Conditions: Dercum's Disease Lipomas
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: no

Brief summary:
Thirty-eight (38) subjects will be included in the study. Subjects will be randomized in a ration of 1:1 to be treated with RZL-012 or placebo. Subjects will be injected with a different doses of RZL-012 according to their lipomas sizes. The total of 38 subjects will be enrolled in 3 clinical sites.

Detailed description:
This is a multi-center, randomized, double blind, placebo controlled clinical trial in DD subjects having lipomas. Subjects will be randomized, in a 1:1 ratio, into two groups injected with either RZL-012 or vehicle.

Once the study ends and codes are opened, 84 days after dosing, placebo-treated subjects will be offered the option of receiving treatment with RZL-012 and followed up for an additional 84 days.

At least 4 lipomas/nodules, preferably 6, and no more than 8, will be injected per subject, two of which will be medium (4-5.9 cm), large (6-7.9 cm) or extra-large (8-10 cm) in diameter. Dosing will be according to lipoma size, where the total injected dose will not exceed 240 mg per patient (48 injections at 5mg/injection).

Arms:
arm 1: A single-treatment injection, multiple subcutaneous injections of RZL-012 administered into 4-8 lipomas in each subject, preferably 6. Dosing will be done according to lipomas size, as will be determined by Ultrasound. Each injection contains 0.1mL RZL-012 (5mg).

Lipomas in the size of:

2-3.9 cm will be dozed with 0.4mL RZL-012 (20mg). 4-5.9 cm will be dozed with 0.8mL RZL-012 (80mg). 6-7.9 cm will be dozed with 1 mL RZL-012 (100mg). 8-10 cm will be dozed with 1.2 mL RZL-012 (120mg). arm 2: A single-treatment injection, multiple subcutaneous injections of vehicle administered into 4-8 lipomas in each subject, preferably 6. Dosing will be done according to lipomas size, as will be determined by Ultrasound. Each injection contains 0.1mL vehicle.

Lipomas in the size of:

2-3.9 cm will be dozed with 0.4mL vehicle. 4-5.9 cm will be dozed with 0.8mL vehicle. 6-7.9 cm will be dozed with 1 mL vehicle. 8-10 cm will be dozed with 1.2 mL vehicle.

Interventions: intervention 1: RZL-012 intervention 2: Vehicle
Intervention descriptions: intervention 1: small synthetic molecule for the treatment of Dercum's Disease lipomas intervention 2: Vehicle of RZL-012 drug product

Protocol document:
Prot_SAP_000.pdf: 
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RZL-012 
 
Version: 1.4 
 
 
CONFIDENTIAL 
1 
29 July 2020 
RZL-012 Study Protocol 
Protocol Number RZL-012-DD-P2bUS-001 
 
A Double Blind, Randomized, Multi-Center, Placebo-Controlled Phase 2B Clinical Trial 
for the Evaluation of Efficacy and Safety of RZL-012 in Subjects having Dercum’s Disease 
Lipomas. 
 
Principal Investigator: 
Dr. Karen Herbst 
Sponsor: 
Raziel Therapeutics 
Prof. Menachem Plaut 10 
Rehovot, Israel 760000 
 
Confidentiality Statement 
This document is a confidential communication of Raziel Therapeutics Ltd. 
Acceptance of this document constitutes agreement by the recipient that no 
unpublished information contained herein will be published or disclosed without 
prior written approval, except for disclosure to the appropriate Institutional 
Review Board and/or Regulatory Authority under the condition that confidentiality 
is maintained 
Protocol Date: 08 January 2020 
Version 1: 08 January 2020 
Version 2: 03 March 2020 
Version 2.1: 23 March 2020 
Version 3: 14 July 2020 
Version 4: 29 July 2020 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS ..........................................................................................................7 
STATEMENT OF COMPLIANCE .................................................................................................8 
INVESTIGATOR SIGNATURE PAGE .........................................................................................9 
PROTOCOL SYNOPSIS ..............................................................................................................10 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
BACKGROUND ........................................................................................................17 
1.1.1. 
Scientific Background and Clinical Rationale ............................................................17 
1.1.2. 
RZL-012 Formulation Development ..........................................................................19 
1.2. 
CLINICAL STUDIES CONDUCTED BY RAZIEL .................................................19 
1.2.1. 
Overall Safety Summary: ...........................................................................................20 
1.2.2. 
Efficacy summary: ......................................................................................................20 
2. 
PURPOSE AND STUDY OBJECTIVES ..................................................................21 
2.1. 
PURPOSE ...................................................................................................................21 
2.2. 
STUDY OBJECTIVES ..............................................................................................21 
2.2.1. 
Primary .......................................................................................................................21 
2.2.2. 
Secondary ...................................................................................................................21 
2.2.3. 
Exploratory .................................................................................................................21 
2.3. 
DESCRIPTION OF STUDY DESIGN ......................................................................22 
2.4. 
DOSE RATIONALE ..................................................................................................22 
2.5. 
DOSING .....................................................................................................................22 
2.5.1. 
Dosing Regimen .........................................................................................................22 
3. 
STUDY ENDPOINTS ................................................................................................23 
3.1. 
PRIMARY ENDPOINTS ...........................................................................................23 
3.2. 
KEY SECONDARY ENDPOINT: .............................................................................24 
3.3. 
OTHER SECONDARY ENDPOINTS ......................................................................24 
3.4. 
EXPLORATORY END POINTS ...............................................................................24 


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3.5. 
OPEN LABEL EXTENSION PHASE ENDPOINTS: ...............................................24 
3.5.1. 
Primary end point: ......................................................................................................24 
3.5.2. 
Secondary end points: .................................................................................................24 
4. 
STUDY POPULATION .............................................................................................24 
4.1. 
INCLUSION CRITERIA ...........................................................................................24 
4.2. 
EXCLUSION CRITERIA ..........................................................................................25 
4.3. 
SUBJECT IDENTIFICATION ..................................................................................25 
4.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF STUDY 
SUBJECTS .................................................................................................................26 
5. 
STUDY PROCEDURES AND ASSESSMENT ........................................................26 
5.1. 
DEFINITIONS OF STUDY PROCEDURES ............................................................26 
5.1.1. 
Informed Consent .......................................................................................................26 
5.1.2. 
Medical History ..........................................................................................................26 
5.1.3. 
Concomitant Medication ............................................................................................27 
5.1.4. 
Physical Examination .................................................................................................27 
5.1.5. 
Pain Measurement ......................................................................................................27 
5.1.6. 
Quality of Life Assessment ........................................................................................27 
5.1.7. 
Vital Signs Measurements ..........................................................................................28 
5.1.8. 
Serology assay ............................................................................................................28 
5.1.9. 
Clinical Laboratory tests .............................................................................................28 
5.1.9.1. 
Hematology .................................................................................................................28 
5.1.9.2. 
Serum Chemistry Analysis .........................................................................................29 
5.1.9.3. 
Urinalysis ....................................................................................................................29 
5.1.9.4. 
Lipid profile ................................................................................................................29 
5.1.10. 
ECG ............................................................................................................................30 
5.1.11. 
Draize Score ................................................................................................................30 
5.1.12. 
Photography of lipomas ..............................................................................................30 
5.1.13. 
Imaging: Ultrasound (US) ..........................................................................................31 
5.1.14. 
Adverse Events ...........................................................................................................32 
5.1.15. 
Evaluation of Response ..............................................................................................32 
5.1.15.1. 
Evaluation of Primary Endpoints................................................................................32 
5.1.15.2. 
Evaluation of Secondary Endpoints............................................................................32 


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5.1.15.3. 
Exploratory endpoints .................................................................................................33 
5.1.15.4. 
Compliance Monitoring ..............................................................................................33 
5.1.15.5. 
Dispensing of RZL-012 Investigational Product ........................................................33 
5.1.15.6. 
Questioning of Study Subjects ....................................................................................33 
5.2. 
STUDY VISITS..........................................................................................................34 
5.2.1. 
Screening Procedures ..................................................................................................34 
5.2.2. 
Study Randomization ..................................................................................................34 
5.2.3. 
Study Treatment ..........................................................................................................35 
5.2.3.1. 
Treatment with RZL-012 Investigational Drug ..........................................................35 
5.2.4. 
Treatment with Placebo ..............................................................................................36 
5.2.5. 
Baseline Visit ..............................................................................................................36 
5.2.6. 
Subject Site Visits .......................................................................................................38 
5.2.7. 
Termination Visit ........................................................................................................38 
5.2.8. 
Unscheduled Visit .......................................................................................................38 
6. 
DESCRIPTION OF THE OPEN LABEL EXTENSION PHASE OF THE 
STUDY .......................................................................................................................39 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR 
INVESTIGATORS .....................................................................................................40 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT 
MEDICATIONS .........................................................................................................40 
7.2. 
SAFETY MEASUREMENTS....................................................................................40 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY............................................41 
7.4. 
PREMATURE STUDY TERMINATION .................................................................41 
7.5. 
DEVIATION FROM STUDY PROTOCOL..............................................................41 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS ................42 
8.1. 
DESCRIPTION OF RZL-012 ....................................................................................42 
8.2. 
FORMULATION, PACKAGING AND LABELING ...............................................42 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE .................................42 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND 
VEHICLE ...................................................................................................................42 
8.4.1. 
Dosage ........................................................................................................................42 
8.4.2. 
Administration and Instructions for Use .....................................................................43 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE ...............................................43 


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9. 
ADVERSE EVENTS..................................................................................................43 
9.1. 
ADVERSE EVENT DEFINITIONS ..........................................................................43 
9.1.1. 
Definition of AE .........................................................................................................43 
9.1.2. 
Definition of Serious Adverse Event ..........................................................................44 
9.1.3. 
Definition of Adverse Drug Reaction .........................................................................44 
9.2. 
ADVERSE EVENT GRADING ................................................................................44 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS .........................................45 
9.4. 
ADVERSE EVENT REPORTING AND MONITORING 
REQUIREMENTS .....................................................................................................45 
9.4.1. 
General ........................................................................................................................45 
9.4.2. 
SAE Reporting ............................................................................................................46 
10. 
STATISTICAL CONSIDERATIONS .......................................................................46 
10.1. 
STUDY DESIGN AND OBJECTIVE .......................................................................46 
10.2. 
STUDY ENDPOINTS ................................................................................................47 
10.2.1. 
Analysis of Efficacy for Primary Endpoint ................................................................47 
10.2.2. 
Analysis of Efficacy for key secondary Endpoint ......................................................48 
10.2.3. 
Analysis of other Secondary Endpoints ......................................................................48 
10.3. 
SAMPLE SIZE JUSTIFICATION .............................................................................49 
10.4. 
STATISTICAL ANALYSIS ......................................................................................49 
10.4.1. 
General ........................................................................................................................49 
10.4.2. 
Subject Disposition .....................................................................................................50 
10.4.3. 
Demographic and Baseline Characteristics ................................................................50 
10.4.4. 
Efficacy Analysis ........................................................................................................50 
10.4.5. 
Safety and Tolerability ...............................................................................................51 
10.5. 
HANDLING OF MISSING DATA ............................................................................51 
10.6. 
INTERIM ANALYSIS ...............................................................................................51 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE ............................................................................................................51 
11.1. 
DATA COLLECTION AND REPORTING ..............................................................51 
11.2. 
RECORD KEEPING ..................................................................................................52 
11.3. 
SOURCE DATA AND SOURCE DOCUMENTS ....................................................52 
11.4. 
STUDY MONITORING ............................................................................................52 


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11.5. 
CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION ...................53 
12. 
HUMAN SUBJECTS .................................................................................................54 
12.1. 
DECLARATION OF HELSINKI ..............................................................................54 
12.2. 
INFORMED CONSENT ............................................................................................54 
12.2.1. 
LIABILITY AND INSURANCE CONDITIONS ......................................................54 
13. 
REFERENCES ...........................................................................................................54 
APPENDIX I:  TRIAL SCHEDULE OF EVENTS ......................................................................56 
APPENDIX II: COMPARATIVE PAIN SCALE .........................................................................58 
APPENDIX III:  SF-36 QUALITY OF LIFE QUESTIONNAIRE ..............................................59 
 
LIST OF TABLES 
Table 1:  Summary of Clinical Trials Conducted by Raziel Therapeutics ....................................19 
Table 2:  Study Design ...................................................................................................................23 
Table 3: Injected volume and dosages of RZL-012 / Placebo according to lipoma size ...............35 
Table 4:  Subject Information and Timeframes for the Placebo controlled Phase of the 
study:...........................................................................................................................37 
Table 5:  Subject Information and Timeframes for the Open Label Extension Phase: .................37 
Table 6:  Dosing of RZ-012 in the Open Label Extension Phase ..................................................39 
Table 7:  RZL-012 Storage Conditions ..........................................................................................42 
Table 8:  Definition of Causality ...................................................................................................45 
 
LIST OF FIGURES 
Figure 1:  RZL-012/ Placebo Injection Sites in DD Subjects ........................................................36 
 
 


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


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


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


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PROTOCOL SYNOPSIS  
Protocol 
Number 
RZL-012-DD-P2bUS-001 
Protocol Title 
A Double Blind, Randomized, Multi-Center, Placebo-Controlled Phase 2B Clinical Trial for the 
Evaluation of Efficacy and Safety of RZL-012 in Subjects having Dercum’s Disease (DD) Lipomas. 
Study Phase 
Phase 2b 
Study Drug 
RZL-012 
Study 
Objectives 
Primary objective:  Evaluation of the efficacy of RZL-012 following injection into lipomas/nodules 
of Dercum’s Disease (DD) subjects. Efficacy will be determined by ultrasound assessment of the 
lipoma/nodule dimensions after treatment vs baseline.  
Secondary objective:  Assessment of lipoma/nodule associated pain using the Comparative Pain 
Scale. Safety will be assessed by frequency of adverse events and by change-from-baseline values for 
vital signs, clinical laboratoryand ECG. 
Exploratory objective: Improvement in Quality of Life – QOL questionnaire 
Study Design 
This is a double blind, multi-center, randomized, placebo-controlled clinical trial in DD subjects 
having lipomas. Subjects will be randomized in a 1:1 ratio into either the RZL-012 or the placebo 
arm. 
Once the study ends and codes are opened, 84 days after dosing, placebo-treated subjects will be 
offered the option of receiving treatment with RZL-012. Subjects who choose this will be followed 
up for an additional 84 days.  
At least 4 lipomas/nodules, preferably 6, and no more than 8, will be injected per subject. Dosing will 
be according to lipoma size, where the total injected dose will not exceed 240 mg per patient (48 
injections of 5mg/injection). 
Study 
Population 
Women and men, 18- 70 years old, diagnosed with DD having lipomas 
Main Inclusion 
Criteria 
 
Subjects must meet all the following to be eligible for study participation: 
1. Women and men, 18- 70 years old. 
2. At least 4 painful lipomas of appropriate size to be injected on a background of DD.   
3. Generally considered healthy according to medical history, physical examination, 
electrocardiogram (ECG) and laboratory evaluation with an emphasis on metabolic parameters 
(fasting glucose concentration < 200 mg/dL). 
4. Subjects must be able to adhere to the visit schedule and protocol requirements and be capable of 
completing the study. 
5. Males or females in the age of fertility are willing to refrain from sexual activity or agree to use a 
double-barrier contraceptive device (e.g., condom and spermicide) for 4 weeks after treatment 
with RZL-012. 
6. Subjects must sign an informed consent indicating they are aware of the investigational nature of 
the study. 


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Main Exclusion 
Criteria 
Subjects meeting any of the following criteria will be excluded: 
1. Unable to tolerate subcutaneous injections. 
2. Pregnant women. 
3. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that in the 
opinion of the investigator places the subject at significant risk.  
4. Positive blood screen for Hepatitis B surface antigen (HbSAg), Hepatitis C virus (HCV), or 
Human immunodeficiency virus (HIV). 
5. Subjects with a clinical history of active primary or secondary immunodeficiency, autoimmune 
disease or subjects taking immunosuppressive drugs such as corticosteroids  
6. Subjects with dysfunctional gallbladder activity, e.g. underwent cholecystectomy or 
cholecystitis. 
7. As a result of medical review and physical examination, the PI (or medically qualified nominee) 
considers the subject unfit for the study.  
8. Known sensitivity to components of the injection formulation.  
9. Prior wound, tattoo or infection in the treated area. 
10. Prior invasive treatment such as surgery or injectable drug at the RZL-012 injected area. 
11. Subjects treated chronically at least 3 months prior to study entry with systemic steroids or 
immunosuppressive drugs.  
12. Subjects treated chronically at least one week prior to study entry with Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs).  
13. Current participation or participation within 3 months prior to the start of this study in a drug or 
other investigational research study. 
Study Drug 
Dosage and 
Administration 
RZL-012 is a solution of 50 mg/ml RZL-012 in a vehicle comprised of water, propylene glycol and 
surfactant. Placebo is a solution comprised of vehicle only.  Each injection of RZL-012 and placebo 
contains 0.1 ml. 
Placebo-Controlled Phase: 
Subjects will be randomized to receive either RZL-012 or vehicle in a ratio of 1:1. Subjects will 
receive their study treatment on a single occasion. Dosing will be calculated according to lipoma size 
(diameter) as determined by ultrasound: 
The table below presents the dosages according to lipoma size: 
 
 
 
 
 
 
 
The maximal total RZL-012 dose will be 240 mg per subject (a total of 48 injections at 
5mg/injection; 33% higher than the highest dose that was tested on humans and 100% the No 
Observed Adverse Effect level [NOAEL]. 
The injections will be spread randomly on the lipoma surface with a distance between injections of at 
least 1 cm. Injections will be given at 90° to the injected skin surface.  
Number of Subjects – 
Active/Placebo 
19/19 
Lipoma/Nodule size – 
diameter (cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Total Dose of RZL-012 
in the RZL group (mg) 
10 
20 
40 
50 
60 
Number of Injections  
2 
4 
8 
10 
12 


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Extension Phase: 
Placebo-treated subjects will be offered the option of receiving treatment with RZL-012 on a single 
occasion. Dosing will be calculated according to lipoma size (diameter) as determined by ultrasound 
and will follow the treatment regimen shown in the table above. 
Visit Schedule 
 
Subject site visits will be performed ± 1 day from scheduled date for Day 28 and Day 56 visit and ±2 
days from scheduled date for Day 84 visit.  All data relevant for the visits should be obtained within 
3 days (e.g., blood test results) of visit.  
Screening Day visit (Day -14 through -1): 
- 
Following signing of the informed consent - assessment of subject eligibility will include:  
medical history, physical examination, vital signs, women in fertile age will be asked for 
pregnancy test, ECG, serology assays (HBV, HCV and HIV), clinical laboratory tests. 
- 
Ultrasound assessing lipoma/nodules size (diameter) and quality to determine which 
lipomas/nodules are to be injected with a total dose of up to 240 mg RZL-012. 
- 
Photography of injection site areas. 
Clinical laboratory tests will include: 
1. Hematology:  Complete blood count (CBC) including White blood cell [WBC] differential 
values, D-dimer, Fibrinogen and coagulation (International normalized ratio [INR], Partial 
thromboplastin time [PTT] and Prothrombin time [PT]). 
2. Serum chemistry will include:   
Albumin, Albumin/Globulin Ratio (calculated), Alkaline Phosphatase, ALT, AST, BUN/Creatinine 
Ratio (calculated), Calcium, Carbon Dioxide, Chloride, Creatinine with GFR Estimated, Globulin 
(calculated), Glucose, Potassium, Sodium, Total Bilirubin, Total Protein, Urea Nitrogen. In addition, 
Amylase, Lactate dehydrogenase [LDH], Creatine-kinase MM [CK-MB], Creatine phosphokinase 
[CPK], Gamma-glutamyl transferase [GGT], Alkaline phosphatase [ALP]) and C-reactive protein 
[CRP] will be tested.  
 
3.    Lipid profile: Total Cholesterol (TC), High Density Lipoprotein (HDL), Low Density 
Lipoprotein (LDL), Triglycerides (TG) and Fasting glucose. 
4. Urinalysis: Protein, Red blood cells (RBC), WBC, Blood, Glucose, Ketone bodies, 
Bilirubin, Urine specific gravity, pH. 
Baseline visit (Day 0):  
- 
Pre-treatment: eligibility confirmation, vital signs, pregnancy test women, Draize score, 
clinical evaluation of local pain and tenderness to pressure (pain assessment) and lipoma/ 
nodules size assessment by ultrasound*, photography, QOL questionnaire  


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- 
Treatment - All injections will be administered 90° to the injected skin surface using a 1 mL 
Luer-lock syringe and a 30 G x 1/2" needle (the hole of the needle pointing into the fat 
layer). 
- 
Post treatment: vital signs (2h ± 30 min post injection). evaluation of skin irritancy by 
Draize score (2h post injection ± 30 min), adverse events (AEs) will be recorded. 
*In case of screening visit that will be conducted only one day before Baseline, ultrasound 
and photographs  at Baseline visit are optional. The ultrasound parameters collected at 
screening will be used at Baseline visit.  
Schedule visits (Day 1-56): 
- 
Day 1 following treatment will include: ECG, vital signs including pulse rate, Draize score, 
clinical laboratory tests, urinalysis, lipid profile, AEs record. Subjects will start applying an 
anti-histamine gel. 
- 
Day 7± 1d from treatment: Phone call for follow up. 
- 
Day 28± 2d from treatment: ECG, physical exam, vital signs, clinical laboratory tests, 
urinalysis, Draize score, lipoma/nodule size assessment by ultrasound, clinical evaluation of 
local pain and tenderness to pressure, photographs, AEs record  
- 
Day 56± 2d from treatment: physical examination, vital signs, Draize score, lipoma/nodule 
size assessment by ultrasound, clinical evaluation of local pain and tenderness to pressure, 
photographs, AEs record. 
- 
Day 84± 2d from treatment: 
Draize score, photographs, assessment of lipomas/nodules size using US, clinical evaluation 
of local pain and tenderness to pressure, QOL questionnaire, AEs record. 
 
In case a specific subject demonstrates elevated levels in one or more of the tested parameters, this 
subject will be followed up on day 56 to confirm return to normal levels. 
 
Open Label Extension Phase: 
Following the opening of the randomization codes, placebo subjects will be offered the option of 
receiving treatment with RZL-012. Subjects who choose this will be followed up for an additional 84 
days for efficacy and safety as described below:  
The physician will set up a date for injection with RZL-012 within 30 days of codes opening. This 
will be the baseline visit, Day 0. The following procedures will take place on Day 0 visit: 
Day 0- Physical exam, Clinical laboratory tests (hematology, chemistry) lipid profile and urinalysis, 
ECG, injection with RZL-012, concomitant medication, vital signs – before and after the injection, 
ultrasound measurement of the lipomas, photography of the lipomas, QOL questionnaire, Draize 
score – before and after injection, pain score and AEs documentation.  
Following RZL-012 injection, subjects will have the following visits: 
Day 1 – ECG, vital signs, Draize score, clinical laboratory tests including urinalysis and lipid profile, 
AEs record. 
Day 7 – Phone call visit. The study coordinator/nurse will call the subjects to ask about adverse 
events and general health. 
Day 28±2 – ECG, physical exam, vital signs, clinical laboratory tests, urinalysis, Draize score, 
ultrasound measurement of the lipomas, photography of the lipomas, pain score and AEs 
documentation. 
Day 56±2 - Physical exam, vital signs, ultrasound measurement of the lipomas, photography of the 
lipomas, Draize score, pain score and AEs documentation.  
Day 84±2 - Ultrasound measurement of the lipomas, photography of the lipomas, QOL 
questionnaire, Draize score pain score, QOL questionnaire and AEs documentation.  


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Study 
Endpoints 
Placebo – Controlled Phase 
Primary Endpoint: 
Average percent reduction in lipoma/nodule height on day 84 after injection vs baseline- evaluated 
by ultrasound in the RZL treatment group compared to the placebo group. 
Key secondary Endpoint: 
Reduction in local pain score per lipoma/nodule on Day 84 vs baseline as measured by the 
comparative Pain Scale 
Other secondary endpoints: 
1. Evaluation of RZL-012 injection safety and tolerability in DD subjects.  
2. Ultrasound evaluated percent lipomas/nodules with height reduction of at least 75% on Day 84 
vs baseline in the RZL treatment group compared to the placebo group 
Exploratory Endpoint 
3. Improvement in Quality of Life – QOL questionnaire  
 
Open Label Extension Phase: 
Primary end point: 
Average percent reduction in lipoma/nodule height on day 84 after injection vs baseline 
Secondary end points: 
1. Reduction in local pain score per lipoma/nodule on Day 84 vs baseline as measured by 
comparative pain scale. 
2. Evaluation of RZL-012 injection safety and tolerability 
3. Improvement in Quality of life – QOL questionnaire 
Sample Size 
This study is a Phase 2b trial. A total of 38 evaluable DD subjects from 3-4 centers will be included 
in the study (19 will be injected with RZL-012 and 19 will receive placebo). Subjects will be 
followed up for 84 days after injection. 
Once the study ends and codes are opened, the 19 placebo-treated subjects will be offered the option 
of receiving treatment with RZL-012. Subjects who choose this will be followed up for an additional 
84 days.  
The statistical considerations described below relate to the placebo-controlled phase of the study. 
Based on primary endpoint: 
Subjects will be randomized into two groups in a 1:1 ratio. 
The rationale for sample size calculation was based on data from Raziel’s open label phase 2a study 
(Study #RZL-012-FD-P2aUS-001) in which a reduction in lipoma/nodule height of about 55% was 
demonstrated in the treatment group. This phase 2a study did not include a placebo group but studies 
reported by other groups show an average reduction from baseline in lipoma/nodule height of about 
7% in the placebo group. Taking these numbers into consideration an effect size of 0.96 is expected 
(effect size = expected effect size in treated (0.55) – expected effects size in placebo group 
(0.07)/expected standard deviation (0.5)).  
Sample size justification: 
A sample size of 19 in each group (total sample size of 38) will have 80% power to detect a 
difference in means of 48 (the difference between a Group 1 mean, 1, of 55 and a Group 2 mean, 
2, of 7) assuming that the common standard deviation is 50 using a two-group t-test with a 0.05 
two-sided significance level. 
Based on key secondary endpoint: 
Subjects will be randomized into two groups with a 1:1 ratio. 
The rationale for sample size calculation was based on data from our open label phase 2a study 
(Study #RZL-012-FD-P2aUS-001) in which reduction in lipoma/nodule pain score of about 76% was 
demonstrated in the treatment group. Our phase 2a study did not include a placebo group but pain 
studies reported by other groups, show a range of reduction in pain score from +10% - -60% in the 


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Version: 1.4 
 
 
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placebo group. Based on Geography, study size and length we selected an expected reduction from 
baseline of 25% in lipoma pain in our placebo group. Taking these numbers into consideration we 
expect an effect size of 1.02 (effect size = expected effect size in treated (0.76) – expected effects 
size in placebo group (0.25)/expected standard deviation (0.5)).  
Sample size justification: 
A sample size of about 19 in each group (total sample size of 38) will have 80% power to detect a 
difference in means of 51 (the difference between a Group 1 mean, 1, of 76 and a Group 2 mean, 
2, of 25) assuming that the common standard deviation is 50 using a two-group t-test with a 0.05 
two-sided significance level. 
Statistical 
Methods 
Descriptive Statistics: 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics.  
For categorical variables summary tables will be provided giving sample size, absolute and relative 
frequency and 95% CI (Confidence Interval) for proportions by study group. 
For continuous variables summary tables will be provided giving sample size, arithmetic mean, 
standard deviation, coefficient of variation (CV%), median, minimum and maximum and 95% CI 
(Confidence Interval) for means of variables by study group.  
All tests will be two-tailed, and a p value of 5% or less will be considered statistically significant. 
The data will be analyzed using the SAS ® version 9.4 (SAS Institute, Cary North Carolina). 
 
Analysis of Efficacy for Primary Endpoint 
• 
Analysis per patient (based on 4-8 lipomas/nodules per patient) 
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 
between study groups in percent reduction of lipoma/nodule height at day 84 after injection vs. 
baseline. 
Analysis of covariance (ANCOVA) model will be applied in order to identify covariate parameters 
suspected as related to reduction in lipoma/nodule height and in order to test the differences in 
percent reduction of lipoma/nodules height between the treatment groups adjusted to the above 
covariates. 
• 
Analysis per lipoma/nodule (based on 4-8 lipomas/nodules per patient) 
The MMRM model (Mixed-effect model for repeated measures) will be applied for analyzing the 
difference between the groups in percent reduction of lipoma/nodule height from baseline to day 84, 
and adjusted for the above covariates as appropriate
 
Analysis of Efficacy for key secondary Endpoint 
• 
Analysis per patient (based on 4-8 lipomas/nodules per patient) 
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 
between study groups in percent reduction of lipoma/nodule pain at day 84 after injection vs. 
baseline. 
Analysis of covariance (ANCOVA) model will be applied in order to identify covariate parameters 
suspected as related to reduction in lipoma/nodule pain and in order to test the differences in percent 
reduction of lipoma/nodules pain between the treatment groups adjusted to the above covariates. 
• 
Analysis per lipoma/nodule (based on 4-8 lipomas/nodules per patient) 
The MMRM model (Mixed-effect model for repeated measures) will be applied for analyzing the 
difference between the groups in percent reduction in local pain score at day 84 vs. baseline between 
the study groups adjusted for the above covariates as appropriate. 


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Analysis of other Secondary Endpoints  
1. Analysis of Safety  
Safety data from the study will be summarized descriptively by treatment.  The incidence of AEs will 
be presented by treatment.  
Descriptive statistics will be calculated for quantitative data and frequency counts and percentages 
will be provided for categorical data.  The nature, frequency, seriousness, severity and relation to 
study drug of AEs will be tabulated for all subjects combined and by treatment.   
Change-from-baseline values for vital signs, clinical laboratory and ECG will be summarized.  
Draize scores will be presented in tabular format by visit and treatment. Serious adverse events 
(SAEs) will be described in narratives as part of the study report. 
2. Analysis of Efficacy 
Clearance of nodules: (Analysis per Lipoma based on 4-8 lipomas per patient): 
95% Confidence Interval (CI) will be calculated for the proportion of responding nodules (response 
will be defined as achieving a reduction in lipoma height of at least 75% vs. baseline) by study 
groups. 
GEE (Generalized Estimating Equations) model will be applied for testing the statistical significance 
of the difference in percent of responding nodules (nodules with at least 75% clearance at day 84 vs. 
baseline) between the study groups, with adjustment to suspected confounders. 
Study Duration 
Study duration for each patient will be 3.5 months, including enrollment, treatment and follow-up 
period. 
Each subject will participate in the study for up to 98 days as part of this protocol. 
Placebo subjects who continue to the open label extension part may participate for an additional 84 
days. 
Study Sites 
4 
 


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1. 
INTRODUCTION 
1.1. 
BACKGROUND 
1.1.1. Scientific Background and Clinical Rationale 
Dercum’s disease (DD) was first described in 1888 by American neurologist Francis Xavier 
Dercum. It is a rare adipose disorder (RAD) and is typically characterized by obesity and chronic 
pain (> 3 months) in the subcutaneous adipose tissue (SAT). The pain associated with DD is 
often debilitating and resistant to typical analgesic treatments. In addition, there are a large 
number of associated symptoms such as fatty deposits (lipomas), easy bruising, sleep 
disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, 
shortness of breath, diabetes, bloating, constipation, fatigue, and joint pain (1). 
DD can be classified into 4 types which include: generalized diffuse, generalized nodular, 
localized nodular, and juxta-articular forms.  The diffuse type is characterized by widespread 
pain from SATs located anywhere from the head to the soles of the feet, without any clear 
lipomas.  Generalized nodular typically occurs with widespread, painful adipose tissue that is 
more painful in the vicinity of lipomas, whereas in the localized nodular type, the pain is 
confined to areas within and around lipomas. Finally, the juxta-articular type is characterized by 
painful folds or nodular fat around joints such as the knees and/or the hips (2). There are 
Dercum’s subjects who have mixed lipomas, i.e. small and large lipomas. 
The etiology of DD is currently unknown.  Several hypotheses have been proposed 
including nervous system dysfunction (3), adipose tissue dysfunction (4), lymphovascular 
disorder, endocrine dysfunction, mechanical pressure on nerves, and a result of trauma (5). 
Interestingly, there are a few reports that suggest that DD can be an inherited autosomal 
dominant disorder with variable expression, however the majority of cases occur sporadically 
without any specific genetic mutations (2).   
The actual prevalence of DD in the USA and around the world has not yet been established.  The 
disease mostly appears between the ages of 35 and 50 years and is six times more common in 
women than in men (6,7).  Recently, an estimation of 3 Key Opinion Leaders (KOLs) in the US, 
estimated that the prevalence of the disease varies between 1,500–115,000 people (8-10).  
No specific treatment exists for DD. Treatment is mainly symptomatic and supportive and is 
primarily focused on easing the characteristic painful episodes. Various analgesics have been 
tried with limited effectiveness (i.e., lidocaine) (11,12). Surgical excision of lipomas may 
temporarily relieve symptoms although recurrences often develop. Liposuction has been used as 
a supportive treatment for some individuals with DD and may provide an initial reduction in pain 
and improvement in quality of life (QOL) (13,14). These effects may lessen over time. 
Psychotherapy and consultation with pain management specialists may be helpful for enabling 
affected individuals to cope with long-term intense pain. 


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Raziel Therapeutics has discovered that a novel synthetic molecule (termed RZL-012) can help 
reduce fat content in human and pigs. Recent data has led Raziel to the understanding that the 
mechanism of action (MOA) of RZL-012 involves liponecrosis at the injection site, followed by 
a transient inflammatory response and finally by a healing process in which fibrotic tissue 
replaces previous fat tissue. Studies in pigs show that necrosis of fat tissue at the injection site is 
seen as early as 24 hours after injection and is still evident 2 weeks later but is completely 
cleared at 12 weeks post dosing. A macrophage-mediated inflammatory response was also very 
prominent at 24 hours and 14 days after injection with only minimal signs of inflammation 
remaining at 12 weeks post dosing. Fibrosis showed a different pattern compared with 
liponecrosis and inflammation - it started at 14 days post dosing and became much more 
prominent at 12 weeks post dosing. In essence, RZL-012 enables de-novo generation of fibrotic 
tissue to replace excess fat tissue at selected anatomical sites.   
Recently, RZL-012 was evaluated as a treatment for local fat reduction among obese and 
overweight subjects in two clinical studies and was evaluated for the treatment of fat disorders 
diseases such as DD and lipedema.   
In the initial exploratory clinical trial that was conducted (RZL-012-P0US-001.3 under IND 
119941) to test safety and thermogenesis-induction of RZL-012 in overweight and obese 
subjects, RZL-012 was found to be safe with mainly transient and local adverse events (AEs). A 
thermogenic effect (a rise of 1 °C in temperature at the injected site compared to the untreated 
collateral side) was evident in the RZL-012-treated subjects of the highest dose cohort 
(20 mg/subject). Moreover, MRI at 28 days after injection demonstrated that fat mass was 
reduced at the injection site compared to matched fat mass at the non-injected contralateral site, 
in RZL-012 but not in vehicle-treated subjects.  
In a Phase 2a study that was conducted in 32 overweight and obese subjects (RZL-012-P2aUS-
001.4 under IND 133324), the highest injected RZL-012 dose was 180 mg/subject. RZL-012 
demonstrated a dose dependent reduction in Subcutaneous Fat Mass (SFM) ratio at doses of 80 
mg/subject (8.6% ± 3.6% reduction), 120 mg/subject (10.5% ± 3.4% reduction) and 
180 mg/subject (18.1% ± 4.9% reduction) vs vehicle (3.6% ± 1.6% increase), 56 days following 
injection. The reduction of local fat mass was still evident 6 months following RZL-012 
injection. Safety and tolerability were good with only mild or moderate adverse events, mostly 
transient and localized to the injection site.  
An additional Phase 2a study (RZL-012-FD-P2aUS-001.7 under IND 135762) was conducted to 
evaluate the safety and pharmacodynamic response to RZL-012 in lipedema and DD subjects. 
Five (5) DD subjects had a 55% reduction in height of 18 injected lipomas. In addition, a 
significant reduction in lipoma pain was noted.  Safety and tolerability were good. The Adverse 
Events (AEs) that were categorized as definitely related to the study drug were transient and 
localized to the injection site. 


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Based on the above, Raziel concludes that the safety profile of RZL-012 is good and acceptable 
and the compound is efficacious in long-term reduction of local subcutaneous fat mass (SFM). 
Thus, Raziel-012 will be further tested in a larger population of DD subjects and its efficacy will 
be compared to placebo treatment in a double-blind placebo-controlled trial. 
1.1.2. RZL-012 Formulation Development 
The active ingredient RZL-012 drug substance was manufactured by Pharmacore, High Point 
NC, USA. The drug product, 5 % RZL-012 in F12 liquid formulation (250 mg RZL/5 mL vial = 
50 mg RZL/mL), was manufactured and packaged at Nextar Ltd, Ness-Ziona, Israel.  RZL-012 
in F12, which was once defined as RZL-012 F12, is now defined as RZL-012.  The active 
ingredient and formulation manufacturing and packing were in accordance with clinical Good 
Manufacturing Practices (cGMPs). 
1.2. 
CLINICAL STUDIES CONDUCTED BY RAZIEL 
RZL-012 has been tested in 3 clinical trials, having a total of 54 exposed subjects at single doses 
of up to 180 mg/subject. Table 1 describes the clinical trials conducted by Raziel Therapeutics. 
Table 1:  Summary of Clinical Trials Conducted by Raziel Therapeutics  
Study ID 
STATUS 
Phase 
Country 
Study Title 
Study Design 
Dosing Regimen 
Study Population 
RZL-012-P0US-
001.3 
 
 
COMPLETED 
 
0 
USA 
Phase 0 Study for 
evaluation of safety and 
thermogenesis in 
Overweight Healthy 
Volunteers injected 
with 3 escalating Doses 
of RZL-012 
A randomized, 
double-blind, 
vehicle-controlled, 
dose-escalation 
study with 8 
subjects/cohort, 
(6  active and 
2 controls) 
Cohort 1: 5 mg 
Cohort 2: 10 mg 
Cohort 3: 20 mg 
 
Healthy, 20-40 year old, 
overweight by Body 
Mass Index (BMI) 
definition (25 < BMI 
≤ 34.9), adult males.  
 
RZL-012-P2aUS-
001.4 
 
 
COMPLETED 
 
2A 
(obese) 
USA 
A Double Blind, 
Randomized, Placebo 
Controlled, Dose 
Escalation Phase 2a 
Clinical Trial for the 
Evaluation of Safety 
and Thermogenesis-
induction of RZL-012 
in Overweight and 
Obese Volunteers 
A randomized, 
double-blind, 
placebo-controlled, 
consecutive 4 
cohort, dose 
escalation clinical 
trial 
 
Cohort 1: 40 mg 
Cohort 2: 80 mg 
Cohort 3: 120 mg 
Cohort 4: 180 mg 
 
Adult male subjects 20–
60 years old, with 
27.5 < BMI ≤ 34.9 


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Study ID 
STATUS 
Phase 
Country 
Study Title 
Study Design 
Dosing Regimen 
Study Population 
RZL-012-FD-
P2aUS-001 
 
 
COMPLETED 
2A 
(DD 
and 
lipede
ma) 
USA 
An Open Label, Phase 
2a Clinical Trial for the 
Evaluation of Safety 
and Efficacy of RZL-
012 for the Treatment 
of Women with 
Lipedema Involving 
Substantial Fat above 
the Knee or of Women 
and Men with Nodular 
Dercum’s Disease 
Open-label safety 
and efficacy 
clinical trial  
Cohort 1 DD: up 
to 40 mg RZL-
012 per subject 
in 6 subjects 
Cohort 2 
Lipedema: up to 
80 mg RZL-012 
per subject in 6 
subjects 
DD :  men 20–65 years 
old and post-
menopausal (at least 
2 years) women <65 
years old with nodular 
Dercum’s disease 
Lipedema :  post-
menopausal (at least 
2 years) women 
<65 years old with 
lipedema involving 
substantial fat above the 
knee  
1.2.1. Overall Safety Summary: 
The majority of adverse events (AE)s after RZL-012 injection were related to local injection 
site reactions. There was no correlation between RZL-012 dose increase and severity or 
duration of local reaction. Most injection site reactions were transient and were not observed 
for more than 28 days following injection. There were no significant changes in blood 
parameter values except for 2 cases as reported in the 2 studies indicated for obesity. In study 
RZL-012-P0US-01.3 (Phase 0) there was one subject injected with 20 mg of RZL-012 who 
demonstrated a significant increase in liver enzymes. However, when these parameters were 
reviewed carefully among other subjects injected with higher doses of RZL-012 (up to 9 times 
i.e., 180 mg), this phenomenon was not repeated. In preclinical studies which were conducted 
by Raziel, a rise in aspartate aminotransferase (AST) enzyme levels was observed at high 
doses in female rats (20 mg/rat equivalent to a human dose >>500 mg/subject), getting back to 
normal levels within 14 days following injection. The relationship between RZL-012 injection 
and increased levels of liver enzymes in this subject is not completely understood. Raziel 
Therapeutics continues to monitor closely for any changes in liver enzymes.  
The second case was reported in RZL-012-P2aUS-01.4 study (Phase 2a in obese subjects). 
Subjects which were injected with the maximal dose of 180 mg had an average 3-fold increase 
of D-dimer values at Day 3 compared to Day -1. However, levels went down by Day 7.  
1.2.2. Efficacy summary: 
Measurements of lipoma size in 6 DD subjects who participated in study RZL-012-FD-
P2aUS-001, included ultrasound measurements of height, width and length for 21 injected 
lipomas. Each subject was dosed up to 40mg of RZL-012 that was injected into several 
lipomas. The mean reduction in lipomas height on day 56 after injection vs. baseline was 
47.9±44.1% (P<0.001).  


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Lipoma pain was measured by the comparative pain scale in 19 of 21 injected lipomas in 6 
DD pts (specific pain assessment per each lipoma). The mean reduction in lipoma pain on day 
56 after injection vs. baseline was 70.7±36.9% (P<0.0001).  
Further details are provided in the IB. 
The current clinical trial in DD subjects will have a single injection session of RZL-012 at doses 
up to 240 mg/subject, (up to 48 injections) and will be the first trial to assess efficacy of RZL-
012 vs. placebo in DD subjects. 
2. 
PURPOSE AND STUDY OBJECTIVES 
2.1. 
PURPOSE 
This is a double blind, randomized, multi-center, placebo controlled 2b clinical trial for the 
evaluation of efficacy and safety of RZL-012 in women or men having DD lipomas. 
2.2. 
STUDY OBJECTIVES 
The primary and secondary endpoints described below relates to the placebo-controlled study. 
2.2.1. Primary  
To evaluate the average percent reduction in lipoma/nodule height on day 84 after injection vs 
baseline- evaluated by ultrasound in the RZL treatment group compared to the placebo group. 
2.2.2. Secondary 
The secondary objectives are to evaluate the efficacy and safety of RZL-012 subcutaneous 
injections in the lipomas vs. placebo by: 
- 
Evaluating the reduction in local pain score per lipoma/nodule on Day 84 vs baseline as 
measured by the comparative pain scale. This secondary endpoint will be a key endpoint.   
- 
Evaluating safety and tolerability of RZL-012 injection in DD subjects.  
- 
Evaluating percent lipomas/nodules with height reduction of at least 75% on Day 84 vs 
baseline as measured by ultrasound. 
2.2.3. Exploratory 
- 
Improvement in Quality of Life – using a QOL questionnaire 


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2.3. 
DESCRIPTION OF STUDY DESIGN 
This is a multi-center, randomized, double blind, placebo controlled clinical trial in DD subjects 
having lipomas. Subjects will be randomized, in a 1:1 ratio, into two groups injected with either 
RZL-012 or vehicle. 
Once the study ends and codes are opened, 84 days after dosing, placebo-treated subjects will be 
offered the option of receiving treatment with RZL-012 and followed up for an additional 84 
days. 
At least 4 lipomas/nodules, preferably 6, and no more than 8, will be injected per subject. Dosing 
will be according to lipoma size, where the total injected dose will not exceed 240 mg per patient 
(48 injections at 5mg/injection). 
2.4. 
DOSE RATIONALE 
In all previous completed clinical trials, the maximal RZL-012 dose per injection site was 5 mg, 
and a distance of 1-3 cm between injection points was maintained. The highest total overall 
RZL-012 dose tested to date was 180 mg, which is 75% of the NOAEL. No serious adverse 
events were associated with this dose per injection site, with the distance maintained between 
injection sites or with the maximal overall dose. 
In the current trial, a maximal dose of up to 240 mg (33% higher than the maximal dose tested in 
humans) will be injected per subject. This will allow injection of the desired number of lipomas 
per patient (4-8 lipomas).  
The dosage of RZL-012 per each lipoma was set according to its size (diameter), as determined 
by ultrasound, and is higher than dosage per lipoma in the previous study. This alteration was 
made to enhance efficacy of RZL-012. Injections will be comprised of 5 mg each, and will be 
spread randomly on lipoma surface with a distance between injections of at least 1 cm.  A 
distance of 1 cm will allow a good distribution RZL-012 into lipoma fat.  
2.5. 
DOSING 
2.5.1. Dosing Regimen 
All subjects will receive a single treatment of RZL-012 or placebo in multiple injection sites 
according to lipomas size, as shown in Table 2 below. 
All subjects assigned to the RZL-012 treatment group will be dosed at a maximal dose of 240 mg 
RZL-012. Dosing will be calculated according to lipoma size (diameter) as determined by 
ultrasound in a dose of 5mg per in a volume of 0.1ml. Placebo treated subjects will be dosed with 
the same vehicle volume as calculated for the RZL-012 group. 


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Table 2:  Study Design 
 
 
 
 
 
 
Injections will be given perpendicular (90°) to injected skin surface and will be spread randomly, 
at least 1cm apart. 
Dosing of subjects in Open Label Extension Phase: 
Dosing will be calculated according to lipoma size (diameter) as determined by ultrasound and 
will follow the treatment regimen as shown in Table 2.  
3. 
STUDY ENDPOINTS 
The primary and secondary endpoints described below relates to the placebo-controlled phase of 
the study: 
3.1. 
PRIMARY ENDPOINTS 
The primary endpoint for this trial is the average percent reduction in lipoma/nodule height on 
day 84 after injection vs baseline, in the RZL treated group as compared to the placebo treated 
group. Lipoma height will be assessed by ultrasound. 
A total of 38 subjects will be randomized to receive active treatment or placebo (1:1) at 4 clinical 
sites. Subjects will be dosed according to size/diameter of selected lipomas with a dose of up to 
240 mg RZL-012/patient in the RZL-012 group or up to 4.8mL vehicle/patient in the placebo 
group.  
Number of Subjects – 
Active/Placebo 
19/19 
Dose of RZL-012(mg)/vehicle 
(mL) per single injection 
5mg/0.1mL 
Lipoma/Nodule size – diameter 
(cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Total Dose of RZL-012 in the RZL 
group (mg) 
10 
20 
40 
50 
60 
Number of Injections  
2 
4 
8 
10 
12 


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3.2. 
KEY SECONDARY ENDPOINT: 
The key secondary endpoint for this trial is the average percent reduction in lipoma/nodule pain 
on day 84 after injection vs baseline, in the RZL-treated group as compared to the placebo-
treated group. Lipoma pain will be assessed by the Comparative Pain Scale. 
3.3. 
OTHER SECONDARY ENDPOINTS 
1. Safety and tolerability of RZL-012 dosing to DD subjects vs. placebo dosed subjects.  
2. Percent responding lipomas/nodules (a responding lipoma is defined as having more than 
75% height reduction on day 84 after injection vs baseline), in the RZL treated group as 
compared to the placebo treated group. 
3.4. 
EXPLORATORY END POINTS 
Assessment of Improvement in Quality of Life using QOL questionnaire following treatment.  
3.5. 
OPEN LABEL EXTENSION PHASE ENDPOINTS:  
3.5.1. Primary end point: 
Average percent reduction in lipoma/nodule height on day 84 after injection vs baseline 
3.5.2. Secondary end points: 
1. Reduction in local pain score per lipoma/nodule on Day 84 vs baseline as measured by 
comparative pain scale. 
2. Evaluation of RZL-012 injection safety and tolerability 
3. Improvement in Quality of life – QOL questionnaire 
4. 
STUDY POPULATION 
4.1. 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria will be eligible for study participation: 
1. Women and men, 18- 70 years old. 
2. At least 4 painful lipomas of appropriate size to be injected on a background of DD.   
3. Generally considered healthy according to medical history, physical examination, 
electrocardiogram (ECG) and laboratory evaluation with an emphasis on metabolic 
parameters (fasting glucose concentration < 200 mg/dL). 


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4. Subjects must be able to adhere to the visit schedule and protocol requirements and be 
capable of completing the study. 
5. Males or females in the age of fertility are willing to refrain from sexual activity or agree 
to use a double-barrier contraceptive device (e.g., condom and spermicide) for 4 weeks 
after treatment with RZL-012. 
6. Subjects must sign an informed consent indicating they are aware of the investigational 
nature of the study. 
4.2. 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded: 
1. Unable to tolerate subcutaneous injections. 
2. Pregnant women. 
3. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that 
in the opinion of the investigator places the subject at significant risk.  
4. Positive blood screen for Hepatitis B surface antigen (HbSAg), Hepatitis C virus (HCV), 
or Human immunodeficiency virus (HIV). 
5. Subjects with a clinical history of active primary or secondary immunodeficiency, 
autoimmune disease or subjects taking immunosuppressive drugs such as corticosteroids.  
6. Subjects with dysfunctional gallbladder activity, e.g. underwent cholecystectomy or 
cholecystitis. 
7. As a result of medical review and physical examination, the PI (or medically qualified 
nominee) considers the subject unfit for the study. 
8. Known sensitivity to components of the injection formulation.  
9. Prior wound, tattoo or infection in the treated area. 
10. Prior invasive treatment such as surgery or injectable drug at the RZL-012 injected area. 
11. Subjects treated chronically at least 3 months prior to study entry with systemic steroids 
or immunosuppressive drugs. 
12. Subjects treated chronically at least one week prior to study entry with Non-Steroidal 
Anti-Inflammatory Drugs (NSAIDs). 
13. Current participation or participation within 3 months prior to the start of this study in a 
drug or other investigational research study. 
4.3. 
SUBJECT IDENTIFICATION 
At each site, a unique code number will be assigned by the investigator to the trial subject rather 
than the subjects’ names, personal identification numbers, and/or addresses to protect the 
subject's identity. The code numbers will be used in lieu of the subject's name when the 
investigator reports AEs and/or other trial related data. 


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4.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF STUDY 
SUBJECTS 
Study subjects withdrawing prior to injection (withdrawal between screening and baseline visits) 
will be replaced. Subjects withdrawing after injection on baseline visit will not be replaced and 
will be followed up as possible. Subjects experiencing serious side effects will be withdrawn 
from the study and followed up until the event resolves or becomes stable. 
5. 
STUDY PROCEDURES AND ASSESSMENT 
5.1. 
DEFINITIONS OF STUDY PROCEDURES 
5.1.1. Informed Consent 
Prior to initiation of any study procedures, each subject will undergo an Informed Consent 
process in which the subject voluntarily confirms their willingness to participate in the trial, after 
having been informed of all aspects of the trial relevant to their decision to participate. The 
investigator, or a person designated by the investigator, will fully inform the subject of all 
pertinent aspects of the trial. In addition, the investigator, or a person designated by the 
investigator, will inform the subject that he is free to refuse to enter the study or to withdraw 
from the study at any time, for any reason. 
The Informed Consent Form (ICF) approved by the IRB/EC will contain a description of the 
study’s purpose, procedures, inconveniences and potential risks, and anticipated benefits. 
Prior to a subject’s participation in the trial, an ICF will be signed and personally dated by the 
subject and by the person who conducted the Informed Consent discussion.  
If a subject is unable to read, he/she may not participate in the study. 
Prior to participation in the trial, the subject will receive a copy of the signed and dated written 
ICF. During participation in the trial, the subject will receive a copy of the signed and dated 
consent form updates. 
The investigator should document in the source data that the Informed Consent was signed prior 
to subject's participation in the study and according to the International Conference on 
Harmonization Good Clinical Practice (ICH-GCP) guidelines, as described above. 
5.1.2. Medical History 
Subjects' medical history should be fully documented at Screening Day (14 through 1 day prior 
to baseline), to ensure compliance with study inclusion criteria and the absence of circumstance 
mentioned in the exclusion criteria. Medical history information must include, but not be limited 


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to, past and present medical conditions, concomitant non-drug treatments and hypersensitivity to 
drugs. 
5.1.3. Concomitant Medication 
All concomitant medication given 1 month prior to study entry, including blood and blood 
products, dietary supplements, and non-prescription drugs will be listed at screening/baseline. 
Each entry will include the treatment's start date, treatment name (Generic), reason for use, 
dosing regimen (dose and frequency of use), route of administration, and stop date (if 
applicable). The clinical significance of the medication use will be decided by the investigator. 
Study subjects will be routinely questioned for changes in the administration of concomitant 
medication during the trial and changes should be updated from medical records as well. 
5.1.4. Physical Examination 
The investigator (or medically qualified nominee) will conduct a complete physical examination, 
height and weight measurements at Screening Day (performed 14 through 1 day prior to 
baseline).  Clinically significant abnormal findings except overweight and obesity should be 
discussed with the Sponsor. 
Additional physical examination to assess subject's safety will be performed on study visit on 
Day 28 and 56 following treatment. 
5.1.5. Pain Measurement  
Local lipoma pain, as determined by the Comparative Pain Scale, will be measured at Baseline 
visit prior to injection, in order to establish a baseline for comparison following drug injection. 
Subjects will complete a comparative pain scale score for each lipoma selected for injection. 
Additional pain measurements for the treated lipomas will be performed on study visit Days 28, 
56, and 84 after injection. 
A description of the comparative pain sale is presented in Appendix II. 
5.1.6. Quality of Life Assessment  
QOL will be measured in subjects at Baseline visit in order to establish a baseline for comparison 
after drug injection. For this purpose, the Short Form 36 questionnaire (See Appendix III) will be 
used to evaluate the improvement in the QOL of active vs. placebo group subjects.  
Additional assessment of QOL will be performed on the Day 84 visit.  


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5.1.7. Vital Signs Measurements 
Subjects' vital signs will be measured at Screening Day (performed 14 through 1 day prior to 
baseline) in order to ensure compliance with study inclusion criteria.  
Vital signs measurements will include systolic and diastolic sitting position blood pressure, pulse 
rate, respiratory rate, and body oral temperature.  
Additional vital signs measurements to assess subject's safety will be performed on baseline visit 
(Day 0) prior to drug injection, 2h ± 30min following drug injection, the following day (Day 1) 
after drug injection (24h ± 2h) and on study visits Day 28 and Day 56 following injection. 
5.1.8. Serology assay 
Assays for Hepatitis C virus (HCV), Hepatitis B Surface Antigen (HbSAg), and human 
immunodeficiency virus (HIV) will be conducted on Screening Day 1 (performed 14 through 1 
day prior to baseline) in order to ensure compliance with study inclusion criteria. 
5.1.9. Clinical Laboratory tests 
Clinical laboratory tests will be conducted on Screening Day (performed 14 through 1 days prior 
to baseline) in order to ensure compliance with study inclusion criteria.  Additional studies will 
be conducted on different study visits according to schedule as written below for each set of 
tests.  The maximum total blood volume will be 30 mL per visit.  Every out-of-range value will 
be assessed by a physician and deemed as either clinically significant or clinically not 
significant. Values that represent a change from baseline in subject’s medical status according to 
the laboratory normal ranges will be adequately documented as an AE as described in Section 8. 
5.1.9.1. 
Hematology 
Hematology tests will be conducted at Screening Day (performed 14 through 1 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  Additional Hematology 
testing will be conducted to assess subject's safety on study visit Day 1 and Day 28 following 
injection. 
Hematology tests will include Complete blood count (CBC) including White blood cell (WBC) 
differential values, D-dimer, Fibrinogen and coagulation (International normalized ratio (INR), 
Partial thromboplastin time (PTT) and Prothrombin time (PT)). 
In case a specific subject demonstrates elevated blood levels in one or more of the tested 
parameters, this subject will be followed up on day 56 to confirm return to normal levels. 
 


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5.1.9.2. 
Serum Chemistry Analysis 
Testing of blood chemistry values will be conducted on Screening Day (performed 14 through 1 
days prior to baseline) in order to ensure compliance with study inclusion criteria.   
Additional Serum Chemistry testing will be conducted on Day 0 (before injection), 24hr ± 2hr 
following injection and on study visit Day 1 and Day 28 following injection. 
Serum chemistry will include:   
Albumin, Albumin/Globulin Ratio (calculated), Alkaline Phosphatase, ALT, AST, 
BUN/Creatinine Ratio (calculated), Calcium, Carbon Dioxide, Chloride, Creatinine with GFR 
Estimated, Globulin (calculated), Glucose, Potassium, Sodium, Total Bilirubin, Total Protein, 
Urea Nitrogen. In addition, Amylase, Lactate dehydrogenase [LDH], Creatine-kinase MM [CK-
MB], Creatine phosphokinase [CPK], Gamma-glutamyl transferase [GGT], Alkaline 
phosphatase [ALP]) and C-reactive protein [CRP] will be tested.  
In case a specific subject demonstrates elevated blood levels in one or more of the tested 
parameters, this subject will be followed up on day 56 to confirm return to normal levels. 
5.1.9.3. 
Urinalysis 
Urinalysis will be conducted at Screening Day (performed 14 through 1 days prior to baseline) in 
order to ensure compliance with study inclusion criteria and to allow differential diagnosis in 
case of urinary tract associated AE.  Additional urinalysis testing will be conducted on study visit 
Day 1 and 28 following injection. 
Urinalysis will include: Protein, Red blood cells (RBC), WBC, Blood, Glucose, Ketone bodies, 
Bilirubin, Urine specific gravity and pH. 
In case a specific subject demonstrates elevated blood levels in one or more of the tested 
parameters, this subject will be followed up on day 56 to confirm return to normal levels. 
 
5.1.9.4. 
Lipid profile 
Lipid profile will be conducted on Screening Day (performed 14 through 1 days prior to 
baseline) in order to allow differential diagnosis in case of lipid circulation in blood following 
injection.  
Additional lipid profile testing will be conducted on Day 1 visit following injection. 


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Lipid profile will include: Total Cholesterol (TC), High Density Lipoprotein (HDL), Low 
Density Lipoprotein (LDL), Triglycerides (TG) and Fasting glucose. 
5.1.10. ECG 
Subjects' ECG will be performed on Screening Day (performed 14 through 1 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  ECG is to be performed on 
at least a triplicate of heartbeats for all measurements and will be recorded at a speed of 25 
mm/sec.  Additional ECGs will be performed at Day 1 and Day 28 visits following injection. 
Computerized ECG analysis will include:  Heart rate, Rhythm, PR interval, QRS axis, and QRS 
duration.  The corrected QT interval and QTc will be calculated manually according to the 
Frederica formula.  ECG will be recorded at a standard speed of 25 mm/sec and standard 
amplitude of 10 mm/mV. 
5.1.11. Draize Score 
Subjects' skin irritancy will be evaluated by Draize score. Draize score will be assessed for each 
selected lipoma for injection before treatment in order to establish a baseline for comparison 
following drug injection.  
 Additional skin irritancy evaluation to assess skin condition will be performed on baseline visit 
2h ± 30min following injection and on study visits Day 1, 28, 56 and 84 following injection.   
Skin irritancy observations at the injected sites will be scored using the Draize scale for scoring 
skin reaction: 
 
Erythema and eschar formation 
Edema formation 
No erythema 
0 
No edema 
0 
Very slight erythema (barely perceptible) 
1 
Very slight edema (barely perceptible) 
1 
Well defined erythema 
2 
Slight edema (edges are well defined by 
definite raising) 
2 
Moderate to severe erythema 
3 
Moderate edema (raised approximately 1mm) 
3 
Severe erythema (beet redness) to slight 
eschar formation (injuries in depth) 
4 
Severe edema (raised more than 1mm 
extending beyond area of exposure) 
4 
 
5.1.12. Photography of lipomas 
Documentation of the lipoma location and its skin condition in the injected area will be 
conducted at Screening Day (performed 14 through 1 days prior to baseline).  Additional 
photography will be performed at Baseline visit pre injection, Day 28, Day 56 and Day 84 visit. 
 


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Photography with a digital camera will include: 
a. A picture from above – will be taken perpendicular to lipoma top at a minimum 
distance of 5 cm or less and the distance noted and repeated throughout the study 
b. A side picture – will be taken parallel to lipoma to at a minimum distance of 5 cm 
or less and the distance noted and repeated throughout the study. 
5.1.13. Imaging: Ultrasound (US) 
Evaluation of Ultrasound will be conducted at Screening (performed 14 through 1 days prior to 
baseline) to ensure compliance with study inclusion criteria and establishing a baseline. Nodule 
size and tissue characteristics will be documented. Additional US will be performed on Day 0. In 
case of screening visit that will be conducted only one day before Baseline, ultrasound and 
photographs at Baseline visit are optional. The ultrasound parameters and phots collected at 
screening will be used at Baseline visit. In case the study personnel decide to inject different 
lipomas than those that were chosen at the screening visit, then ultrasound evaluation is 
mandatory on Day 0 . Additional US measurements for the injected lipomas will be done at Days 
28, 56 and 84 visits and the change in dimensions will be compared to the recorded dimensions 
at baseline.  
Ultrasound imaging will be conducted on Day 0 (before injection) in order to ensure proper dose 
injection according to measured nodule size/diameter. In case of screening visit that will be 
conducted only one day before Baseline, ultrasound and photographs at Baseline visit are 
optional. The ultrasound parameters collected at screening will be used at Baseline visit. 
Assessment of nodular size will be by diameter (mm) and surface (mm2) in three dimensions as 
illustrated below: 
- 
Height 
- 
Width 
- 
Length 
- 
 


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5.1.14. Adverse Events  
The information obtained during periodic subject questioning, review of subject’s compliance 
record, physical examinations, vital signs measurements, blood testing, and by any other means 
will be evaluated in light of baseline medical data and thus provide the basis for adverse events 
identification and grading.  
Thirty-eight (38) subjects (19 active and 19 placebo) will be injected with a dose of up to 240 
mg/subject in the RZL-012 group or with up to 4.8 mL of vehicle in the placebo group. 
The AEs reported during the trial will be graded (see Section 9), documented, and assessed in 
light of their clinical significance and relation to investigational product. In addition, the 
following information regarding the AE must be obtained: AE description, start date, end date (if 
applicable) or ongoing, severity, seriousness, relationship to study drug, outcome (e.g., resolved / 
unresolved), and action taken (e.g., concomitant medication). The sponsor or the sponsor 
representative will provide information regarding serious adverse event (SAE) expectedness 
based on data included in the IB. AE monitoring will be conducted throughout subject’s 
participation up to 84 days after injection. 
5.1.15. Evaluation of Response 
Evaluation of response will be conducted on Days 28, 56, and 84 following injection. 
5.1.15.1. Evaluation of Primary Endpoints 
5.1.15.1.1. Ultrasound to assess lipoma/nodule dimension after treatment 
Local fat reduction will be evaluated by ultrasound. Local fat reduction is defined as the 
reduction in nodule height at the injected area as compared to baseline and as a function of 
treatment (active/placebo). Ultrasound of the injected lipomas/nodules will be conducted at 
baseline and on Days 28, 56 and 84 following treatment. 
5.1.15.2. Evaluation of Secondary Endpoints 
5.1.15.2.1. Pain – A key secondary endpoint  
Improvement in local pain will be assessed by pain scoring of each lipoma/nodule on study Days 
28, 56 and 84 following injection and comparing to baseline assessments. This evaluation will be 
done using the comparative pain scale. 
5.1.15.2.2. Safety monitoring 
Safety and tolerability will be assessed, according to definitions and guidelines, by the medical 
staff (e.g., PI, site coordinator, and study nurse) and the study subjects:  


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1. AEs and SAEs, including severity, relation to study treatment and classification by 
whether or not these events comprise intolerable side effects. 
2. Physical exams, Draize score and vital signs measurements. 
3. Urine testing. 
4. Blood laboratory testing for changes in hematology and chemistry values. 
5. Lipid profile. 
6. ECG. 
Subjects questioning - full medical history during screening, routine AE reporting and 
tolerability monitoring.  
5.1.15.3. Exploratory endpoints 
5.1.15.3.1. Improvement in QOL 
QOL of RZL-012 treated vs. placebo subjects will be assessed 84 Days vs. baseline visit in order 
to compare whether there is an improvement in subject’s QOL as a function of treatment. 
5.1.15.4. Compliance Monitoring 
Compliance monitoring will include the following procedures:  
• Compliance assessment by site coordinator at the study visit, including but not limited to 
subject questioning. 
5.1.15.5. Dispensing of RZL-012 Investigational Product 
The RZL-012 investigational product will be dispensed to the study site under monitored 
conditions by Nextar Ltd. All procedures connected to investigational product's allocation (kits 
received at site, returned kits) will be properly documented, dated and signed in a designated site 
folder to allow full product tracking. Source documents will be kept for the duration required by 
local regulations and ICH-GCP (whichever is longer). 
5.1.15.6. Questioning of Study Subjects 
Questioning of study subjects during site visits and any unscheduled conversations (e.g., by 
phone) with site staff will be fully documented in subject file. Whenever possible, subject 
questioning should include, but not be limited to, inquiring information regarding occurrence and 
severity of AEs, treatment tolerability and compliance to future scheduled procedures and visits. 


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5.2. 
STUDY VISITS 
Study visits will be fully documented in the CRF as described in Section 11. Documentation will 
be completed in a timely manner and within 5 working days to ensure protocol adherence and 
compliance with ICH-GCP. 
5.2.1. Screening Procedures 
All information collected and documented during screening procedures will be reviewed to 
ensure eligibility in reference to study inclusion and exclusion criteria, and fully documented in 
subject file. 
Screening visit should be performed 14 days ahead and no later than 1 day prior to baseline visit.  
Study Screening Day procedures will include the following:  
• Informed Consent - Section 5.1.1 
• Medical History - Section 5.1.2 
• Concomitant Medication - Section 5.1.3 
• Physical Examination - Section 5.1.4 
• Vital signs Measurement –Section 5.1.7 
• ECG – Section 5.1.10 
• Serology – 5.1.8 
• Clinical laboratory tests – Section Error! Reference source not found. 
• Photography of injected lipomas – Section Error! Reference source not found. 
• Ultrasound to measure lipoma/nodule dimensions - Section 5.1.13 
Subjects may be rescreened if they were screened and did not completed their blood and urine 
tests and not dosed within 14 days. The following procedures will be performed: Clinical 
Laboratory Tests (hematology, serum chemistry, and urinalysis), vital signs, Draize score and 
photography. 
5.2.2. Study Randomization 
Subjects will be randomized to each study group, i.e., investigational therapy or control, 
according to a predefined randomization scheme in a ratio of 1:1 (active:placebo) among the 
4 clinical sites. The investigational therapy group will be treated with RZL-012 and the control 
group will be treated with the same formulation (vehicle) as with RZL-012, absent active 
medication. 


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Assignment to study group will be disclosed only after subject eligibility is confirmed and 
immediately before treatment initiation. The investigator and the clinical staff will be masked to 
the treatment. The subjects will also be blinded and will not know whether he or she is injected 
with active or placebo treatment. 
5.2.3. Study Treatment 
5.2.3.1. 
Treatment with RZL-012 Investigational Drug  
RZL-012 or vehicle will be supplied as a single vial for a single treatment session per subject. Up 
to 48 injections will be dosed to 4-8 lipomas per each subject. 
Overall dose, dosing regimen and injection technique is crucial for safety of study participants. 
Syringes will be filled with the desired volume for injection of RZL-012 or vehicle. All 
injections will be administered at 90° to injected skin, using a 1 mL Luer-lock syringe and a 30 
G x 1/2" needle.  
The hole of the needle should be pointing into the fat layer. An attempt to pull the plunger should 
be made before injecting to ensure that no blood is coming out. If so, the plunger should be 
pushed down to inject the medicine. The formulation is viscous and therefore resistance is 
expected while injecting. 
The injected volume will be calculated according to lipoma size (Table 3): 
Table 3: Injected volume and dosages of RZL-012 / Placebo according to lipoma size 
 
 
 
 
 
 
Number of Subjects – 
Active/Placebo 
19/19 
Lipoma/Nodule size – diameter 
(cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Total Dose of RZL-012 in the RZL 
group (mg) 
10 
20 
40 
50 
60 
Number of Injections  
2 
4 
8 
10 
12 


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Injections will be given perpendicular (90°) to injected skin surface towards the center of the 
nodule and the distance between injections in a nodule will be at least 1 cm (Figure 1). The 
dosing will be done in gradual injections of each 0.1mL into the tissue. 
Figure 1:  RZL-012/ Placebo Injection Sites in DD Subjects 
 
 
 
 
 
 
 
Each RZL-012 kit contains 1 vial (250 mg/5 mL) enabling injection of the maximal dose per 
subject, 240mg. RZL-012 or vehicle will be injected on study Day 0 visit (baseline). 
After completing injections of lipomas, an ice/cold pack will be applied onto the injection sites 
for immediate pain relief and will be held by the subject for at least 2 minutes. Following 
completion of injection procedures, subjects will remain in the clinic for an additional 2 hours 
±30min for medical supervision and in order to follow adverse events after injection. During the 
stay in the clinic there are no restrictions in terms of activity or diet. 
5.2.4. Treatment with Placebo 
Nineteen (19) subjects randomly assigned to the study will be injected with placebo, which will 
be a vehicle control (tween-80, propylene glycol, benzyl alcohol and water) in the same manner 
as mentioned above (Section 5.2.3.1).  
5.2.5. Baseline Visit 
Baseline visit on day 0 will be performed to complete screening evaluation, and to review all 
procedures necessary to confirm subject eligibility prior to dosing. Subjects will stay under 
supervision in the study center for 2 hours ± 30 minutes following drug injection. 
Screening information may be considered for baseline data if acquired within the adequate 
timeframe as described in Table 4. 


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Table 4:  Subject Information and Timeframes for the Placebo controlled Phase of the Study: 
Information 
Timeframe 
Follow-up Timeframe 
Informed Consent Form 
Signed prior to any study 
dedicated procedure 
 
Medical History  
At Screening Day visit 
 
RZL-012 dosing 
At baseline (day 0) 
 
Concomitant Medications 
At screening Day visit, Day 0, 
1,7,28,56,84  
 
Physical examination  
At Screening Day visit and at 
Days 28, 56 
 
Vital Signs  
At Screening Day visit and at 
Days 0 (pre- and following 
injection), 1, 28, 56 
 
Pregnancy test (women only) 
Will be performed at Baseline 
 
ECG 
At screening, Day 1, 28 
 
Draize Score at the Injected Site 
At Days 0 (pre- and following 
injection), 1, 28, 56 
Day 84 
Ultrasound for nodule size assessment 
At Screening Day visit and at 
Days 0*, 28, 56 
Day 84 
Photography of the Injected Sites 
At Screening Day visit and at 
Days 0*, 28, 56 
Day 84 
Pain assessment using Comparative Pain 
Scale 
At Days 0, 28, 56 
Day 84 
QOL assessment 
At day 0 
Day 84 
Serology assays (HbSAg, HCV and HIV) 
At Screening Day visit  
 
Serum chemistry and Hematology 
At Screening Day and at Days 
1, 28 
 
Urinalysis  
At Screening Day and at Days 
1, 28 
 
Lipid Profile 
At Screening Day and at Day 1  
AEs assessment 
At Days 0, 1, 7, 28, 56 
Day 84 
* In case of screening visit that will be conducted only one day before Baseline, ultrasound at 
Baseline visit is optional. The ultrasound parameters and photography collected at screening will 
be used at Baseline visit. 
Table 5:  Subject Information and Timeframes for the Open Label Extension Phase: 
Information 
Timeframe 
Follow-up Timeframe 
RZL-012 dosing 
At baseline (day 0) 
 
Concomitant Medications 
At Day 0, 1,7,28,56,84  
 
Physical examination  
At Day 0, 28, 56 
 


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Information 
Timeframe 
Follow-up Timeframe 
Vital Signs  
At Days 0 (pre- and following 
injection), 1, 28, 56 
 
ECG 
At Day 0, 1, 28 
 
Draize Score at the Injected Site 
At Days 0 (pre- and following 
injection), 1, 28, 56 
Day 84 
Ultrasound for nodule size assessment 
At Day 0 visit and at days 28, 
56 
Day 84 
Photography of the Injected Sites 
At Day 0 visit and at days 28, 
56 
Day 84 
Pain assessment using Comparative Pain 
Scale 
At Days 0, 28, 56 
Day 84 
QOL assessment 
At day 0 
Day 84 
Serum chemistry and Hematology 
At Day 0 and at Days 1, 28 
 
Urinalysis  
At Day 0 and at Days 1, 28 
 
Lipid Profile 
At Day 0 and at Day 1 
 
AEs assessment 
At Days 0, 1, 7, 28, 56 
Day 84 
 
5.2.6. Subject Site Visits 
Subject site visits will be performed ± 2 days from scheduled date (for study visit Days 28, 56  
and 84). Day 7 phone call to the subject will be performed ±1 day from scheduled day. 
For site visits that result in study discontinuation, see termination visit in Section 5.2.7. 
5.2.7. Termination Visit 
Once study is discontinued, all reasonable measures should be taken to perform a termination 
visit. Termination visit should include all procedures necessary to complete subjects' records:  
AE reporting, evaluation of response and updating of subject contact information. An effort 
should be made to perform all activities conducted on visit Day 84 for subjects who participates 
in the double-blind randomized placebo controlled study. 
5.2.8. Unscheduled Visit 
Unscheduled visits will be performed upon investigator's discretion, upon Sponsor request to 
redo tests with unusual results or complete missing results and may occur upon subject’s 
decision with no notification in advance. Unscheduled visits will include any study procedure 
deemed necessary, as described in Section 5.1. 


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6. 
DESCRIPTION OF THE OPEN LABEL EXTENSION PHASE OF THE STUDY 
At study completion, the randomization codes will be opened. Nineteen (19) Subject who were 
injected with placebo will be offered to be treated with RZL-012.  
At least 4 lipomas/nodules, preferably 6, and no more than 8, will be injected per subject. Dosing 
will be according to lipoma size, where the total injected dose will not exceed 240mg per patient 
(48 injections at 5mg/injection). 
Dosing will be done according to lipoma size, as described in Table 6: 
Table 6:  Dosing of RZ-012 in the Open Label Extension Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The injection with RZL-012 will be done within 30 days of randomization codes opening. 
The day that will be set up by the physician for RZL-012 injection will be the baseline visit, Day 
0. 
On this day, each subject will have the procedures, as described in Section 5.1: 
Day 0- Physical exam, Clinical laboratory tests (hematology, chemistry) lipid profile and 
urinalysis, ECG, injection with RZL-012, concomitant medication, vital signs – before and after 
the injection, ultrasound measurement of the lipomas*, photography of the lipomas, QOL 
questionnaire, Draize score – before and after injection, pain score and AEs documentation. 
Day 1 – ECG, vital signs, Draize score, clinical laboratory tests including urinalysis and lipid 
profile, AEs record. 
 Day 7 – Phone call visit. The study coordinator/nurse will call the subjects to ask about adverse 
events and general health. 
Number of Subjects – 
Active/Placebo 
19/19 
Lipoma/Nodule size – diameter 
(cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Total Dose of RZL-012 in the RZL 
group (mg) 
10 
20 
40 
50 
60 
Number of Injections  
2 
4 
8 
10 
12 


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Day 28±2 – ECG, physical exam, vital signs, clinical laboratory tests, urinalysis, Draize score, 
ultrasound measurement of the lipomas, photography of the lipomas, pain score and AEs 
documentation. 
Day 56±2 - Physical exam, vital signs, ultrasound measurement of the lipomas, photography of 
the lipomas, Draize score, pain score and AEs documentation. 
Day 84±2 - Ultrasound measurement of the lipomas, photography of the lipomas, QOL 
questionnaire, Draize score pain score, QOL questionnaire and AEs documentation. 
Schedule of events of the open label extension part is presented in Appendix 2. 
 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR INVESTIGATORS 
Adherence to protocol monitoring procedures along with the following safety guidance will aid 
and promote subject safety. 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT MEDICATIONS 
Subjects may not receive the following medications at least 3 months prior to study entry:  
• Chronic treatment with systemic steroids or immunosuppressive drugs.  
• Any investigational product other than RZL-012.  
Subjects may not receive the following medications at least one week prior to study entry:  
• Chronic treatment with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). 
Before dosing, topical analgesic gels such as Lidocaine (e.g., Emla) or Pramoxine may be used 
to numb the injected site. An ice pack should be applied onto the sites of injection immediately 
following dosing to help reduce pain. 
On Day 1 following injection, application of the antihistamine Benadryl Gel (Diphenhydramine 
hydrochloride  for topical use only), or any other antihistamine generic gel may be initiated 
prophylactically, according to drug instructions for use, to avoid itching at the injected area. 
Benadryl Gel or other generic gel should be applied for 7 days or as needed.  
7.2. 
SAFETY MEASUREMENTS  
Simple measures may help avoid specific AEs associated with the use of the RZL-012 
investigational product.  Thus, study subjects must be informed of possible AEs that occurred in 
animal studies and in previous clinical studies, as introduced in the ICF. 


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The AEs of RZL-012 vs. placebo will be evaluated for their frequency, severity and duration.  
7.3. 
PREMATURE DISCONTINUATION FROM STUDY 
Study may be prematurely discontinued in any of the following cases: 
• Subject's request.  
• Any life-threatening AE.  
• Systemic hypersensitivity reaction.  
• Any serious or severe ADR (defined in Section 9.3) clinically evaluated by the PI and/or 
Sponsor as warranting subject discontinuation.  
• Non-compliance: Subject's non-compliance with study procedures, evaluated by PI 
and/or Sponsor as warranting subject discontinuation. 
• Other reasons regarded by PI as warranting subject's discontinuation. 
• Premature study termination as described in Section 7.4. 
Subjects who discontinue the study prematurely will be queried whether an AE contributed to 
their decision. 
7.4. 
PREMATURE STUDY TERMINATION 
The study will be prematurely terminated in any of the following cases:  
• Recurring serious or severe ADR (defined in Section 9.1) clinically evaluated by PI 
and/or Sponsor as warranting study termination. 
• A decision made by Sponsor and/or IRB/EC and/or local regulatory agency to terminate 
the study. 
7.5. 
DEVIATION FROM STUDY PROTOCOL 
The investigator shall not deviate from study protocol without first obtaining a written approval 
from the Sponsor, or its official designee, and if applicable, from the local IRB/EC according to 
local regulations. 
In the event of medical emergencies, the investigator shall use appropriate medical judgment and 
will remove the subject from any immediate hazard, then notify the Sponsor or its official 
designee and if applicable, the local IRB/EC, within 2 days, of the type of emergency and course 
of action taken. 
Any other changes to or deviations from the protocol will be made as an amendment to the 
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before they can be implemented. Accordingly, the Sponsor will not assume responsibility or 
liability for any unauthorized deviation from or change to the protocol. 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS 
8.1. 
DESCRIPTION OF RZL-012 
RZL-012 is an investigational drug administered in a single treatment session via multiple 
injections into subcutaneous fat. 
8.2. 
FORMULATION, PACKAGING AND LABELING  
The RZL-012 drug is a ready to use solution to be injected into subcutaneous fat, supplied in a 
1 vial kit. 1 vial contains 250 mg/5 mL RZL-012 in formulation F12. 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE  
The RZL-012 kit and vehicle will be stored on site at monitored room temperature conditions 
(22 ± 7 ᵒC) protected from light. Storage space will be separate, designated and adequately 
labeled as containing investigational product. 
Drug product stability has successfully reached 3 years. Site inventory will be managed by the 
Sponsor according to accumulating stability data. Suitability of the product's expiration date 
must take into consideration and comply with FIFO (First In First Out) principals. 
The storage conditions are summarized in Table 7. 
Table 7:  RZL-012 Storage Conditions  
Storage Conditions 
Maximal Storage Duration 
Individual vials:  
Room temperature (15-30 ᵒC) 
According to expiration date as will be 
provided by manufacturer. 
*  Drug product stability program has successfully reached 3 years. 
 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND VEHICLE 
8.4.1. Dosage 
RZL-012 therapy is available in vials of 250 mg/5 mL. 
The vehicle is available in vials of 5 mL. 


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8.4.2. Administration and Instructions for Use 
Each individual vial must be kept and handled at room temperature.  
The vial should be manually shaken before consumption. 
1 mL Luer-lock syringes with RZL-012 solution should be filled with 30 G 1/2" sterile needle 
according to lipoma size (assessed by US), as described below: 
Number of Subjects – Active/Placebo 
19/19 
Lipoma/Nodule size – diameter (cm) 
1-1.9 
2-3.9 
4-5.9 
6-7.9 
8-10 
Number of Injections -  Active/Placebo 
2 
4 
8 
10 
12 
 
One vial will be used for dosing of one subject. Breached vials will not be re-used for other 
subjects. Each vial must be placed back into the container. All open vials must be kept until the 
end of the study for the Sponsor to decide either to discard or return to the Sponsor. 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE  
The RZL-012 investigational product was manufactured by PharmaCore (USA) and complies 
with cGMP requirements. Formulation and packing were done by Nextar (Israel) and complies 
with cGMP requirements. 
The vehicle was manufactured and packed by Nextar (Israel) and complies with cGMP 
requirements. 
The RZL-012 investigational product and vehicle will be supplied in kits, in quantities as needed 
to comply with the treatment of site subjects according to the study protocol. 
Site coordinator will notify the Sponsor or its official designee, in a timely manner and no less 
than 14 working days in advance, of any supply requirements to prevent shortage. 
Shipment, storage and inventory documentation will be updated regularly and kept in the 
investigation files at the site to allow inspection and trace of the supplied product. 
9. 
ADVERSE EVENTS 
9.1. 
ADVERSE EVENT DEFINITIONS 
9.1.1. Definition of AE 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 


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relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. This definition includes any abnormalities or anomalies that were not seen at 
baseline or which worsened during the course of the study, if present at baseline. 
9.1.2. Definition of Serious Adverse Event 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• death  
• a life-threatening AE, as defined below  
• subject hospitalization or prolongation of existing hospitalization  
• a persistent or significant disability/incapacity  
• a congenital anomaly/birth defect  
• important medical event, as defined below  
A life-threatening AE is any AE that places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred (i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death).  
An important medical event is an AE that may not result in death, be life-threatening, or require 
hospitalization but may be considered a serious AE when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. It can also include AEs otherwise judged to be serious by 
either the investigator or the Sponsor. 
9.1.3. Definition of Adverse Drug Reaction 
AEs associated with the use of investigational product (i.e., probably or possibly related to 
treatment as defined in Section 9.3) are also termed ADRs. 
9.2. 
ADVERSE EVENT GRADING 
AE will be documented in each study visit. 
AEs severity will be graded as follows: 
• Mild:  Sign or symptom, usually transient, requiring no special treatment and generally 
not interfering with usual activities. 


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• Moderate:  Sign or symptom, which may be ameliorated by simple therapeutic measures, 
may interfere with usual activity. 
• Severe:  Sign or symptom that is intense or debilitating and that interferes with usual 
activities and/or requires hospitalization.  Recovery is usually aided by therapeutic 
measures and the discontinuation of the study product may be required. 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS  
All AEs will be evaluated by the investigator and assigned an estimated relationship to the 
RZL-012 investigational product. The terms "related" or "non-related" refer to the association 
with the use of the investigational product, as defined below in Table 8. 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, confounding factors such as concomitant 
medication, concomitant diseases and relevant history. 
Assessment of causal relationship should be recorded directly in subjects’ CRF. 
Definition of AEs causality is specified in the table below. (Table 8). 
Table 8:  Definition of Causality 
TERM 
DEFINITION 
Non-related  This category applies to those AEs which, after careful consideration, are clearly due to 
extraneous causes (disease, environment, etc.) 
Related 
This category applies to those AEs which, after careful medical consideration at the time they 
are evaluated, are felt with high degree of certainty to be related to the study 
procedures/investigational product. 
 
9.4. 
ADVERSE EVENT REPORTING AND MONITORING REQUIREMENTS 
9.4.1. General 
All AEs, serious and non-serious, will be fully documented in both source documents and CRFs 
as described in Section 5.1.14, and each AE will be assessed in light of its clinical significance.  
For each AE, the investigator will provide the onset, end, intensity, treatment required, outcome, 
seriousness and action taken with the investigational drug. The investigator will determine the 
relationship to the investigational drug, i.e., causality assessment, for each AE. 
Any AE occurring prior to initiation of first dose, after initiation of the first dose and or during 
any point throughout the study should be recorded on the AE page of the CRF. All AEs 
occurring until subject is terminated from the study (84 days after the injection of RZL-012), 
should be captured in the CRF. AEs should be recorded in the CRF using the medical 


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terminology found in the source documentation. Whenever possible, diagnoses should be given 
when signs and symptoms are due to a common etiology. 
Occurrence of any serious or severe ADR must warrant clinical evaluation by the treating 
investigator and reported to the Sponsor/medical monitor within 24 hours. 
ADRs will be followed-up until resolution, or for a maximal duration of 6 months after RZL-012 
injection, whichever occurs first. 
9.4.2. SAE Reporting 
The PI or his designee must report to the Sponsor any SAE occurring after injection of the study 
treatment, regardless of their relationship to the investigational product. 
Sponsor contact details for SAE reporting: 
Dr. Sarina Tanimoto, RazielSafety@pacificlinkconsulting.com or fax: 858-769-0288. 
An initial report must be faxed or emailed to RazielSafety@pacificlinkconsulting.com or fax: 
858-769-0288 within 24 hours of becoming aware of the event and must include SAE general 
description, start date, end date (if applicable), the reason for evaluation as a SAE, basic subject 
information, assessment of the relationship to the investigational product, expectedness, and 
study therapy information. 
Follow-up information, including outcome and treatment, shall be faxed or emailed within 
48 hours. Source documents to support the SAE (e.g., discharge summary, test results) shall be 
included in the report. 
A complete SAE report must be sent to the Sponsor at the first possible date and no later than 
7 calendar days after SAE end date. In addition to the information described in the initial report, 
this report will include AEs description and grading, treatment given (if applicable), SAE 
outcome, an assessment of the relationship to the investigational product, and expectedness. 
SAE will be recorded on designated CRF forms in a timely manner and no later than 7 calendar 
days after its end date. 
The PI or his designee will submit the SAE report to IRB/EC according to applicable local 
regulations and will update the Sponsor. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. STUDY DESIGN AND OBJECTIVE 
The statistical analysis described below relates to the place-controlled phase of the study. 


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This study will be a double blinded, randomized, placebo-controlled, Phase 2b trial to assess 
RZL-012 efficacy on DD subjects. A total of 38 eligible subjects will be randomized to receive a 
single injection session with either RZL-012 or placebo (vehicle) in a 1:1 ratio and will be 
monitored for safety and efficacy during 84 days of follow up. 
Once study ends and codes opened, the 19 placebo-treated subjects will be offered to be treated 
with RZL-012 and followed up for an additional 84 days. The efficacy and safety results that will 
be collected during the open label extension phase of the study will be reported in a separate 
statistical report. 
Primary end point: 
Average percent reduction in lipoma/nodule height on day 84 after injection vs baseline, in the 
RZL treated group as compared to the placebo treated group. Lipoma height will be assessed by 
ultrasound. 
Key secondary Endpoint: 
Average percent reduction in lipoma/nodule pain on day 84 after injection vs baseline, in the 
RZL-012 treated group as compared to the placebo treated group. Lipoma pain will be assessed 
by the Comparative Pain Scale. 
 
Additional secondary endpoints: 
 
1. RZL-012 injection safety and tolerability in DD subjects.  
2. Percent responding lipomas/nodules (a responding lipoma is defined as having more than 
75% height reduction on day 84 after injection vs baseline), in the RZL-012 treated group as 
compared to the placebo treated group. 
10.2. STUDY ENDPOINTS 
10.2.1. Analysis of Efficacy for Primary Endpoint 
• Analysis per patient (based on 4-8 lipomas/nodules per patient) 
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 between study groups in percent reduction of lipoma/nodule height at day 84 after 
injection vs. baseline. 
Analysis of covariance (ANCOVA) model will be applied in order to identify covariate 
parameters suspected as related to reduction in lipoma/nodule height and in order to test the 
differences in percent reduction of lipoma/nodules height between the treatment groups adjusted 
to the above covariates. 
• Analysis per lipoma/nodule (based on 4-8 lipomas/nodules per patient) 


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The MMRM model (Mixed-effect model for repeated measures) will be applied for analyzing 
the difference between the groups in percent reduction of lipoma/nodule height from baseline to 
day 84 and adjusted for the above covariates as appropriate. 
10.2.2. Analysis of Efficacy for key secondary Endpoint 
• Analysis per patient (based on 4-8 lipomas/nodules per patient) 
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 between study groups in percent reduction of lipoma/nodule pain at day 84 after 
injection vs. baseline. 
Analysis of covariance (ANCOVA) model will be applied in order to identify covariate 
parameters suspected as related to reduction in lipoma/nodule pain and in order to test the 
differences in percent reduction of lipoma/nodules pain between the treatment groups adjusted to 
the above covariates. 
• Analysis per lipoma/nodule (based on 4-8 lipomas/nodules per patient) 
The MMRM model (Mixed-effect model for repeated measures) will be applied for analyzing 
the difference between the groups in percent reduction in local pain score at day 84 vs. baseline 
between the study groups adjusted for the above covariates as appropriate. 
10.2.3. Analysis of other Secondary Endpoints  
• Analysis of Safety  
Safety data from the study will be summarized descriptively by treatment.  The incidence of 
intolerable side effects will be presented by treatment.  
Descriptive statistics will be calculated for quantitative data and frequency counts and 
percentages will be provided for categorical data.  The nature, frequency, seriousness, severity 
and relation to study drug of AEs will be tabulated for all subjects combined and by treatment.   
Change-from-baseline values for vital signs, clinical laboratory and ECG will be summarized.  
Draize scores will be presented in tabular format by visit and treatment. Serious adverse events 
(SAEs) will be described in narratives as part of the study report. 
 
• Analysis of Efficacy  
Clearance of nodules: (Analysis per Lipoma based on 4-8 lipomas per patient): 
95% Confidence Interval (CI) will be calculated for the proportion of responding nodules 
(response will be defined as achieving a reduction in lipoma height of at least 75% vs. baseline) 
by study groups. 
GEE (Generalized Estimating Equations) model will be applied for testing the statistical 
significance of the difference in percent of responding nodules (nodules with at least 75% 
clearance at day 84 vs. baseline) between the study groups, with adjustment to suspected 
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10.3. SAMPLE SIZE JUSTIFICATION 
Based on primary endpoint: 
The rationale for sample size calculation was based on interim data from Raziel’s open label 
phase 2a study (Study #RZL-012-FD-P2aUS-001) in which reduction in lipoma/nodule height of 
about 55% was demonstrated in the treatment group. Raziel’s phase 2a study did not include a 
placebo group but studies reported by other groups (15,16) show an average reduction from 
baseline in lipoma/nodule height of about 7% in the placebo group. Taking these numbers into 
consideration Raziel expect an effect size of 0.96 (effect size = expected effect size in treated 
(0.55) – expected effects size in placebo group (0.07)/expected standard deviation (0.5)).  
Sample size justification: 
A sample size of 19 in each group (total sample size of 38) will have 80% power to detect a 
difference in means of 48 (the difference between a Group 1 mean, µ1, of 55 and a Group 2 
mean, µ2, of 7) assuming that the common standard deviation is 50 using a two-group t-test with 
a 0.05 two-sided significance level. 
Based on key secondary endpoint: 
The rationale for sample size calculation was based on data from our open label phase 2a study 
(Study #RZL-012-FD-P2aUS-001) in which reduction in lipoma/nodule pain score of about 76% 
was demonstrated in the treatment group. Our phase 2a study did not include a placebo group but 
pain studies reported by other groups (17) show a range of reduction in pain score from +10% - -
60% in the placebo group. Based on Geography, study size and length we selected an expected 
reduction from baseline of 25% in lipoma pain in our placebo group. Taking these numbers into 
consideration we expect an effect size of 1.02 (effect size = expected effect size in treated (0.76) 
– expected effects size in placebo group (0.25)/expected standard deviation (0.5)).    
Sample size justification: 
A sample size of about 19 in each group (total sample size of 38) will have 80% power to detect 
a difference in means of 51 (the difference between a Group 1 mean, µ1, of 76 and a Group 2 
mean, µ2, of 25) assuming that the common standard deviation is 50 using a two-group t-test 
with a 0.05 two-sided significance level. 
10.4. STATISTICAL ANALYSIS 
10.4.1. General  
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. 


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For categorical variables summary tables will be provided giving sample size, absolute and 
relative frequency and 95% CI (Confidence Interval) for proportions by study group. 
For continuous variables summary tables will be provided giving sample size, arithmetic mean, 
standard deviation, coefficient of variation (CV%), median, minimum and maximum and 95% 
CI (Confidence Interval) for means of variables by study group. 
All tests will be two-tailed, and a p value of 5% or less will be considered statistically 
significant. 
Subject Disposition 
A detailed description of subject accountability including count of subjects included, exposed, 
completed (i.e., subjects who complete the study treatment) and discontinued along with the 
main reason for discontinuation will be generated for each treatment group and for all subjects. 
All withdrawals from the study, taking place on or after study drug injection, will be fully 
documented in the body of the Clinical Study Report. 
Note that the actual study duration is for a period of maximum 3.5 months, with efficacy 
analyses being conducted at Day 28, 56, and 84 visits. 
At the end of the period, when the follow up of subjects will be completed, randomization codes 
will be opened. 
Placebo subjects who would like to be treated with RZL-012 at the end of the study will be 
injected (within a period of 30 days from codes opening) and will be followed up for efficacy for 
additional 84 days.   The efficacy information that will be collected for the open label extension 
study will not be included in the randomized double blinded study report but will be used for 
internal information. 
10.4.2. 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 visit. 
Baseline safety data will be presented along with subsequent safety values assessed during or 
after dosing. 
10.4.3. Efficacy Analysis 
The change from baseline lipoma height will be presented in tabular form by treatment group. 


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The changes from baseline in pain score as a function of treatment group will be presented in 
tabular form per treatment group. 
10.4.4. Safety and Tolerability 
Safety analyses will be descriptive in nature. 
All reported AEs will be coded to a standard set of terms using MedDRA coding dictionary 
(V.22 or higher) treatment. 
AEs and tolerability data will be presented descriptively by study cohort. AEs will be tabulated 
by body system, preferred term, seriousness, severity and relation to study drug by cohort. 
10.5. HANDLING OF MISSING DATA 
No imputation of missing data will be performed. 
10.6. INTERIM ANALYSIS 
No interim analysis is planned. 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
11.1. DATA COLLECTION AND REPORTING 
Each study subject will be assigned an individual CRF that will contain all of the relevant study 
information. The investigator shall ensure that all data is completely and accurately recorded on 
the CRFs throughout trial duration. 
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
All fields and blanks in the CRFs will be completed. The following abbreviations are to be used 
when values or answers are not available: NA = Not applicable, ND = Not done, 
UNK = Unknown, CONT = Continued. 
Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry (i.e., an audit trail should be maintained). If an entry on a 
CRF form is changed, the correction will be made as follows: A single line will be drawn 
through the incorrect entry, the date and initials of the reporting individual will be added beside 
the entered change and/or correction, and an explanation will be added when applicable. 
When a subject withdraws from the study, regardless of cause, all final study evaluations should 
be attempted. 


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If a subject is lost to follow-up, (i.e., fails to return for scheduled visits) every reasonable effort 
must be made to contact the subject in order to determine why the subject failed to return. All 
actions taken in this regard will be documented and dated in the CRF. 
Once completed, a copy of each completed CRF will be signed and dated by the investigator or a 
designated representative and submitted to the Sponsor. 
11.2. RECORD KEEPING 
The investigator will maintain all records for this study including medical records, laboratory 
reports, ICFs, safety reports, subjects' CRF, and any other pertinent data. All records are to be 
retained by the investigator for a period of seven years after completion of the study. 
11.3. SOURCE DATA AND SOURCE DOCUMENTS 
ICH-GCP defines source data as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
Source documents are defined as original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, subject files, and records kept at departments 
involved in the clinical trial, etc.). 
The following data is to be recorded directly on the RZL-012 trial forms or CRF, which will be 
considered to be the source data: 
• Subjects' questioning, e.g., pain, itching, topical antihistamine application. 
• Assessment of AEs relation to investigational product, i.e., causality assessment, and 
expectedness reported by investigator. 
The investigator should maintain the trial's essential documents as required by ICH-GCP 
guidelines and the applicable regulatory requirements and take measures to prevent accidental or 
premature destruction of these documents. 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the investigator will 
ensure direct access to all requested trial-related records. 
11.4. STUDY MONITORING 
Monitoring procedures are required to assure compliance to ICH-GCP guidelines, the study 
protocol and local regulations. 


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The investigator shall allow the Sponsor or its official designee to monitor and audit periodically, 
at mutually convenient times, all CRF and corresponding subject records. The monitoring 
schedule will be based on Sponsor’s monitoring plan and will be done by competent monitors 
per GCP by either Sponsor personnel or sponsor’s designee such as a Clinical Research 
Organization (CRO). 
11.5. CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION 
In order to protect subject confidentiality, a consecutive identification number will be attributed 
to each subject enrolled to the trial, at each site. In order to avoid identification errors, this 
number will identify the subject and must be included on all CRFs. The investigator will 
complete subject identification on a confidential site log, which will be used for subjects' 
traceability and follow-up. 
Individual subject medical information obtained as a result of this study is to be considered 
confidential and disclosure to third parties other than the regulatory authorities, or other persons 
or organizations designated by the Sponsor, is prohibited. Any medical information may be 
provided to the subject’s personal physician or to appropriate medical personnel responsible for 
the subject’s care. Additionally, data generated from this study is to be provided, upon request, to 
the Sponsor’s monitors, as well as to the local IRB/EC. Subject confidentiality is to be further 
assured by utilizing subject identification code numbers to identify subject data. 
All information supplied by Raziel Therapeutics Ltd. in connection with this study and not 
previously published, is considered confidential information. This information includes, but is 
not limited to, the IB, clinical protocol, CRF, and other scientific data. Any data collected during 
the study are also considered confidential. This confidential information shall remain the sole 
property of Raziel Therapeutics Ltd, shall not be disclosed to others without the written consent 
of the Sponsor, and shall not be used except in the performance of this study. The information 
developed during the conduct of this clinical study is also considered confidential and will be 
used by the Sponsor in connection with the development of the product. The information may be 
disclosed as deemed necessary by the Sponsor. To allow the use of the information derived from 
this clinical study, the investigator is obliged to provide Raziel Therapeutics Ltd. with complete 
test results and all data developed in this study. 
The Sponsor has full ownership of the original CRFs completed as part of the study. 
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement. 
The information obtained during this study may be made available to other investigators who are 
conducting similar studies. 


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It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol. 
Raziel Therapeutics Ltd. will disclose the results of the trial on the basis of the final analysis and 
following the revision of a draft manuscript by the investigators, unless posting would 
compromise publication in a peer-reviewed medical journal or contravene national laws or 
regulations. Study results may also be disclosed through presentations and abstract submissions 
at professional scientific meetings. 
12. 
HUMAN SUBJECTS 
12.1. DECLARATION OF HELSINKI 
Both the PI and the Sponsor will ensure that the study is conducted in agreement with the 
Declaration of Helsinki, ICH-GCP, and the local laws and regulation. 
12.2. INFORMED CONSENT 
As described in Section 5.1.1. 
12.2.1. LIABILITY AND INSURANCE CONDITIONS 
Raziel Therapeutics Ltd. holds a clinical trial liability insurance policy. 
A copy of the policy summary will be filled in the investigator's site file. 
13. 
REFERENCES 
1. Hansson E, Svensson H, Brorson H. Review of Dercum’s Disease and proposal of diagnostic 
criteria, diagnostic methods, classification and management. Orphanet J Rare Dis. 2012;7:23. 
2.  Cook JC, Gross GP. Adiposis Dolorosa (Dercum, Anders Disease). In: StatPearls. Treasure 
Island (FL): StatPearls Publishing LLC.; 2018. 
3.  Dalziel K. The nervous system and adipose tissue. Clin Dermatol. 1989;7(4):62-77. 
4. Blomstrand R, Juhlin L, Nordenstam H, Ohlsson R, Werner B, Engström J. Adiposis 
dolorosa associated with defects of lipid metabolism. Acta Derm Venereol. 1971;51(4):243-
250. 
5. Campen R, Mankin H, Louis DN, Hirano M, Maccollin M. Familial occurrence of adiposis 
dolorosa. J Am Acad Dermatol. 2001;44(1):132-136. 
6.  Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol 
Sin. 2012;33(2):155-172. 


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7. Herbst KL, S A-B. Adiposis dolorosa is more than painful fat. . The 
Endocrinologist 2007;17:326–334. 
8. Herbst KL, Letter August 2019 
9. Wright TF, Letter September 2019 
10. Mozayeni RB, Letter January 2019 
11. Desai MJ, Siriki R, Wang D. Treatment of pain in Dercum's disease with Lidoderm 
(lidocaine 5% patch): a case report. Pain Med. 2008;9(8):1224-1226. 
12. Petersen P, Kastrup J. Dercum's disease (adiposis dolorosa). Treatment of the severe pain 
with intravenous lidocaine. Pain. 1987;28(1):77-80. 
13. Hansson E, Svensson H, Brorson H. Liposuction may reduce pain in Dercum's disease 
(adiposis dolorosa). Pain Med. 2011;12(6):942-952. 
14. Held JL, Andrew JA, Kohn SR. Surgical amelioration of Dercum's disease: a report and 
review. J Dermatol Surg Oncol. 1989;15(12):1294-1296. 
15. Clinical Trials.gov -  A Double Blind Study to Evaluate the Efficacy of Collagenase 
Histolyticum in the Treatment of Lipoma - NCT02249052 
16. Clinical Trials.gov - Phase 2 Study for the Treatment of Superficial Lipomas - 
NCT00608842 
17. Tuttle et al, Increasing placebo responses over time in U.S. clinical trials of neuropathic pain, 
Pain. 2015; 156(12):2616-26 


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APPENDIX I:  TRIAL SCHEDULE OF EVENTS 
 
Double Blind, Randomized, Placebo Controlled 
Open Label extension for Placebo 
subjects (will be done within 30 days 
of study completion)  
Study 
Procedure 
Screening Day 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Visit Schedule (Day 0 to 84) 
Study Day 
Day (-14) 
through 
Day (-1) 
Day a 0 
Day 
1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Day 
d  0  
Day 
1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Signed 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam 
X 
 
 
 
X 
X 
 
X 
 
 
X 
X 
 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
kit test 
(women)b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
X 
Prec X post c 
X 
 
X 
X 
 
Prec 
X 
post 
c 
X 
 
X 
X 
 
Injection of 
RZL-
012/Placebo 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
ECG 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
Serology 
assay 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Draize Score  
 
Pre c X post c 
X 
 
X 
X 
X 
Pre c 
X 
post 
c 
X 
 
X 
X 
X 
Ultrasound 
measure of 
lipomas 
X 
Xe 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Photography 
of lipomas  
X 
Xe 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Serum 
chemistry 
and 
hematology 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
Urinalysis 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 


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a. 
Day 0 defines the day of RZL-012/placebo injection in the double blinded randomized study 
b. 
At screening visit women will be asked whether they are pregnant, test will be performed at baseline visit before dosing 
c. 
Pre/post – refers to before/after injection, respectively 
d. 
Day 0 defines the day of RZL-012 injection in the open label study 
e. 
In case of screening visit that will be conducted only one day before Baseline, ultrasound and photography at Baseline visit 
is optional. The ultrasound parameters and photography  collected at screening will be used at Baseline visit. 
 
 
Double Blind, Randomized, Placebo Controlled 
Open Label extension for Placebo 
subjects (will be done within 30 days 
of study completion)  
Study 
Procedure 
Screening Day 
Baseline 
(Treatment) 
Visit Schedule (Days 1 to 84) 
Visit Schedule (Day 0 to 84) 
Study Day 
Day (-14) 
through 
Day (-1) 
Day a 0 
Day 
1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Day 
d  0  
Day 
1 
Day 
7 
Day 
28 
Day 
56 
Day 
84 
Lipid profile 
X 
 
X 
 
 
 
 
X 
X 
 
 
 
 
Pain 
assessment 
of each 
lipoma 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
QOL 
questionnaire 
 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
AEs 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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APPENDIX II: COMPARATIVE PAIN SCALE 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX III:  SF-36 QUALITY OF LIFE QUESTIONNAIRE 
 
Please answer the 36 questions of the Health Survey completely, honestly, and without 
interruptions. 
 
GENERAL HEALTH: 
 
In general, would you say your health is: 
☐Excellent ☐Very Good ☐Good ☐Fair Poor 
 
Compared to one year ago, how would you rate your health in general now? 
☐Much better now than one year ago 
☐Somewhat better now than one year ago 
☐About the same 
☐Somewhat worse now than one year ago 
☐Much worse than one year ago 
 
LIMITATIONS OF ACTIVITIES: 
The following items are about activities you might do during a typical day. Does your health 
now limit you in these 
activities? If so, how much? 
 
Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports. 
☐Yes, Limited a lot  ☐Yes, Limited a Little   ☐No, Not Limited at all 
 
Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing 
golf 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
 
Lifting or carrying groceries 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
 
Climbing several flights of stairs 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
Climbing one flight of stairs 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
Bending, kneeling, or stooping 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
Walking more than a mile 
☐Yes, Limited a Lot  ☐Yes, Limited a Little  ☐No, Not Limited at all 
Walking several blocks 
☐Yes, Limited a Lot ☐Yes, Limited a Little  
☐No, Not Limited at all 


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Walking one block 
☐Yes, Limited a Lot ☐Yes, Limited a Little  
☐No, Not Limited at all 
Bathing or dressing yourself 
☐Yes, Limited a Lot ☐Yes, Limited a Little 
 
☐ No, Not Limited at all 
 
PHYSICAL HEALTH PROBLEMS: 
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as 
a result of your physical health? 
 
Cut down the amount of time you spent on work or other activities 
☐Yes  ☐No 
Accomplished less than you would like 
☐Yes  ☐No 
Were limited in the kind of work or other activities 
☐Yes  ☐No 
Had difficulty performing the work or other activities (for example, it took extra effort) 
☐Yes  ☐No 
 
EMOTIONAL HEALTH PROBLEMS: 
During the past 4 weeks, have you had any of the following problems with your work or other 
regular daily activities as 
a result of any emotional problems (such as feeling depressed or anxious)? 
 
Cut down the amount of time you spent on work or other activities 
☐Yes  ☐No 
Accomplished less than you would like 
☐Yes  ☐No 
Didn't do work or other activities as carefully as usual 
☐Yes  ☐No 
 
SOCIAL ACTIVITIES: 
 
Emotional problems interfered with your normal social activities with family, friends, 
neighbors, or groups? 
☐Not at all 
 ☐Slightly 
☐ Moderately  
☐ Severe  
☐ Very Severe 
 
PAIN: 
 
How much bodily pain have you had during the past 4 weeks? 
☐None 
 ☐Very Mild  
☐ Mild Moderate  
☐ Severe   
☐Very Severe 
 


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During the past 4 weeks, how much did pain interfere with your normal work (including 
both work outside the 
home and housework)? 
☐Not at all  ☐A little bit Moderately  
☐ Quite a bit Extremely 
 
ENERGY AND EMOTIONS: 
 
These questions are about how you feel and how things have been with you during the last 4 
weeks. For each 
question, please give the answer that comes closest to the way you have been feeling. 
 
Did you feel full of pep? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Have you been a very nervous person? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Have you felt so down in the dumps that nothing could cheer you up? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Have you felt calm and peaceful? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 


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Did you have a lot of energy? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Have you felt downhearted and blue? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Did you feel worn out? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Have you been a happy person? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
Did you feel tired? 
☐All of the time 
☐Most of the time 
☐A good Bit of the Time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 


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SOCIAL ACTIVITIES: 
 
During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with 
your social activities (like visiting with friends, relatives, etc.)? 
☐All of the time 
☐Most of the time 
☐Some of the time 
☐A little bit of the time 
☐None of the Time 
 
GENERAL HEALTH: 
 
How true or false is each of the following statements for you? 
 
I seem to get sick a little easier than other people 
☐Definitely true ☐Mostly true ☐Don't know ☐Mostly false ☐Definitely false 
I am as healthy as anybody I know 
☐Definitely true ☐Mostly true ☐Don't know ☐Mostly false ☐Definitely false 
I expect my health to get worse 
☐Definitely true ☐Mostly true ☐Don't know ☐Mostly false ☐Definitely false 
My health is excellent 
☐Definitely true ☐Mostly true ☐Don't know ☐Mostly false ☐Definitely false