Clinical trial NCT03492840
Conditions: Lipedema Dercum Disease
Sponsor: Raziel Therapeutics Ltd.
Start date: 2018-06-28; Completion date: 2019-05-02
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label, 2 cohort, clinical trial in women with lipedema with substantial fat above the knee and men with Dercum's disease. Each cohort will have 6 subjects who will receive RZL-012.

Detailed description:
This is an open label, 2 cohort, clinical trial in women with lipedema with substantial fat above the knee and men with Dercum's disease.

* The 1st cohort will be comprised of subjects with Dercum's disease.
* The 2nd cohort will be comprised of subjects with lipedema with substantial fat above the knee

Within each cohort dosing of the subjects will progress consecutively from one individual to the other with a minimum 7 days between subjects to asses safety. The study design will allow the physicians to monitor safety for at least 7 days prior to dosing the next subject. Cohort 2 will be conducted in a dose escalation manner and the decision to proceed to the next dose level will be made after reviewing all safety data collected by Day 14 within 2+/-1 day of the last dosed subject. The trial will proceed within a cohort provided that no more than one subject experience intolerable side effects in a cohort, and based on the decision made by the Principal Investigator (PI) and the medical monitor.

Arms: arm 1: Nodular size - diameter (cm) 2-2.9, 3-3.9, 4-8 Total dose of RZL-012(mg) 10 15 20 Dose per NOAEL 1/25th , 1/18.75th, 1/12.5th Number of injections: 2,3,4 arm 2: Total dose of RZL-012 (mg) 60 , 80 Dose per NOAEL: 1/4.6888, 1/3.125 Number of injections: 12, 16
Interventions: intervention 1: RZL-012
Intervention descriptions: intervention 1: The dosing regimen will be a single dose treatment injection of RZL-012 in multiple sites

Protocol documents:
Prot_002.pdf: 
Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
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RZL-012 Study Protocol 
Protocol Number RZL-012-FD-P2aUS-001.7 
 
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. 
 
 
Principal Investigator: 
Karen Herbst 
Sponsor: 
Raziel Therapeutics LTD 
Hadassah Ein-Karem, JBP building, P.O.B. 12157 
Jerusalem, Israel 9112101 
Confidentiality Statement 
This document is a confidential communication of Raziel Therapeutics Ltd. 
Acceptance of this document constitutes agreement by the recipient that no 
unpublished information contained herein will be published or disclosed without 
prior written approval, except for disclosure to the appropriate Institutional 
Review Board and/or Regulatory Authority under the condition that confidentiality 
is maintained 
Protocol Date:  4 June 2017 
Version 1:  4 June 2017 
Version 2: 11 November 2017 
Version 3: 26 January 2018 
Version 4: 8 March 2018 
Version 5: 12 July 2018 
Version 6: 23 July 2018 
Version 7: 03 Jan 2019 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
STATEMENT OF COMPLIANCE ...............................................................................................11 
INVESTIGATOR SIGNATURE PAGE .......................................................................................12 
PROTOCOL SYNOPSIS ..............................................................................................................13 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
BACKGROUND ........................................................................................................21 
1.1.1. 
Scientific Background and Clinical Rationale ............................................................21 
1.1.2. 
RZL-012 Formulation Development ..........................................................................23 
1.2. 
NONCLINICAL ASSESSMENTS ............................................................................24 
1.2.1. 
Pharmacology .............................................................................................................24 
1.2.1.1. 
Efficacy In-vivo and In-vitro Studies .........................................................................24 
1.2.1.2. 
Safety Pharmacology ..................................................................................................25 
1.2.2. 
Toxicology ..................................................................................................................25 
1.2.2.1. 
Extended Single Dose Toxicity Studies .....................................................................25 
1.2.3. 
Additional Nonclinical Studies ...................................................................................27 
1.2.4. 
Clinical Studies ...........................................................................................................28 
2. 
PURPOSE AND STUDY OBJECTIVES ..................................................................30 
2.1. 
PURPOSE ...................................................................................................................30 
2.2. 
STUDY OBJECTIVES ..............................................................................................31 
2.2.1. 
Primary .......................................................................................................................31 
2.2.2. 
Secondary ...................................................................................................................31 
3. 
STUDY DESIGN .......................................................................................................31 


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3.1. 
DESCRIPTION OF STUDY DESIGN ......................................................................31 
3.2. 
DOSE RATIONALE ..................................................................................................31 
3.3. 
DOSING .....................................................................................................................32 
3.3.1. 
Dosing Regimen .........................................................................................................32 
3.3.2. 
Intolerable Side Effect ................................................................................................33 
4. 
STUDY ENDPOINTS ................................................................................................35 
4.1. 
PRIMARY ENDPOINTS ...........................................................................................35 
4.2. 
SECONDARY ENDPOINTS .....................................................................................35 
5. 
STUDY POPULATION .............................................................................................36 
5.1. 
INCLUSION CRITERIA ...........................................................................................36 
5.2. 
EXCLUSION CRITERIA ..........................................................................................36 
5.3. 
SUBJECT IDENTIFICATION ..................................................................................37 
5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF 
SUBJECTS FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE 
EFFECTS ....................................................................................................................37 
6. 
STUDY PROCEDURES AND ASSESSMENT ........................................................37 
6.1. 
DEFINITIONS OF STUDY PROCEDURES ............................................................37 
6.1.1. 
Informed Consent .......................................................................................................37 
6.1.2. 
Medical History ..........................................................................................................38 
6.1.3. 
Concomitant Medication ............................................................................................38 
6.1.4. 
Physical Examination .................................................................................................38 
6.1.5. 
Pain Measurement ......................................................................................................38 
6.1.6. 
Quality of Life and Function Measurement ................................................................39 
6.1.7. 
Vital Signs Measurements ..........................................................................................39 
6.1.8. 
Serology Assays ..........................................................................................................39 
6.1.9. 
Clinical Laboratory Tests ...........................................................................................39 
6.1.9.1. 
Hematology .................................................................................................................40 
6.1.9.2. 
Serum Chemistry Analysis .........................................................................................40 
6.1.9.3. 
Urine Drug Screen ......................................................................................................40 
6.1.9.4. 
Urinalysis ....................................................................................................................40 
6.1.10. 
ECG ............................................................................................................................41 
6.1.11. 
Draize Score ................................................................................................................41 
6.1.12. 
Photography of the Injected Site .................................................................................41 


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6.1.13. 
Leg Circumference .....................................................................................................42 
6.1.14. 
Imaging: Ultrasound (US) ..........................................................................................42 
6.1.15. 
Adverse Events ...........................................................................................................44 
6.1.16. 
Evaluation of Response ..............................................................................................44 
6.1.16.1. 
Evaluation of Primary Endpoints................................................................................44 
6.1.16.2. 
Evaluation of Secondary Endpoints............................................................................45 
6.1.16.3. 
Compliance Monitoring ..............................................................................................45 
6.1.16.4. 
Dispensing of RZL-012 Investigational Product ........................................................46 
6.1.16.5. 
Questioning of Study Subjects ....................................................................................46 
6.2. 
STUDY VISITS..........................................................................................................46 
6.2.1. 
Screening Procedures ..................................................................................................46 
6.2.2. 
Study Randomization ..................................................................................................47 
6.2.3. 
Study Treatment ..........................................................................................................47 
6.2.3.1. 
Treatment with RZL-012 Investigational Therapy .....................................................47 
6.2.4. 
Baseline Visit ..............................................................................................................50 
6.2.5. 
Subject Site Visits .......................................................................................................51 
6.2.6. 
Termination Visit ........................................................................................................51 
6.2.7. 
Unscheduled Visit .......................................................................................................51 
7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR 
INVESTIGATORS .....................................................................................................52 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT 
MEDICATIONS .........................................................................................................52 
7.2. 
SAFETY MEASUREMENTS....................................................................................52 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY............................................53 
7.4. 
PREMATURE STUDY TERMINATION .................................................................54 
7.5. 
DEVIATION FROM STUDY PROTOCOL..............................................................54 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS ................54 
8.1. 
DESCRIPTION OF RZL-012 ....................................................................................54 
8.2. 
FORMULATION, PACKAGING AND LABELING ...............................................54 
8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE .................................55 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND 
VEHICLE ...................................................................................................................55 
8.4.1. 
Dosage ........................................................................................................................55 


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8.4.2. 
Administration and Instructions for Use .....................................................................55 
8.5. 
ACCOUNTABILITY OF RZL-012 AND VEHICLE ...............................................56 
9. 
ADVERSE EVENTS..................................................................................................56 
9.1. 
ADVERSE EVENT DEFINITIONS ..........................................................................56 
9.1.1. 
Definition of AE .........................................................................................................56 
9.1.2. 
Definition of Serious Adverse Event ..........................................................................56 
9.1.3. 
Definition of Adverse Drug Reaction .........................................................................57 
9.2. 
ADVERSE EVENT GRADING ................................................................................57 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS .........................................57 
9.4. 
UNEXPECTEDNESS OF ADVERSE DRUG REACTIONS ...................................59 
9.5. 
ADVERSE EVENT REPORTING AND MONITORING 
REQUIREMENTS .....................................................................................................59 
9.5.1. 
General ........................................................................................................................59 
9.5.2. 
SAE Reporting ............................................................................................................60 
9.5.3. 
Expedited Reporting ...................................................................................................60 
10. 
STATISTICAL CONSIDERATIONS .......................................................................61 
10.1. 
STUDY DESIGN AND OBJECTIVE .......................................................................61 
10.2. 
STUDY ENDPOINTS ................................................................................................61 
10.2.1. 
Primary Safety Endpoints ...........................................................................................61 
10.2.2. 
Secondary Efficacy Endpoints ....................................................................................61 
10.2.3. 
Safety and Tolerability Endpoints ..............................................................................62 
10.3. 
SAMPLE SIZE JUSTIFICATION .............................................................................62 
10.4. 
ANALYSIS SETS ......................................................................................................62 
10.4.1. 
Safety Analysis Set (SA) ............................................................................................62 
10.4.2. 
Efficacy Analysis Set (EF) .........................................................................................62 
10.4.3. 
Statistical Analysis of Analysis Sets...........................................................................62 
10.5. 
STATISTICAL ANALYSIS ......................................................................................63 
10.5.1. 
General ........................................................................................................................63 
10.5.2. 
Subject Disposition .....................................................................................................63 
10.5.3. 
Demographic and Baseline Characteristics ................................................................63 
10.5.4. 
Primary Safety Endpoint .............................................................................................63 
10.5.5. 
Efficacy Analysis ........................................................................................................64 
10.5.6. 
Safety and Tolerability ...............................................................................................64 


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10.6. 
HANDLING OF MISSING DATA ............................................................................64 
10.7. 
INTERIM ANALYSIS ...............................................................................................64 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA 
DISCLOSURE ............................................................................................................64 
11.1. 
DATA COLLECTION AND REPORTING ..............................................................64 
11.2. 
RECORD KEEPING ..................................................................................................65 
11.3. 
SOURCE DATA AND SOURCE DOCUMENTS ....................................................65 
11.4. 
STUDY MONITORING ............................................................................................66 
11.5. 
CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION ...................66 
12. 
HUMAN SUBJECTS .................................................................................................67 
12.1. 
DECLARATION OF HELSINKI ..............................................................................67 
12.2. 
INFORMED CONSENT ............................................................................................67 
12.2.1. 
LIABILITY AND INSURANCE CONDITIONS ......................................................67 
13. 
REFERENCES ...........................................................................................................68 
 


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LIST OF TABLES 
Table 1:  Phase 0 Clinical Trial Design .........................................................................................28 
Table 2:  Subject Information and Timeframes .............................................................................50 
Table 3:  RZL-012 Storage Conditions ..........................................................................................55 
Table 4:  Definition of Causality ...................................................................................................58 
 
LIST OF FIGURES 
Figure 1:  RZL-012 Injection Design in Dercum's Disease Subjects ............................................48 
Figure 2:  RZL-012 Injection Sites in Dercum's Disease Subjects ................................................48 
Figure 3:  RZL-012 Injection in Lipedema ....................................................................................48 
Figure 4:  RZL-012 Injection Sites in Lipedema Subjects ............................................................49 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the concentration-time curve 
BAT 
Brown-like adipose tissue 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence Interval 
CK-MM 
Creatine-kinase MM 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Efficacy analysis set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIFO 
First In First Out 
FOB 
Functional Observational Battery  
GLP 
Good Laboratory Practice 
GTTP 
Gamma-glutamyltransferase 
HbSAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 


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Abbreviation or Specialist Term 
Explanation 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical 
Practice 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LEFS 
Lower Extremity Functional Scale 
LPL 
Lipoprotein lipase 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No observed adverse effect level 
NORD 
National Organization for Rare Disorders 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QOL 
Quality of life 
RBC 
Red blood cells 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SAT 
Subcutaneous adipose tissue 
SFM 
Subcutaneous fat mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Terminal half-life 
TAG 
Triacylglycerols  
TG 
Triglycerides 
TLA 
Tumescent Liposuction (Local Anesthesia) 
Tmax 
Time of maximum observed sample concentration 
UCP1 
Uncoupling protein 1 
US/USA 
United States/United States of America 
WAL 
Water Assisted Liposuction 
WAT 
White adipose tissue 


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Abbreviation or Specialist Term 
Explanation 
WBC 
White blood cells 
 


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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).  
 
 
 
 
_Karen L. Herbst_______  
__
__________________ 
 
 
_10/22/2019_ 
Investigator's name 
 
 
Investigator’s Signature  
 
Date 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
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PROTOCOL SYNOPSIS 
Protocol 
Number 
RZL-012-FD-P2aUS-001 
Protocol Title 
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 women and men with 
nodular Dercum's disease. 
Study Phase 
Phase 2a 
Study Drug 
RZL-012 
Study 
Objectives 
Primary objective:  Evaluation of the overall safety of RZL-012 following injection into the 
subcutaneous fat in patients with lipedema.  
Secondary objective:  Evaluation of local fat reduction, its extent, duration and tissue associated 
changes, in response to RZL-012 treatment, utilizing minimal invasive means (ultrasound) following 
subcutaneous injection of RZL-012 into fatty tissue below the skin. 
Sample Size 
12 subjects 
Study Design 
This is an open label, 2 cohort clinical trial in women with lipedema with substantial fat above the 
knee or women and men with nodular Dercum's disease. Each cohort will have 6 subjects who will 
receive RZL-012. 
• 
The 1st cohort will be comprised of subjects with Dercum's disease  
• 
The 2nd cohort will be comprised of subjects with lipedema with substantial fat above the 
knee.  
Within each cohort, dosing of the subjects will progress consecutively from one individual to the 
other with a minimum of 7-days between subjects to assess safety. This study design will allow the 
physicians to monitor safety for at least 7 days prior to dosing the next subject. Cohort 2 will be 
conducted in a dose escalation manner and the decision to proceed to the next dose level will be 
made after reviewing all safety data collected by Day 14 within 2 ± 1d of the last dosed subject. The 
trial will proceed within a cohort provided that no more than one subject experiences intolerable side 
effects in a cohort, and based on the decision made by the Principal Investigator (PI) and the Medical 
Monitor.   
Study 
Population 
Post-menopausal women no more than 65 years old, with lipedema involving substantial fat above 
the knee or nodular Dercum's disease in such women and in men 20- 65 years with nodular Dercum's 
disease. 


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Main Inclusion 
Criteria 
 
Subjects must meet all the following to be eligible for study participation: 
1. Post-menopausal (at least 2 years) women no more than 65 years old, with lipedema involving 
substantial fat above the knee or nodular Dercum's disease in such women and in men 20 - 65 
years with nodular Dercum's disease.  
2. For Dercum's disease subjects – at least 2 nodules to be injected of at least 2cm diameter, each, 
as determined by ultrasound  
3. For lipedema subjects - Significant subcutaneous fat above the knee as determined by 
circumference of 50cm  
4. Generally considered healthy according to medical history, physical examination, 
electrocardiogram (ECG) and laboratory evaluation with a special emphasis on metabolic 
parameters (fasting glucose concentration < 200 mg/dL, normal blood pressure). 
5. Subjects must be able to adhere to the visit schedule and protocol requirements and be available 
to complete the study. 
6. Subjects must sign an informed consent indicating that they are aware of the investigational 
nature of the study. 
Main Exclusion 
Criteria 
Subjects meeting any of the following criteria will be excluded: 
1. Unable to tolerate subcutaneous injection. 
2. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that in the 
opinion of the investigator put the subject at significant risk, are not eligible.  
3. Positive blood screen for Hepatitis B surface antigen (HbSAg), Hepatitis C virus (HCV), or 
Human immunodeficiency virus (HIV), or positive urine screen for alcohol or drugs of abuse 
(unless prescribed by a physician). 
4. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune disease 
or subjects taking immunosuppressive drugs such as corticosteroids are ineligible.  
5. As a result of medical review, physical examination, the PI (or medically qualified nominee) 
considers the subject unfit for the study.  
6. Known sensitivity to components of the injection formulation.  
7. Prior wound, tattoo or infection in the treated area. 
8. Prior invasive treatment such as surgery or injectable drug at the RZL-012 injected area. 


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Intolerable Side 
Effect Definition 
An intolerable side effect defined as any of the following treatment-related adverse drug reactions 
(ADRs): 
• 
Any Grade 3 or greater event except for the following (For the following events, a 
discussion will be held by the PI and the Medical Monitor to decide whether considered as 
an intolerable side effects): 
o 
Flu-like symptoms and fever that responds to standard treatment within 72 hours 
o 
Localized edema and erythema 
o 
Pruritus 
o 
Pain 
o 
Skin/soft tissue inflammation 
o 
Fat Atrophy 
o 
Liver enzymes abnormality 
o 
Non-significant lab abnormalities, lasting less than 7 days (See Section 3.3.2) 
Subjects experiencing an intolerable side effect will be withdrawn from the study, but followed until 
the event resolves or becomes stable; all actions taken are to be fully documented in source 
documents and Case Report Forms (CRFs).  To be considered an intolerable side effect, such an 
event must be considered to be possibly or probably related to the study drug 
The study may also be prematurely terminated in any of the following cases:  
• 
Recurring serious or severe ADR clinically evaluated by PI as warranting study termination.  
• 
A decision made by Sponsor and/or Institutional Review Board (IRB)/Ethics Committee 
(EC) and/or local regulatory agency to terminate the study.  
Study Drug 
Dosage and 
Administration 
The 1st cohort will be comprised of subjects with Dercum's disease: all subjects will be injected with 
RZL-012. Dosing will be calculated according to the size of the nodule (diameter) as determined by 
ultrasound: 5mg/cm2 reaching a maximal dose of 40mg per subject (1/6.25 the No observed adverse 
effect level [NOAEL] based on Human Equivalent Dose [HED] from Good Laboratory Practice 
[GLP] toxicology study).  
Nodule of 2-2.9cm diameter, as determined by ultrasound, will be injected 2 injections (0.1 mL each, 
1 cm apart); total of 10 mg RZL-012.  
Nodules of 3-3.9cm diameter, as determined by ultrasound, will be injected 3 injections (0.1 mL 
each, 1 cm apart); total of 15 mg RZL-012.  
Nodules of 4-8cm diameter, as determined by ultrasound, will be injected 4 injections (0.1 mL each, 
1 cm apart); total of 20 mg RZL-012. 
 
Cohort 1 
Number of Subjects – Active 
6 
Nodule size – diameter (cm) 
2-2.9 
3-3.9 
4-8 
Total Dose of RZL-012 (mg) 
10 
15 
20 
Dose per NOAEL* 
1/25th 
1/18.75th 
1/12.5th 
Number of Injections 
2 
3 
4 
 
Subjects will receive a single treatment in multiple sites (2-8) of injection according to the design in 
the picture below: 
 


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Injections will be diagonally (45 °) to the skin surface and towards the center of the nodule and the 
distance between injections in a nodule will be 1 cm (see picture below). 
 
The 2nd cohort will be comprised of subjects with lipedema with substantial fat above the knee.  
The first 3 subjects will receive 30 mg RZL-012 in 6 injections (0.1mL each) in one leg followed by 
30mg RZL-012 (6 injections, 0.1mL each) in the second leg adding up to 12 injections of 60mg 
RZL-012 (1/4.688th the NOAEL based on HED from GLP toxicology study).  
The last 3 subjects will receive 40mg RZL-012 in 8 injections (0.1mL each) in one leg followed by 
40mg RZL-012 (8 injections, 0.1mL each) in the second leg adding up to 16 injections of 80mg 
RZL-012 (1/3.125th the NOAEL based on HED from GLP toxicology study). 
  
 
 
 
 
 
 
* based on HED from GLP toxicology study 
 
A grid line will be drawn with a makeup pencil in a horizontal plane (Figure 2) 4-6 cm from the 
suprapatellar fat and its distance from the floor recorded. An attempt should be made to find palpable 
nodules along the grid line. The injection sites will be marked in circles with a non-erasable pen. This 
mark should be intensified upon following visits. Injections will be given in multiple sites (4-8 in 
each leg), diagonally (45 °) to palpable nodules, in the fat above the knee.  An attempt should be 
made to lift the nodule and inject into the middle of the fat-mass. If no nodules are noted in the 
horizontal plane, drug will be injected in to the fatty tissue (in this case small nodules seen in 
ultrasound will be followed for changes). Injections will be on the same horizontal plane.  
 
 
Cohort 2 
Number of Subjects – Active 
3 
3 
Total Dose RZL-012 (mg) 
60 
80 
Dose per NOAEL* 
1/4.688 
1/3.125 
Number of Injections 
12 
16 


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Injections will be spread as much as possible and the distance between injected sites will be at least 
2-3 cm, according to the number of injections (see picture below). 
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.  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.  
Subjects may not receive the following medications while on study:  
• 
Chronic treatment with systemic steroids or immunosuppressive drugs. 
• 
 Chronic treatment with Non Steroid Anti-Inflammatory Drugs (NSAIDs) and aspirin.  
• 
Any investigational product other than RZL-012.  
Before dosing, analgesic gels or creams such Lidocaine (e.g., Emla) or Pramoxine should be used to 
numb the injected site.  An ice pack may be applied on the site of injection following dosing to help 
reduce pain.  At day 1 following injection, application of the anti-histamine Benadryl Gel 
(Diphenhydramine hydrochloride 1 %for topical use only) should be initiated prophylactically, 
according to drug instructions for use, to avoid itching at the injected area.  Benadryl Gel should be 
applied for 7 days. 
Use of nattokinase is prohibited and the use of other supplements or complementary 
medicines/botanicals should be approved by the PI, except for conventional multivitamin 
supplements. The use of prohibited supplements should be stopped a week before injection. 
Study 
Procedure 
Study activities upon study entry will include, but not be limited to: 
Informed Consent, full medical history, physical examination, vital signs measurements, ECGs, 
clinical laboratory tests, photography and skin irritancy evaluation of site injection, ultrasound, 
height and weight measurements, Quality of Life (QOL) and function questionnaire in lipedema 
subjects, and pain assessment. 
Periodical site visits will allow assessment of treatment safety and efficacy. 
Subjects will be advised to keep their regular diet and physical activity.  
Visit Schedule 
(See Table 2) 
 
Subject site visits will be performed ± 1 day from scheduled date for study visits Day 0-28 and 2± 1 
days from schedule date for follow-up visits (Day 56).  All data relevant for the visit needs to be 
obtained within 3 days (e.g., blood tests results) of visit.  
Screening Day visit (Day -14 through -2): 
- 
Following signing the informed consent - assessment of subject eligibility will include: 
medical history, physical examination, vital signs, ECG, serology assays (HBV, HCV and 
HIV), clinical laboratory tests, drug screen.   
Clinical laboratory tests will include: 


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1. Hematology:  Complete blood count (CBC) including White blood cell [WBC] differential 
values, Fibrinogen, and coagulation (International normalized ratio [INR], Partial 
thromboplastin time [PTT] and Prothrombin time [PT]). 
2. Serum chemistry analysis:  sodium, calcium, potassium, phosphorus, glucose, liver 
enzymes (Aspartate aminotransferase [AST], Alanine aminotransferase [ALT], Lactate 
dehydrogenase [LDH], Creatine-kinase MM [CK-MM], Gamma-glutamyltransferase 
[GTTP], Alkaline phosphatase [ALP]), Bilirubin, Creatinine, Blood urea nitrogen [BUN], 
Total protein, Albumin, Amylase, Creatine phosphokinase [CPK], C-reactive protein 
[CRP]). 
3. Urinalysis: Nitrite, Sodium, Potassium, Calcium, Phosphate, Protein, Red blood cells 
(RBC), WBC, Blood, Glucose, Ketone bodies, Bilirubin, Urobilirubin, Urine specific 
gravity, Osmolality, and pH. 
- 
In addition, photography and evaluation of skin irritancy by Draize score of the injection 
site area. 
- 
For Dercum's disease subjects – ultrasound assessing nodules size (diameter) and quality. 
Determining which nodules are to be injected with a total of 40mg RZL-012. 
- 
For lipedema subjects – measurement of leg circumference above the knee and assessing fat 
thickness and nodular quality by ultrasound. 
- 
For lipedema subjects - QOL and function questionnaires. 
Baseline visit (Day 0):  
- 
Pre-treatment: eligibility confirmation, vital signs, Draize score, leg circumference, clinical 
evaluation of local pain and tenderness to pressure and nodules size and/or numbers, blood 
sample for serum chemistry, and hematology baseline level will be taken.  
- 
Treatment - All injections will be administered 45 ° to the skin surface using a 1 mL Luer-
lock syringe and a 30 G x 1/2" needle (the hole of the needle pointing into the fat layer). 
- 
Post treatment: ECG (4h and 8h ± 30min post injection), pulse rate (1h, 2h, 4h, 8h, 24h post 
injection in the opposite hand of blood sampling), vital signs (2h ± 30 min post injection), 
Draize score (2h post injection ± 30 min), adverse events (AEs) will be recorded. 
Schedule visits (Day 1-28): 
- 
Day 1 following treatment will include: ECG, vital signs including pulse rate, Draize score, 
and photographs of the treated area, clinical evaluation of local pain and tenderness to 
pressure. Subjects will start applying an anti-histamine gel. 
- 
For safety reasons 24hr ± 2hr following injection, Blood samples for serum chemistry and 
hematology will be taken 
- 
Day 3 following treatment will include Serum chemistry and hematology.   
- 
Visits will take place every 7 days ± 1d from treatment till Day 28.  During visits, all tests 
(physical exam, vital signs, ECG, clinical laboratory tests, urinalysis, Draize score, leg 
circumference above the knee, weight measurement,  QOL and function questionnaires in 
lipedema subjects, clinical evaluation of local pain and tenderness to pressure and reduction 
in nodules size and/or numbers, photographs and ultrasound will be performed according to 
schedule (Table 2). 
- 
Subjects will be questioned for AEs every visit. 
- 
Subjects will record their daily use of analgesics. Diaries will be checked and data will be 
captured in the CRFs. 
Follow-up visit (Day 56):  
- 
Subjects will be followed on Day 56 following injection. 
- 
A week before Day 56 visit, subjects will record their daily use of analgesics. Diaries will be 
checked and data will be captured in the CRFs. 
- 
Evaluation of the injected area will be performed by Draize score, photographs, QOL and 
function questionnaires in lipedema subjects, clinical evaluation of local pain and tenderness 
to pressure and reduction in nodules size and/or numbers. 


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- 
For Dercum's disease subjects – ultrasound assessing nodules size (diameter) and quality. 
- 
For lipedema subjects – measurement of leg circumference above the knee and assessing fat 
thickness and nodular quality by ultrasound. 
- 
Subjects will be questioned for AEs. 
Safety Analysis 
Safety data from the study will be summarized descriptively by treatment and cohort.  Descriptive 
statistics will be calculated for quantitative data and frequency counts and percentages will be 
provided for categorical data.  The nature, frequency, seriousness, severity and relation to study drug 
of 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.  Shift tables of normal / abnormal 
versus baseline may be presented as well. Draize scores will be presented in tabular format by visit, 
treatment, and cohort. Serious adverse events (SAEs) will be described in narratives as part of the 
study report. 
Study 
Endpoints 
Primary Endpoint: 
Evaluation of the overall safety of RZL-012 injection into the subcutaneous fat in Derdum's 
disease and lipedema. 
The primary safety endpoint is the incidence of intolerable side effects. 
Secondary Endpoints: 
1. For lipedema subjects - The reduction in local subcutaneous fat in the injection site region as 
compared to baseline based on ultrasound (reduction in nodules size and/or numbers) and leg 
circumference above the knee assessments. 
2. For Dercum's disease subjects - The reduction in local subcutaneous fat in the injection site 
region as compared to baseline based on ultrasound (reduction in nodules size and/or numbers).  
3. Extended duration of the fat reduction effect.  To that end, ultrasound images and above the knee 
circumference measurement will be followed for 56 days. 
4. Elucidation of the tissue changes by ultrasound of the injection site to include reduction in fat 
thickness and nodular quality. 
5. Improvement in local pain as measured by Comparative Pain Scale and by the reduction in the 
use of analgesics. 
6. Improvement in QOL and function in lipedema subjects as measured by questionnaire (such as 
The Lower Extremity Functional Scale (LEFS)). 


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Sample Size 
This study is planned as a Phase 2a trial. A maximum of 12 evaluable subjects will be included in the 
study (6 Dercum's disease subjects and 6 lipedema subjects) and followed for as long as 56 days. 
Statistical 
Methods 
Statistical analyses will be mainly descriptive in nature where study data will be tabulated and 
summarized using the mean, standard deviation or standard error, median, minimum, maximum and 
number of subjects by cohort for continuous data.  For categorical data, results will be summarized 
via a count and percentage by cohort.  The results will be presented overall, per cohort and per cohort 
and dose. The effects of noncompliance, dropouts, and covariates may be assessed to determine the 
impact on the general applicability of results from this study. 
If any statistical tests are performed, they will be two-sided.  The required significance level of 
findings will be equal to or lower than 5%.  Nominal p-values will be presented. 
Where confidence limits are appropriate, the confidence level will be 95%. 
Incidence of intolerable side effects will be tabulated by study drug by cohort along with 95% 
confidence intervals. 
Change from baseline will be presented in a tabular form by visit treatment. 
AEs and tolerability data will be presented descriptively by treatment and cohort.  AEs will be 
tabulated by body system, preferred term, seriousness, severity and relation to study drug by cohort.  
Where applicable, changes in values over time (e.g., lab values, vital signs, ECGs) will be presented; 
this will include clinical laboratory evaluations (including CBC, blood chemistry and urinalysis), 
coagulation (INR, PTT and PT), vital signs, and ECGs.  Shift tables of normal / abnormal versus 
baseline may be presented as well. 
Draize scores will be presented in tabular format by visit, treatment, and cohort 
Study Duration 
Study duration is 2.5 months, including enrollment, treatment and follow-up period. 
Each subject will participate in the study for up to 42 days as part of this protocol. 
Study Site 
University of Arizona Medical Center, Tucson, Arizona 
 


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1. 
INTRODUCTION 
1.1. 
BACKGROUND 
1.1.1. Scientific Background and Clinical Rationale 
Obesity, a major health concern today, is a direct result of food-intake in excess of body energy 
expenditure.  However, there is a vast amount of published information that proves that for some 
people, obesity is not the result of excessive food consumption, poor food choices, and failure to 
exercise (1). Problems with mitochondria, leaky lymphatics and other mutations can drive and 
maintain fat growth that cannot be lost through traditional diet and exercise (2). Dercum’s 
Disease (Adiposis Dolorosa), Madelung’s Disease, lipedema and Familial Multiple Lipomatosis 
or Angiolipomatosis are names of some of such fat disorders. These are known as Rare Adipose 
Disorders; they are painful, progressive disorders that result in abnormal accumulations of fat in 
the form of lipomas, excess lymphatic fluid, and many other symptoms. 
Lipedema is a chronic condition, initially described in 1940, that occurs almost exclusively in 
women and manifests as symmetrical buildup of painful fat and swelling in the limbs, sparing the 
hands and feet (3). Fat tissue expands primarily in the lower limbs, from buttocks to ankles, as 
well as in the arms. Upon palpation of the fat, tiny pebbles or pea like nodules are felt. As the 
disease advances the nodules may increase in size and in number and may form strands of 
nodules(4). There are no diagnostic tools or tests for lipedema. Diagnosis of lipedema involves a 
clinical assessment and discussion of the individual’s medical history, a process that is difficult 
to scale within the current healthcare system. The absence of diagnostic tools to streamline or 
confirm a clinical diagnosis is a key unmet need, which if addressed, has the potential to 
dramatically change the trajectory of the disease (5). Individuals who suffer from the disease are 
further impacted by the lack of public and medical awareness of lipedema, and the stigma 
associated with weight gain. As a result, the epidemiology of lipedema is unknown (6).  
The etiology of lipedema and other types of fatty tissue enlargement is still unknown, though a 
genetic cause is suspected.  Other possible causes of lipedema include metabolic, inflammatory, 
or hormonal involvement. Although the disease is reported to occur during puberty and other 
periods of hormonal changes, why this happens is not understood.  
Lipedema is sometimes accompanied by co-morbidities, often secondary diseases, which 
complicate the patient’s health. Psychosocial issues are prevalent in women with lipedema, 
contributing to health burden and complexity of disease management. The painful fat and 
swelling in some patients can be so debilitating that their mobility is impaired. Furthermore, 
many patients develop the disease alongside obesity; however, diet, exercise, and weight loss 
surgery have limited effect on lipedema fat. 
A critical issue is the poorly understood disease, which for diagnosed patients results in limited 
treatment options that, at best, ameliorate the symptoms of lipedema. Early detection and 
treatment can significantly reduce the debilitation of the patient.  Early weight and diet changes 


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through nutrition and exercise may be helpful in reducing non-lipedemic fat and 
reducing inflammation.  This approach may possibly prevent the lower body from enlarging as 
much as it would if the patient were to become obese. However, even with strict diet and 
exercise regimens the disease may progress and further treatments may be necessary. While there 
is no proven effective treatment for lipedema, the swelling may be somewhat managed with 
compression garments, manual lymphatic drainage and/or Complete Decongestive 
Therapy.  Unfortunately, some products such as garments may not be well tolerated by all 
patients if the patient experiences pain. Liposuction as a treatment for lipedema was developed in 
Germany in the late 1980s and is becoming more common. However, given the fact that 
liposuction is a surgery, it is not a risk-free procedure.  While it has helped some patients when 
done by a skilled surgeon knowledgeable about lipedema, very few physicians in the United 
States have the knowledge and experience of physicians in Europe. Currently, different 
liposuction procedures (Water Assisted Liposuction [WAL] and Tumescent Liposuction [TLA]) 
used for lipedema patients are available but not all surgeries are suitable for all patients (7).  
Dercum's disease was first described in the medical literature in 1882 by an American 
neurologist named Francis Xavier Dercum’s. Dercum’s disease is an extremely rare disorder 
(listed by NORD [National Organization for Rare Disorders]) characterized by multiple, painful 
growths consisting of fatty tissue (lipomas). These growths mainly occur on the trunk, the upper 
arms and upper legs and are subcutaneous. Pain associated with Dercum's disease can often be 
severe. Pain may be caused by these growths pressing on nearby nerves. Some individuals with 
Dercum’s may experience swelling of various areas of the body, especially the hands. Swelling 
occurs for no apparent reason and often disappears without treatment. In some cases, affected 
individuals may also experience weight gain, depression, lethargy, and/or confusion.  
The etiology of Dercum's disease is unknown, though a genetic cause is suspected (autosomal 
dominant).  Other possible causes playing a role in the development of Dercum's disease include 
autoimmune disorder, disturbances in endocrine function, improper metabolism of fat and the 
use of high-doses of corticosteroids. 
The prevalence of Dercum’s disease is unknown. Dercum’s disease affects females more often 
than males with some reports citing the disease is as 20 times more common in women. 
Dercum’s disease can affect individuals of any age. The majority of cases are women between 
the ages of 45-60, especially overweight, postmenopausal women.  
No specific treatment exists for Dercum’s disease. Treatment is mainly symptomatic and 
supportive and is primarily focused on easing the characteristic painful episodes. Various 
analgesics have been tried with limited effectiveness. Surgical excision of fatty tissue deposits 
around joints may temporarily relieve symptoms although recurrences often develop. 
Liposuction has been used as a supportive treatment for some individuals with Dercum’s disease 
and may provide an initial reduction in pain and improvement in quality of life (QOL) (8). 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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RZL-012 is a novel synthetic molecule enabling the conversion of white adipose tissue (WAT) 
into an activated thermogenic tissue at targeted anatomical sites.  A single injection of RZL-012 
into WAT is sufficient to trigger robust tissue remodeling.  A chain of events begins with 
removal of WAT adipocytes by macrophages (liponecrosis), followed by an activation of 
remodeled cells that generate a futile cycle of ongoing energy conversion into heat. Temperature 
measurements of the site treated by RZL-012 reveal a persistent local increase in temperature 
(about 4 months in pigs). As long as these cells are active, the ensuing thermogenic tissue will 
consume free fatty acids (FFA) from the nearby surrounding adipose depots and further from 
glucose and FFA supplied via the blood stream.  
The overall clinical plan for RZL-012 includes the completed exploratory (phase 0) study to 
evaluate the safety, thermogenesis, and pharmacodynamic response to RZL-012.  An additional 
phase 2 study (Study RZL-012-P2aUS-001.1) in overweight and obese subjects to confirm the 
safety and pharmacodynamic effects of RZL-012 for the treatment of obesity will be initiated 
soon to explore the response to higher doses prior to the initiation of larger studies.  The initial 
exploratory study (Study RZL-012-P0US-001.3) demonstrated that RZL-012 is well tolerated 
with no serious adverse events reported and that thermogenesis was evident at the injection site 
(abdomen) of RZL-012-treated obese subjects.  Although not statistically significant (due to the 
initially tested low dose and a small-size study group, n=6), there was a decrease in subcutaneous 
fat mass (SFM) over time (compared to baseline) in the abdomen, as measured by Magnetic 
Resonance Imaging (MRI), in 5 out of 6 RZL-012 treated subjects, but none in vehicle treated 
ones. 
Raziel Therapeutics believes that RZL-012 effects of adipose-tissue replacement thermogenic 
tissue and the ongoing lipolysis and consumption of FFA from nearby adipose tissue by the 
remodeled cells can be beneficial to patients with fat disorders such as lipedema and Dercum's 
disease. Local fat reduction and tissue remodeling at selected sites such as at the medial knee in 
lipedema patients and at lipomas in Dercum's disease patients may bring pain relief and 
improvement in QOL.  
The current Phase 2a study is aimed to evaluate the safety and pharmacodynamics response to 
RZL-012 in lipedema and Dercum's disease patients.  
 
1.1.2. RZL-012 Formulation Development 
The active ingredient RZL-012 drug substance was manufactured by Pharmacore, High Point 
NC, USA.  The drug product, 5 % RZL-012 in F12 liquid formulation (RZL-012 in F12 is 5 
g/vial, RZL-012 is 250 mg/vial) was manufactured and packed at Nextar Ltd, Ness-Ziona, Israel.  
RZL-012 in F12, which was once defined as RZL-012 F12, is now defined as RZL-012.  The 
active ingredient and formulation manufacturing and packing were in accordance with current 
Good Manufacturing Practices (cGMPs). 


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1.2. 
NONCLINICAL ASSESSMENTS 
1.2.1. Pharmacology 
Studies in rats and pigs concluded that RZL-012 triggers remodeling of WAT to brown-like 
adipose tissue (BAT) tissue, thereby activating thermogenesis.  The dose of RZL-012 to be used 
in clinical trials was extrapolated from the safety data obtained during animal testing no observed 
adverse effect level (NOAEL). 
1.2.1.1. 
Efficacy In-vivo and In-vitro Studies 
Nonclinical studies were conducted to prove the efficacy of RZL-012 in several in-vivo and in-
vitro models. 
The in vivo studies (in pigs and rats) involving local administration of RZL-012, focused on two 
main endpoints: fat tissue reduction and conversion of WAT to BAT, measured by several 
parameters, including; 
1. Subcutaneous or epididymal fat reduction following RZL-012 treatment. 
2. Fat tissue remodeling involving non-inflammatory liponecrosis, followed by tissue 
"browning", where WAT is converted to BAT in rodents and smooth-muscle-like tissue 
in larger mammals.  This conversion can be determined by: 
a. Histological fat tissue changes:  While white adipocytes are large and resemble a 
single large oil drop, with a characteristic condensed nucleus, the cells of BAT are 
smaller, contain multiple mitochondria and a euchromatic nucleus.  
b. Uncoupling protein 1(UCP-1) levels: UCP-1 is a mitochondrial inner membrane 
protein present in BAT that can dissipate the proton gradient before it can be used 
to provide the energy for oxidative phosphorylation.  UCP-1 normally does not 
exist in WAT.  
c. Smooth-muscle-like thermogenic tissue: In pigs, examination of tissue-sections 
taken from the site of injection, where robust thermogenesis was observed, 
revealed smooth-muscle-like histology, including typical molecular markers such 
as SMA.  
3. Assessment of body-surface temperature: Thermogenic tissue, e.g. classical BAT, is 
typified by futile burning of fatty acids (i.e., heat production instead of adenosine 
triphosphate [ATP]), which can be assessed utilizing infrared camera that can measure 
differences in body surface temperature. 
The objective of the in-vitro studies was to reveal the mechanism of action of RZL-012 in 
adipocytes.  Studies were conducted on the 3T3-L1 adipocytes line, which is considered a model 
for WAT.  


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1.2.1.2. 
Safety Pharmacology 
The effect of RZL-012 on the central and peripheral nervous systems was evaluated using the 
Functional Observational Battery (FOB) in male Sprague Dawley rats.  RZL-012 was 
administered subcutaneously to rats (n = 8/group) as 10 mg/rat.  From the results, it was 
concluded that RZL-012 did not affect any of the central nervous system (CNS) functions tested 
using FOB in rats. 
The effect of RZL-012 was evaluated on respiratory functions in male Sprague Dawley rats 
using head-out plethysmography.  RZL-012 was administered subcutaneously at a fixed dose of 
10 recorded to cover the entire predetermined time points: Pre-dose, 1, 2, 3, and 4 h post dose.  
RZL-012 did not affect any of the parameters tested; hence it was concluded that RZL-012 has 
no effects on the respiratory system at the tested dose of 10 mg/rat.  
A board-certified veterinary cardiologist conducted a qualitative and quantitative review of the 
electrocardiograms (ECGs) obtained pretest, pre-dose, 4 and 24 hours post-dose following the 
subcutaneous injection of 500 mg 5.0 % RZL-012 or vehicle in Domestic Yorkshire Crossbred 
Swine.  There was no effect of the subcutaneous injection of 5.0 % RZL-012 on qualitative or 
quantitative ECG parameters or blood pressure. 
1.2.2. Toxicology 
The study design was to evaluate the safety of RZL-012 according to Food and Drug 
Administration (FDA) guidelines for Exploratory Investigational New Drug (IND) appropriate 
for first-in-man clinical trial.  An extended single-dose toxicity study was performed according 
to FDA guidance in two species (rat and pig) to establish the NOAEL. 
1.2.2.1. 
Extended Single Dose Toxicity Studies 
1.2.2.1.1. Rats 
Single subcutaneous administration of test item RZL-012 at the doses of 5, 10, and 20 mg/kg in 
Sprague-Dawley rats resulted in non-systemic effects and or local effects at the treated skin area.  
Few changes observed in haematological parameters (white blood cells [WBC] count, 
neutrophils, monocytes and eosinophils) were considered secondary effects due to inflammatory 
response (local skin reactions).  The changes observed in clinical chemistry parameters 
(increased blood urea nitrogen [BUN] in males and females and increased creatinine and 
aspartate aminotransferase [AST] levels in females) at all the doses tested and histopathological 
changes in kidneys (necrosis in tubular epithelium) at 20 mg/kg were considered systemic 
effects.  Methods and results from the extended single dose toxicity study are described in the 
Investigator's Brochure (IB). 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
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Considering skin changes as non-systemic effects and or local effects, the NOAEL was 
determined at 5 mg/rat with an average body weight of 258.9 g, under the test conditions and 
doses employed. 
1.2.2.1.2. Pigs 
This study was conducted to evaluate the potential local and systemic toxicity as well as efficacy 
of the test article, RZL-012 (50 mg/mL), in domestic Yorkshire crossbred swine following 
subcutaneous injection into the subcutaneous abdominal fat on Day 0.  Methods and results from 
the extended single dose toxicity in pigs study are described in detail in the IB. 
Assessment of toxicity was based on mortality, clinical observations, body weight, qualitative 
food consumption, body temperature, subcutaneous fat temperature, blood pressure, physical and 
electrocardiographic examinations, and anatomic and clinical pathology.  Blood samples were 
collected and analyzed for porcine stress syndrome testing and toxicokinetic assessment of the 
test article. 
Administration of the test article was not associated with any mortality, clinical observations 
(with the exception of transient redness and swelling at injection sites), body weight or food 
consumption changes, effects on electrocardiographic endpoints, or changes in clinical chemistry 
or coagulation parameters.  It should be noted that three animals died during the post anesthesia 
recovery period.  The cause of death was considered to be related to perioperative complications 
associated with the anesthesia and not related to RZL-012 or saline administration.  These three 
animals were replaced on study.  This nonclinical laboratory study was conducted in accordance 
with the United States Food and Drug Administration (FDA) Good Laboratory Practice (GLP) 
Regulations, 21 Code of Federal Regulations (CFR) Part 58 and the Organization for Economic 
Cooperation and Development (OECD) Principles on GLP [as revised in 1997; 
ENV/MC/CHEM(98)17].  A complete postmortem necropsy was conducted on these dead pigs, 
and protocol-designated tissues were saved and processed for microscopic evaluation under 
ambient conditions to Alizée Pathology, Thurmont, Maryland.  Two of these animals were 
controls and one treated. Pigs are very sensitive to anesthesia and these were complications due 
to it. Attached is the study report - you can find mortality results and discussion on page 26-27. 
A slight elevation in body temperatures was noted in males treated with the test article from 
Days 14-16 until Days 77-79.  In addition, several animals were observed with perioperative 
hyperthermia and/or hypothermia.  To determine if the perioperative hyperthermia and/or 
hypothermia was caused by Porcine Stress Syndrome all remaining animals on study were tested 
and determined to be normal (negative). 
Administration of the test article was associated with changes in subcutaneous fat temperatures, a 
mild increase in neutrophils, and macroscopic and microscopic observations.  
A noticeable difference in subcutaneous fat temperatures was noted between treatment groups.  
Beginning as early as Day 4-5, an increase in temperature was noted at all test article treated sites 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
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in both males and females.  The increase in temperature was noted through Days 58-63.  At 
study termination, subcutaneous fat temperatures at treated sites were comparable to vehicle 
control. 
Subcutaneous administration of RZL-012 (50 mg/mL) to farm pigs resulted in mild increases in 
neutrophils in both sexes at the 24-hour post-dose collection, which were most typical of an 
inflammatory response.  Increases in neutrophils had resolved by the Day 14 collection. 
Analysis of the plasma samples following subcutaneous administration of RZL-012 (Group 4) 
found that both female and male farm pigs were exposed to RZL-012.  Mean systemic exposure 
(area under the concentration versus time curve between zero and the 24 hour time point 
[AUC0-24hr]) and maximum observed concentration (Cmax) values, were 3700 (hr*ng/mL) and 
529 (ng/mL), respectively, for males and mean systemic exposure (AUC0-24hr) and Cmax values, 
were 2940 (hr*ng/mL) and 528 (ng/mL), respectively, for females. 
Upon evaluation of the injection site photographs, no irritation was observed but transient 
redness was noted.  Upon microscopic evaluation at 24 hours and 14 days, test article related 
findings in the injected subcutaneous tissue was noted.  These findings were characterized by 
necrosis of the subcutaneous fat and muscle accompanied by acute inflammation at 24 hours 
post-dose.  At 14 days, residual necrotic tissue in the injected areas was noted with evidence of 
on-going healing characterized by chronic inflammation and fibrosis.  There was no evidence of 
systemic toxicity at 24 hours or 14 days 
The 14 day interim results of this study demonstrated that administration of 5.68 to 7.14 mg/kg 
to males and 5.32 to 6.33 mg/kg to females of RZL-012 (test article) over 20 injection sites in the 
pig was associated with expected changes in subcutaneous fat temperatures, transient changes in 
neutrophils, and marked localized irritation and tissue necrosis.  The increase in subcutaneous fat 
temperature was considered to be related to the mechanism of action of RZL 012, and an 
indication of the efficacy of the test article.  The microscopic changes noted at 24 hours were 
beginning to resolve at 14 days.  The results of the final time point at 84 days will allow for 
assessment of the resolution of these findings.  
1.2.3. Additional Nonclinical Studies 
• Secondary pharmacology (searching for off-target receptors).  
• Establishing pharmacokinetic (PK) parameters and investigation of RZL-012 
metabolism by liver enzymes and half maximal inhibitory concentration (IC50) in 
cell-culture.  
• Testing RZL-012 mutagenicity, utilizing the Ames test. 
• Pyrogenicity in rabbits. 
• Assessment of RZL-012 binding to the β3 receptor in cellular and nuclear receptor 
functional assays.  


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• Assessment of RZL-012 uptake by the 5-HT neurotransmitter in the absence and 
presence of a 5-HT2B agonist. 
• Assessment RZL-012 effect on 5-HT neurotransmitter uptake and release in cellular 
and nuclear receptor functional assays. 
• ADME-Toxicology 
• Genotoxicity 
Methods and results from these safety studies are described in the Investigator's Brochure. 
1.2.4. Clinical Studies 
Raziel Therapeutics has conducted an Exploratory phase 0, randomized, double-blind, vehicle-
controlled study aimed at the evaluation of safety and thermogenesis-induction of three 
escalating doses of RZL-012 drug product in overweight and obese volunteers.  In each cohort, 
8 subjects were enrolled, 6 active and 2 control.  Study design is presented in the following table: 
Table 1:  Phase 0 Clinical Trial Design 
 
Cohort 1 
Cohort 2 
Cohort 3 
Number of Subjects – Active/Placebo 
6/2 
6/2 
6/2 
Total Dose RZL-012 (mg) 
5 
10 
20 
Dose per NOAEL* 
1/50th  
1/25th  
1/12.5th  
Number of Injections 
1 
2 
4 
 
Primary objective:  Evaluation of the overall safety of RZL-012 subcutaneous injection and the 
existence of a thermogenic effect. 
Secondary objective:  Determination of RZL-012 pharmacodynamics and pharmacokinetics.  
Evaluation of the extent, duration and tissue associated changes of the thermogenic response to 
RZL-012, via minimal invasive means including injected-site thermogenesis imaging, MRI, and 
punch biopsy following injection into the subcutaneous fat. 
Primary Endpoints: 
Safety - The primary safety endpoint was no more than two subjects experiencing a dose-limiting 
toxicity (DLT) event.  
Efficacy - The primary efficacy endpoint was a significant thermogenesis at the injected site 
compared with the contra-lateral, non-injected site.  This was monitored by sensitive (± 0.1 °C) 
infra-red thermal camera.  A thermogenic effect was defined by an increase of 1 °C in the 
injected site when compared to the surroundings and/or the contra-lateral (non-injected site), 
apparent at least 28 days after injection and non-related to inflammatory response as determined 


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by inflammatory cytokines.  The primary efficacy evaluation was supported by results from 
secondary endpoints, including MRI, biopsy, and biomarkers. 
Secondary Efficacy Endpoints: 
1. The key secondary efficacy endpoint was the duration of the thermogenic effect in those 
subjects demonstrating clear thermogenesis by 28 days after injection.  
2. Local reduction in fat mass as determined by MRI. 
3. Clinical laboratory changes, including improvement in fasting blood glucose and lipid 
profile. 
4. Anthropometric changes, including body weight change. 
5. Establishing pharmacokinetic profile for RZL-012 
6. Elucidation of the histological changes account for the thermogenic effect by biopsy of the 
injection site. 
7. Exploration of mode of action by evaluation of inflammatory markers and cytokines 
Results: 
This was a dose escalation exploratory clinical trial of RZL-012, a first-in-class, new chemical 
entity.  
RZL-012 was generally found to be safe in all cohorts.  There were no clinically significant 
changes in vital signs, ECG and almost all blood laboratory tests.  Most adverse events (AEs) 
associated with RZL-012 injection occurred confined to the injection site and were transient.  
Biopsy from the injected site revealed no damage to the skin 56 days following RZL-012 
injection.  The only significant local AE was an abscess in one subject in the lower abdomen on 
the injected side, but at a considerable distance from the site of injection. 
In another patient, a severe elevation of alanine aminotransferase (ALT) blood levels and a 
moderate elevation of AST blood levels were seen 14 days following injection.  This elevation 
was transient (resolved within 14 days).  In light of the pre-clinical findings (increased AST 
blood levels in female rats sacrificed on Day 2 following RZL-012 injection) and in light of the 
findings in this clinical trial, Raziel therefore plans to monitor closely (on 24hr, Day 3, Day 7, 
Day 14, Day 21, Day 28 and will follow further if necessary) liver functions in the next clinical 
trial.  There were no other systemic clinically significant AEs. 
The exploration of thermogenesis induction by RZL-012 in humans was successful.  A raise in 
temperature at the injection site was mostly evident in cohort 3 (the highest dose) at Day 14 or 
Day 21 following injection in RZL-012 treated subjects only.  This change in temperature was 
captured and recorded by the infra-red camera.  


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Although not statistically significant, a drop in the change from baseline in SFM ratio 
(treated/control) over time by MRI in RZL-012 treated subject of cohort 3 was evident in 5 of 
6 treated subjects.  The drop in subcutaneous fat associated with a drop in weight (more than 
1 kg) and Body Mass Index (BMI) when compared to baseline and is evident in 4 of 6 RZL-012 
treated subjects of cohort 3 on Day 28 and/or Day 56, while controls gained weight and 
increased BMI.  
Biopsy did not yield enough tissue (because punch biopsy did not penetrate deep enough to reach 
the remodeled tissue), and therefore, it was not possible to demonstrate that thermogenesis is due 
to adipose tissue remodeling. 
Although not statistical significant, a decrease in TC and FFA blood levels was evident in 
subjects of the RZL-012 treated group in cohort 3.  This may imply to the mode of action of 
RZL-012 as stimulation of a thermogenic tissue such as BAT, is known to cause a systemic 
effect via the mobilization of glucose and FFA from the blood stream to feed the ongoing local 
thermogenesis.  Thus, lipolysis of WAT triacylglycerols (TAG) stores is accelerated and the 
uptake of FFA derived from blood-born lipoproteins is increased due to the action of lipoprotein 
lipase (LPL).  Raziel assumes that circulating FFA utilization by the RZL-012-induced 
thermogenic tissue resulted in lower levels of FFA in the blood, a process that may be beneficial 
for health.  There was no consistent pattern to suggest a connection between inflammation 
markers and cytokines levels and changes in thermogenic activity reflecting the intended effect 
of the drug as opposed to local inflammation and distinguish between events related to M1 and 
M2 macrophages.  Though, an increase in Adiponectin blood level was evident at Day 21 and 
Day 28 in 3 of 6 subjects treated with RZL-012, but not in controls.  Adiponectin was found to 
be an obligatory mediator of cold-induced browning of WAT (9).  Adiponectin can be elevated 
under various conditions, including those that trigger tissue remodeling in favor of 
thermogenesis such as chronic cold exposure.  Although we do not know what triggered 
elevation of adiponectin in this study, it is known that downstream effects of adiponectin can 
promote the type of tissue remodeling we are expecting. 
Raziel concludes that the potential risk-benefit balance for RZL-012 is favorable, and that it is 
likely that higher doses of RZL-012 will generate better results.  This will be assessed in the next 
clinical trial. 
Methods and results of this exploratory study are described in the IB. 
2. 
PURPOSE AND STUDY OBJECTIVES 
2.1. 
PURPOSE 
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 women and men 
with nodular Dercum's disease. 


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2.2. 
STUDY OBJECTIVES 
2.2.1. Primary 
The primary objective is the evaluation of the overall safety of RZL-012 following injection into 
the subcutaneous fat in patients with lipedema.  
2.2.2. Secondary 
The secondary objective is the evaluation of local fat reduction, its extent, duration and tissue 
associated changes and the extent of pain relief, in response to RZL-012 treatment, utilizing 
minimal invasive means (ultrasound) following subcutaneous injection of RZL-012 into fatty 
tissue below the skin.  
3. 
STUDY DESIGN 
3.1. 
DESCRIPTION OF STUDY DESIGN 
This is an open label, 2 cohort, clinical trial in women with lipedema with substantial fat above 
the knee or women and men with nodular Dercum's disease. Each cohort will have 6 subjects 
who will receive RZL-012. 
3.2. 
DOSE RATIONALE 
The initial dose was determined by the NOAEL established by the Good Laboratory Practice 
(GLP) extended single dose toxicology study and by the previous phase 0 clinical trial in which 
20mg RZL-012 was the highest dose achieved.  This initial study is an escalating dose study.  If 
no more than 1 subject experiences intolerable side effects within 14 days following the injection 
of the last dosed group, according to schedule, an additional cohort of volunteers will be 
administrated the next dose level. 
Cohort 1- will be comprised of subjects with Dercum's disease. All subjects will be injected with 
RZL-012. Dosing will be calculated according to the size of the nodule (diameter) as determined 
by ultrasound: 5mg/cm2 reaching a maximal dose of 40 mg RZL-012 per subject (1/6.25 the 
NOAEL based on the Human Dose Equivalent [HED] GLP Toxicology studies). 
Cohort 2 - will be comprised of subjects with lipedema with substantial fat above the knee and 
will be conducted in a dose escalation manner. 
The first 3 subjects will receive 60mg RZL-012 (1/4.688th the NOAEL based on HED from GLP 
toxicology study).                                                                                      
The last 3 subjects will receive 80mg RZL-012 (1/3.125th the NOAEL based on HED from GLP 
toxicology study).                                                                                                                                                       


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3.3. 
DOSING 
3.3.1. Dosing Regimen 
The dosing regimen will be a single dose treatment injection of RZL-012 in multiple sites. 
Six subjects in cohort 1, all assigned to the RZL-012 treatment group will be dosed at a maximal 
dose of 40 mg RZL-012 (approximately 1/6.25th the NOAEL as determined in the GLP 
toxicology study). Dosing will be calculated according to the size of the nodule (diameter) as 
determined by ultrasound in a dose of 5mg/cm2: 
Nodule of 2-2.9cm diameter, as determined by ultrasound, will be injected 2 injections (0.1 mL 
each, 1 cm apart); total of 10 mg RZL-012.  
Nodules of 3-3.9cm diameter, as determined by ultrasound, will be injected 3 injections (0.1 mL 
each, 1 cm apart); total of 15 mg RZL-012.  
Nodules of 4-8cm diameter, as determined by ultrasound, will be injected 4 injections (0.1 mL 
each, 1 cm apart); total of 20 mg RZL-012. 
Cohort 1 – Dercum's disease 
Number of Subjects – Active 
6 
Nodule size – diameter (cm) 
2-2.9 
3-3.9 
4-8 
Total Dose of RZL-012 (mg) 
10 
15 
20 
Dose per NOAEL* 
1/25th 
1/18.75th 
1/12.5th 
Number of Injections 
2 
3 
4 
 
Six subjects in cohort 2, all assigned to the RZL-012 treatment group, will be dosed as follows: 
The first 3 subjects will receive 30mg RZL-012 in 6 injections (0.1mL each) in one leg followed 
by 30mg RZL-012 (6 injections, 0.1mL each) in the second leg adding up to 12 injections of 
60mg RZL-012 (1/4.688th the NOAEL based on HED from GLP toxicology study).  
The last 3 subjects will receive 40mg RZL-012 in 8 injections (0.1mL each) in one leg followed 
by 40mg RZL-012 (8 injections, 0.1mL each) in the second leg adding up to 16 injections of 
80mg RZL-012 (1/3.125th the NOAEL based on HED from GLP toxicology study).  
*based on HED from GLP toxicology  
 
 
 
Cohort 2 - Lipedema 
Number of Subjects – Active 
2 
2 
Total Dose RZL-012 (mg) 
60 
80 
Dose per NOAEL* 
1/4.688 
1/3.125 
Number of Injections 
12 
16 


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Dosing of subjects in each cohort will progress consecutively from one individual to the other at 
7-day intervals. This study design will allow the physicians to monitor safety for at least 7 days 
prior to dosing the next subject. For cohort 2 the decision to proceed to the next dose level will 
be made after reviewing all safety data collected by Day 14 within 2 ± 1d of the last dosed 
subject. The trial will proceed within a cohort provided that no more than one subject 
experiences intolerable side effects in a cohort, and based on the decision made by the Principal 
Investigator (PI) and the Medical Monitor.   
3.3.2. Intolerable Side Effect 
An intolerable side effect defined as any of the following treatment-related adverse drug 
reactions (ADRs): 
Any Grade 3 or greater event except for the following (For the following events, a discussion 
will be held by the PI and the Medical Monitor to decide whether considered as an intolerable 
side effects): 
o Flu-like symptoms and fever that responds to standard treatment within 72 hours 
o Localized edema and erythema 
o Pruritus 
o Pain 
o Skin/soft tissue inflammation 
o Fat Atrophy 
o Liver enzymes abnormality 
o Non-significant lab abnormalities, lasting less than 7 days  
 
To establish a threshold for clinical abnormalities and liver enzyme abnormalities the following 
tables were formed for main expected side effects. For the following abnormalities, associated 
with the injection site or treatment intolerable side effect would be any Grade 3 or greater event: 


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Clinical Abnormalities Table 
* Erythema – the measured local reaction at the greatest single diameter beyond the injected area surface of all 
injections (For Dercum's disease – nodules of 2-2.9 cm diameter 2*2 cm, nodules of 3-3.9 cm diameter 3*2 cm 
nodules of 4-8 cm diameter 4*2 cm. For lipedema -12*2 cm for the first subjects, 15*2cm for the following subjects 
and 16*2cm for the last subjects), the measurement should be recorded as a continuous variable.  
**Induration –– the measured local reaction at the greatest single diameter beyond the injected area surface of all 
injections (For Dercum's disease – nodules of 2-2.9 cm diameter 2*2 cm, nodules of 3-3.9 cm diameter 3*2 cm 
nodules of 4-8 cm diameter 4*2 cm. For lipedema -12*2 cm for the first subjects, 15*2cm for the following subjects 
and 16*2cm for the last subjects), the measurement should be recorded as a continuous variable.  
Liver Enzyme Abnormalities Table 
 
Study discontinuation is to be considered by the investigator in any case of an intolerable side 
effect and the actions taken are to be fully documented in source documents and Case Report 
Forms (CRFs).  
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain  
Does not interfere 
with activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours 
Interferes with 
activity 
Any use of narcotic 
pain reliever beyond 
7 days following 
injection or prevents 
daily activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness  
Discomfort to touch 
or with movement 
Significant 
discomfort at 
rest 
Prevents daily 
activity 
ER visit or 
hospitalization 
Erythema/Redness*  
2.5 - 7 cm 
7.1 - 15 cm 
> 15 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling**  2.5 - 7 cm and does 
not interfere with 
activity 
7.1 - 15 cm or 
interferes with 
activity 
>15 cm or prevents 
daily activity 
Necrosis 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Liver Function Tests –ALT, AST 
increase by factor 
3 x ULN 
3 – 5 x ULN 
5-10 x ULN 
beyond 10 days  
> 10 x ULN 
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To be considered an intolerable side effect, such an event must be considered to be possibly or 
probably related to the study drug. 
Subjects experiencing an intolerable side effect will be withdrawn from the study, but followed 
for toxicity. 
The study may also be prematurely terminated in any of the following cases:  
• Recurring serious or severe ADR clinically evaluated by PI as warranting study 
termination.  
• A decision made by Sponsor and/or IRBEC and/or local regulatory agency to terminate 
the study.  
 
4. 
STUDY ENDPOINTS 
4.1. 
PRIMARY ENDPOINTS 
The primary endpoint will be the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat in Dercum's disease and lipedema. The trial will proceed within a cohort 
provided that no more than one subject experiences intolerable side effects in a cohort.  
4.2. 
SECONDARY ENDPOINTS 
Following are the study's secondary endpoints:  
1. For lipedema subjects - The reduction in local subcutaneous fat in the injection site 
region as compared to baseline as assessed by leg circumference above the knee 
assessments, see definition in Section 6.1.16.2.1 and by the reduction in nodules size 
and/or numbers assessed by ultrasound, see definition in Section 6.1.14.2.2. 
2. For Dercum's disease subjects - The reduction in local subcutaneous fat in the injection 
site region as compared to baseline assessed by the reduction in nodules size and/or 
numbers by ultrasound, see definition in Section 6.1.14.2.2. 
3. Extended duration of the fat reduction effect.  To that end, ultrasound images and 
circumference measurement will be followed for 56 days, see definition in Section 
Error! Reference source not found.. 
4. Elucidation of the tissue changes by ultrasound of the injection site to include reduction 
in fat thickness and nodular quality, see definition in Section 6.1.16.2.4. 
5. Improvement in local pain as measured by Comparative Pain Scale and by the reduction 
in the use of analgesics, see definition in Section 6.1.16.2.4. 


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6. Improvement in QOL and function in lipedema subjects as measured by questionnaire 
(such as The Lower Extremity Functional Scale (LEFS)), see definition in 
Section 6.1.16.2.5. 
5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria will be eligible for study participation: 
1. Post-menopausal (at least 2 years) women no more than 65 years old, with lipedema 
involving substantial fat above the knee or nodular Dercum's disease in such women and 
in men 20 - 65 years with nodular Dercum's disease.  
 
2. For Dercum's disease subjects – at least 2 nodules to be injected of at least 2cm diameter 
each, as determined by ultrasound  
3. For lipedema subjects - Significant subcutaneous fat above the knee as determined by 
circumference of 50cm  
4. Generally considered healthy according to medical history, physical examination, ECG 
and laboratory evaluation with a special emphasis on metabolic parameters (fasting 
glucose concentration < 200 mg, normal blood pressure). 
5. Subjects must be able to adhere to the visit schedule and protocol requirements and be 
available to complete the study. 
6. Subjects must sign an informed consent indicating that they are aware of the 
investigational nature of the study. 
5.2. 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded: 
1. Unable to tolerate subcutaneous injection. 
2. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorders, that 
in the opinion of the investigator, put the subject at significant risk, are not eligible.  
3. Positive blood screen for Hepatitis B surface antigen (HbSAg), Hepatitis C virus (HCV), 
or Human immunodeficiency virus (HIV), or positive urine screen for alcohol or drugs of 
abuse (unless prescribed by a physician). 
4. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune 
disease or subjects taking immunosuppressive drugs such as corticosteroids are ineligible.  
5. As a result of medical review, physical examination, the PI (or medically qualified 
nominee) considers the subject unfit for the study. 
6. Known sensitivity to components of the injection formulation.  
7. Prior wound, tattoo or infection in the treated area. 


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8. Prior invasive treatment such as surgery or injectable drug at the RZL-012 injected area. 
5.3. 
SUBJECT IDENTIFICATION 
A unique code numbers will be assigned by the investigator to the trial subject rather than the 
subjects’ names, personal identification numbers, and/or addresses to protect the subject's 
identity.  The code numbers and initials will be used in lieu of the subject's name when the 
investigator reports AEs and/or other trial related data. 
5.4. 
REMOVAL, REPLACEMENT OR EARLY WITHDRAWAL OF SUBJECTS 
FROM ASSESSMENT NOT DUE TO INTOLERABLE SIDE EFFECTS 
Subjects experiencing an intolerable side effect will be withdrawn from the study, but followed 
until the event resolves or becomes stable. If only one subject is withdrawn or removed from the 
study, and no more than one subject experience intolerable side effects, then the subject will not 
be replaced.   
6. 
STUDY PROCEDURES AND ASSESSMENT 
6.1. 
DEFINITIONS OF STUDY PROCEDURES 
6.1.1. Informed Consent 
Prior to initiation of any study procedures, each subject will undergo an Informed Consent 
process in which the subject voluntarily confirms their willingness to participate in the trial, after 
having been informed of all aspects of the trial relevant to their decision to participate.  The 
investigator, or a person designated by the investigator, will fully inform the subject of all 
pertinent aspects of the trial.  In addition, the investigator, or a person designated by the 
investigator, will inform the subject that he is free to refuse to enter the study or to withdraw 
from the study at any time, for any reason. 
The Informed Consent Form (ICF) approved by the IRB/EC will contain a description of the 
study’s purpose, procedures, inconveniences and potential risks, and anticipated benefits.  
Prior to a subject’s participation in the trial, an ICF will be signed and personally dated by the 
subject and by the person who conducted the Informed Consent discussion.  
If a subject is unable to read, he may not participate in the study. 
Prior to participation in the trial, the subject will receive a copy of the signed and dated written 
ICF.  During participation in the trial, the subject will receive a copy of the signed and dated 
consent form updates and a copy of any amendments to the written information provided to 
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The investigator should document in the source data that the Informed Consent was signed prior 
to subject's participation in the study and according to the International Conference on 
Harmonization Good Clinical Practice (ICH-GCP) guidelines, as described above. 
6.1.2. Medical History 
Subjects' medical history should be fully documented at Screening Day (14 through 2 days prior 
to baseline), to ensure compliance with study inclusion criteria and the absence of circumstance 
mentioned in the exclusion criteria.  Medical history information must include, but not be limited 
to, past and present medical conditions, concomitant non-drug treatments and hypersensitivity to 
drugs. 
6.1.3. Concomitant Medication 
All concomitant medication given 1 month prior to study entry, including blood and blood 
products, dietary supplements, and non-prescription drugs will be listed at screening/baseline.  
Each entry will include the treatment's start date, treatment name (Generic), reason for use, 
dosing regimen (dose and frequency of use), route of administration, and stop date (if 
applicable).  The clinical significance of the medication use will be decided by the investigator.  
Study subjects will be routinely questioned for changes in the administration of concomitant 
medication during the trial and changes should be updated from medical records as well.  
6.1.4. Physical Examination 
The investigator (or medically qualified nominee) will conduct a complete physical examination, 
height and weight measurements at Screening Day (performed 14 through 2 days prior to 
baseline).  Clinically significant abnormal findings except overweight and obesity should be 
discussed with the Sponsor. 
Additional physical examination to assess subject's safety and weight measurement will be 
performed on study visit on Day 28. 
6.1.5. Pain Measurement  
Local pain as measured by Comparative Pain Scale (Appendix II) will be measured at Screening 
Day (performed 14 through 2 days prior to baseline) in order to establish a baseline to compare 
following drug injection. For lipedema subjects Comparative Pain Scale will be measured for 
each leg and for Dercum's disease subjects for each selected lipoma for injection. 
Additional pain measurements will be performed on study visits Day 14, 28, and 56.   
Pain will be also assessed by Subject's self-recording the daily use of analgesics in a diary. 
Subjects will receive a diary on Screening Day and will start recording daily painkiller use along 
the trial till Day 28. A week before Day 56 visit, subjects will record their daily use of 


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analgesics. Diaries will be checked routinely on each study visit and data will be captured in the 
CRFs. 
6.1.6. Quality of Life and Function Measurement 
QOL and function assessed by the LEFS questionnaire (Appendix III)  will be measured in 
lipedema subjects at Screening Day (performed 14 through 2 days prior to baseline) in order to 
establish a baseline to compare following drug injection.  
Additional pain measurements will be performed on study visits Day 14, 28 and 56. 
6.1.7. Vital Signs Measurements 
Subjects' vital signs will be measured at Screening Day (performed 14 through 2 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  
Vital signs measurements will include systolic and diastolic sitting position blood pressure, pulse 
rate, respiratory rate, and body oral temperature.  
Additional vital signs measurements to assess subject's safety will be performed at baseline visit 
(Day 0) prior to drug injection, 2h ± 30min following drug injection, the following day (Day 1) 
after drug injection (24h ± 2h) and on study visits every 7 days thereafter, i.e., Day 7, Day 14, 
etc. 
Additional pulse rate measurements to assess subject's safety will be performed at baseline visit 
(Day 0) prior to drug injection and 1h, 2h, 4h, 8h, 24h following injection in the opposite hand of 
blood sampling. 
6.1.8. Serology Assays 
Assays for HCV, HbSAg, and HIV will be conducted at Screening Day 1 (performed 14 through 
2 days prior to baseline) in order to ensure compliance with study inclusion criteria. 
6.1.9. Clinical Laboratory Tests 
Clinical laboratory tests will be conducted at Screening Day (performed 14 through 2 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.  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 9. 


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6.1.9.1. 
Hematology 
Hematology tests will be conducted at Screening Day (performed 14 through 2 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 baseline visit prior to injections, at 24hr ± 
2h following injection and on study visit Day 3, 7, 14 and 28. 
Hematology tests will include Complete blood count (CBC) (including White blood cells [WBC] 
differential values) and coagulation tests: White blood cells (WBC), Red blood cells (RBC), 
Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin 
(MCH), Mean corpuscular hemoglobin concentration (MCHC), Red cell distribution width 
(RDW), Platelets, Mean platelet volume (MPV), Fibrinogen, International normalized ratio 
(INR), Partial thromboplastin time (PTT) and Prothrombin time (PT). 
6.1.9.2. 
Serum Chemistry Analysis 
Testing of blood chemistry values will be conducted at Screening Day (performed 14 through 2 
days prior to baseline) in order to ensure compliance with study inclusion criteria.   
Additional Serum Chemistry testing will be conducted at Day 0 (before injection), 24hr ± 2hr 
following injection and on study visit Day 3, 7, 14 and 28. 
Serum chemistry will include:  Sodium, Calcium, Potassium, Phosphorus, Glucose, Liver 
enzymes (AST, ALT, Lactate dehydrogenase [LDH], Creatine-kinase MM [CK-MM], Gamma-
glutamyltransferase [GTTP], Alkaline phosphatase [ALP]), Bilirubin, Creatinine, BUN, Total 
protein, Albumin, Amylase, Creatine phosphokinase [CPK], C-reactive protein [CRP]). 
In case of CK-MM >x5 ULN, subjects will undergo clinical assessment for symptoms and 
alternative causes, and renal function will be assessed (including urinalysis). 
6.1.9.3. 
Urine Drug Screen 
Urine drug screen will be conducted at Screening Day (performed 14 through 2 days prior to 
baseline) in order to ensure compliance with study exclusion criteria.   
Drugs of abuse will include: amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, alcohol, opiates, phencyclidine and propoxyphene. 
6.1.9.4. 
Urinalysis 
Urinalysis will be conducted at Screening Day (performed 14 through 2 days prior to baseline) in 
order to ensure compliance with study inclusion criteria and to allow differential diagnosis in 
case of urinary tract associated AE.  Additional urinalysis testing will be conducted on study visit 
Day 14 and 28. 


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Urinalysis will include: Nitrite, Sodium, Potassium, Calcium, Phosphate, Protein, Red blood 
cells (RBC), WBC, Blood, Glucose, Ketone bodies, Bilirubin, Urobilirubin, Urine specific 
gravity, Osmolality, and pH. 
6.1.10. ECG 
Subjects' ECG will be performed at Screening Day (performed 14 through 2 days prior to 
baseline) in order to ensure compliance with study inclusion criteria.  ECG is to be performed on 
at least a triplicate of heartbeats for all measurements and will be recorded at a speed of 25 
mm/sec.  Additional ECGs will be performed at 4h ± 30min, 8h ± 30min and 24h ± 2h following 
drug injection (Day 0-1) and on Days 14 and 28. 
Computerized ECG analysis will include:  Heart rate, Rhythm, PR interval, QRS axis, and QRS 
duration.  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. 
6.1.11. Draize Score 
Subjects' skin irritancy will be evaluated by Draize score at Screening Day (performed 14 
through 2 days prior to baseline) in order to establish a baseline to compare following drug 
injection. For lipedema subjects evaluation of Draize score will be performed for each leg and 
for Dercum's disease subjects for each selected lipoma for injection. 
Additional skin irritancy evaluation to assess subject's safety will be performed at baseline visit 
prior to injection, and on 2h ± 30min following injection, on the following day 24h ± 2h after 
drug injection and on study visits Day 7, 14, 21, 28 and 56.   
Skin irritancy observations in the injected sites and contra-lateral sites will be scored using the 
Draize scale for scoring skin reaction: 
Erythema and eschar formation 
Edema formation 
No erythema 
0 
No edema 
0 
Very slight erythema (barely perceptible) 
1 
Very slight edema (barely perceptible) 
1 
Well defined erythema 
2 
Slight edema (edges are well defined by 
definite raising) 
2 
Moderate to severe erythema 
3 
Moderate edema (raised approximately 1mm) 
3 
Severe erythema (beet redness) to slight 
eschar formation (injuries in depth) 
4 
Severe edema (raised more than 1mm 
extending beyond area of exposure) 
4 
6.1.12. Photography of the Injected Site 
Documentation of the skin condition and fat reduction effect in the injected area will be 
conducted at Screening Day (performed 14 through 2 days prior to baseline).  Additional 


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photography will be performed at Day 1 (24h ± 2h following drug injection) and on study visits 
Day 7, 14, 21, 28 and 56. 
Photography with a digital camera will include: 
1. For Dercum's disease – Each of the injected site 
a. A picture from above 
b. A side picture 
For each lipoma, the distance away from the lipoma with the best view of the skin will be 
recorded and fixed throughout the study to assess lipoma size changes.  
2. For lipedema  
a. Both sites above the knees 
b. Sites of each knee separately 
c. A side picture of each knee 
Photography with a digital camera will be performed according to a detailed written manual. 
 
6.1.13. Leg Circumference 
Leg circumference measurement will be conducted at Screening (performed 14 through 2 days 
prior to baseline) to ensure compliance with study inclusion criteria and at Day 0 (before 
injection) to establish a baseline. Additional leg circumference measurements will be performed 
on Day 28 and 56. 
The subject will be instructed to remove all garments from the legs and stand upright barefoot. 
The technician will stand on the subject’s side and will palpate the knee area to locate the 
suprapatellar fat. If there is no excess to the suprapatellar fat measure 4-6 cm from the knee. 
With a cosmetic pencil, draw a horizontal line and record its distance from the floor. Extend the 
measuring tape around the leg. Position the tape in a horizontal plane at the level of the 
measurement mark.  Check that the tape sits parallel to the floor and lies snug but does not 
compress the skin.  Always position the zero end of the tape below the section containing the 
measurement value.  Take the measurement in centimeters to the nearest 0.1 cm (one digit after 
the decimal point). The technician will take three measurements of leg circumference. When the 
measurement is measured the same twice (±0.5cm), that measurement will be used. If 
measurement are taken and all three are different, a fourth measurement will be taken until the 
same measurement is achieved twice. 
6.1.14. Imaging: Ultrasound (US) 
Evaluation of Ultrasound (Vevo 2100 or 3100 with transducers at 20, 50 or 70 mHz; or Esaote 
MyLab Gamma Ultrasound System with 20 mHz transducer) will be conducted at Screening 


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(performed 14 through 2 days prior to baseline) to ensure compliance with study inclusion 
criteria and establishing a baseline. For Dercum's disease subjects - nodule size and quality will 
be assessed, for lipedema subjects – nodular size (if applicable), nodular quality and fat thickness 
will be assessed.  Additional US will be performed on Day 28 and 56. 
Nodular quality for Dercum's subjects will be assessed according to the following parameters: 
capsule visibility, hyperechoic or hypoechoic tissue, reverse starry sky (small black dots all over 
consistent with angiolipoma), flurry or snowstorm appearance, location measured to the skin and 
vascularity internal or around the lipoma. 
Nodular quality for lipedema subjects will be assessed according to the following parameters: 
hyperechoic or hyperechoic tissue, flurry or snowstorm, internal hypoechoic rounded area 
consistent with a vessel and distance from skin. 
Additional ultrasound imaging will be conducted at Day 0 (before injection):  
- 
For Dercum's disease subjects - nodule size evaluation to ensure proper dose injection. 
The selected nodules for injection will be marked in circles with a non-erasable pen. This 
mark should be strengthened on every visit.  
Assessment of nodular size will be by diameter (mm) and surface (mm2) in three dimensions as 
illustrated below: 
- 
Height 
- 
Width 
- 
Length 
- 
 
- 
For lipedema subjects – assessment of presence of nodules to be injected along the 
horizontal plane 4-6 cm in the suprapatellar fat. The selected nodules for injection will be 
marked in circles with a non-erasable pen. This mark should be strengthened on every 
visit. If no nodules are noted in the horizontal plane, drug will be injected in to the fatty 
tissue and in this case small nodules seen in ultrasound will be followed for changes. 


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6.1.15. Adverse Events 
The information obtained during weekly subjects questioning, review of subject’s compliance 
record, physical examinations, vital signs measurements, blood testing, and by any other means 
will be evaluated in light of baseline medical data and thus provide the basis for adverse events 
identification and grading.  
The trial will proceed within a cohort and from one cohort to the next as long as no more than 
one subject experiences intolerable side effects and based on the decision made by the PI.  
Proceeding from one subject to the next will be based on the decision made after reviewing all 
safety data collected by Day 7 within 2 ± 1d of the last dosed subject in each cohort. 
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 56 days after injection.   
6.1.16. Evaluation of Response 
Evaluation of response will be conducted on Day 7 and every 7 days thereafter till Day 28. 
6.1.16.1. Evaluation of Primary Endpoints 
6.1.16.1.1. Safety and Tolerability Monitoring 
For determination of the study's primary end point, evaluation of safety and tolerability will be 
conducted according to definitions and guidelines below. 
Safety and tolerability will be assessed by the study medical staff (e.g., PI, site coordinator, and 
study nurse) and the study subjects on the basis of the following:  
1. AEs and 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. ECG 


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6. Subjects questioning - full medical history during screening, routine AE reporting, 
tolerability monitoring and through review of subject’s analgesics use diary. 
6.1.16.2. Evaluation of Secondary Endpoints 
6.1.16.2.1. Local Fat Reduction for Lipedema Subjects  
For lipedema subjects, local reduction in fat mass will be evaluated by measurement of the 
circumference of the leg above the knee.  A local fat reduction is defined as a reduction 
(compared to baseline) in the circumference of the leg above the knee. 
6.1.16.2.2. Local Fat Reduction   
Local fat reduction in all subjects will be evaluated by ultrasound.  Local fat reduction is defined 
as the reduction in nodules size and/or numbers in the injected area as compared to baseline. 
Ultrasound will be evaluated in all subjects at baseline and at Day 28. 
6.1.16.2.3. Duration of the fat reduction effect 
The duration of the local fat reduction in all subjects will be evaluated by ultrasound and by leg 
circumference above the knee in lipedema subjects at Day 56 compared to baseline and to Day 
28. 
6.1.16.2.4. Tissue Changes 
Tissue changes will be evaluated by ultrasound.  Tissue changes are defined as changes in fat 
thickness and nodular quality at Day 28 and Day 56 as compared to baseline. 
6.1.16.2.5. Improvement in Local Pain 
Improvement in local pain will be assessed by Comparative Pain Scale and by reduction in the 
use of analgesics (dose and/or times a day) by Day 28 and Day 56 with comparing to baseline.   
6.1.16.2.6.  Improvement in Quality of Life and Function  
Improvement in QOL and function in lipedema subjects as measured by questionnaire (such as 
LEFS) by comparing to baseline at Day 28 and Day 56. 
6.1.16.3. Compliance Monitoring 
Compliance monitoring will include the following procedures:  
• Compliance assessment by site coordinator at the study visit, including but not limited to 
subject questioning. 
• Completion of analgesics use diary by the subject. 


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6.1.16.4. Dispensing of RZL-012 Investigational Product 
The RZL-012 investigational product will be dispensed to the study site under monitored 
conditions by Nextar Ltd.  All procedures connected to investigational product's allocation (kits 
received at site, returned kits) will be properly documented, dated and signed in a designated site 
folder to allow full product tracking.  Source documents will be kept for the duration required by 
local regulations and ICH-GCP (whichever is longer). 
6.1.16.5. Questioning of Study Subjects 
Questioning of study subjects during site visits and any unscheduled conversations (e.g., by 
phone) with site staff will be fully documented in subject file.  Whenever possible, subject 
questioning should include, but not be limited to, inquiring information regarding occurrence and 
severity of AEs, treatment tolerability and compliance to future scheduled procedures and visits. 
6.2. 
STUDY VISITS 
Study visits will be fully documented in the CRF as described in Section 11.  Documentation 
will be completed in a timely manner and within 5 working days to ensure protocol adherence 
and compliance with ICH-GCP. 
6.2.1. Screening Procedures 
All information collected and documented during screening procedures will be reviewed to 
ensure eligibility in reference to study inclusion and exclusion criteria, and fully documented in 
subject file. 
Screening visit should be performed no later than 2 days prior to baseline visit for all cohorts.  
Study Screening Day procedures will include the following:  
• Informed Consent - Section 6.1.1 
• Medical History - Section 6.1.2 
• Concomitant Medication - Section 6.1.3 
• Physical Examination - Section 6.1.4 
• Pain Measurement – Section 6.1.5 
• QOL Measurement –Section 6.1.6 
• Vital Signs and Measurements - Section 6.1.5 
• Serology Assays – Section 6.1.8 
• Clinical Laboratory Tests - Section 6.1.9 
• ECG - Section 6.1.10 


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• Draize Score – Section 6.1.11 
• Photography of Injected Site – Section 6.1.12 
• Leg Circumference – Section 6.1.12 
• Ultrasound – Section 6.1.12 
Subjects may be rescreened if they were screened and not dosed within 14 days.  The following 
procedures will be performed: Clinical Laboratory Tests (hematology, serum chemistry, and 
urinalysis), vital signs, Draize score and photography. 
6.2.2. Study Randomization 
This is an open label study where all subjects will receive the investigational drug (RZL-012). 
6.2.3. Study Treatment 
6.2.3.1. 
Treatment with RZL-012 Investigational Therapy 
RZL-012 is an investigational product supplied as a single dose single treatment injection in 
multiple sites (2-16) of injections.  Before injection, subjects will be advised to keep their regular 
diet and physical activity. 
The injection dosing regimen and technique is crucial for the therapy safety and efficacy.  
Syringes will be filled with 0.1 mL RZL-012 and the number of syringes will be compatible with 
the number of injections.  All injections will be administered diagonally in 45 °, using a 1 mL 
Luer-lock syringe and a 30 G x 1/2" needle. 
The hole of the needle should be pointing into the fat layer and the injection direction should be 
towards earth.  An attempt to pull the plunger should be made before injecting to ensure that no 
blood is coming out.  If so, the plunger should be pushed down to inject the medicine.  The 
formulation is viscose, therefore resistance is expected while injecting. 
For Dercum's disease - The 1st cohort will be comprised of subjects with Dercum's disease. 
Subjects will receive a single treatment in multiple sites (2-8) according to the design below 
Figure 2). 
 
 


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Figure 1:  RZL-012 Injection Design in Dercum's Disease Subjects 
 
 
 
 
Injections will be diagonally (45 °) to the skin surface towards the center of the nodule and the 
distance between injections in a nodule will be 1 cm (Figure 2). 
Figure 2:  RZL-012 Injection Sites in Dercum's Disease Subjects 
 
 
 
 
 
For Lipedema - The 2nd cohort will be comprised of subjects with lipedema with substantial fat 
above the knee. A grid line will be drawn with a makeup pencil in a horizontal plane (Figure 3) 
4-6 cm from the suprapatellar fat and its distance from the floor recorded. An attempt should be 
made to find palpable nodules along the grid line. The injection sites will be marked in circles 
with a non-erasable pen. This mark should be intensified upon following visits. Injections will be 
given in multiple sites (4-8 in each leg), diagonally (45 °) to palpable nodules, in the fat above 
the knee.  An attempt should be made to lift the nodule and inject into the middle of the fat-mass. 
If no nodules are noted in the horizontal plane, drug will be injected into the fatty tissue (in this 
case small nodules seen in ultrasound will be followed for changes). Injections will be on the 
same horizontal plane.  
Figure 3:  RZL-012 Injection in Lipedema  
 
 
 
 


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Injections will be spread as much as possible along the grid line and the distance between 
injected sites (Figure 4) will be: 
• At least 3 cm - For subjects receiving 8 and 12 injections. 
• At least 2cm - For subjects receiving 16 injections. 
Figure 4:  RZL-012 Injection Sites in Lipedema Subjects 
 
In lipedema subjects study will be performed in a dose escalation manner:  
The first 2 subjects will receive 20mg RZL-012 in 4 injections (0.1mL each) in one leg followed 
by 20mg RZL-012 (4 injections, 0.1mL each) in the second leg adding up to 8 injections of 
40mg RZL-012 (1/6.25th the NOAEL based on HED from GLP toxicology study).  
The next 2 subjects will receive 30mg RZL-012 in 6 injections (0.1mL each) in one leg followed 
by 30mg RZL-012 (6 injections, 0.1mL each) in the second leg adding up to 12 injections of 
60mg RZL-012 (1/4.688th the NOAEL based on HED from GLP toxicology study).  
The last 2 subjects will receive 40mg RZL-012 in 8 injections (0.1mL each) in one leg followed 
by 40mg RZL-012 (8 injections, 0.1mL each) in the second leg adding up to 16 injections of 
80mg RZL-012 (1/3.125th the NOAEL based on HED from GLP toxicology study).  
Within each cohort, dosing of the subjects will progress consecutively from one individual to the 
other with a minimum of 7-days between subjects to assess safety. This study design will allow 
the physicians to monitor safety for at least 7 days prior to dosing the next subject.  For cohort 2 
the decision to proceed to the next dose level will be made after reviewing all safety data 
collected by Day 14 within 2 ± 1d of the last dosed subject. The trial will proceed within a cohort 
provided that no more than one subject experiences intolerable side effects in a cohort, and based 
on the decision made by the PI and the Medical Monitor.   


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Each RZL-012 kit contains 1 vial (250 mg/5 mL) corresponding to the number of subjects 
receiving treatment in each cohort. 
RZL-012 will be injected on baseline study visit. 
6.2.4. Baseline Visit 
Baseline visit is defined in the study as Day 0.  Baseline visit will be performed to complete 
screening evaluation, and to review all procedures necessary to confirm subject eligibility.  
Subjects will stay under supervision in the study center till 8h + 3h following drug injection. 
Screening information may be considered for baseline data if acquired within the adequate 
timeframe as described in Table 2. 
Table 2:  Subject Information and Timeframes 
Information 
Timeframe 
Follow-up Timeframe 
Informed Consent Form 
Signed prior to any study 
dedicated procedure 
 
Medical History and Concomitant 
Medications 
At Screening Day visit 
 
Physical examination  
At Screening Day visit and at 
Day 28 
 
Pain Measurement 
At Screening Day visit and at 
Days 14, 28 
At Day 56 
QOL Measurement in lipedema subjects 
At Screening Day visit and at 
Days 14, 28 
At Day 56 
Vital Signs  
At Screening Day visit and at 
Days 0 (pre and following 
injection), 1, 7, 14, 21, 28 
 
Pulse rate 
At Day 0 (following injection) 
and at Day 1 
 
ECG 
At screening Day 1 visit, at 
Day 0 (following injection) 
and at Days 1, 14, 28 
 
Draize Score at the Injected Site 
At Screening Day and at Days 
0 (pre- and following 
injection), 1, 7, 14, 21, 28 
At Day 56 
Serology assays (HbSAg, HCV and HIV) 
At Screening Day visit  
 
Drug screen 
At Screening Day visit  
 
Serum chemistry and Hematology 
At Screening Day and at Day 
1, 3, 7, 14 and 28 
 
Urinalysis  
At Screening Day visit and at 
Days 14 and 28 
 


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Information 
Timeframe 
Follow-up Timeframe 
Ultrasound for nodules quality and size. 
Fat thickness – for lipedema 
At Screening Day visit and at 
Day 28 
At Day 56 
Ultrasound for nodules size and selection 
for injection 
At Days 0 (pre- injection) 
 
Photography of the Injected Sites 
At Screening Day visit and at 
Days 1, 7, 14, 21, 28 
At Day 56 
AE Assessment  
At Days 1, 3, 7, 14, 21, 28 
At Day 56 
 
6.2.5. Subject Site Visits 
Subject site visits will be performed ± 1 day from scheduled date. All data relevant for the visit 
needs to be obtained within 3 days (e.g., blood tests) of visit.  
Subject sites visits will include procedures as described in Appendix I. 
For site visit that results in study discontinuation, see termination visit in Section 6.2.6. 
6.2.6. Termination Visit 
Once study is discontinued, all reasonable measures should be taken to perform a termination 
visit.  Termination visit should include all procedures necessary to complete subjects' records:  
AE reporting, any clinical laboratory test needed to evaluate unresolved AEs, evaluation of 
response, recovery of all clinical supplies and compliance diaries, and updating of subject 
contact information. An effort should be made to perform all activities conducted on visit Day 
28. 
6.2.7. Unscheduled Visit 
Unscheduled visits will be performed upon investigator's discretion, upon Sponsor request to 
redo tests with unusual results or complete missing results and may occur upon subject’s 
decision with no notification in advance.  Unscheduled visits will include any study procedure 
deemed necessary, as described in Section 6.1. 
 
 
 
 


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7. 
SAFETY CONSIDERATIONS AND GUIDANCE FOR INVESTIGATORS 
Adherence to protocol monitoring procedures along with the following safety guidance will aid 
and promote subject safety. 
7.1. 
STUDY RESTRICTIONS REGARDING CONCOMITANT MEDICATIONS 
Subjects may not receive the following medications while on study:  
• Chronic treatment with systemic steroids or immunosuppressive drugs.  
• Chronic treatment with Non Steroid Anti-Inflammatory Drugs (NSAIDs) and aspirin.  
• Any investigational product other than RZL-012.  
Before dosing, analgesic gels such as Lidocaine (e.g., Emla) or Pramoxine should be used to 
numb the injected site.  An ice pack may be applied on the site of injection following dosing to 
help reduce pain.  At day 1 following injection application of the anti-histamine Benadryl Gel 
(Diphenhydramine hydrochloride 1 %for topical use only) should be initiated prophylactically, 
according to drug instructions for use, to avoid itching at the injected area.  Benadryl Gel should 
be applied for 7 days. 
Use of nattokinase is prohibited and the use of other supplements or complementary 
medicines/botanicals should be approved by the PI, except for conventional multivitamin 
supplements. The use of prohibited supplements should be stopped a week before injection. 
7.2. 
SAFETY MEASUREMENTS  
Simple measures may help avoid specific AEs associated with the use of the RZL-012 
investigational product.  Thus, study subjects must be informed of possible AEs that occurred in 
animal studies (rats and pigs): 
• Any injection site reaction may occur.  Pain, swelling, itching, edema, erythema, 
hematoma, etc. 
• Slight transient injection site bleeding following injection may occur. 
• Itching in the injected area may occur, and study subjects should be advised to use an 
antihistamine gel for topical use according to drug recommendations, wear wide cotton 
shirts, prevent touch with irritable clothing, avoid scratching and avoid exposure to direct 
sun.  Itching is expected till 7 days following drug injection. 
• Local erythema in the injected area. 
• Local heat in the injection area. 
• Study restrictions regarding concomitant medications are listed in Section 7.1.  
• The local subcutaneous fat reduction may appear as a slight dip in the skin surface.  This 
decline may be temporary and transient. 


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• Transient increase (72%) in the WBC count by 24 hours following injection, which 
returned to basal level after 14 days.  Probably associated with the inflammatory response 
at the site of injection and involve neutrophils, monocytes and eosinophils.  
• Increased level of BUN and of creatinine and minimal single cell necrosis was observed 
in tubular epithelium at cortico medullary junction of kidney in rats receiving a dose 25 
times the highest dose in this study.  All abnormalities were found to be reversible by 
Day 14. 
• Increased AST level which is most typical of myofiber injury associated with study 
related procedures.  This elevation was found to be reversible by Day 14. 
• Transient increase of serum CRP levels (in rats) which returned to the basic level by 
14 days. 
• Marked irritancy in the injected subcutaneous tissue resulting in coagulation necrosis of 
relatively large areas in the subcutaneous tissue planes acutely.  Necrosis persisted for up 
to 14 days and was accompanied by early evidence of healing in the form of chronic 
inflammation and fibrosis. 
• Local inflammation (minimal to moderate) with muscle degeneration, epidermal/dermal 
necrosis (minimal to severe) and parakeratosis (minimal).  Inflammation observed at 
injection site was also extended to adjacent subcutaneous adipose tissue (SAT).  By 56 
days the inflammation was minimal, muscle degeneration was not evident and 
inflammation to adjacent SAT was present.  
• A slight elevation in body temperatures was noted in male pigs. 
• Sinus tachycardia (in pigs), occurring at the 4 hour interval post dosing. 
• In addition, other acceptable treatment to relieve drug-related AE's should be used at 
Investigator's discretion. 
Study subjects must be informed of possible AEs that occurred in clinical studies (phase 0): 
• At the injection site -local and transient: erythema, edema, pruritus, anesthesia, pain, 
mass (subcutaneous scar). 
• Abdominal abscess 
• Transient moderate to severe elevation of the liver enzymes: ALT and AST. 
7.3. 
PREMATURE DISCONTINUATION FROM STUDY 
Study will be prematurely discontinued in any of the following cases:  
• Subject's request.  
• Any life-threatening (i.e., Grade 4) AE may cause prematurely discontinuation.  
• Systemic hypersensitivity reaction may cause premature discontinuation.  
• Any Grade 3 or 4 ADR (defined in Section 9.3) clinically evaluated by the PI and/or 
Sponsor as warranting subject discontinuation.  
• Non-compliance: Subject's non-compliance with study procedures as evaluated by PI 
and/or Sponsor as warranting subject discontinuation.  


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• Other reasons regarded by PI as warranting subject's discontinuation. 
• Premature study termination as described in Section 7.4.   
Subjects who discontinue the study prematurely will be queried whether an AE contributed to 
their decision. 
7.4. 
PREMATURE STUDY TERMINATION 
The study will be prematurely terminated in any of the following cases:  
• Recurring serious or severe ADR (defined in Section 9.1) clinically evaluated by PI 
and/or Sponsor as warranting study termination.  
• A decision made by Sponsor and/or IRB/EC and/or local regulatory agency to terminate 
the study.  
7.5. 
DEVIATION FROM STUDY PROTOCOL 
The investigator shall not deviate from the study protocol without first obtaining a written 
approval from the Sponsor, or its official designee, and if applicable, from the local IRB/EC 
according to local regulations.  
In the event of medical emergencies, the investigator shall use appropriate medical judgment and 
will remove the subject from any immediate hazard, then notify the Sponsor or its official 
designee and if applicable, the local IRB/EC, within 2 days, of the type of emergency and course 
of action taken.  
Any other changes to or deviations from the protocol will be made as an amendment to the 
protocol and must be approved by the Sponsor or its official designee and the local IRB/EC 
before they can be implemented.  Accordingly, the Sponsor will not assume responsibility or 
liability for any unauthorized deviation from or change to the protocol. 
8. 
INVESTIGATIONAL PRODUCT AND VEHICLE SPECIFICATIONS 
8.1. 
DESCRIPTION OF RZL-012 
RZL-012 investigational drug is intended for a single dose in multiple injections into the 
subcutaneous fat.  The injection dosing regimen and technique is crucial for the therapy safety 
and efficacy. 
8.2. 
FORMULATION, PACKAGING AND LABELING  
The RZL-012 drug is a ready to use liquid to be injected to the subcutaneous fat, supplied in a 
1 vial kit.  1 vial contains 250 mg/5 mL RZL-012 in formulation F12. 


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8.3. 
STORAGE AND STABILITY OF RZL-012 AND VEHICLE 
The RZL-012 kit will be stored in the site pharmacy at monitored room temperature conditions 
(22 ± 7 ᵒC) protected from light.  Storage space will be separate, designated and adequately 
labeled as containing investigational product.  
Stability program of RZL-012 is ongoing and site inventory will be managed by the Sponsor 
according to accumulating stability data.  Suitability of the product's expiration date must take 
into consideration and comply with FIFO (First In First Out) principals. 
The storage conditions are summarized in Table 3. 
Table 3:  RZL-012 Storage Conditions 
Storage Conditions 
Maximal Storage Duration 
Individual vials:  
Room temperature (15-30 ᵒC) 
According to expiration date as will be 
provided by manufacturer. 
* Stability program for RZL-012 is ongoing and site inventory will be managed by the 
Sponsor according to accumulating stability data. 
 
8.4. 
DOSAGE, DISPENSING AND ADMINISTRATION OF RZL-012 AND VEHICLE 
8.4.1. Dosage 
RZL-012 therapy is available in vials of 250 mg/5mL. 
8.4.2. Administration and Instructions for Use 
Each individual vial must be kept and handled at room temperature.  
The vial should be manually shaken before consumption.  
1 mL Luer-lock syringes with RZL-012 solution should be filled with 30 G 1/2" sterile needle as 
described below: 
• Cohort 1 - Dercum's disease subjects:  
Nodule of 2-2.9cm diameter -will be injected 2 * 0.1 mL/syringe/nodule  
Nodules of 3-3.9cm diameter - will be injected 3 * 0.1 mL/syringe/ nodule  
Nodules of 4-8cm diameter - will be injected 4 * 0.1 mL/syringe/ nodule  
In total -A maximum of 8* 0.1 mL/syringe/subject.  


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• Cohort 2 - lipedema subjects:  
First 3 subjects: 6*0.1 mL/syringe/leg, a total of 12* 0.1 mL/syringe/subject. 
Last 3 subjects: 8*0.1 mL/syringe/leg, a total of 16* 0.1 mL/syringe/subject. 
One vial may 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 was done 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 
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  


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• 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 and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 June 14, 2010) (10).  
AE that do not appear in the CTCAE will be graded as follows:  
• Mild (Grade 1):  Sign or symptom, usually transient, requiring no special treatment and 
generally not interfering with usual activities.  
• Moderate (Grade 2):  Sign or symptom, which may be ameliorated by simple therapeutic 
measures, may interfere with usual activity.  
• Severe (Grade 3):  Sign or symptom that is intense or debilitating and that interferes with 
usual activities and/or requires hospitalization.  Recovery is usually aided by therapeutic 
measures and the discontinuation of the study product may be required.  
• Life-threatening or disabling (Grade 4):  Sign or symptom that is life-threatening or 
disabling.  
• Death (Grade 5):  Death related to AE 
9.3. 
CAUSALITY ASSESSMENT OF ADVERSE EVENTS  
All AEs will be evaluated by the investigator and assigned an estimated relationship to the 
RZL-012 investigational product.  The terms "probable", "possible", "unlikely", or "unrelated" 
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Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, confounding factors such as concomitant 
medication, concomitant diseases and relevant history.  
Assessment of causal relationship should be recorded directly in subjects’ CRF. 
Definition of AEs causality is specified in the table below (Table 4). 
Table 4:  Definition of Causality 
TERM 
DEFINITION 
CLARIFICATION 
Unrelated  
This category applies to those AEs 
which, after careful consideration, 
are clearly due to extraneous 
causes (disease, environment, etc.) 
 
Unlikely 
Related 
In general, this category can be 
considered applicable to those 
AEs, which after careful medical 
consideration at the time they are 
evaluated, are judged to be 
unrelated to the study procedures/ 
investigational product. 
An AE may be considered unlikely related if or when (must 
have two):  
▪ It does not follow a reasonable temporal sequence from the 
study procedures/administration of the investigational 
product.  
▪ It could readily have been produced by the subject’s clinical 
state, environmental or toxic factors, or other modes of 
therapy administered to the subject.  
▪ It does not follow a known pattern of response to the study 
procedures/investigational product. 
Possibly 
Related 
This category applies to those AEs 
for which, after careful medical 
consideration at the time they are 
evaluated, a connection with the 
study procedures/investigational 
product administration appears 
unlikely but cannot be ruled out 
with certainty. 
An AE may be considered possibly related if or when (at least 
two of the following):  
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ A causal relationship to the experimental treatment cannot 
necessarily be reasonably excluded and an alternative 
explanation (e.g., concomitant investigational product or 
concomitant disease) cannot be reasonably suggested as 
causing the treatment emergent AE.  
▪ It follows a known pattern of response to the study 
procedures/ investigational product. 
Probably 
Related  
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with a high 
degree of certainty to be related to 
the study 
procedures/investigational 
product. 
An AE may be considered probably related if or when (at least 
three of the following):  
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to 
the subject.  
▪ It disappears or decreases on cessation or reduction in dose.  
There are important exceptions when an adverse event does 
not disappear upon discontinuation of the investigational 
product, yet investigational product-relatedness clearly 
exists.  
▪ It follows a known pattern of response to the study 
procedures/investigational product. 


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TERM 
DEFINITION 
CLARIFICATION 
Definitely 
Related 
This category applies to those AEs 
which, after careful medical 
consideration at the time they are 
evaluated, are felt with definite 
certainty to be related to the study 
procedures/investigational 
product. 
An AE may be considered definitely related if or when all of the 
following apply:  
▪ It follows a reasonable temporal sequence from study 
procedures/administration of the investigational product.  
▪ It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to 
the subject.  
▪ It disappears or decreases on cessation or reduction in dose.  
There are important exceptions when an adverse event does 
not disappear upon discontinuation of the investigational 
product, yet investigational product-relatedness clearly 
exists.  
▪ It follows a known pattern of response to the study 
procedures/investigational product. 
*In this protocol, Unlikely is deemed as Unrelated.  
9.4. 
UNEXPECTEDNESS OF ADVERSE DRUG REACTIONS 
An ADR is considered unexpected when its nature or severity is not consistent with the 
applicable product information (i.e., RZL-012 Investigator's Brochure). 
9.5. 
ADVERSE EVENT REPORTING AND MONITORING REQUIREMENTS 
9.5.1. General 
All AEs, serious and non-serious, will be fully documented in both source documents and CRFs 
as described in Section 6.1.13, 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 (28 days after the injection of RZL-012 and 
in the highest dose cohort until 6 months from injection of RZL-012), should be captured in the 
CRF.  AEs should be recorded in the CRF using the medical terminology found in the source 
documentation.  Whenever possible, diagnoses should be given when signs and symptoms are 
due to a common etiology. 
Occurrence of any Grade 4 and Grade 3 or 4 ADR must warrant clinical evaluation by the 
treating investigator and reported to the Sponsor within 7 calendar days.  
ADRs graded > 1 will be followed-up until resolution, or for a maximal duration of 6 months 
after RZL-012 injection, whichever occurs first. 


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9.5.2. SAE Reporting 
The PI or his designee must report to the Sponsor any SAE occurring after injection of the study 
treatment, regardless of their relationship to the investigational product.  
Sponsor contact details for SAE reporting:  
Racheli Gueta, Rachel.gueta@raziel-therapy.com, fax: 972-2-625-0901. 
An initial report must be faxed or emailed to rachel.gueta@raziel-therapy.com, fax: 972-2-625-
0901 within 24 hours of becoming aware of the event and must include SAE general description, 
start date, end date (if applicable), the reason for evaluation as a SAE, basic subject information, 
assessment of the relationship to the investigational product, expectedness, and study therapy 
information.  
Follow-up information, including outcome and treatment, shall be faxed or emailed within 
48 hours.  Source documents to support the SAE (e.g., discharge summary, test results) shall be 
included in the report.  
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 CTCAE description and grading, treatment given (if applicable), SAE 
outcome, an assessment of the relationship to the investigational product, and expectedness.  
SAE will be recorded on designated CRF forms in a timely manner and no later than 7 calendar 
days after its end date.  
The PI or his designee will submit the SAE report to IRB/EC according to applicable local 
regulations and will update the Sponsor. 
9.5.3. Expedited Reporting 
Expedited reporting by PI to IRB/EC is warranted for all Suspected Unexpected Serious Adverse 
Reactions (SUSAR), i.e., unexpected SAEs that are considered related to study product as 
defined in Sections 9.1.2, 9.1.3, and 9.4).  Additional cases will be communicated by PI to 
IRB/EC via expedited reporting when required by local regulation.  
Expedited reports will be submitted to the applicable regulatory authorities by the Sponsor or 
designee within the required timelines according to local regulations.  
Any pregnancy of a subject and of a partner of a study male subject after dosing is considered an 
immediate reportable event.  
Such events must be reported within one (1) working day of the investigator becoming aware of 
the event.  Pregnancies shall be followed for the duration of the pregnancy.  It is the PI’s 


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responsibility to provide to the Sponsor follow-up information on the outcome of the pregnancy 
including information about any sequelae. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. STUDY DESIGN AND OBJECTIVE 
This is an open label, 2 cohort, clinical trial in women with lipedema with substantial fat above 
the knee or women and men with nodular Dercum's disease. Each cohort will have 6 subjects 
who will receive RZL-012. 
• 
The 1st cohort will be comprised of subjects with Dercum's disease  
• 
The 2nd cohort will be comprised of subjects with lipedema with substantial fat above the 
knee.  
Primary objective:  Evaluation of the overall safety of RZL-012 following injection into the 
subcutaneous fat in patients with lipedema.  
Secondary objective:  Evaluation of local fat reduction, its extent, duration and tissue associated 
changes, in response to RZL-012 treatment, utilizing minimal invasive means (ultrasound) 
following subcutaneous injection of RZL-012 into fatty tissue below the skin. 
10.2. STUDY ENDPOINTS 
10.2.1. Primary Safety Endpoints 
The primary safety endpoint is the incidence of intolerable side effects and AEs. 
10.2.2. Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• For lipedema subjects - The reduction in local subcutaneous fat in the injection site 
region as compared to baseline based on ultrasound (reduction in nodules size and/or 
numbers) and leg circumference above the knee assessments. 
• For Dercum's disease subjects - The reduction in local subcutaneous fat in the injection 
site region as compared to baseline based on ultrasound (reduction in nodules size and/or 
numbers).  
• Extended duration of the fat reduction effect.  To that end, ultrasound images and above 
the knee circumference measurement will be followed for 56 days. 
• Elucidation of the tissue changes by ultrasound of the injection site to include reduction 
in fat thickness and nodular quality. 


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• Improvement in local pain as measured by Comparative Pain Scale and by the reduction 
in the use of analgesics. 
• Improvement in QOL and function in lipedema subjects as measured by questionnaire 
(such as LEFS). 
10.2.3. Safety and Tolerability Endpoints 
Safety endpoints include: 
• Incidence of AEs and SAEs, by severity and relation to study treatment.  AEs will be 
coded using MedDRA version 19.1 (or higher).  
• Physical examination (including Draize score)  
• Vital signs  
• Blood laboratory tests  
• ECG 
10.3. SAMPLE SIZE JUSTIFICATION 
This study is planned following a 6 subjects per group paradigm. A maximum of 12 evaluable 
subjects will be included in the study (6 subjects with Dercum's disease and 6 subjects with 
lipedema) and followed for as long as 2 months. 
10.4. ANALYSIS SETS 
10.4.1. Safety Analysis Set (SA) 
The SA will consist of all enrolled subjects who received the study treatment, (exposed 
population), including subjects prematurely withdrawn. 
All enrolled subjects receiving at least one study drug injection are considered evaluable for the 
SA set. 
10.4.2. Efficacy Analysis Set (EF) 
The EF will consist of all subjects from the SA analysis set without any major protocol violations 
measured at baseline.  Subjects will be analyzed according to the treatment received. 
10.4.3. Statistical Analysis of Analysis Sets 
The SA analysis set will serve as the principal data analysis set for the analyses of the safety 
endpoints. 
The EF analysis set will serve as the principal data analysis set for the analyses of the efficacy 
endpoints. 


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10.5. STATISTICAL ANALYSIS 
10.5.1. General  
Statistical analysis will be performed using SAS V9.3 or higher (SAS Institute, Cary NC, USA). 
Statistical analyses will be mainly descriptive in nature where study data will be tabulated and 
summarized using the mean, standard deviation or standard error, median, minimum, maximum 
and number of subjects by cohort for continuous data.  For categorical data, results will be 
summarized via a count and percentage by cohort.  The results will be presented overall, per 
cohort and per cohort and dose. The effects of noncompliance, dropouts, and covariates, may be 
assessed to determine the impact on the general applicability of results from this study. 
If any statistical tests are performed, they will be two-sided.  The required significance level of 
findings will be equal to or lower than 5%.  Nominal p-values will be presented. 
Where confidence limits are appropriate, the confidence level will be 95%. 
10.5.2. Subject Disposition 
A detailed description of subject accountability including count of subjects included, exposed, 
completed (i.e., subjects who complete the study treatment) and discontinued along with the 
main reason for discontinuation will be generated for each cohort and for all subjects.  All 
withdrawals from the study, taking place on or after study drug injection, will be fully 
documented in the body of the Clinical Study Report. 
Note that the actual study duration is for a period of maximum 2 months, with efficacy analyses 
being conducted at 28 days and 56 days. 
10.5.3. Demographic and Baseline Characteristics 
Baseline will be defined as the last available and evaluable parameter value before and closest to 
the injection.  If a rechecked value is used for baseline, it should be collected under the same 
conditions as for the planned baseline. 
Baseline safety data will be presented along with subsequent safety values assessed during or 
after dosing. 
10.5.4. Primary Safety Endpoint 
The incidence of intolerable side effects will be presented overall and by cohort along with two 
sided 95% exact binomial Confidence Interval (CI). 


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10.5.5. Efficacy Analysis 
Percent changes from baseline in local fat reduction (circumference of the leg above the knee, 
nodules size and/or numbers in the injected area) and tissue changes (fat thickness), will be 
presented in tabular form by visit. 
Changes in nodular quality, local pain, quality of life and function will be presented in tabular 
form by visit and cohort. 
10.5.6. 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 
(V19.1 or higher) treatment.  
AEs and tolerability data will be presented descriptively by treatment and cohort.  AEs will be 
tabulated by body system, preferred term, seriousness, severity and relation to study drug by 
cohort.  Where applicable, changes in values over time (e.g., lab values, vital signs, ECGs) will 
be presented; this will include clinical laboratory evaluations (including CBC, blood chemistry 
and urinalysis), coagulation (INR, PTT and PT), cytokines, vital signs, and ECGs.  Shift tables of 
normal / abnormal versus baseline may be presented as well.  
Draize scores will be presented in tabular format by visit, treatment, and cohort. 
10.6. HANDLING OF MISSING DATA 
No imputation of missing data will be performed. 
10.7. INTERIM ANALYSIS 
No interim analysis is planned. 
 
11. 
DATA COLLECTION, STUDY MONITORING, AND DATA DISCLOSURE 
11.1. DATA COLLECTION AND REPORTING 
Each study subject will be assigned an individual CRF that will contain all of the relevant study 
information.  The investigator shall ensure that all data is completely and accurately recorded on 
the CRFs throughout trial duration.  
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained.  


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All fields and blanks in the CRFs will be completed.  The following abbreviations are to be used 
when values or answers are not available: NA = Not applicable, ND = Not done, UNK = 
Unknown, CONT = Continued.  
White-out or erasure on the CRF is not permitted under any circumstances.  Any change or 
correction to a CRF should be dated, initialed, and explained (if necessary) and should not 
obscure the original entry (i.e., an audit trail should be maintained).  If an entry on a CRF form is 
changed, the correction will be made as follows:  A single line will be drawn through the 
incorrect entry, the date and initials of the reporting individual will be added beside the entered 
change and/or correction, and an explanation will be added when applicable.  
When a subject withdraws from the study, regardless of cause, all final study evaluations should 
be attempted.  
If a subject is lost to follow-up, (i.e., fails to return for scheduled visits) every reasonable effort 
must be made to contact the subject in order to determine why the subject failed to return.  All 
actions taken in this regard will be documented and dated in the CRF.  
Once completed, a copy of each completed CRF will be signed and dated by the investigator or a 
designated representative and submitted to the Sponsor. 
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 fifteen years after completion of the study. 
11.3. SOURCE DATA AND SOURCE DOCUMENTS 
ICH-GCP defines source data as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary 
for the reconstruction and evaluation of the trial.  Source data are contained in source documents 
(original records or certified copies).  
Source documents are defined as original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, subject files, and records kept at departments 
involved in the clinical trial, etc.).  
The following data is to be recorded directly on the RZL-012 trial forms or CRF, which will be 
considered to be the source data:  
• Subjects' questioning, e.g., pain, itching, topical antihistamine application.  
• Assessment of AEs relation to investigational product, i.e., causality assessment, and 
expectedness reported by investigator. 


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The investigator should maintain the trial's essential documents as required by ICH-GCP 
guidelines and the applicable regulatory requirements, and take measures to prevent accidental or 
premature destruction of these documents.  
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the investigator will 
ensure direct access to all requested trial-related records. 
11.4. STUDY MONITORING 
Monitoring procedures are required to assure compliance to ICH-GCP guidelines, the study 
protocol and local regulations.  
The investigator shall allow the Sponsor or its official designee to monitor and audit periodically, 
at mutually convenient times, all CRF and corresponding subject records.  The monitoring 
schedule will be based on Sponsor’s monitoring plan and will be done by competent monitors 
per GCP by either Sponsor personnel or sponsor’s designee such as a Clinical Research 
Organization (CRO). 
11.5. CONFIDENTIALITY, DATA DISCLOSURE, AND PUBLICATION 
In order to protect subject confidentiality, a consecutive identification number will be attributed 
to each subject enrolled to the trial.  In order to avoid identification errors, this number and 
subject’s initials (first letter of first name and the first letters of surname) will identify the subject 
and must be included on all CRFs.  The investigator will complete subject identification on a 
confidential site log, which will be used for subjects' traceability and follow-up.  
Individual subject medical information obtained as a result of this study is to be considered 
confidential and disclosure to third parties other than the regulatory authorities, or other persons 
or organizations designated by the Sponsor, is prohibited.  Any medical information may be 
provided to the subject’s personal physician or to appropriate medical personnel responsible for 
the subject’s care.  Additionally, data generated from this study is to be provided, upon request, 
to the Sponsor’s monitors, as well as to the local IRB/EC.  Subject confidentiality is to be further 
assured by utilizing subject identification code numbers to identify subject data.  
All information supplied by Raziel Therapeutics Ltd. in connection with this study and not 
previously published, is considered confidential information.  This information includes, but is 
not limited to, the 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 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
RZL-012 
 
Version: 7 
 
26 July 2018 
 
 
67 
CONFIDENTIAL 
this clinical study, the investigator is obliged to provide Raziel Therapeutics Ltd. with complete 
test results and all data developed in this study.  
The Sponsor has full ownership of the original CRFs completed as part of the study.  
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement.  
The information obtained during this study may be made available to other investigators who are 
conducting similar studies.  
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by all sites performing the protocol.  
Raziel Therapeutics Ltd. will disclose the results of the trial on the basis of the final analysis and 
following the revision of a draft manuscript by the investigators, unless posting would 
compromise publication in a peer-reviewed medical journal or contravene national laws or 
regulations.  Study results may also be disclosed through presentations and abstract submissions 
at professional scientific meetings. 
12. 
HUMAN SUBJECTS 
12.1. DECLARATION OF HELSINKI 
Both the PI and the Sponsor will ensure that the study is conducted in agreement with the 
Declaration of Helsinki, ICH-GCP, and the local laws and regulation. 
12.2. INFORMED CONSENT 
As described in Section 6.1.1. 
12.2.1. LIABILITY AND INSURANCE CONDITIONS 
Raziel Therapeutics Ltd. holds a clinical trial liability insurance policy.  
A copy of the policy summary will be filled in the investigator's site file. 
 
 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
RZL-012 
 
Version: 7 
 
26 July 2018 
 
 
68 
CONFIDENTIAL 
13. 
REFERENCES 
1. Buck DW, Herbst KL. Lipedema: A Relatively Common Disease with Extremely Common 
Misconceptions. Plast Reconstr Surg Glob Open. 2016;4(9):e1043. 
2. Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin. 
2012;33(2):155-72. 
3. Okhovat JP, Alavi A. Lipedema: A Review of the Literature. Int J Low Extrem Wounds. 
2015;14(3):262-7. 
4. Suga H, Araki J, Aoi N, Kato H, Higashino T, Yoshimura K. Adipose tissue remodeling in 
lipedema: adipocyte death and concurrent regeneration. J Cutan Pathol. 2009;36(12):1293-8. 
5. Warren Peled A, Kappos EA. Lipedema: diagnostic and management challenges. Int J 
Womens Health. 2016;8:389-95. 
6. Fonder MA, Loveless JW, Lazarus GS. Lipedema, a frequently unrecognized problem. J Am 
Acad Dermatol. 2007;57(2 Suppl):S1-3. 
7. Forner-Cordero I, Szolnoky G, Forner-Cordero A, Kemény L. Lipedema: an overview of its 
clinical manifestations, diagnosis and treatment of the disproportional fatty deposition syndrome 
- systematic review. Clin Obes. 2012;2(3-4):86-95. 
8. Hansson E, Svensson H, Brorson H. Liposuction may reduce pain in Dercum's disease 
(adiposis dolorosa). Pain Med. 2011;12(6):942-52. 
9. Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, et al. Adiponectin Enhances Cold-Induced 
Browning of Subcutaneous Adipose Tissue via Promoting M2 Macrophage Proliferation. Cell 
metabolism. 2015;22(2):279-90. 
10. NIH. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 2010 
[Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
 
 
 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
RZL-012 
 
Version: 7 
 
26 July 2018 
 
 
69 
CONFIDENTIAL 
Appendix I:  Trial Schedule of Events 
a. 
Study day is based on Day 0 defined as the day of RZL-012 injection. 
Study Procedure 
Screening Day  
Baseline 
(Treatment) 
 
Visit Schedule (Days 1 to 28) 
Study Daya 
Daya-(-14) 
through Day (-2) 
Day a 0 
Day 1 
Day 3 
Day 7 
Day 14 
Day 21 
Signed informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concomitant Medication 
X 
 
 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
 
 
Pain measurement 
X 
 
 
 
 
X 
 
For lipedema subjects - QOL 
measurement 
X 
 
 
 
 
X 
 
Serology assays (HbSAg, HCV, 
HIV) 
X 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
For Dercum's disease subjects – 
ultrasound assessing nodules size 
(diameter) and quality 
X 
 
 
 
 
 
 
For lipedema subjects – assessing 
fat thickness and nodular quality by 
ultrasound. 
X 
 
 
 
 
 
 
For lipedema subjects – 
measurement of leg circumference 
above the knee  
X 
Pre c X 
 
 
 
 
 
 
 
 
 
 
 
 
 
For lipedema subjects – ultrasound 
assessing  nodules to be injected 
 
Pre c X 
 
 
 
 
 
For Dercum's disease subjects – 
ultrasound re-assessing nodules size 
 
Pre c X 
 
 
 
 
 
Photography of site of injection  
X 
 
X 
 
X 
X 
X 
Serum Chemistry, Hematology b 
X 
Pre c X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
X 
 
Draize score at the injected site d 
X 
Pre c X post c 
X 
 
X 
X 
X 
Vital signs e 
X 
Pre c X post c 
X 
 
X 
X 
X 
Injection of RZL-012 
 
X 
 
 
 
 
 
ECG f 
X 
X post c 
X 
 
 
X 
 
Pulse rate g 
 
X post c 
X 
 
 
 
 
Subjects diary recording of 
analgesics use 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
 
 
X----------------------------------------------------------------


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26 July 2018 
 
 
70 
CONFIDENTIAL 
b. 
CBC, coagulation, serum chemistry analysis, renal and liver function, urinalysis, CPK, amylase measurement: before 
injection,14d and 28d following injection 
c. 
Pre/post – refers to before/after injection respectively 
d. 
Draize score evaluation: before injection, 2h, 24h and 7d, 14d, 21d and 28d following injection 
e. 
Vital signs measurement: before injection, 2h, 24h and 7d, 14d, 21d and 28d following injection 
f. 
ECG is to be performed in triplicate for all measurements in given time point:  4h, 8h, 24h following injection 
g. 
Pulse rate measurements at given time points: 1h, 2h, 4h, 8h, 24h following injection in the opposite hand of blood sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix II: Comparative Pain Scale   


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
RZL-012 
 
Version: 7 
 
26 July 2018 
 
 
71 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix III: Lower Extremity Functional Scale 
 
Activities 
Extreme 
Difficulty or 
Unable to 
Perform Activity 
Quite a Bit 
of 
Difficulty 
Moderate 
Difficulty 
A Little Bit 
of 
Difficulty 
No 
Difficulty 
1 Any of your usual work, 
housework, or school 
activities. 
 0 
 1 
 2 
 3 
 4 
2 Your usual hobbies, re 
creational or sporting 
activities. 
 0 
 1 
 2 
 3 
 4 
3 Getting into or out of the 
bath. 
 0 
 1 
 2 
 3 
 4 
4 Walking between rooms. 
 0 
 1 
 2 
 3 
 4 


Raziel Therapeutics, Ltd.                                                                                      Protocol RZL-012-FD-P2aUS-001.7 
RZL-012 
 
Version: 7 
 
26 July 2018 
 
 
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CONFIDENTIAL 
5 Putting on your shoes or 
socks. 
 0 
 1 
 2 
 3 
 4 
6 Squatting. 
 0 
 1 
 2 
 3 
 4 
7 Lifting an object, like a bag 
of groceries from the floor. 
 0 
 1 
 2 
 3 
 4 
8 Performing light activities 
around your home. 
 0 
 1 
 2 
 3 
 4 
9 Performing heavy 
activities around your home. 
 0 
 1 
 2 
 3 
 4 
10 Getting into or out of a 
car. 
 0 
 1 
 2 
 3 
 4 
11 Walking 2 blocks. 
 0 
 1 
 2 
 3 
 4 
12 Walking a mile. 
 0 
 1 
 2 
 3 
 4 
13 Going up or down 10 
stairs (about 1 flight of 
stairs). 
 0 
 1 
 2 
 3 
 4 
14 Standing for 1 hour. 
 0 
 1 
 2 
 3 
 4 
15 Sitting for 1 hour. 
 0 
 1 
 2 
 3 
 4 
16 Running on even ground. 
 0 
 1 
 2 
 3 
 4 
17 Running on uneven 
ground. 
 0 
 1 
 2 
 3 
 4 
18 Making sharp turns while 
running fast. 
 0 
 1 
 2 
 3 
 4 
19 Hopping. 
 0 
 1 
 2 
 3 
 4 
20 Rolling over in bed. 
 0 
 1 
 2 
 3 
 4 
 
Source: Binkley et al (1999): The Lower Extremity Functional Scale (LEFS): Scale 
development, measurement properties, and clinical application. Physical Therapy. 79:371-383. 

SAP_003.pdf: 
 
DOCUMENT NUMBER: 050-BST-PLN-001 
PAGE: 1 of 24 
TITLE: Statistical Analysis Plan of Protocol Number RZL-012-FD-P2aUS-001 
EFFECTIVE DATE : 02/05/2019  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
Revision History 
 
Revision 
Revision Date 
Reason for Revision/Change Request 
Revised By 
1.0 
04-April-2019 
Original Release 
Alexandra Perez-Alterman , 
Senior Biostatistician 
2.0 
02-May-2019 
Update following Raziel.Ltd comments 
Alexandra Perez-Alterman , 
Senior Biostatistician 
3.0 
20-May-2019 
Update following Raziel.Ltd comments 
Alexandra Perez-Alterman , 
Senior Biostatistician 
 
 
 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-FD-P2aUS-001 
EFFECTIVE DATE : 02/05/2019  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
 
 
 
 
Statistical Analysis Plan 
 
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 
 
 
Protocol Number RZL-012-FD-P2aUS-001 
 
 
 
 
 
 
 
 
 
 
 


 
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TITLE: Statistical Analysis Plan of Protocol Number RZL-012-FD-P2aUS-001 
EFFECTIVE DATE : 02/05/2019  
REVISION NUMBER : 1.0 
 
Medistat Ltd. Confidential 
 
TABLE OF CONTENTS 
 
SIGNATURES PAGE .................................................................................................................... 4 
1. 
DEFINITIONS AND/OR ABBREVIATIONS ...................................................................... 5 
2. 
PURPOSE ............................................................................................................................... 9 
3. 
SCOPE .................................................................................................................................... 9 
4. 
RESPONSIBILITies ............................................................................................................. 10 
4.1 
Medistat Ltd. Responsibilities ........................................................................................ 10 
4.2 
Raziel Therapeutics’s Responsibilities........................................................................... 10 
5. 
PROCEDURE ....................................................................................................................... 11 
5.1 
Introduction .................................................................................................................... 11 
5.2 
Rationale......................................................................................................................... 11 
5.3 
Study Objectives and Endpoints .................................................................................... 12 
5.4 
Overall study design and plan ........................................................................................ 12 
5.5 
Selection of study population ......................................................................................... 16 
5.6 
Statistical Analysis Software and Data Management .................................................... 16 
5.7 
Subject Population for analyses ..................................................................................... 16 
5.8 
Statistical Analysis ......................................................................................................... 17 
6. 
RELATED DOCUMENTS (optional) .................................................................................. 19 
6.1 
Study Protocol:  Protocol V7 - RZL-012-FD-P2aUS-001.7_CLEAN.docx .................. 19 
7. 
RELATED FORMS (optional) ............................................................................................. 19 
8. 
REFERENCES ..................................................................................................................... 19 
9. 
Appendices (optional) ........................................................................................................... 20 
9.1 
APPENDIX I: TABLE SHELLS ................................................................................... 20 
9.2 
APPENDIX II: LISTINGS SHELLS ......................................................................... 2322 
 


 
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SIGNATURES PAGE 
 
Alexandra Perez-Alterman, author  
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date: 11/06/1019 
 
 
David Israel 
Senior Biostatistician & SAS programmer 
MediStat Ltd.                                                                                  Date:  
 
 
 
Rachel Gueta 
Raziel Therapy Ltd.                                                                         Date:  
 
 
 


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


 
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CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EF 
Efficacy analysis set 
FDA 
Food and Drug Administration 
FFA 
Free fatty acids 
FIFO 
First In First Out 
FOB 
Functional Observational Battery 
GLP 
Good Laboratory Practice 
GTTP 
Gamma-glutamyltransferase 
HbSAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization Good Clinical Practice 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDL 
Low-density lipoprotein 
LDH 
Lactate dehydrogenase 


 
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LPL 
Lipoprotein lipase 
MEDDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No observed adverse effect level 
NORD 
National Organization for Rare Disorders 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKA 
PK Analysis set 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QA 
Quality Assurance 
QOL 
Quality of life 
RBC 
Red blood cells 
RDW 
Red cell distribution width 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SAT 
Subcutaneous adipose tissue 
SC 
Subcutaneous 
SFM 
Subcutaneous fat mass 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Terminal half-life 
TAG 
Triacylglycerols 


 
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TG 
Triglycerides 
TLA 
Tumescent Liposuction (Local Anesthesia) 
Tmax 
Time of maximum observed sample concentration 
UCP1 
Uncoupling protein 1 
US/USA 
United States/United States of America 
WAL 
Water Assisted Liposuction 
WAT 
White adipose tissue 
WBC 
White blood cells 
WHO 
World health organization 
 


 
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2. PURPOSE 
2.1 The purpose of this document is to describe in detail the Statistical Analysis Plan of clinical study 
procedures carried out by Medistat Ltd.  
2.2 This document serves Medistat Ltd. as a guiding document for all statistical analyses performed at 
the end of each clinical study. 
2.3 This SAP is specific to Raziel Therapeutics Ltd., study RZL-012-FD-P2aUS-001. 
2.4 This SAP aims to provide details on: sample size calculation, efficacy analyses and safety analyses. 
3. SCOPE 
3.1 This document applies to all members of the statistical & data management units in Medistat Ltd.  
3.2 This document includes the main and interim study trial analysis. 


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


 
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5. PROCEDURE  
5.1 Introduction 
5.1.1 
This Statistical Analysis Plan (SAP) is based on the study protocol version 7, dated 03 
January, 2019. 
5.1.2 
This Statistical Analysis Plan (SAP) contains details of the statistical analyses that will be 
performed, providing a more detailed description of the approach defined in the study 
protocol. Definitions of variables and populations used for the analyses are also included. 
The SAP will be finalized and signed prior to hard lock of the database. 
5.1.3 
General output specifications are provided; examples are given of calculations of derived 
variables. 
5.2 Rationale 
5.2.1 
The initial dose was determined by the NOAEL established by the Good Laboratory 
Practice (GLP) extended single dose toxicology study and by the previous phase 0 clinical 
trial in which 20mg RZL-012 was the highest dose achieved. This initial study is an 
escalating dose study.  If no more than 1 subject experiences intolerable side effects within 
14 days following the injection of the last dosed group, according to schedule, an additional 
cohort of volunteers will be administrated the next dose level. 
5.2.2 
Cohort 1- will be comprised of subjects with Dercum's disease. All subjects will be injected 
with RZL-012. Dosing will be calculated according to the size of the nodule (diameter) as 
determined by ultrasound: 5mg/cm2 reaching a maximal dose of 40 mg RZL-012 per 
subject (1/6.25 the NOAEL based on the Human Dose Equivalent [HED] GLP 
Toxicology studies). 
5.2.3 
Cohort 2 - will be comprised of subjects with lipedema with substantial fat above the knee 
and will be conducted in a dose escalation manner. 
5.2.4 
The first 3 subjects will receive 60mg RZL-012 (1/4.688th the NOAEL based on HED 
from GLP toxicology study).                                                                                      
5.2.5 
The last 3 subjects will receive 80mg RZL-012 (1/3.125th the NOAEL based on HED 
from GLP toxicology study).      
                                                                                                                                                                                        


 
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5.3 Study Objectives and Endpoints 
5.3.1 
Primary Objective 
5.3.1.1 The primary endpoint will be the evaluation of the overall safety of RZL-012 injection into the 
subcutaneous fat in Dercum's disease and lipedema. The trial will proceed within a cohort 
provided that no more than one subject experiences intolerable side effects in a cohort.  
5.3.2 
Secondary Objective 
5.3.2.1 For lipedema subjects - The reduction in local subcutaneous fat in the injection site region as 
compared to baseline as assessed by leg circumference above the knee assessments and by 
the reduction in nodules size and/or numbers assessed by ultrasound. 
5.3.2.2 For Dercum's disease subjects - The reduction in local subcutaneous fat in the injection site region 
as compared to baseline assessed by the reduction in nodules size and/or numbers by 
ultrasound. 
5.3.2.3 Extended duration of the fat reduction effect.  To that end, ultrasound images and circumference 
measurement will be followed for 56 days. 
5.3.2.4 Elucidation of the tissue changes by ultrasound of the injection site to include reduction in fat 
thickness and nodular quality. 
5.3.2.5 Improvement in local pain as measured by Comparative Pain Scale and by the reduction in the 
use of analgesics. 
5.3.2.6 Improvement in QOL and function in lipedema subjects as measured by questionnaire (such as 
The Lower Extremity Functional Scale (LEFS)). 
5.4 Overall study design and plan 
5.4.1 
Study Design  
5.4.1.1 Six subjects in cohort 1, all assigned to the RZL-012 treatment group will be dosed at a maximal 
dose of 40 mg RZL-012 (approximately 1/6.25th the NOAEL as determined in the GLP 
toxicology study). Dosing will be calculated according to the size of the nodule (diameter) as 
determined by ultrasound in a dose of 5mg/cm2: 
5.4.1.2 Six subjects in cohort 2, all assigned to the RZL-012 treatment group, will be dosed as follows: 


 
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Medistat Ltd. Confidential 
 
5.4.1.3 The first 3 subjects will receive 30mg RZL-012 in 6 injections (0.1mL each) in one leg followed 
by 30mg RZL-012 (6 injections, 0.1mL each) in the second leg adding up to 12 injections of 
60mg RZL-012 (1/4.688th the NOAEL based on HED from GLP toxicology study).  
5.4.1.4 The last 3 subjects will receive 40mg RZL-012 in 8 injections (0.1mL each) in one leg followed 
by 40mg RZL-012 (8 injections, 0.1mL each) in the second leg adding up to 16 injections of 
80mg RZL-012 (1/3.125th the NOAEL based on HED from GLP toxicology study). 
5.4.1.5 Dosing of subjects in each cohort will progress consecutively from one individual to the other at 
7-day intervals. This study design will allow the physicians to monitor safety for at least 7 
days prior to dosing the next subject. For cohort 2 the decision to proceed to the next dose 
level will be made after reviewing all safety data collected by Day 14 within 2 ± 1d of the 
last dosed subject. The trial will proceed within a cohort provided that no more than one 
subject experiences intolerable side effects in a cohort, and based on the decision made by 
the Principal Investigator (PI) and the Medical Monitor.   
 
5.4.2 
Schedule of Assessments 
Study Procedure 
Screening Day  
Baseline 
(Treatm
ent) 
 
Visit Schedule (Days 1 to 28) 
Follow-
up 
Study Daya 
Daya-(-14) 
through Day 
(-2) 
Day a 0 
Day 
1 
Day 
3 
Day 7 
Day 
14 
Day 
21 
Day 
28 
Day 56 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
 
 
 
 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
 
 
X 
 
Pain measurement 
X 
 
 
 
 
X 
 
X 
X 
For lipedema subjects - 
QOL measurement 
X 
 
 
 
 
X 
 
X 
X 


 
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Medistat Ltd. Confidential 
 
Serology assays (HbSAg, 
HCV, HIV) 
X 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
Height and weight 
X 
 
 
 
 
For Dercum's disease 
subjects – ultrasound 
assessing nodules size 
(diameter) and quality 
X 
 
 
 
 
For lipedema subjects – 
assessing fat thickness and 
nodular quality by 
ultrasound. 
X 
 
 
 
 
For lipedema subjects – 
measurement of leg 
circumference above the 
knee  
X 
Pre c X 
 
 
 
 
 
 
 
 
 
For lipedema subjects – 
ultrasound assessing  
nodules to be injected 
 
Pre c X 
 
 
 
For Dercum's disease 
subjects – ultrasound re-
assessing nodules size 
 
Pre c X 
 
 
 
Photography of site of 
injection  
X 
 
X 
 
X 
Serum Chemistry, 
Hematology b 
X 
Pre c X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
Draize score at the injected 
site d 
X 
Pre c X 
post c 
X 
 
X 


 
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a. 
Study day is based on Day 0 defined as the 
day of RZL-012 injection. 
b. 
CBC, coagulation, serum chemistry analysis, 
renal and liver function, urinalysis, CPK, 
amylase measurement: before injection,14d 
and 28d following injection 
c. 
Pre/post – refers to before/after injection 
respectively 
d. 
Draize score evaluation: before injection, 2h, 
24h and 7d, 14d, 21d and 28d following 
injection 
e. 
Vital signs measurement: before injection, 2h, 
24h and 7d, 14d, 21d and 28d following 
injection 
f. 
ECG is to be performed in triplicate for all 
measurements in given time point:  4h, 8h, 
24h following injection 
g. 
Pulse rate measurements at given time points: 
1h, 2h, 4h, 8h, 24h following injection in the 
opposite hand of blood sampling 
 
 
Vital signs e 
X 
Pre c X 
post c 
X 
 
X 
Injection of RZL-012 
 
X 
 
 
 
ECG f 
X 
X post c 
X 
 
 
Pulse rate g 
 
X post c 
X 
 
 
Subjects diary recording of 
analgesics use 
X 
X 
X 
X 
X 
AE assessment 
 
 
X----------------------------
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5.4.3 
Randomization, Blinding and Un-blinding 
5.4.3.1 This is an open label study where all subjects will receive the investigational drug (RZL-012). 
5.5 Selection of study population 
5.5.1 
Study Population 
5.5.1.1 Post-menopausal women no more than 65 years old, with lipedema involving substantial fat 
above the knee or nodular Dercum's disease in such women and in men 20- 65 years with 
nodular Dercum's disease. 
5.5.2 
Rationale Sample Size Calculation 
5.5.2.1 This study is planned following a 6 subjects per group paradigm. A maximum of 12 evaluable 
subjects will be included in the study (6 subjects with Dercum's disease and 6 subjects with 
lipedema) and followed for as long as 2 months. 
5.6 Statistical Analysis Software and Data Management 
5.6.1 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed using SAS® version 9.3 or higher for 
Windows. If the use of other software is warranted, the final statistical methodology report 
will detail what software was used for what purposes. 
5.6.2 
Data Management 
5.6.3 
Data management for the study is performed by Medistat. 
5.6.4 
Medical Coding 
5.6.5 
Concomitant medications entered into the database  are coded using the WHO (World 
Health Organization) Drug Public Website Dictionary named WHOCC-ATC/DDD 
index, which employs the Anatomical Therapeutic Chemical classification system.  
5.6.6 
Adverse events are coded using the most updated version of Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. 
5.6.7 
Medical history events are coded using the most updated version of Medical Dictionary 
for Regulatory Activities (MedDRA) terminology 
5.6.8 
Handling of Missing data 
5.6.9 
No imputation of missing data will be performed 
5.7 Subject Population for analyses 


 
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5.7.1 
The SA will consist of all enrolled subjects who received the study treatment, (exposed 
population), including subjects prematurely withdrawn. 
5.7.2 
All enrolled subjects receiving at least one study drug injection are considered evaluable 
for the SA set.The SA analysis set will serve as the principal data analysis set for the 
analyses of the safety endpoints. 
5.7.3 
The EF will consist of all subjects from the SA analysis set without any major protocol 
violations measured at baseline.  Subjects will be analyzed according to the treatment 
received. 
5.7.4 
The SA analysis set will serve as the principal data analysis set for the analyses of the safety 
endpoints. 
5.7.5 
The EF analysis set will serve as the principal data analysis set for the analyses of the 
efficacy endpoints. 
5.8 Statistical Analysis 
5.8.1 
General 
5.8.2 
Statistical analyses will be mainly descriptive in nature where study data will be tabulated 
and summarized using the mean, standard deviation or standard error, median, minimum, 
maximum and number of subjects by cohort for continuous data.  For categorical data, 
results will be summarized via a count and percentage by cohort.  The results will be 
presented overall, per cohort and per cohort and dose. The effects of noncompliance, 
dropouts, and covariates, may be assessed to determine the impact on the general 
applicability of results from this study. 
5.8.3 
If any statistical tests are performed, they will be two-sided.  The required significance level 
of findings will be equal to or lower than 5%.  Nominal p-values will be presented. 
5.8.4 
Where confidence limits are appropriate, the confidence level will be 95%. 
5.8.5 
The data  is analyzed using the SAS ® version 9.3 or higher (SAS Institute, Cary North 
Carolina).  
5.8.6 
Statistical methods presented in the SAP may be slightly different from those that are 
presented in the protocol. Differences are clearly stated and the SAP supersedes the 
protocol only with regard to the way data will be handled and analysed. 


 
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5.8.7 
Subject Disposition 
5.8.8 
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 cohort and for all 
subjects.  All withdrawals from the study, taking place on or after study drug injection, will 
be fully documented in the body of the Clinical Study Report. 
5.8.9 
Note that the actual study duration is for a period of maximum 2 months, with efficacy 
analyses being conducted at 28 days and 56 days. 
5.8.10 Demographic and Baseline Characteristics 
5.8.11 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. 
5.8.12 Baseline safety data will be presented along with subsequent safety values assessed during 
or after dosing. 
5.8.13 The incidence of intolerable side effects will be presented overall and by cohort along with 
two sided 95% exact binomial Confidence Interval (CI). 
5.8.14 Percent changes from baseline in local fat reduction (circumference of the leg above the 
knee, nodules size and/or numbers in the injected area) and tissue changes (fat thickness), 
will be presented in tabular form by visit. 
5.8.15 Changes in nodular quality, local pain, quality of life and function will be presented in 
tabular form by visit and cohort. 
5.8.16 Safety and Tolerability 
5.8.17 Safety analyses will be descriptive in nature.  
5.8.18 All reported AEs will be coded to a standard set of terms using MedDRA coding dictionary 
(V22.0 or higher) treatment.  


 
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5.8.19 AEs and tolerability data will be presented descriptively by treatment and cohort.  AEs will 
be tabulated by body system, preferred term, seriousness, severity and relation to study 
drug by cohort.  Where applicable, changes in values over time (e.g., lab values, vital signs, 
ECGs) will be presented; this will include clinical laboratory evaluations (including CBC, 
blood chemistry and urinalysis), coagulation (INR, PTT and PT), cytokines, vital signs, 
and ECGs.  Shift tables of normal / abnormal versus baseline may be presented as well.  
5.8.20 Draize scores will be presented in tabular format by visit, treatment, and cohort. 
5.8.21 Concomitant medication verbatim terms (as recorded on the CRFs) will be coded to 
Anatomical Therapeutic Chemical (ATC) Level 2 and 4 using the World Health 
Organization (WHO) dictionary. 
 
 
6. RELATED DOCUMENTS (OPTIONAL) 
6.1 Study Protocol:  Protocol V7 - RZL-012-FD-P2aUS-001.7_CLEAN.docx  
 
7. RELATED FORMS (OPTIONAL) 
Not Applicable 
8. REFERENCES 
Not Applicable 
 
 
 
 
 
 


 
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9. APPENDICES (OPTIONAL) 
9.1 APPENDIX I: TABLE SHELLS 
14.1 Demographic Data 
Table 14.1-1: Disposition of Subjects 
Table 14.1-2: Analysis populations 
Table 14.1-3: Demographic Data (Part 1 of 2) 
Table 14.1-3: Demographic Data (Part 2 of 2) 
Table 14.1-4: Medical History 
Table 14.1-5: Disease-Related Medical History 
14.1-6: Disease characteristics 
Table 14.1-6-1: Dercum's cohort lipoma type 
Table 14.1-6-2: Lipedema disease characteristics (Part 1 of 2) 
Table 14.1-6-2: Lipedema disease characteristics (Part 2 of 2) 
14.2 Drug administration 
Table 14.2-1 Drug administration 
14.3 Efficacy Assessment 
Table 14.3-1 Pain by comparative scale by cohort 
Table 14.3-2 Reduction in Pain from baseline by visit 
Table 14.3-3 Relative Change in local pain 
14.3-4 Dercum's disease cohort 
Table 14.3-4-1 Number of Lipomas by visit 
Table 14.3-4-2 Reduction of number of Lipomas from baseline by visit 
Table 14.3-4-3 Relative Change in Number of lipomas 
Table 14.3-4-4 Size of lipomas by visit and type 


 
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Table 14.3-4-5 Reduction** in Size of lipomas by visit and type 
Table 14.3-4-6 Relative change in Size of lipomas by visit and type 
Table 14.3-4-7 Lipoma description 
14.3-4.8 Correlation between pain and size of lipomas 
Table 14.3-4.8-1 Correlation between lipoma size and pain for lipomas with Fibrotic tissue 
not associated with the capsule 
Table 14.3-4.8-2 Correlation between lipoma size and pain for lipomas with Fibrotic tissue 
associated with the capsule 
Table 14.3-4.8-3 Correlation between reduction in lipoma size and reduction in pain for all 
lipomas 
14.3-5 Lipedema cohort 
Table 14.3-5-1 Number of fat locations by visit 
Table 14.3-5-2 Thickness of fat locations by visit for right/left leg 
Table 14.3-5-3 Reduction** in fat locations Thickness by visit and type 
Table 14.3-5-4 Relative change in fat locations Thickness by visit and type 
Table 14.3-5-5 Fat tissue description 
Table 14.3-5-6 Nodule description 
Table 14.3-5.7 Correlation between reduction in nodule size and reduction in pain 
Table 14.3-5-8 Additional measurements 
Table 14.3-5-9 Reduction** in additional measurements 
Table 14.3-5-10 Relative change in additional measurements 
14.4 Safety Data and Other Assessments 
14.4.1 Adverse Events 
Table 14.4.1-1: Frequency of Any Adverse Events 


 
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Table 14.4.1-2: Frequency of any intolerable side effects 
Table 14.4.1-3: Summary of Adverse Events by SOC and PT by treatment 
Table 14.4.1-4: Summary of Adverse Events by SOC, PT, severity and by treatment 
Table 14.4.1-5: Summary of Adverse Events by SOC, PT, relationship to study treatment 
and by treatment 
14.4.2 Other Assessments 
Table 14.4.2-1: Summary of Vital signs 
Table 14.4-2.2 Changes in Vital signs 
Table 14.4-2.3 Relative Changes in Vital signs 
Table 14.4-2.4: Laboratory tests 
Table 14.4-2.5: Draize Score 
Table 14.2-3.6 ECG results 
Table 14.2-3.7 Changes in ECG results 
Table 14.2-3.8 Relative Changes in ECG results 
 
 
 
 
 
 
 


 
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9.2 APPENDIX II: LISTINGS SHELLS 
16.2.1 Subject Disposition 
 
Listing 16.2.1-1: Subject Disposition 
Listing 16.2.1-2: Visit dates per subject 
 
Listing 16.2.1-3: Unscheduled Visit  
16.2.2 Protocol Deviations 
 
Listing 16.2.2-1: Inclusion/Exclusion criteria violations 
 
16.2.3 Demographic Data and Baseline Assessments 
 
Listing 16.2.3-1: Demographic Data  
Listing 16.2.3-2: Medical History 
 
Listing 16.2.3-3: Disease-Related Medical History  
16.2.3-4: Disease characteristics 
 
Listing 16.2.3-4-1: Dercum's disease cohort lipoma type 
 
Listing 16.2.3-4-2: Lipedema cohort disease characteristics 
16.2.4 Compliance/Exposure/Drug Concentration Data 
 
Listing 16.2.4-1: Injection of RZL-012 (Part 1 of 2)  
Listing 16.2.4-1: Injection of RZL-012 (Part 2 of 2)  
16.2.5 Individual Efficacy/Response Data 
 
Listing 16.2.5-1: Comparative pain for both cohort  
16.2.5-2 Ultrasound and measurements Dercum's cohort 
 
Listing 16.2.5-2-1: Number of Lipomas 
 
Listing 16.2.5-2-2: Lipomas description 
 
Listing 16.2.5-2-3: Size of Lipomas  
16.2.5-3 Ultrasound and measurements Lipedema cohort 
 
Listing 16.2.5-3-1: Number of Injected Fat Locations 
 
Listing 16.2.5-3-2: Fat tissue description 
 
Listing 16.2.5-3-3: Fat tissue description 
 
Listing 16.2.5-3-4: Thickness of Fat Tissue  
Listing 16.2.5-3-5: Thickness of Fat Tissue - Shift table 
 
Listing 16.2.5-3-6: Average reduction in Thickness of Fat Tissue  


 
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Listing 16.2.5-3-7: Additional measurements 
 
Listing 16.2.5-3-8: Additional measurements - Shift table  
16.2.6 Adverse Events listings 
 
Listing 16.2.6-1: All Adverse events (Part 1 of 2) 
 
Listing 16.2.6-1: Adverse events (Part 2 of 2) 
 
Listing 16.2.6-2: Serious Adverse Events (Part 1 of 2) 
 
Listing 16.2.6-2: Serious Adverse Events (Part 2 of 2) 
 
16.2.7 Laboratory and other safety parameters 
 
Listing 16.2.7-1: Laboratory tests (Part1 of 2) 
 
Listing 16.2.7-1: Laboratory tests (Part 2 of 2) 
 
Listing 16.2.7-2: ECG Results* (Part 1 of 2)  
Listing 16.2.7-2: ECG Results* (Part 2 of 2)  
Listing 16.2.7-3: Vital signs (Part 1 of 2) 
 
Listing 16.2.7-3: Vital signs (part 2 of 2) 
 
Listing 16.2.7-4: Draize Score 
 
Listing 16.2.7-5: Benadryl 
 
Listing 16.2.7-6: Concomitant Medications (Part 1 of 3) 
 
Listing 16.2.7-6: Concomitant Medications (Part 2 of 3) 
 
Listing 16.2.7-6: Concomitant Medications (Part 3 of 3) 
 
Listing 16.2.7-7: Comments