Clinical trial NCT05466448
Conditions: Submental Fat
Sponsor: Raziel Therapeutics Ltd.
Start date: 2022-07-29; Completion date: 2023-06-15
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, open label study that will consist of a screening period, baseline period in which subjects will receive a single treatment session and a follow-up period. The single treatment session will consist of multiple injections of RZL-012 into the submental area under the chin. Blood samples will be collected from all subjects for PK analyses in the first 30 hours after dosing. Subjects will thereafter be monitored for safety and efficacy for at least 84 days.

Detailed description:
• RZL-012 (concentration of injected solution 50 mg/mL RZL-012) of 7.5 mg/0.15 mL/injection point that results in a total dose/volume of 240±30mg mg/4.8±0.6 mL RZL-012

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 dose of 270 mg RZL-012 .

Arms: arm 1: small synthetic molecule for submental fat reduction
Interventions: intervention 1: RZL-012
Intervention descriptions: intervention 1: concentration of injected formulation 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

Protocol documents:
Prot_000.pdf: 
Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMFC-P2US-001 
RZL-012 
Version: 1.3 
19 September 2022 
Page 1 of 48 
CONFIDENTIAL 
 
 
RAZIEL THERAPEUTICS LTD. 
 
INVESTIGATIONAL NEW DRUG PROTOCOL 
 
RZL-012 
PROTOCOL NUMBER RZL-012-SMFC-P2US-001 
VERSION 1.3 
19 SEPTEMBER 2022 
 
AN OPEN-LABEL PHASE 2 STUDY TO COMPARE THE PHARMACOKINETICS, 
EFFICACY AND SAFETY OF RZL-012 IN CHINESE SUBJECTS SEEKING 
SUBMENTAL FAT REDUCTION VS. NON-CHINESE 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document constitutes agreement by the recipient that no unpublished information contained herein 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 JUNE 2022 
Version 1.1: 5 JULY 2022 
Version 1.2: 26 JULY 2022 
Version 1.3: 19 SEPTEMBER 2022 


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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 
Racheli Gueta, PhD 
Raziel Therapeutics 
Director, Clinical Development 
Cell:  +972-50-7837597 
E-mail: racheli@raziel-therapy.com 
 
Study Medical Monitor 
Patricia Walker, MD Medical Monitor,  
E-mail: dr.patricia.walker@gmail.com 
 
Serious Adverse Event Reporting 
 
 
 
 
 
 
 
SAE Hotline: 888-746-7231 
SAE Fax Line: 888-746-3293 
SAE Email: 
rho_productsafety@rhoworld.com 
 
 
 


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TABLE OF CONTENTS 
LIST OF TABLES .......................................................................................................................... 6 
LIST OF FIGURES ........................................................................................................................ 6 
LIST OF APPENDICES ................................................................................................................. 6 
STATEMENT OF COMPLIANCE ................................................................................................ 9 
INVESTIGATOR STATEMENT ................................................................................................ 10 
1.0 
PROTOCOL SUMMARY ................................................................................................. 12 
1.1 
Protocol Synopsis............................................................................................................... 12 
1.2 
Schedule of Activities ........................................................................................................ 18 
2.0 
INTRODUCTION ............................................................................................................. 20 
1.1. 
Study Rationale .................................................................................................................. 20 
1.2. 
Scientific Background ........................................................................................................ 20 
1.2.1. 
Non-Clinical Studies ........................................................................................................ 20 
1.2.2. 
Clinical Studies ................................................................................................................ 21 
1.3. 
Risk-Benefit Assessment ................................................................................................... 22 
1.3.1. 
Identified RZL-012 Risks ................................................................................................ 22 
1.3.2. 
Benefits ............................................................................................................................ 23 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 24 
3.1 
Study Objectives ................................................................................................................ 24 
3.1.1 Primary Objective .............................................................................................................. 24 
3.1.2 Secondary Objectives......................................................................................................... 24 
3.2 
Study Endpoints ................................................................................................................. 24 
3.2.1 Primary Endpoint ............................................................................................................... 24 
3.2.2 Exploratory Endpoints ....................................................................................................... 25 
3.2.3 Additional Exploratory Endpoints ..................................................................................... 25 
4.0 
STUDY DESIGN............................................................................................................... 25 
4.1 
Overall Design ................................................................................................................... 25 
4.2 
Rationale for Study Design ................................................................................................ 26 
4.3 
Rationale for Study Dose ................................................................................................... 26 
5.0 
STUDY POPULATION .................................................................................................... 26 
5.1 
Inclusion Criteria ............................................................................................................... 26 
5.2 
Exclusion Criteria .............................................................................................................. 27 


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6.0 
STUDY INTERVENTION ................................................................................................ 28 
6.1 
Study Intervention Administration .................................................................................... 28 
6.1.1 Study Intervention Description .......................................................................................... 28 
6.1.2 Dosing and Administration ................................................................................................ 28 
6.2 
Preparation/Handling/Storage/Accountability ................................................................... 29 
6.3 
Study Intervention Compliance ......................................................................................... 30 
6.4 
Prior and Concomitant Medications .................................................................................. 30 
7.0 
STUDY INTERVENTION DISCONTINUATION .......................................................... 31 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 31 
8.1 
Medical History ................................................................................................................. 31 
8.2 
Height ................................................................................................................................. 31 
8.3 
Weight ................................................................................................................................ 31 
8.4 
Pregnancy Tests ................................................................................................................. 31 
8.5 
Complete Physical Examination ........................................................................................ 32 
8.6 
Pharmacokinetics ............................................................................................................... 32 
8.7 
Clinician-Chin Assessment Tool (C-CAT) ........................................................................ 32 
8.8 
Subject – Self-Chin Assessment Tool (S-CAT) ................................................................ 33 
8.9 
2-D Standardized Photography and Physician Global Assessment Improvement Scale 
(GAIS)........................................................................................................................................... 34 
8.10 Subject’s Satisfaction Questionnaire ................................................................................. 35 
8.11 Caliper Measurements ....................................................................................................... 36 
8.12 Subject’s Impact Questionnaires........................................................................................ 36 
8.13 Subject Global Assessment ................................................................................................ 37 
8.14 Biochemistry ...................................................................................................................... 38 
8.15 Vital Signs .......................................................................................................................... 39 
8.16 ECG.................................................................................................................................... 39 
8.17 Adverse Events and Serious Adverse Events .................................................................... 39 
8.17.1 Collection of Adverse Events Data .................................................................................... 39 
8.17.2 Serious Adverse Events ..................................................................................................... 40 
8.17.3 Reporting Requirements for Serious Adverse Events ....................................................... 41 
8.17.4 Reporting pregnancy .......................................................................................................... 41 
8.17.5 Recording of Serious Adverse Events ............................................................................... 42 


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9.0 
STATISTICAL CONSIDERATIONS............................................................................... 42 
9.1 
Sample Size Determination................................................................................................ 42 
9.2 
Analysis Data Sets ............................................................................................................. 42 
9.3 
Endpoints Analyses ............................................................................................................ 42 
9.4 
Safety ................................................................................................................................. 43 
9.5 
Efficacy .............................................................................................................................. 43 
10.0 DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE ............ 43 
10.1 Data Collection and Reporting........................................................................................... 43 
10.2 Study Monitoring ............................................................................................................... 43 
10.3 Audit and Inspection .......................................................................................................... 44 
10.4 Deviation from Clinical Trial Protocol .............................................................................. 44 
10.5 Retention of Records.......................................................................................................... 44 
10.6 Data Disclosure and Subject Confidentiality ..................................................................... 45 
11.0 PROTECTION OF HUMAN SUBJECTS ........................................................................ 45 
11.1 Basic Principles .................................................................................................................. 45 
11.2 Institutional Review Board/Ethics Committee .................................................................. 46 
11.3 Informed Consent............................................................................................................... 46 
11.4 Subject Health Injury and Insurance .................................................................................. 46 
11.5 Completion of the Study .................................................................................................... 47 
 


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LIST OF TABLES 
Table 1 
Estimated Cumulative Exposure from Clinical Studies ............................................. 21 
Table 2 
Clinician Chin Assessment Tool (C-CAT) ................................................................. 33 
Table 3 
Self Chin Assessment Tool (S-CAT) ......................................................................... 34 
Table 4 
Physician Global Assessment Improvement Scale (GAIS) ........................................ 34 
Table 5 
Subject Impact Questionnaire ..................................................................................... 36 
Table 6 
Severity Assessment of Adverse Events .................................................................... 40 
Table 7 
Contact Information for SAE Reporting .................................................................... 41 
 
LIST OF FIGURES 
Figure 1 
Submental Injection Pattern........................................................................................ 29 
 
LIST OF APPENDICES 
Appendix A:   Photographic Standards of the Face Area ....................................................... 48 
 


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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 
CBC 
Complete blood count 
C-CAT 
Clinician Chin Assessment Tool 
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 
FSH 
Follicle-Stimulating Hormone 
GAIS 
Global Aesthetics Improvement Scale 
GLP 
Good Laboratory Practice 
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 


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ABBREVIATION 
DEFINITION 
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 
SAE 
Serious adverse event 
S-CAT 
Subject Chin Assessment Tool 
SMF 
Submental fat 
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 


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


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INVESTIGATOR 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 Error! Reference source not found. 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. 
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. 
 


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______________________     ______________________________       
________________ 
Investigator’s Name                Investigator’s Signature 
 
 
Date 
 


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1.0 PROTOCOL SUMMARY 
1.1 
Protocol Synopsis 
Study Title 
An Open-Label Phase 2 Study to Compare the Pharmacokinetics, Efficacy and Safety of  
RZL-012 in Chinese Subjects Seeking Submental Fat Reduction vs. Non-Chinese Subjects 
Seeking Submental Fat Reduction (RZL-012-SMFC-P2US-001) 
Phase 
Phase 2 
Study Drug 
RZL-012 
Study Objectives 
and Endpoints 
Primary Objective:  
• 
To compare the pharmacokinetic profile of RZL-012 in subjects that are dosed in the 
submental fat (SMF) in a Chinese vs. a non-Chinese population. 
Secondary Objectives: 
• 
To compare the efficacy of RZL-012 in SMF reduction measured on Day 84 versus 
baseline using the Clinician Assessment Tool (C-CAT) in Chinese vs. non-Chinese 
population.  
• 
To determine the efficacy of RZL-012 in SMF reduction measured on Day 84 versus 
baseline using both Subject Self-Chin Assessment Tool (S-CAT) and the Clinician 
Assessment Tool (C-CAT) in a Chinese vs. a non-Chinese population. 
• 
To compare the reduction in SMF on Day 84 versus baseline using the caliper measured 
submental thickness in a Chinese vs. a non-Chinese population  
• 
To assess the safety of RZL-012 in the treatment of SMF reduction. 
Primary Endpoint: 
• 
Characterization of RZL-012 pharmacokinetic (PK) profile in a Chinese vs. non-Chinese 
population based on 
• 
Cmax - Maximum concentration achieved. 
• 
Tmax - Time to reach maximum concentration (hours). 
• 
AUClast – The area under the concentration vs. time curve, calculated as sum of 
AUCs using linear trapezoidal summation from time 0 to the last measurable data 
point. 
• 
AUCpartial – The area under the concentration vs. time curve, calculated as sum of 
AUCs using linear trapezoidal summation from time 0 to the maximal 
measurement (Tmax). 
• 
z (Lambdaz)- Individual estimate of the terminal elimination rate constant, will be 
calculated using log-linear regression of the terminal portions of the plasma 
concentration-versus-time curves.  
• 
AUCinf - The area under the plasma concentration-time curve extrapolated to 
infinity, calculated as:  
AUClast + Clast/z, where Clast is the last measurable concentration. 
• 
T1/2 - Apparent terminal elimination half-life time (hours), defined as 0.693/z. 
 


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Exploratory Endpoints: 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the C-CAT on Day 84 versus baseline. 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the S-CAT on Day 84 versus baseline. 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
• 
Comparison of the proportion of subjects in both populations who have at least a 2-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
• 
Comparison of the reduction in SMF thickness measured with caliper (Day 84 versus 
baseline) in a Chinese vs. non-Chinese population 
• 
Safety of RZL-012 in the treatment of SMF reduction. 
• 
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 2, open-label study that will consist of a screening period, baseline period in 
which subjects will receive a single treatment session and a follow-up period.  The single 
treatment session will consist of multiple injections of RZL-012 for a maximal total dose of 
270 mg into the submental area under the chin. Blood samples will be collected from all 
subjects for PK analyses in the first 30 hours after dosing.  Subjects will thereafter be 
monitored for safety and efficacy for at least 84 days. 
Sample Size 
20 subjects (10 Chinese and 10 non-Chinese): 
No formal sample size calculation was performed. The planned sample size of 10 subjects 
per study arm is sufficient to compare the PK profile between the 2 study populations. 
Study 
Population 
Adult volunteers age 18 to 65 years who have consented to participate in this study and seek 
submental fat reduction. 
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  kg/m2 and <40  kg/m2. 
3. If enrolled for Chinese arm, subjects have to be ethnically pure, i.e., were born in China 
(Certificate birth) with all four grandparents being Chinese or at least have parents that 
were born in China (Certificate birth of the parents).    
4. Has a SMF bulge that is contiguous and fits to 32±4 injections sites according to a grid 
with 1 centimeter (cm) distance between injection points. 
5. Has grade 3 to 4 of SMF as rated by both the C-CAT and S-CAT. 
6. Has a visible or large pocket of submental fat- according to physician global 
assessment. 
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 


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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 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 any uncontrolled systemic disease that is not stabilized (i.e., cardiovascular disease, 
mental illness). 
3. 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. 
4. Has any scars, unshaven hair, tattoos, facial hair or jewelry on or near the proposed 
treatment area. 
5. 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.  
6. Has a fat bulge under the chin that is too large to be adequately treated by 32±4 
contiguous injections on a 1cm grid . 
7. Has a fat bulge under the chin that is of an insufficient volume to allow 32±4 injections 
within a contiguous 1 cm grid.  
8. 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. 
9. Has an active bacterial, fungal, or viral infection in the proposed treatment area. 
10. Has a pre-existing skin condition in the submental region that, at the Investigator’s 
discretion, may confound evaluation or analysis. 
11. 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. 
12. Has pre-existing neurological or gastrointestinal condition leading to dysphagia, 
dysphonia, or facial nerve palsy. 


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13. Has Dercum’s Disease. 
14. Has allergic reactions to injectables. 
15. 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. 
16. Has a planned fat reduction procedure of any variety to the submental region for the 
duration of the study. 
17. Has medication or a history of coagulopathy. 
18. Has a history or family history of venous thrombotic disease. 
19. Has been treated chronically at least three (3) months prior to study entry with systemic 
steroids or immunosuppressive drugs. 
20. Has been treated chronically at least one (1) week prior to study entry with non-
steroidal anti-inflammatory drugs (NSAIDs)  
21. Has used anticoagulation therapies that may increase bleeding or bruising (i.e., aspirin, 
ibuprofen, warfarin, vitamins, and herbal preparations) for seven (7) days prior to 
treatment. 
22. Has had treatment with botulinum toxin injections in the neck or chin area within 9 
months prior to screening. 
23. Current participation or participation within three (3) months prior to the start of this 
study in a drug or other investigational research study. 
 
Dosage and 
Administration 
of Study Drug 
All subjects will receive a single multi-injection session of RZL-012 in accordance with the 
table below:  
 
 
 
 
 
 
 
 
 
Subjects will undergo a single treatment session with 32±4 injections. The total number of 
injections will be 32±4 with a dose of 240±30 mg RZL-012. Each injection point will be 
dosed with 7.5 mg RZL-012 in a volume of 0.15 mL/injection site. The total injection 
volume for all groups will be 4.8 mL±0.6. 
Subjects will be injected with RZL-012 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. 
 
Number of subjects 
N=20 
RZL-012 dose  
240mg±30mg/4.8 ±0.6 mL 
RZL-012 Dose (mg)/volume 
(mL) per single injection 
7.5mg/0.15mL 
Number of Injections per subject 
32±4 


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Safety  
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. For 
subjects for whom AEs are unresolved by Day 84, an unscheduled visit will be set 6-8 
weeks after Day 84 to verify the resolution of the AE.  
Other safety measures will include vital sign measurements, Lab parameters follow up on 
Day 1, 7, 28 and 84 following injection, ECG, 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.  


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Statistical 
Analysis 
A sample size of 20 subjects will be included in the study. All will be injected with the same 
dose of RZL-012. A total of 10 subjects will be Chinese and 10 subjects will be non-
Chinese.  
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. 
Primary endpoint: 
A total of 10 subjects per group will be used  to compare between PK profile of both 
populations.  
Individual plasma PK parameters will be listed by study arm and summarized in tables 
presenting sample size (N), mean, Standard deviation, Standard Error, Median, minimum 
and maximum values, Coefficient of variation (CV%) and 95% CI (Confidence Interval) for 
means of variables by treatment.  
PK assessments will be compared between the 2 study populations. 
Graphical displays will be generated presenting mean concentration by study arm as well as 
individual graphs per subject. 
Exploratory endpoints: 
The difference between study groups in proportion of subjects who have 1-grade 
improvement in the C-CAT, S-CAT, and who have 1-grade and 2-grade improvement in 
both  C-CAT and S-CAT on Day 84 versus baseline will be tested using a two-sided test of 
equality of binomial proportions at the alpha=0.05 level of significance. 
All other endpoints will be tested using a two-sided test at the alpha=0.05 level of 
significance. 
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 study 
group. 
The data will be analyzed using the SAS version 9.4 (SAS Institute, Cary North Carolina). 
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.  
Study Centers 
Single center   


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1.2 
Schedule of Activities 
Study Procedure 
Screening 
Day  
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Study Day 
Day (-28) 
through 
Day (-1) 
Day  0 
Day 1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Signed informed 
consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
 
 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
Pregnancy ß-hCG 
X 
 
 
 
 
 
 
Pregnancy urine 
test (women) 
 
X 
 
 
 
 
X 
Caliper 
measurement of 
submental fat 
X 
 
 
 
X 
X 
X 
Weight 
measurements  
X 
X 
 
 
X 
X 
X 
Biochemistry Lab 
parameters 
X 
 
X 
X 
X 
 
X 
Pharmacokinetics 
 
X 
X 
 
 
 
 
ECG 
X 
 
X 
 
 
 
X 
Vital signs  
X 
Pre X post 
X 
X 
X 
X 
X 
Injection of RZL-
012 
 
X 
 
 
 
 
 
Clinician Chin 
Assessment Tool 
(C-CAT) 
X 
X 
 
 
X 
X 
X 
Subject- Self-Chin 
Assessment Tool 
(S-CAT) 
X 
X 
 
 
X 
X 
X 
Physician Global 
Assessment 
Improvement Scale 
X 
 
 
 
X 
X 
X 


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Study Procedure 
Screening 
Day  
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Study Day 
Day (-28) 
through 
Day (-1) 
Day  0 
Day 1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
(GAIS) and 
physician global 
assessment 
Subject’s 
Satisfaction 
questionnaire for 
SMF appearance 
X 
 
 
 
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 
AEs  
 
X 
X 
X 
X 
X 
X 


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2.0 INTRODUCTION 
1.1. 
Study Rationale 
Two clinical trials have been conducted to assess the efficacy and safety of RZL-012 in reducing 
fat in the submental area. One trial (study RZL-012-SMF-P2a-US-001) was a single-blind, 
randomized, placebo-controlled, phase 2a, 2-cohort study. The second trial (study RZL-012-SMF-
P2b-US-001) was a double-blind, randomized, three-arm, placebo-controlled Phase 2b study. 
These studies demonstrated that a single treatment session of RZ-012 into the subcutaneous tissue 
of the submental area reduces fat and improves appearance of this area. Since RZL-012 will be 
targeted to a multiracial population and the majority of subjects included in the trials were white, 
Raziel will conduct a bridging study to compare the pharmacokinetics, efficacy and safety of RZL-
012 in Chinese subjects seeking submental fat reduction vs. non-Chinese subjects seeking 
submental fat reduction. 
1.2. 
Scientific Background  
RZL-012 is a cytolytic drug - it disrupts cell membrane integrity which results in necrotic cell 
death. RZL-012 demonstrated a cell killing effect on cultured adipocyte, fibroblasts and HepG2 
cells with IC50 values ranging between 20-100 µM. In vivo pig studies demonstrated liponecrosis 
at the injection site, followed by a transient inflammatory response and finally, a healing process 
in which fibrotic tissue replaces previous fat tissue. Necrosis of fat tissue at the injection site was 
seen as early as 24 hours after injection and was still evident 2 weeks later but completely cleared 
by 12 weeks post dosing. A macrophage-mediated inflammatory response was also prominent at 
24 hours and 14 days after injection with only minimal signs of inflammation remaining by 12 
weeks post dosing. Fibrosis showed a different pattern compared with liponecrosis and 
inflammation, starting at 14 days post dosing and becoming much more prominent at 12 weeks 
post dosing. In essence, RZL-012 enabled 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 119941, 133324), lipomas 
of Dercum’s Disease patients and SMF (IND 135762) and SMF and flank reduction (IND 154260). 
Across all clinical trials approximately 222 subjects have received single doses of RZL-012 
ranging from 5 mg to 412 mg per subject. 
1.2.1. Non-Clinical Studies 
The mechanism of action of RZL-012 has been studied in in-vitro studies and in in-vivo studies in 
pigs (domestic Yorkshire crossbred swine). Pigs were chosen for these studies because their 
subcutaneous fat resembles that of humans. RZL-012 injected into SC pig fat first caused 
liponecrosis at the injection site, followed by a transient inflammatory response and finally by a 
healing process in which fibrotic tissue replaced previous fat tissue.  
Safety pharmacology studies of RZL-012 in male Sprague Dawley rats demonstrated that RZL-
012 has no effects on the central nervous system functions, or on the respiratory system, on  ECG 


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parameters or blood pressure.  Safety pharmacology studies of RZL-012 in domestic Yorkshire 
crossbred swine demonstrated no effects on ECG parameters or blood pressure. 
Single and chronic toxicology studies were conducted in Sprague-Dawley rats and in pigs. Local, 
dose-related skin reactions included fibrosis, inflammation, degeneration/necrosis, atrophy and 
epidermal hyperplasia. Systemic reactions included increased blood urea nitrogen [BUN], 
increased creatinine and aspartate aminotransferase [AST] levels and histopathological changes in 
kidneys (necrosis in tubular epithelium). 
Rat embryo-fetal development (EFD) and fertility and early embryo-fetal development (FEED; 
fertility) studies demonstrated no changes on fertility and reproduction in males and females. 
Further details on mechanism of action, safety pharmacology, and toxicology of RZL-012 are 
provided in the investigator’s brochure (IB). 
1.2.2. Clinical Studies 
To date, approximately 222 subjects have received single doses of RZL-012 ranging from 5 mg 
to 412 mg per subject across 8 clinical trials (Table 1). 
Table 1 
Estimated Cumulative Exposure from Clinical Studies 
Study Number 
Study Population 
RZL-012 
Placebo 
N 
Dose (mg) 
N 
RZL-012-P0-US-001 
Healthy Subjects (Phase 0 obesity) 
18 
5-20 
6 
RZL-012-P2a-US-001 
Healthy subjects (Phase 2a obesity) 
24 
40-180 
7 
RZL-012-FD-P2a-US-001 
Lipedema (Phase 2a) 
6 
60-80 
0 
RZL-012-FD-P2a-US-001 
DD (Phase 2a) 
6 
30-40 
0 
RZL-012-DD-P2b-US-001 
DD (Phase2b) 
29 
40-240 
18 
RZL-012-SMF-P2a-US-001 Submental Fat (Phase 2a) 
18 
70-210 
10 
RZL-012-hADMEC14-001 
Human ADME study 
6 
72.9 
0 
RZL-012-SMF-P2b-US-001 Submental Fat (Phase 2b) 
103 
142-270 
48 
RZL-012-FL-P2US-001 
Subjects with Flank Fat 
12 
412 
0 
Overall Total Number of Subjects 
222 
- 
89 
All clinical trials were conducted in the US, and in all trials RZL-012 was administered via 
multiple injections during a single injection session.  
1.2.2.1. 
Clinical Trials in SMF 
Two clinical trials have been conducted to assess the efficacy and safety of RZL-012 in reducing 
fat in the submental area. One trial (study RZL-012-SMF-P2a-US-001) was a single-blind, 


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randomized, placebo-controlled, phase 2a, 2-cohort study. The second trial (study RZL-012-SMF-
P2b-US-001) was a double-blind, randomized, three-arm, placebo-controlled Phase 2b study. 
Study RZL-012-SMF-P2a-US-001 
Study RZL-012-SMF-P2a-US-001.2 was a single-blind study conducted in 28 subjects with 
submental fat. An assessment of efficacy was based on the Physician global assessment scale, SMF 
volume change (MRI), and subject's Face-Q satisfaction questionnaire. 
All subjects received a single dosing session and were followed up for 84 days. RZL-012 low dose 
(N=8) received an average injected dose of 80 mg/subject, RZL-012 high dose (N=10) an average 
injected dose of 158.5 mg/subject. Ten subjects received placebo. Based on a physician global 
assessment scale (physicians were not blinded to study treatment), 17/18 of RZL-012 treated 
subjects demonstrated an improvement in submental fat appearance on 84 days after treatment vs. 
baseline. None of the placebo subjects demonstrated any change in submental fat appearance on 
Day 84 vs. baseline. According to the Subject Face-Q Questionnaire (subjects were blinded to 
study treatment), subjects reported satisfaction regarding perceived effects of RZL-012 on 
submental fat appearance. The RZL-012 low dose group had a 2.4-fold increase in mean subject 
satisfaction score, the RZL-012 high dose group showed a 2.5-fold increase in mean subject 
satisfaction score while the placebo group did not demonstrate an improvement in satisfaction on 
Day 84 vs. baseline. These Clinician Reported Outcome (CRO) and Patient Reported Outcome 
(PRO) were correlated with the objective measure of MRI, determined on Day 84 vs. baseline. 
The high dose RZL-012 group showed a volume reduction of -22.2% ± 14.9 (p<0.05 vs the placebo 
group), the low dose RZL-012 group showed a volume reduction of -10.6% ± 14.5 (p=0.67 vs the 
placebo group, NS) and the placebo group demonstrated a volume reduction of -0.4% ± 13.9. 
Study RZL-012-SMF-P2b-US-001 
Study RZL-012-SMF-P2b-US-001 was a double-blind, randomized, three-arm, placebo-controlled 
Phase 2b study conducted in 151 subjects with submental fat. Forty-eight subjects were 
randomized to the placebo group, 53 subjects to the RZL-012 low dose (183.6 mg) group and 50 
subjects to the RZL-012 high dose (270 mg) group. An assessment of efficacy was based on the 
Clinician Assessment Tool (C-CAT), Subject Self-Chin Assessment Tool (S-CAT); and SMF 
volume via MRI and caliper-measured submental thickness. Raziel met the primary and secondary 
endpoints of the study. The proportion of subjects that had an improvement of at least 1 grade 
using the C-CAT and proportion of subjects who had an improvement of at least 2 grades in both 
C-CAT and S-CAT in the same subject were statistically significant in RZL-012 high dose vs. 
placebo.  The MRI results demonstrated a volume reduction of -14.9%, -8.3% and no reduction in 
volume in RZL-012 high dose, low dose and placebo, respectively. Results were statistically 
significant. 
1.3. 
Risk-Benefit Assessment 
1.3.1. Identified RZL-012 Risks 
Adverse Events 
Identified risks are local injection-site reactions including injection-site bruising, induration, 
edema, pain, and erythema which are commonly reported after injection of RZL-012. Most 


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injection site reactions are transient and are not observed for more than 28-56 days following 
injection. None of these identified risks are serious in nature. 
Submental swelling and dysphagia have also been identified as common risks. These two are 
transient and have not been serious in nature. 
Laboratory - D-Dimer 
Treatment with RZL-012 causes a transient increase in D-dimer without any 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 (Spahr-2020).  
Laboratory – ALT and AST 
In study RZL-012-P0US-01.3, there was one subject injected with 20 mg of RZL-012 who 
demonstrated a significant transient increase in alanine aminotransferase (ALT) blood levels 
(Levels had x7-9-fold increase from the upper limit of normal (ULN) on Days 14 and 21, 
respectively) and a moderate elevation of aspartate aminotransferase (AST) blood levels (~4 fold 
increase from ULN) 14 days following injection of the highest dose of active treatment (20 
mg/subject). Resolution for AST elevated levels and reduction for ALT levels to Grade 1 (mild), 
occurred 14 days following detection (i.e. 28 days after dosing). ALT levels were normal on the 
next visit on Day 56. Other liver enzymes such as GGT and alkaline phosphatase, as well as 
bilirubin levels remained within normal range. 
Study RZL-012-SMF-P2b-US-001 also demonstrated increases in AST on Day 1 following  
RZL-012 treatment. These increases were transient and were resolved by next study visit (Day 7). 
There were no notable changes in ALT, GGT, alkaline phosphatase or bilirubin. 
The relationship between RZL-012 injection and a potential increase in liver enzymes is not 
completely understood. In preclinical studies which were conducted by Raziel, a rise in AST 
enzyme levels was observed in the high doses female rat group (20 mg/rat (about 80 mg/kg), 
equivalent to a human dose >900 mg/subject), returning to normal levels within 14 days of 
recovery. Raziel Therapeutics continues to monitor closely for any changes in liver enzymes. 
1.3.2. Benefits 
The cytolytic effect of RZL-012 has been demonstrated in non-clinical in-vitro and in-vivo studies. 
When administered into subcutaneous tissue, this cytolytic effect translates into a reduction in 
subcutaneous tissue. The reduction in submental fat has been demonstrated in Phase 2a and Phase 
2b studies. Confirmatory Phase 3 studies will be conducted.  
 


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3.0 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of this study is to compare the pharmacokinetic profile of RZL-012 in 
subjects that are dosed in the submental fat (SMF) in a Chinese vs. a non-Chinese population. 
3.1.2 
Secondary Objectives 
• To compare the efficacy of RZL-012 in SMF reduction measured on Day 84 versus baseline 
using the Clinician Assessment Tool (C-CAT) in Chinese vs. non Chinese population.  
• To compare the efficacy of RZL-012 in SMF reduction measured on Day 84 versus baseline 
using the Subject Assessment Tool (S-CAT) in Chinese vs. non Chinese population.  
• To determine the efficacy of RZL-012 in SMF reduction measured on Day 84 versus baseline 
using both Subject Self-Chin Assessment Tool (S-CAT) and the Clinician Assessment Tool 
(C-CAT) Chinese vs. non Chinese population; 
• To compare the reduction in SMF on Day 84 versus baseline using the caliper measured 
submental thickness in a Chinese vs. non Chinese population  
• To assess the safety of RZL-012 in the treatment of SMF reduction. 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint 
The pharmacokinetic profile of RZL-012 will be compared in a Chinese vs. a non-Chinese 
population based on: 
• 
Cmax - Maximum concentration achieved. 
• 
Tmax - Time to reach maximum concentration (hours). 
• 
AUClast – The area under the concentration vs. time curve, calculated as sum of AUCs using 
linear trapezoidal summation from time 0 to the last measurable data point. 
• 
AUCpartial – The area under the concentration vs. time curve, calculated as sum of AUCs 
using linear trapezoidal summation from time 0 to the maximal measurement (Tmax). 
• 
z (Lambdaz) - Individual estimate of the terminal elimination rate constant, was calculated 
using log-linear regression of the terminal portions of the plasma concentration-versus-time 
curves.  
• 
AUCinf - The area under the plasma concentration-time curve extrapolated to infinity, 


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calculated as:  
AUClast + Clast/z, where Clast is the last measurable concentration. 
• 
T1/2 - Apparent terminal elimination half-life time (hours), defined as 0.693/z. 
3.2.2 
Exploratory Endpoints 
The secondary endpoints for the study are: 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the C-CAT on Day 84 versus baseline. 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the S-CAT on Day 84 versus baseline. 
• 
Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
• 
Comparison of the proportion of subjects in both populations who have at least a 2-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
• 
Comparison of the reduction in SMF thickness measured with caliper (Day 84 versus 
baseline) in a Chinese vs. a non-Chinese population 
• 
Safety of RZL-012 in the treatment of SMF reduction. 
3.2.3 
Additional 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. 
4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2, open-label study that will consist of a screening period, baseline period in which 
subjects will receive a single treatment session of RZL-012 and a follow-up period.  The single 
treatment session will consist of multiple injections of RZL-012 into the submental area under the 
chin. Blood samples will be collected from all subjects for PK analyses in the first 48 hours after 
dosing.  Subjects will thereafter be monitored for safety and efficacy for at least 84 days. 
All subjects will be treated with a total dose of 270 mg RZL-012. 


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4.2 
Rationale for Study Design 
Since all subjects will receive the same study treatment, the study will employ an open-label 
design. 
4.3 
Rationale for Study Dose 
The Phase 2b study (RZL-012-SMF-P2b-US-001) demonstrated that a single treatment session of 
RZL-012 at a maximal dose of 270 mg into the subcutaneous tissue of the submental area reduces 
fat and improves appearance of this area. 
5.0 STUDY POPULATION 
5.1 
Inclusion Criteria 
For a subject to be eligible for this study, he or she must meet all of the following inclusion 
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  kg/m2 and <40  kg/m2. 
3. If enrolled for Chinese arm, subjects have to be ethnically pure, i.e., Chinese passport holders 
with all four grandparents being Chinese.    
4. 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. 
5. Has grade 3 to 4 of SMF as rated by both the C-CAT and S-CAT. 
6. Has a visible or large pocket of submental fat- according to physician global assessment. 
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. 


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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. 
 
5.2 
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 any uncontrolled systemic disease that is not stabilized (i.e., cardiovascular disease, mental 
illness). 
3. 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. 
4. Has any scars, unshaven hair, tattoos, facial hair or jewelry on or near the proposed treatment 
area. 
5. 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.  
6. Has a fat bulge under the chin that is too large to be adequately treated by 32±4 contiguous 
injections on a 1cm grid. 
7. Has a fat bulge under the chin that is of an insufficient volume to allow 32±4 injections within 
a contiguous 1 cm grid.  
8. 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. 
9. Has an active bacterial, fungal, or viral infection in the proposed treatment area. 
10. Has a pre-existing skin condition in the submental region that, at the Investigator’s discretion, 
may confound evaluation or analysis. 
11. 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. 


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12. Has pre-existing neurological or gastrointestinal condition leading to dysphagia, dysphonia, or 
facial nerve palsy. 
13. Has Dercum’s Disease. 
14. Has allergic reactions to injectables. 
15. 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. 
16. Has a planned fat reduction procedure of any variety to the submental region for the duration 
of the study. 
17. Has medication or a history of coagulopathy. 
18. Has a history or family history of venous thrombotic disease. 
19. Has been treated chronically at least three (3) months prior to study entry with systemic steroids 
or immunosuppressive drugs. 
20. Has been treated chronically at least one (1) week prior to study entry with non-steroidal anti-
inflammatory drugs (NSAIDs)  
21. Has used anticoagulation therapies that may increase bleeding or bruising (i.e., aspirin, 
ibuprofen, warfarin, vitamins, and herbal preparations) for seven (7) days prior to treatment. 
22. Has had treatment with botulinum toxin injections in the neck or chin area within nine (9) 
months prior to screening. 
23. Current participation or participation within three (3) months prior to the start of this study in 
a drug or other investigational research study. 
6.0 STUDY INTERVENTION 
6.1 
Study Intervention Administration 
6.1.1 
Study Intervention Description 
RZL-012 is provided as a sterile liquid solution suitable for injection. It has a concentration of 
50 mg/mL. It is packaged in glass vials and supplied in study kits. 
6.1.2 
Dosing and Administration 
Subjects will undergo a single treatment session with 36 injections of 7.5 mg RZL-012 each for a 
total RZL-012 dose of 270 mg. The total injection volume for all groups will be 4.8 mL±0.6. 
Subjects will be injected with RZL-012 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 1 below. The Investigator will choose 32±4 


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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 1 
Submental Injection Pattern 
 
6.2 
Preparation/Handling/Storage/Accountability 
The RZL-012 solution is supplied ready to use. The RZL-012 kits, each comprised of 2 vials, 
should be stored in the site pharmacy or clinic at monitored room temperature conditions (22 ± 7 
°C) and protected from light. They should be kept in a secure location physically separated from 
standard clinic or office drug supplies. 
RZL-012 is administered to the subject on the study site by the study investigator. The vials should 
be manually shaken prior to injection. 
The following procedures prior to injection will be applied: 
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. 


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6. Syringes will be filled with 1 mL RZL-012 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 27G/29G x 1/2” needle, respectively. 
8. The hole of the needle should be pointing into the middle of 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. 
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. Total injection 
volume and number of injection per subject should be recorded on medical records. 
All study drug received by the Investigator will be inventoried and accounted for in a Dispensing 
Log. 
A maximal of 2 vials will be used for each subject. All open vials will be kept until the end of 
study when the Sponsor will determine if study drug should be returned or destroyed.  
6.3 
Study Intervention Compliance 
Study treatment consists of a single administration session administered by the study investigator.  
6.4 
Prior and Concomitant Medications 
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). 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. 


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7.0 STUDY INTERVENTION DISCONTINUATION 
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. 
8.0 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Medical History 
A medical history will be obtained at screening.  Subject’s medical history should be fully 
documented to confirm study eligibility. Medical history must include, but not limited to, past and 
present medical conditions, concomitant non-drug treatments, and hypersensitivity to drugs. 
8.2 
Height  
Height will be measured at screening.  It will be reported in centimeters. A subject’s height together 
with weight will be used to calculate a subject’s BMI. 
8.3 
Weight 
Body weight will be measured at screening, baseline and at the study visit Day 28, Day 56 and 
study visit Day 84. Weight will be reported in kilograms (kg). A subject’s weight at screening 
together with height will be used to calculate a subject’s BMI. 
8.4 
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 12 weeks), if pregnancy is 
suspected. Urine pregnancy test will be done to females of childbearing potential on Day 84. 


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8.5 
Complete Physical Examination 
The Investigator (or medically qualified nominee) will perform a complete physical examination 
at screening and on Day 1, Day 7 and  Day 84 visit.  
8.6 
Pharmacokinetics 
Blood samples for testing of RZL-012 pharmacokinetics will be taken from all subjects at the 
baseline visit prior to injection, at 30 and 60 minutes post dosing and at 2h, 3h, 4h, 6h , 8h, 24h,  
30 and 48 hours post injection. 
Each sample (10 mL each) will be collected in K2EDTA vials which will be stored on an ice block 
or wet ice until centrifuged with 60 minutes of collection.  Samples will be centrifuged at 1200 g 
in 4 °C for 10 minutes.  Plasma will be removed and placed in aliquots (4 aliquots of 1 mL each) 
within 20 minutes of centrifugation and flash frozen on dry ice.  Processed samples will be placed 
in frozen (-60 to -90 °C) storage.  Levels of RZL-012 in K2EDTA human plasma will be 
determined using a validated method of Liquid Chromatography-Tandem Mass Spectrometry. 
Two  aliquots from each time point will be retained for possible future analysis from all subjects  
8.7 
Clinician-Chin Assessment Tool (C-CAT) 
SMF ratings using the C-CAT will be conducted by a fixed and well trained 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. 
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. 


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Table 2 
Clinician Chin Assessment Tool (C-CAT) 
 
8.8 
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). 
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. 


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Table 3 
Self Chin Assessment Tool (S-CAT) 
 
 
8.9 
2-D Standardized Photography and Physician Global Assessment Improvement 
Scale (GAIS) 
Standardized photography (2-dimensional) of the face (SMF area) will be conducted at screening 
and on study visits Day 1, Day 7, Day 28, Day 56, and Day 84.  
Photographs will be taken with a digital camera according to photography standards in 
dermatology surgeries for the face/neck area (see Appendix A). 
The investigator will assess the improvement of the submental area by comparing the photographs 
of the subject and using the scale presented in Table 4 below 
Table 4 
Physician Global Assessment Improvement Scale (GAIS) 
Grade 
Description 
0 
Completely clear 
No evidence of fat; 100% improvement 
1 
Almost clear 
Very significant clearance (≥90% to <100%); only trace remain 
2 
Marked improvement 
Significant improvement (≥75% to <90%); some evidence of  fat remains 
3 
Moderate improvement 
Intermediate between slight and marked improvement (≥50% to <75%) 
4 
Slight improvement 
Some improvement (≥25% to <50%); significance evidence of fat 
remains 
5 
No change 
Fat has not changed from baseline condition (±25%) 
6 
Worse 
Fat is worse than at baseline evaluation by ≥25% or more  


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8.10 
Subject’s Satisfaction Questionnaire  
Subject’s satisfaction questionnaire (yes/no questions) will be conducted by the subjects at 
screening and on study visits Day 28, Day 56 and Day 84.  
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 
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 satisfied 
1 
Satisfied 
2 
Somewhat satisfied 
3 
Somewhat dissatisfied 
4 
Dissatisfied 


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5 
Very dissatisfied 
How likely would you be to recommend this procedure to friends and family*? 
Score 
Grade 
0 
Extremely likely 
1 
Very likely 
2 
Somewhat likely 
3 
A little likely 
4 
Not at all likely 
8.11 
Caliper Measurements 
Caliper measurements of submental fat thickness will be taken at screening and at study visits Day 
28, Day 56 and Day 84. 
To make the measurement, the subject’s head should be maintained in a neutral position and the 
caliper positioned to pinch the skin at 15 mm on either side of the center point of the submental 
area. 
The change from baseline in caliper-measured submental thickness will be calculated as an 
exploratory  efficacy endpoint. 
8.12 
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. 
Table 5 
Subject Impact Questionnaire 
Question/Score 
0 
1 
2 
3 
4 
How self-conscious are you 
about your appearance as it 
relates to your chin fat? 
Not at all 
self-
conscious 
A little 
self-
conscious 
Moderately 
self-
conscious 
 
Very self-
conscious 
Extremely self-
conscious 
 
How bothered are you by 
the appearance of your chin 
fat? 
Not at all 
bothered 
A little 
bothered 
Moderately 
bothered 
Very bothered Extremely 
bothered 
How much do you think 
that the appearance of your 
chin fat effects your career 
or work life? 
Not at all 
A little bit 
A 
moderate 
amount 
A great deal 
An extreme 
amount 


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How much does the 
appearance of your chin fat 
effect your relationships? 
Not at all 
A little bit 
A 
Moderate 
amount 
A great deal 
An extreme 
amount 
How much does the 
appearance of your chin fat 
effect your self-confidence? 
Not at all 
A little bit 
A 
moderate 
amount 
A great deal 
An extreme 
amount 
Do you feel self-conscious 
about the appearance of 
your chin fat when you 
look at photographs? 
Not at all 
A little bit 
 
A 
moderate 
amount 
A great deal 
An extreme 
amount 
Do you try to hide or 
camouflage your chin fat? 
For example, make-up and 
hair styles, beard hair, 
clothing or neck/head 
position? 
Not at all 
A little bit 
 
A 
moderate 
amount 
A great deal 
 
An extreme 
amount 
Do you feel self-conscious 
when you look at your chin 
fat in the mirror? 
Not at all 
A little bit 
 
A 
moderate 
amount 
A great deal 
 
An extreme 
amount 
How do you think the 
appearance of your neck 
effects your relationships? 
Not at all 
A little bit 
A 
moderate 
amount 
A great deal 
 
An extreme 
amount 
How heavy or thin do you 
think your chin fat makes 
you look? 
I look 
more than 
10 pounds 
thinner 
than I am 
I look 10 
pounds 
thinner 
I look 5 
pounds 
thinner 
I look my 
weight 
 
I look 5 pounds 
heavier 
 
Score 5- I look 
10 pounds 
heavier* 
 
Score 6 - I look 
more than 10 
pounds heavier* 
The only item in this questionnaire with potential scores of 5 and 6 
8.13 
Subject Global Assessment  
At screening and study visits Day 28, 56 and 84 subjects 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 


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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 
 
At each study visit (Day 28,56 and 84), the subject will be asked to assess their 
improvement degree based on the following scale: 
Score 
Grade 
0 
Extremely improved 
1 
Very much improved 
2 
Improved 
3 
No Change 
4 
Worse 
5 
Very much worsened 
6 
Extremely worsened 
 
8.14 
Biochemistry 
Blood samples for the laboratory evaluation of biochemistry parameters will be collected at 
screening and at study visits Day 1, Day 7, 28 and Day 84. 
If there are clinically significant alerts obtained on Day 7, an unscheduled visit will be added for 
additional blood sampling. 
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]).A 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).  
Biochemistry parameters will be collected for safety assessments. 


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8.15 
Vital Signs 
Vital signs (systolic and diastolic sitting position blood pressure, pulse rate, respiratory rate, and 
body oral temperature) will be obtained at screening, baseline (pre and post dose) and at study 
visits Day 1, Day 7, Day 28, Day 56 and Day 84. 
Vital signs will be collected for safety assessments. 
8.16 
ECG 
ECG tests will be performed at screening and at study visits Day 1 and Day 84. ECG will be 
performed in triplicates. 
ECGs will be collected for safety assessments. 
8.17 
Adverse Events and Serious Adverse Events 
8.17.1 
Collection of Adverse Events Data 
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 for severity. In case the AE severity is changed 
from one severity grade to the another the date of AE start and AE end of the specific AE 
severity should be recorded.  
 
The reporting period for AEs starts after dosing of study drug and will end at final study visit .If 
an AE remains unresolved at discharge, 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”.    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.  


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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. 
AEs will be graded for severity according to the following definitions: 
Table 6 
Severity Assessment of Adverse Events  
Common Term 
Description 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Assisted Daily Living 
(ADL). 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL. 
Life-Threatening 
Life-threatening consequences; urgent intervention indicated. 
Death 
Death related to AE  
8.17.2 
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 


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• 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. 
8.17.3 
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 
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  
SAE Hotline: 888-746-7231 
SAE Fax Line: 888-746-3293 
SAE Email: rho_productsafety@rhoworld.com 
 
Table 7 
Contact Information for SAE Reporting 
Primary Contact 
Sponsor Contact 
Lead Product Safety Specialist 
Medical Monitor 
Bonnie Graham, RN, BSN 
Patricia Walker, MD 
Phone: 
1-919-680-5516 
Mobile: 
1-805-705-5853 
Email: 
bonnie_graham@rhoworld.com 
Email: 
dr.patricia.walker@gmail.com 
8.17.4 
Reporting pregnancy 
Pregnancy testing must be performed 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 


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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 performed. 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 8.17.3.  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.   
8.17.5 
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. 
9.0 STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Determination 
A total of 20 subjects will be included in the study. All subjects will be treated with RZL-012. 
9.2 
Analysis Data Sets 
Subjects who receive study treatment will be included in the safety analyses.  
9.3 
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 
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). 


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9.4 
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, blood 
parameters, ECG . 
AE assessment and treatment area evaluation including, but not limited to evaluation of edema, 
pain, bruising, erythema, induration, numbness, paresthesia, tenderness, 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.  
AE data will be listed individually and summarized by SOC and by PT within a system organ 
class. 
Skin irritancy AEs related to the injection procedure will be evaluated for frequency, severity and 
duration by treatment group.  
Laboratory tests and ECG results will be summarized in appropriate table. 
9.5 
Efficacy 
The exploratory endpoints will be analyzed as follows: 
Secondary endpoints (improvement in 1 point in C-CAT, improvement in 1 point in S-CAT, 
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 endpoints will be tested using a two-sided test at the alpha=0.05 level of significance. 
10.0 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
10.1 
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. 
10.2 
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 


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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. 
10.3 
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.  
10.4 
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 
possible stating this and the reason. It must be submitted to the sponsor and the director of the 
study site. 
10.5 
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. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMFC-P2US-001 
RZL-012 
Version: 1.3 
19 September 2022 
Page 45 of 48 
CONFIDENTIAL 
 
10.6 
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 other government authorities 
where the clinical data will be used for new drug registration, 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. 
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. 
11.0 
PROTECTION OF HUMAN SUBJECTS 
11.1 
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. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMFC-P2US-001 
RZL-012 
Version: 1.3 
19 September 2022 
Page 46 of 48 
CONFIDENTIAL 
 
11.2 
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). 
11.3 
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). In addition, a brochure that describes potential adverse events and treatment success 
rates will be also shared with the subjects. 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 Section 1.2. 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 5.0. 
11.4 
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. 


Raziel Therapeutics, Ltd. 
Protocol RZL-012-SMFC-P2US-001 
RZL-012 
Version: 1.3 
19 September 2022 
Page 47 of 48 
CONFIDENTIAL 
 
11.5 
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-SMFC-P2US-001 
RZL-012 
Version: 1.3 
 
19 September 2022                                              48 of 48                                                CONFIDENTIAL 
                                   
 
Appendix A:  Photographic Standards of the Face Area  
 
 
 
 
 
 
 

SAP_001.pdf: 
 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 1 of 20 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
EFFECTIVE DATE : 03/08/2022 
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
  
Revision History 
 
Revision 
Revision Date 
Reason for Revision/Change Request 
Revised By 
1.0 
03/08/2022 
Original Release 
Einan Farhi , Senior 
Biostatistician 
 
 
 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
EFFECTIVE DATE : 03/08/2022 
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
 
 
Statistical Analysis Plan 
                                  Study Title:  
 
An Open-Label Phase 2 Study to Compare the Pharmacokinetics, Efficacy and Safety of  
RZL-012 in Chinese Subjects Seeking Submental Fat Reduction vs. Non-Chinese Subjects 
Seeking Submental Fat Reduction (RZL-012-SMFC-P2US-001) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
DOCUMENT NUMBER: 140-BST-PLN-001 
PAGE: 3 of 20 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
EFFECTIVE DATE : 03/08/2022 
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
TABLE OF CONTENTS 
 
SIGNATURES PAGE .................................................................................................................... 4 
1. 
DEFINITIONS AND/OR ABBREVIATIONS ...................................................................... 5 
2. 
PURPOSE ............................................................................................................................... 6 
3. 
SCOPE .................................................................................................................................... 6 
4. 
RESPONSIBILITIES ............................................................................................................. 6 
5. 
PROCEDURE ......................................................................................................................... 7 
6. 
STATISTICAL ANALYSIS ................................................................................................ 14 
7. 
RELATED DOCUMENTS (OPTIONAL) ........................................................................... 20 
8. 
RELATED FORMS (OPTIONAL) ...................................................................................... 20 
9. 
REFERENCES ..................................................................................................................... 20 
10. 
APPENDICES ................................................................................................................... 20 
 


 
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Medistat Ltd. Confidential 
 
 
SIGNATURES PAGE 
Author : Einan Farhi  
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 03 August 2022 
 
Reviewer: David Israel 
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 03 August 2022 
 
 
Approved by: Racheli Gueta 
 
Director, clinical development 
Raziel Therapy Ltd.                                                                         Date: 03 August 2022 
 
 
 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
EFFECTIVE DATE : 03/08/2022 
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
1. DEFINITIONS AND/OR ABBREVIATIONS  
AE 
Adverse event 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
C-CAT 
Clinician-Chin Assessment Tool 
S-CAT 
Self-Chin Assessment Tool 
ECG 
Electrocardiograms 
GAIS 
Global Aesthetics Improvement Scale 
ICF 
Informed Consent Form 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
PP 
Per-Protocol 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SMF 
Submental Fat 
WHO 
World health organization 
 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
EFFECTIVE DATE : 03/08/2022 
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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-SMFC-P2US-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) 
Einan Farhi 
Senior Biostatistician 
& SAS Programmer 
Statistical Report and listing  
Einan Farhi 
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 
 
 


 
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Medistat Ltd. Confidential 
 
5. PROCEDURE  
 Introduction 
This Statistical Analysis Plan (SAP) is based on RZL-012-SMFC-P2US-001 study protocol 
version 1.2, dated 26 July 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 compare the pharmacokinetic profile of RZL-012 in subjects that are dosed in the submental 
fat (SMF) in a Chinese vs. a non-Chinese population.  
 
Secondary Objectives: 
1. To compare the efficacy of RZL-012 in SMF reduction measured on Day 84 versus 
baseline using the Clinician Assessment Tool (C-CAT) in Chinese vs. non-Chinese 
population.  
2. To determine the efficacy of RZL-012 in SMF reduction measured on Day 84 versus 
baseline using both Subject Self-Chin Assessment Tool (S-CAT) and the Clinician 
Assessment Tool (C-CAT) in a Chinese vs. a non-Chinese population. 
3. To compare the reduction in SMF on Day 84 versus baseline using the caliper measured 
submental thickness in a Chinese vs. a non-Chinese population  
4. To assess the safety of RZL-012 in the treatment of SMF reduction. 
 
 


 
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Medistat Ltd. Confidential 
 
Primary Endpoints: 
Characterization of RZL-012 pharmacokinetic (PK) profile in a Chinese vs. non-Chinese 
population based on 
 Cmax - Maximum concentration achieved. 
 Tmax - Time to reach maximum concentration (hours). 
 AUClast – The area under the concentration vs. time curve, calculated as sum of AUCs 
using linear trapezoidal summation from time 0 to the last measurable data point. 
 AUCpartial – The area under the concentration vs. time curve, calculated as sum of AUCs 
using linear trapezoidal summation from time 0 to the maximal measurement (Tmax). 
 z (Lambdaz)- Individual estimate of the terminal elimination rate constant, will be 
calculated using log-linear regression of the terminal portions of the plasma 
concentration-versus-time curves.  
 AUCinf - The area under the plasma concentration-time curve extrapolated to infinity, 
calculated as:  
AUClast + Clast/z, where Clast is the last measurable concentration. 
 T1/2 - Apparent terminal elimination half-life time (hours), defined as 0.693/z. 
 
Exploratory Endpoints: 
 Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the C-CAT on Day 84 versus baseline. 
 Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in the S-CAT on Day 84 versus baseline. 
 Comparison of the proportion of subjects in each population who have at least a 1-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
 Comparison of the proportion of subjects in both populations who have at least a 2-grade 
improvement in both the C-CAT and S-CAT (Day 84 versus baseline). 
 Comparison of the reduction in SMF thickness measured with caliper (Day 84 versus 
baseline) in a Chinese vs. non-Chinese population 
 Safety of RZL-012 in the treatment of SMF reduction. 
 
 
 


 
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Medistat Ltd. Confidential 
 
 
 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 2, open-label study that will consist of a screening period, baseline period in 
which subjects will receive a single treatment session and a follow-up period.  The single 
treatment session will consist of multiple injections of RZL-012 for a maximal total dose of 270 
mg into the submental area under the chin. Blood samples will be collected from all subjects for 
PK analyses in the first 30 hours after dosing.  Subjects will thereafter be monitored for safety 
and efficacy for at least 84 days. 
20 adult volunteers (10 Chinese and 10 non-Chinese) whose age is within 18 to 65 years who 
have consented to participate in this study and seek submental fat reduction will be enrolled into 
the study.  
All subjects will receive a single multi-injection session of RZL-012 in accordance with the table 
below:  
Number of subjects 
N=20 
RZL-012 dose  
240mg±30mg/4.8 ±0.6 mL 
RZL-012 Dose (mg)/volume 
(mL) per single injection 
7.5mg/0.15mL 
Number of Injections per subject 
32±4 
 
Subjects will undergo a single treatment session with 32±4 injections. The total number of 
injections will be 32±4 with a dose of 240±30 mg RZL-012. Each injection point will be dosed 
with 7.5 mg RZL-012 in a volume of 0.15 mL/injection site. The total injection volume for all 
groups will be 4.8 mL±0.6. 


 
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Medistat Ltd. Confidential 
 
Subjects will be injected with RZL-012 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. 
 
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. For subjects 
for whom AEs are unresolved by Day 84, an unscheduled visit will be set 6-8 weeks after Day 
84 to verify the resolution of the AE.  
Other safety measures will include vital sign measurements, Lab parameters follow up on Day 1, 
7, 28 and 84 following injection, ECG, 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. 
 
 


 
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Medistat Ltd. Confidential 
 
 Schedule of Assessments 
Study Procedure 
Screening 
Day  
Baseline 
(Treatment) 
Visit 
Schedule 
(Days 1 to 
84) 
 
 
 
 
Study Day 
Day (-28) 
through 
Day (-1) 
Day  0 
Day 1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Signed informed 
consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
 
 
X 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
Pregnancy ß-hCG 
X 
 
 
 
 
 
 
Pregnancy urine 
test (women) 
 
X 
 
 
 
 
X 
Caliper 
measurement of 
submental fat 
X 
 
 
 
X 
X 
X 
Weight 
measurements  
X 
X 
 
 
X 
X 
X 
Biochemistry Lab 
parameters 
X 
 
X 
X 
X 
 
X 
Pharmacokinetics 
 
X 
X 
 
 
 
 
ECG 
X 
 
X 
 
 
 
X 
Vital signs  
X 
Pre X post 
X 
X 
X 
X 
X 
Injection of RZL-
012 
 
X 
 
 
 
 
 


 
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Medistat Ltd. Confidential 
 
 
 
 
 
 
Clinician Chin 
Assessment Tool 
(C-CAT) 
X 
X 
 
 
X 
X 
X 
Subject- Self-Chin 
Assessment Tool 
(S-CAT) 
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 
X 
 
 
 
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 
AEs  
 
X 
X 
X 
X 
X 
X 


 
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Medistat Ltd. Confidential 
 
 Rationale Sample Size Calculation 
20 adult volunteers (10 Chinese and 10 non-Chinese) whose age is within 18 to 65 years who 
have consented to participate in this study and seek submental fat reduction will be enrolled into 
the study. 
No formal sample size calculation was performed. The planned sample size of 10 subjects per 
study arm is sufficient to compare the PK profile between the 2 study populations. Any p-value 
which may be shown in the final report, will be presented only to establish trends. 
 
 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.  
 
 
 


 
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Medistat Ltd. Confidential 
 
 Subject Population for analyses 
The Intent-to-treat population  (ITT) will consist of all enrolled subjects who received the study 
treatment (i.e. exposed population), including subjects prematurely withdrawn. The ITT 
population will serve as the principal data analysis set for analyses of efficacy and safety 
endpoints. 
PK analysis will be performed on all ITT patients for whom sufficient PK data was collected. 
 
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 by study group. Confidence intervals (95% degree of confidence) for 
proportions will be presented for selected endpoints. 
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 study arm (Chinese vs. non-Chinese) 
and for all subjects. All withdrawals from the study will be fully documented in the body of the 
Clinical Study Report. 
 
 


 
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Medistat Ltd. Confidential 
 
 Demographic and Baseline Characteristics 
Baseline will be defined as the last available and evaluable parameter value before and closest to 
the injection.  If a rechecked value is used for baseline, it should be collected under the same 
conditions as for the planned baseline. 
Baseline data including demographics, weight, height, BMI, prior medications, medical history 
and pregnancy tests will be listed and tabulated with the appropriate descriptive statistics by 
study arm and for all subjects in ITT population. 
Baseline safety data such as vital signs, ECG, safety laboratory assessments and physical 
examination will be presented along with subsequent safety values assessed during or after 
injections. 
 
 Analysis of Primary Endpoint 
 
• 
The characterization of RZL-012 pharmacokinetic (PK) profile and comparison 
in a Chinese vs. a non-Chinese population 
 
The following parameters will be evaluated for RZL-012 injection treatment for every subject: 
Cmax: 
Maximum measured plasma concentration over the time span specified. 
Tmax: 
Time to maximum measured plasma concentration. If the maximum value is observed 
at more than one time point, Tmax will be defined as the first time point observed with 
this value. 
AUC0-t: 
 
The area under the plasma concentration versus time curve, from time 0 to the last 
measurable concentration, as calculated by the linear trapezoidal method. 
AUC0-inf: 
The area under the plasma concentration versus time curve from time 0 to infinity. 
AUC0-inf  is calculated as the sum of AUC0-t and the ratio of the last measurable plasma 
concentration to the elimination rate constant. 
kel (λz): 
Apparent first-order terminal elimination rate constant calculated from a semilog 
plot of the plasma concentration versus time curve. The parameter will be calculated 
by linear least-squares regression analysis using the maximum number of points in 
the terminal log-linear phase. (e.g., three or more non-zero plasma concentrations). 
T½: 
 
Apparent first-order terminal elimination half-life will be calculated as 0.693/kel. 
Clast / λz: 
Clast is the last measurable concentration. 
Other pharmacokinetic parameters may be calculated if deemed necessary. 


 
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A total of 10 subjects per group will be used to compare between PK profile of both populations.  
PK assessments will be compared between the 2 study populations. The individual values of for 
RZL-012 plasma concentration and evaluated PK parameters will listed by subject. 
Summary tables will be generated for RZL-012 concentration by time point and for all derived 
PK parameters presenting sample size (N), mean, Standard deviation, Standard Error, Median, 
minimum and maximum values, Coefficient of variation (CV%) and 95% CI (Confidence 
Interval) for means by study arm.  
Graphical displays will be generated presenting mean concentration by study arm as well as 
individual graphs per subject. 
 
 Analysis of Safety Endpoints (Exploratory) 
 
Safety data will be summarized by study arm. Descriptive statistics will be provided for actual 
values and change from baseline values for vital signs, safety laboratory assessments, physical 
examinations, blood parameters, ECG . 
 
• 
Adverse Events (AEs) 
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. 
AE assessment and treatment area evaluation including, but not limited to evaluation of edema, 
pain, bruising, erythema, induration, numbness, paresthesia, tenderness, and pruritus. 
AE data will be listed individually including the nature, body system, seriousness, severity and 
relationship of AEs to study drug. 
The incidence of AEs and percentage of patients experiencing AEs will be tabulated by the 
nature of AEs (all AEs, Serious AEs (SAEs), Severe AEs AEs related to study drug, AEs that led 
to study/treatment discontinuation) for each study arm. Different features may be crossed such as 
severity and relationship to study drug to provide additional percentages. 
The incidence and percentage of patients experiencing AEs will also be summarized by SOC and 
by PT within a system organ class and further by severity and relationship to treatment if needed 
for each study arm. 
Serious adverse events (SAEs) will be described in narratives as part of the study report. 


 
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• 
Skin irritancy 
Skin irritancy AEs related to the injection procedure will be evaluated for frequency, severity 
and duration by treatment group.  
Fisher's Exact test will be applied for testing the statistical significance of the difference in 
percent of subjects that experienced Skin irritancy AEs related to the injection procedure 
between the study groups. 
 
• 
Safety Laboratories 
All safety laboratory parameters will be summarized using continuous variable descriptive 
statistics where applicable. Changes and relative changes from baseline will be calculated and 
summarized as well. 
The normal/abnormal status and clinical signifcance of observations will be summarized using 
counts and percentages per study arm and per visit. 
 
• 
Vital Signs 
All vital signs will be summarized using continuous variable descriptive statistics where 
applicable. Changes and relative changes from baseline will be calculated and summarized as 
well. 
 
• 
ECG 
ECG results will be summarized in appropriate tables using descriptive statistics by study arm. 
Changes from baseline values will be summarized as well to indicate if there has been any 
change. 
 
 Analysis of Efficacy Endpoints (Exploratory) 
 
The exploratory endpoints will be analyzed as follows: 
 
• 
The proportion of subjects in each population who have at least a 1-grade 
improvement in the C-CAT on Day 84 versus baseline will be calculated and 
summarized by study arm along with 95% CIs for proportions (Fisher's Exact method). 


 
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A two-sided test of equality of binomial proportions will be applied for testing the 
statistical significance of the difference in percent of subjects who have at least a 1-
grade improvement in the C-CAT on Day 84 versus baseline between study arms. 
 
• 
The proportion of subjects in each population who have at least a 1-grade 
improvement in the S-CAT on Day 84 versus baseline will be calculated and 
summarized by study arm along with 95% CIs for proportions (Fisher's Exact method). 
A two-sided test of equality of binomial proportions will be applied for testing the 
statistical significance of the difference in percent of subject who have at least a 1-
grade improvement in the S-CAT on Day 84 versus baseline. 
 
• 
The proportion of subjects in each population who have at least a 1-grade 
improvement in both the C-CAT and S-CAT on Day 84 versus baseline will be 
calculated and summarized by study arm along with 95% CIs for proportions (Fisher's 
Exact method). 
A two-sided test of equality of binomial proportions will be applied for testing the 
statistical significance of the difference in percent of subject who have at least a 1-
grade improvement in both the C-CAT and S-CAT on Day 84 versus baseline. 
 
• 
The proportion of subjects in each population who have at least a 2-grade 
improvement in both the C-CAT and S-CAT on Day 84 versus baseline will be 
calculated and summarized by study arm along with 95% CIs for proportions (Fisher's 
Exact method). 
A two-sided test of equality of binomial proportions will be applied for testing the 
statistical significance of the difference in percent of subject who have at least a 2-
grade improvement in both the C-CAT and S-CAT on Day 84 versus baseline. 
 
• 
SMF thickness measured with caliper will be summarized by study visit 
(Screening, Day 28, Day 56, Day 84) and by study arm using continuous descriptive 
statistics. Change and relative change from baseline will be calculated and tabulated in 
the same manner. 
The Paired T-test or Signed rank test for two means (paired observations) (as is 
appropriate) will be applied for testing the statistical significance of the reduction 
(change and relative change from baseline) in SMF thickness measured with caliper 
(Day 84 versus baseline) in each study arm. 
The two-sample T-test or Non-parametric Wilcoxon-Mann-Whitney Rank sum test for 
independent samples (as is appropriate) will be applied for testing the statistical 
significance of the difference in reduction in SMF thickness measured with caliper 
(Day 84 versus baseline) between Chinese population and non-Chinese population. 
 
 


 
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The additional exploratory endpoints will be analyzed as follows: 
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 subject's 
impact questionnaire will be summarized at each timepoint and by study group. 
• 
The physician global assessment will be summarized using categorical descriptive 
statistics by study visit for each study arm. Shift from baseline will be evaluated and tabulated in 
the same manner. 
• 
The Physician Global Assessment Improvement Scale (GAIS) will be summarized using 
categorical descriptive statistics by study visit for each study arm. 
• 
The Subject Global Self-Assessment scale will be summarized using categorical 
descriptive statistics by study visit for each study arm. Shift from baseline will be evaluated and 
tabulated in the same manner. 
• 
The Subject Global Assessment of Change Scale will be summarized using categorical 
descriptive statistics by study visit for each study arm. 
• 
Subject’s satisfaction questionnaires answers will be summarized using desciptive 
statistics by study visit for each study arm. Shift from baseline will be evaluated and tabulated in 
the same manner. 
Two Subject satisfaction binary variables will be defined for every subject in the ITT population 
based on the satisfaction questionnaire for each one of the questions: 
1. Subjects who at any point in time answered "Extremely Satisfied" or "Satisfied" (Grades 
0,1). 
2. Subjects who at their last assessment answered "Extremely Satisfied" or "Satisfied" 
(Grades 0,1). 
Subjects with no assessment will be considered as non-responders. The proportion of satisfied 
subjects (according to said binary variables) will be calculated along with 95% exact confidence 
intervals for each treatment group. Fisher's Exact test will be applied for testing the statistical 
significance of the difference in percent of satisfied subjects between treatment groups. 
• 
SMF improvement using Subject’s Impact Questionnaire answers will be summarized 
using descriptive statistics by study visit for each study arm. Shift from baseline will be 
evaluated and tabulated in the same manner. 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-SMFC-P2US-001 
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7. RELATED DOCUMENTS (OPTIONAL) 
RZL-012_PK SMFC_protocol 1.2, 26 July 2022_TC.docx  
 
8. RELATED FORMS (OPTIONAL) 
Not Applicable 
 
9. REFERENCES 
Not Applicable 
 
10. APPENDICES 
Not Applicable