X 
X 
X 
 
 
Subject’s Satisfaction 
questionnaire for SMF 
appearance 
Xg 
 
 
 
X 
X 
X 
 
 
Subject’s impact 
questionnaire 
X 
 
 
 
X 
X 
X 
 
 
Subject Global 
Assessment of Change 
and subject self 
assessment 
X 
 
 
 
X 
X 
X 
 
 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version:1.6 
08 March 2022                                                     Page 84 of 87                                              CONFIDENTIAL 
                             
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
b. 
Including Fitzpatrick skin type, height, BMI 
c. A serum (ß-hCG) pregnancy test will be administered to females of childbearing potential at screening and a urine pregnancy test will be administered at baseline prior to dosing  
d. In case of clinically significant values at any visit, an unscheduled visit will be added 
e. Pre/post – refers to before/after injection, respectively 
f. MRI (performed during screening period) will be conducted after subject qualifies on all screening criteria. Post-treatment period MRI will be completed 84 days (± 14 days) after the 
subject’s last treatment session. 
g. Subjects will be asked on their neck appearance satisfaction at screening visit 
h. Physical exam will be done only to the treated area 
 
Study Procedure 
Screening Day 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Additional follow up of RZL-012 
treated subjects (6 and 12 months 
after injection) 
Study Daya 
Day (-28) 
through 
Day (-1) 
Day a 0 
Day 1 
Day 7 
Day 28 
Day 56 
Day 84 
6 months 
12 months 
2D Standardized 
photography 
X 
 
X 
X 
X 
X 
X 
X 
X 
MRI 
Xf 
 
 
 
 
 
X 
 
 
AEs  
 
X 
X 
X 
X 
X 
X 
X 
X 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version:1.6 
08 March 2022                                                     Page 85 of 87                                              CONFIDENTIAL                                    
 Appendix B:  Photographic Standards of the Face Area  
 
 
 
 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version:1.6 
08 March 2022                                                     Page 86 of 87                                              CONFIDENTIAL                                    
Appendix C:  Clinician Chin Assessment Tool 
 
RZL-SFSD-US-001_C
-CAT.pdf
 
 


Raziel Therapeutics Ltd. 
Protocol RZL-012-SMF-P2bUS-001 
RZL-012 
Version:1.6 
08 March 2022                                                     Page 87 of 87                                              CONFIDENTIAL                                    
Appendix D:   Subject Chin Assessment Tool 
RZL-SFSD-US-001_S
-CAT.pdf