Clinical trial NCT03309605
Conditions: Genetic Disease Nonsense Mutation
Keywords: Translational read through
Sponsor: Eloxx Pharmaceuticals, Inc.
Start date: 2017-10-11; Completion date: 2019-07-17
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1 Multiple Ascending Dose Study in Normal Healthy Volunteers

Detailed description:
This is a study in humans of ELX-02, an advanced synthetic aminoglycoside optimized as a translational read-through drug (TRID) for the treatment of genetic conditions caused by nonsense mutations. This is a classical Phase 1b study designed as a randomized, double-blinded, placebo-controlled, multiple dose escalation to evaluate the safety, tolerability, and pharmacokinetics of ELX-02 in healthy adult volunteers.

Arms: arm 1: Placebo arm 2: ELX-02
Interventions: intervention 1: ELX-02 intervention 2: Placebo
Intervention descriptions: intervention 1: ELX-02 is a synthetic, designer eukaryotic ribosomal specific glycoside (ERSG) optimized as a translational read-through drug intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 


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Summary of Changes: Protocol ELX-02 Dated 26 February 2019 to Protocol ELX-02 Dated 
29 May 2019 
Synopsis and Section 3.2 Progression to Next Cohort Dose Escalation were revised to include 
additional language regarding dose interruption and resumption during the study related to high 
frequency threshold shifts.  
 
  




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Signature of Investigator 
 
A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Third Party Open, 
Multiple Dose Escalation Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Subcutaneously Administered ELX-02 in Independent 
Consecutive Cohorts of Healthy Subjects  
 
 
Name: 
 
 
 
I declare that I have read and understood this study protocol. I agree to abide by this 
protocol (subject to any amendments agreed in writing between the Sponsor and Principal 
Investigator). Any changes in procedure will only be made if necessary to protect the 
safety, rights, or welfare of the subjects. 
This study will be conducted according to Good Clinical Practice (GCP), local regulations 
and to all stipulations, clinically and administratively, as stated in the protocol, including 
all statements as to confidentiality. It is agreed that the conduct and results of this study 
will be kept confidential. 
It is agreed that the protocol contains all necessary information required to conduct the 
study as outlined in the protocol, and that the study will not be initiated without the 
approval of the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
and the local health autority. 
 
 
 
Signature: 
 
Date: 
 
 
 


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Signature of Investigator 
 
A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Third Party Open, 
Multiple Dose Escalation, Study to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Subcutaneously Administered ELX-02 in Independent 
Consecutive Cohorts of Healthy Subjects  
 
 
Name: 
 
 
 
I declare that I have read and understood this study protocol. I agree to abide by this 
protocol (subject to any amendments agreed in writing between the Sponsor and Principal 
Investigator). Any changes in procedure will only be made if necessary to protect the 
safety, rights, or welfare of the subjects. 
This study will be conducted according to Good Clinical Practice (GCP), local regulations 
and to all stipulations, clinically and administratively, as stated in the protocol, including 
all statements as to confidentiality. It is agreed that the conduct and results of this study 
will be kept confidential. 
It is agreed that the protocol contains all necessary information required to conduct the 
study as outlined in the protocol, and that the study will not be initiated without the 
approval of the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
and the local health autority. 
 
 
 
Signature: 
 
Date: 
 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................... 6 
PROTOCOL SUMMARY ...................................................................................................... 11 
ABBREVIATIONS ................................................................................................................. 23 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................ 26 
1. INTRODUCTION ............................................................................................................... 27 
1.1. Mechanism of Action/Indication ............................................................................ 27 
1.1.1. The Effect of Aminoglycosides on Nonsense Mutations ........................... 27 
1.1.2. ELX-02 ....................................................................................................... 27 
1.2. Background and Rationale ...................................................................................... 29 
1.2.1. Non-Clinical Studies .................................................................................. 29 
1.2.2. Clinical Studies .......................................................................................... 30 
1.2.3. Overall Rationale for the Study .................................................................. 31 
1.2.4. Risk Benefit Analysis .................................................................................. 33 
2. STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 34 
2.1. Objectives ............................................................................................................... 34 
2.1.1. Primary Objective ...................................................................................... 34 
2.1.2. Secondary Objectives ................................................................................. 34 
2.2. Endpoints ................................................................................................................ 34 
2.2.1. Primary Endpoints ...................................................................................... 34 
2.2.2. Secondary Endpoints .................................................................................. 34 
3. STUDY DESIGN ................................................................................................................ 35 
3.1. Overall Study Design .............................................................................................. 35 
3.2. Progression to Next Cohort and Dose Escalation ................................................... 36 
4. SUBJECT SELECTION ..................................................................................................... 40 
4.1. Inclusion Criteria .................................................................................................... 40 
4.2. Exclusion Criteria ................................................................................................... 41 
4.3. Prohibitions ............................................................................................................. 43 
4.4. Lifestyle Guidelines ................................................................................................ 43 
4.5. Sponsor’s Qualified Medical Personnel ................................................................. 43 
4.6. Contact Cards .......................................................................................................... 43 


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4.7. Rater Qualifications ................................................................................................ 43 
4.8. Subject Identification .............................................................................................. 44 
4.9. Re-Screening of Subjects ........................................................................................ 44 
4.10. Screening Failures ................................................................................................ 44 
4.11. Removal, Replacement or Early Withdrawal ....................................................... 44 
4.12. Early Study Termination ....................................................................................... 45 
5. STUDY TREATMENTS .................................................................................................... 46 
5.1. Allocation to Treatment .......................................................................................... 46 
5.1.1. Randomization and Blinding ...................................................................... 46 
5.1.2. Breaking the Blind ..................................................................................... 47 
5.2. Subject Compliance ................................................................................................ 47 
5.3. Investigational Product Supplies ............................................................................ 47 
5.3.1. Dosage Form(s) and Packaging ................................................................. 48 
5.4. Administration ........................................................................................................ 49 
5.5. Investigational Product Storage .............................................................................. 49 
5.6. Investigational Product Accountability .................................................................. 50 
5.7. Destruction of Investigational Product Supplies .................................................... 50 
6. STUDY RESTRICTIONS .................................................................................................. 51 
6.1. Concomitant Treatments ......................................................................................... 51 
6.2. Limit of Noise Exposure ......................................................................................... 51 
6.3. Meals and Dietary Restrictions ............................................................................... 52 
6.4. Activity ................................................................................................................... 52 
6.5. Contraception .......................................................................................................... 52 
6.5.1. Female Subjects ......................................................................................... 52 
6.5.2. Male Subjects ............................................................................................. 53 
7. STUDY PROCEDURES ..................................................................................................... 54 
7.1. Timing of Assessments ........................................................................................... 54 
7.2. Allowed Time Window Deviations ........................................................................ 65 
7.3. Safety Evaluations .................................................................................................. 66 
7.3.1. Adverse Events (AEs) ................................................................................ 66 
7.3.2. Concomitant Medications .......................................................................... 66 
7.3.3. Vital Signs .................................................................................................. 66 
7.3.4. Physical Examination ................................................................................. 67 


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7.3.5. ECG Examination ...................................................................................... 67 
7.3.6. Auditory and Vestibular Assessments ....................................................... 67 
7.3.7. Local Reaction of Injection Site ................................................................. 68 
7.3.8. Pregnancy Testing ...................................................................................... 68 
7.3.9. Safety Blood and Urine, and Blood Sampling for Retention ..................... 68 
7.4. ELX-02 Pharmacokinetic Assessments .................................................................. 71 
7.4.1. Blood Sampling .......................................................................................... 71 
7.4.2. Urine Collection ......................................................................................... 72 
7.4.3. Bioanalysis ................................................................................................. 74 
7.4.4. Pharmacokinetic Parameters ...................................................................... 74 
7.5. Pharmacodynamics ................................................................................................. 75 
7.5.1. Renal Injury Biomarkers ............................................................................ 75 
7.5.2. Potential Read-Through of Housekeeping Protein .................................... 75 
7.6. Mitochondrial Mutations Testing ........................................................................... 76 
8. ADVERSE EVENT REPORTING ..................................................................................... 76 
8.1. Adverse Events ....................................................................................................... 76 
8.2. Reporting Period ..................................................................................................... 76 
8.3. Definition of an Adverse Event .............................................................................. 77 
8.4. Adverse Events of Interest ...................................................................................... 77 
8.4.1. Criteria for Nephrotoxicity ......................................................................... 78 
8.4.2. Criteria for Ototoxicity ............................................................................... 78 
8.5. Medication Errors ................................................................................................... 80 
8.6. Abnormal Test Findings ......................................................................................... 80 
8.7. Serious Adverse Events .......................................................................................... 80 
8.8. Hospitalization ........................................................................................................ 81 
8.9. Severity Assessment ............................................................................................... 82 
8.10. Causality Assessment ........................................................................................... 82 
8.11. Action Taken Regarding the Study Drugs ............................................................ 83 
8.12. Outcome ................................................................................................................ 84 
8.13. Unexpected Adverse Event ................................................................................... 84 
8.14. Exposure During Pregnancy ................................................................................. 84 
8.15. Follow-up of Adverse Events ............................................................................... 86 
8.16. Independent Data and Safety Monitoring Board (DSMB) ................................... 86 


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8.17. Occupational Exposure ......................................................................................... 87 
8.18. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal) .............................................................................................................. 87 
8.19. Eliciting Adverse Event Information .................................................................... 87 
8.20. Recording of Adverse Events ............................................................................... 87 
8.21. Reporting Requirements ....................................................................................... 87 
8.21.1. Serious Adverse Event Reporting Requirements ..................................... 88 
8.21.2. Nonserious Adverse Event Reporting Requirements ............................... 88 
8.21.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................ 88 
9. STATISTICAL METHODS ............................................................................................... 89 
9.1. Sample Size Determination .................................................................................... 89 
9.2. Pharmacokinetic Analysis ...................................................................................... 89 
9.3. Safety Analysis ....................................................................................................... 90 
9.4. Interim Analysis ...................................................................................................... 90 
10. ETHICS ............................................................................................................................. 91 
10.1. Institutional Review Board/Ethics Committee ..................................................... 91 
10.2. Ethical Conduct of the Study ................................................................................ 92 
10.3. Subject Information and Consent ......................................................................... 93 
10.4. Subject Recruitment .............................................................................................. 94 
10.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ... 94 
11. ADMINISTRATIVE REQUIREMENTS ......................................................................... 95 
11.1. Protocol Amendments .......................................................................................... 95 
11.2. Subject Identification, Enrollment, and Screening Logs ...................................... 95 
11.3. Source Documentation .......................................................................................... 95 
11.4. Case Report Form Completion ............................................................................. 96 
11.5. Monitoring ............................................................................................................ 96 
11.6. Data Management ................................................................................................. 96 
11.7. Data Quality Assurance ........................................................................................ 97 
11.8. On-Site Audits ...................................................................................................... 97 
11.9. Study Termination ................................................................................................ 97 
11.10. Record Retention ................................................................................................ 98 
11.11. Use of Information and Publication .................................................................... 98 
11.11.1. Communication of Results by Eloxx Pharmaceuticals .......................... 98 


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11.11.2. Publications by Investigators ................................................................. 99 
11.12. Registration of Clinical Studies and Disclosure of Results .............................. 100 
11.13. Confidentiality .................................................................................................. 100 
12. REFERENCES ................................................................................................................ 101 
13. APPENDIX ..................................................................................................................... 103 
13.1. Site Reactions to Injections and Infusions DAIDS Grading Table .................... 103 
13.2. Dizziness Handicap Inventory ............................................................................ 104 
13.3. Tinnitus Handicap Inventory .............................................................................. 106 
13.4. Document History ............................................................................................... 108 
 
LIST OF TABLES 
Table 1:  
Time and Events Schedule ................................................................................... 18 
Table 2: 
Safety Test ............................................................................................................ 70 
 
LIST OF FIGURES 
Figure 1: 
Chemical Structure of ELX-02 ............................................................................ 28 
Figure 2: 
Study Design Scheme .......................................................................................... 39 
 
 


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PROTOCOL SUMMARY  
Study Title: 
A Phase 1, randomized, double-blinded, placebo-controlled, third party open, multiple dose 
escalation study to evaluate the safety, tolerability and pharmacokinetics of subcutaneously 
administered ELX-02 in independent consecutive cohorts of healthy subjects.  
Protocol No.: 
EL-002 
Phase 
1b 
Eudra CT Number 
2016-005249-21 
IND Number 
137391 
Test Drug 
ELX-02: 6'-(R)-Methyl-5-O-(5-amino-5,6-dideoxy-α-L-talofuranosyl)- paromamine sulfate 
Reference Drug 
NaCl 0.9% 
Study Objectives: 
Primary 
1. To assess the safety and tolerability of multiple ascending subcutaneously (SC) 
administered doses of ELX-02. 
2. To study the pharmacokinetics (PK) of ELX-02 administered as multiple SC doses. 
Secondary 
1. To assess whether a maximum tolerated dose (MTD) is attained within the given 
dose range. 
2. To assess linearity between ascending SC doses and PK parameters.  
Study Endpoints 
Primary  
1. Incidence and characteristics of adverse events (AEs) and other changes in safety 
parameters at ascending doses. 
2. Blood and urine PK parameters of ELX-02. 
Secondary  
1. Assessment, based on the safety profile, whether dose-limiting toxicity (DLT) and 
MTD are attained within the tested dose range. 
2. Dose linearity of PK parameters within the administered SC doses range. 
Study Design and 
Procedures: 
This is a Phase 1, randomized, double-blinded, placebo-controlled, multiple dose escalating 
study in healthy male and female subjects. 
The study includes at least 5 cohorts of 9 subjects each (both males and females need to be 
enrolled in each cohort, a significant number of female subjects needs to be enrolled). 
Subjects will be randomized to receive multiple doses of ELX-02 or placebo at a ratio of 2:1 
in each cohort: Six subjects will receive ELX-02 and three will receive placebo: 
 Cohort 1: ELX-02 0.1 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 2: ELX-02 0.3 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 3: ELX-02 1.0 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 4: ELX-02 2.5 mg/kg (100 mg/mL) or placebo SC twice a week for 9 doses; 
 Cohort 5: ELX-02 up to 2.5 mg/kg (50 mg/mL per injection) or placebo SC twice a week 
for 9 doses; 
 Cohort 6: ELX-02 2.5 to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
 Cohort 7: ELX-02 up to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
Dose escalation to the next cohort will not be performed until after the 14-day observation 
period for the previous cohort, to allow for detection of unanticipated delayed adverse event 
(AE)s.  
Changes to the planned dose may be made in any cohort, depending on safety and any 
available PK data. The dose will not exceed 5.0 mg/kg. Additional cohorts or subjects may 


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be added to reaffirm safety of ELX-02.   
The investigational drug, ELX-02, is formulated as a solution for SC injection, containing 
200 mg/mL. The placebo control will consist of a SC injection of normal saline at matching 
volumes.  
The study will comprise the following periods for each subject: 
 A screening period, within 42 days before dosing up to Day -2 (including an ear, nose, 
and throat (ENT) exam with auditory and vestibular assessment (up to Day -8). An 
additional baseline ENT exam with auditory and vestibular assessment will be performed 
between Day -7 and Day -1 (may be combined on the same day 2-3 hours apart).  
 An in-house treatment and follow-up period consisting of a predose day (Day -1), dosing 
day (Day 1) and follow-up days (Days 2 and 3). Subjects will be released from the 
Clinical Pharmacological Unit (CPU) approximately 48h after dosing.  
 Subject will return to the ENT specialist for auditory and vestibular tests on Day 3 
(-1 day). 
 A return visit to the CPU for treatment and testing on Day 4. 
 An in-house treatment period consisting of a predose day (Day 7) and a dosing day 
(Day 8) 
 A return visit for performing audiometric and vestibular tests on Day 10 (-1 day) 
 A return visit to the CPU for treatment and testing on Day 11. 
 An in-house treatment period consisting of a predose day (Day 14) and a dosing day 
(Day 15). 
 A return visit for performing audiometric and vestibular tests on Day 17 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 18. 
 An in-house treatment period consisting of a predose day (Day 21) and a dosing day 
(Day 22).   
 A return visit for performing audiometric and vestibular tests on Day 24 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 25. 
 An in-house treatment and follow-up period consisting of a pre-last dose day (Day 28), 
dosing day (Day 29) and follow-up days (Days 30 and 31). Subjects will be released from 
the CPU approximately 48h after the last dosing.   
 A return visit to the CPU on Day 32. 
 An End-of-Study (EOS) visit will take place 7-10 days after last dosing. The additional 
ENT exam may be performed 7-11 days after last dosing. 
Dose escalation 
The decision to proceed to a higher dose level will be following the recommendations of 
both the general and auditory and vestibular Data Safety Monitoring Boards (DSMB, 
AVDSMB) based on the dose-escalation stopping rules (see below). The decision will be 
based on review of the blinded safety data, any available blinded PK data, and the results of 
audiologic tests and questionnaires collected up to the DSMB meeting. The AVDSMB will 
provide recommendation to the general DSMB following review of the results of audiologic 
tests and questionnaires. The next cohort will be dosed after the general DSMB and 
AVDSMB have evaluated the safety data and any available PK data and have recommended 
to escalate. 


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The principles of dose escalation, determination of DLT and MTD, are as follows: 
Per Common Terminology Grades for Adverse Events (CTCAE) guidelines, 
 Grade-1 drug-related toxicity will allow dose escalation to the next dose level. 
 Grade-2 drug-related toxicity:  
- 
Cohort 1: 
o 
If the total number of subjects with this drug-related toxicity does not exceed 
3, dose escalation is allowed to Cohort 2. 
o 
If the total number of subjects with this drug-related toxicity is 4 or more, this 
will be considered a DLT and dose escalation to Cohort 2 will not be 
authorized. 
- 
Cohorts 2 and above: 
o 
If this toxicity occurs in up to 1 subject per cohort, dose escalation to the next 
dose level is permitted. 
o 
If this toxicity occurs in 3 subjects per cohort, 6 subjects receiving ELX-02 
and 3 subjects receiving placebo will be added to the current dose level: 
 
If the number of subjects of the repeated dose level with this drug-related 
toxicity does not exceed 3, dose escalation is permitted.  
 
If 4 or more subjects of the repeated dose level have this drug-related 
toxicity, this will be considered a DLT and dose escalation to the next 
dose level will not be authorized. The previous dose level will be 
determined as the MTD. 
 Grade-3, 4 or 5 drug-related toxicity: if it occurs at any dose level and in any cohort, this 
will be considered a DLT and the previous dose level will be determined as the MTD. 
Outside of CTCAE guidelines: 
For abnormalities in high frequency audiometry (HFA), an ototoxic event is defined as the 
loss of >25 dB averaged at three consecutive frequencies in at least one ear. 
 For confirmed ototoxic event in HFA in any cohort:  
- 
If an HFA ototoxic event occurs in 2 subjects receiving ELX-02 in any cohort, 6 
subjects receiving ELX-02 and 3 subjects receiving placebo will be added to the 
current dose level, unless it is determined by the Sponsor with the AVDSMB 
following a thorough medical review that the study may resume. In this instance 
additional subjects will not need to be added. 
- 
If an HFA ototoxic event occurs in ≥3 subjects receiving ELX-02 in any cohort, 
this will be considered a DLT and dose escalation to the next dose level will not be 
authorized. The previous dose level will be determined as the MTD. 
If the criteria for stopping a dose for an individual subject has been met during a cohort, the 
study may be temporarily suspended immediately, to allow for further medical evaluation 
with additional assessments of the proported event, as appropriate. If any subject/subjects 
meet dose stopping or significant change criteria the sponsor, after discussion with PI, may 
pause the study for another careful review of data for all subjects; Study may be resumed for 
the remaining subjects after discussions between the sponsor and site occur, taking into 
consideration the safety surveillance of the discontinued participants, as well as, the dosed 
ones.If this occurs, the following process will be initiated: 
 
Subjects will continue their participation with the same dose in order to assure that 
all subjects receive their entire complement of nine doses per cohort. 
 
Subjects who have received the required number of injections for a dose on a dosing 
day prior to study suspension will continue with their next administration, 
regardless of the treatment day, in order to receive their total of 9 doses per cohort. 
 
Subjects who did not receive the required number of injections on a dosing day 
prior to study suspension will not need to repeat that dosing day, they will proceed 
to the next administration, regardless of the treatment day, in order to receive their 
total of nine doses per cohort.  


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The discontinued subjects who met the significant change or dose stopping criteria  will be 
followed for safety and surveillance audiology tests; the monitoring period will continue 
either until the resolution of the event, such time that  it is determined that changes are 
permanent or the subject is lost to follow-up. The determination for permanency will be 
made by the AVDSMB and does not have a specified time frame. 
  
*Note: The number of subjects with a particular drug-related toxicity reflects those with the 
same preferred term according to the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA). 
**Note: toxicity will be rated according to the CTCAE grading rules. For adverse events of 
interest related to Ear and Labyrinth Disorders, the adjudication committee will assess the 
grading according to the CTCAE guidelines. 
***Note: specific laboratory grading rules will be specified in the protocol for kidney injury 
molecule (KIM-1) and clusterin based on the laboratory’s Normal Ranges for these 
parameters. 
****Note: injection site reactions will be assessed according to the Division of Aids 
(DAIDS) criteria. 
Investigational Product 
ELX-02 is a synthetic aminoglycoside formulated as a solution with water for SC injection, 
containing 200 mg/mL. A 0.9% sodium chloride (NaCl) sterile solution for injection will be 
used to prepare the appropriate dilutions of ELX-02. 
Placebo 
Solution for SC injection containing saline (NaCl 0.9%), at matching volumes. 
Mode of Administration 
 SC injection(s) will be administered to the abdominal region around the umbilicus or to 
any area with a significant subcutaneous adipose tissue (e.g. thigh). 
Safety and Tolerability 
Assessments  
 Adverse events (AE) monitoring 
 Incidence of events of special interest (hypersensitivity, nephrotoxicity, auditory, and 
vestibular toxicity) 
 Local reaction of injection site 
 Safety lab tests (blood and urine) 
 Vital signs (supine blood pressure (BP), heart rate (HR), respiratory rate (RR), and oral 
temperature) 
 12-lead electrocardiogram (ECG) taken after 5 minutes in a supine position 
 Physical examination 
Other Assessments 
 Concomitant medications  
 Urine drug screen (UDS) 
 Seum alcohol test 
 Blood or urine pregnancy test (all women, regardless of childbearing potential) 
 Renal injury biomarkers (KIM-1 and clusterin) 
 Potential read-through of housekeeping proteins 
PK Assessments  
Blood and urine samples will be collected for ELX-02 determination.   
The following PK parameters will be determined for ELX-02: Cmax, Cpredose, C1h, tmax, AUCt, 
AUC24h, AUC48h, AUC72h, AUCinf, t1/2, volume of distribution (Vd/F), clearance (CL/F), 
accumulation ratio (Rac), and an estimation of ELX-02 dose linearity of PK parameters. 
Subjects should consume at least 500 mL of water within 120 minutes before dosing. The 
predose PK blood sample will be taken right before study drug administration. The study 
staff will encourage the subjects to drink at least one glass of fluids every hour up to 10h 
after dosing. The following parameters will be calculated based on ELX-02 urine 
concentrations: urinary excretion (Ae) of ELX-02 (in mass and %dose - fe) for each 
collection interval, cumulated urinary excretion (in %dose) for each collection interval, total 
excretion (in %dose) and renal clearance (using the AUC and Ae for the same time interval).  


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Number of Subjects: 
Up to 63 healthy adult subjects will participate in the study: 9 in each cohort randomized 2:1 
to ELX-02 and placebo. Both males and females need to be enrolled in each cohort. 
Additional cohorts or subjects may be added to reaffirm safety of ELX-02.   
Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Be able and willing to provide written Informed Consent indicating that the subject has 
been informed of all pertinent aspects of the study. 
2. Healthy female subjects and male subjects who, at the time of screening, are between 
the ages of 18 and 55 years, inclusive.  
Healthy is defined as no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including BP and pulse rate measurement, 12-lead 
ECG, and clinical laboratory tests.  
3. 
Female subjects of non-childbearing potential must meet at least one of the following 
criteria: 
 Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause; post-menopausal status will be confirmed by a serum follicle-stimulating 
hormone level; 
 Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
 Have medically confirmed ovarian failure. 
All other female subjects (including females with tubal ligations) will be considered to 
be of childbearing potential and may be enrolled if they have negative pregnancy tests 
at screening and admission day and agree to use a highly effective method of 
contraception for 14 days before first study drug administration and 28 days after last 
study drug administration. Female subjects of childbearing potential must agree to 
undergo repeated pregnancy tests. 
4. Male subjects must be willing to use an effective method of contraception. They must 
agree to use a condom consistently and correctly, during the course of the study until 28 
days after last study drug administration. 
5. Not using any prescription medication and dietary supplements within 30 days or 5 half-
lives (whichever is longer) prior to the first study drug administration, except for 
contraceptives – nor be taking any over-the-counter (OTC) herbal or medicinal products. 
As an exception, acetaminophen/paracetamol may be used at doses of ≤2 g/day.  
6. Non-smoking and no use of any tobacco or nicotine products (by declaration) for a 
period of at least 6 months prior to screening visit. 
7. Be on no medication with potential to impair renal function (e.g., non-steroidal 
anti-inflammatory [NSAID]s) or with ototoxic potential (e.g., quinine, salicylates, 
aminoglycosides). 
8. Normal renal function (glomerular filtration rate >60 mL/min/1.73m2) based on 
creatinine plasma concentration and the Modification of Diet in Renal Disease (MDRD) 
equation for estimated glomerular filtration rate. Subjects with lower MDRD clearance 
can be included on the condition that they have a normal 24h creatinine clearance 
(determined by a 24h urine collection). 
9. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (HCV Ab) serology tests at screening. 
10. No history of alcohol or DOA. Negative UDS and serum alcohol test at screening and 
Day -1.  
11. No personal history (or current) or hereditary hearing loss, persistent tinnitus, persistent 
vertigo, persistent imbalance, persistent unsteadiness and no regular exposure to 
excessive noise (such as employment in a factory, music teacher, etc). 
12. Body Mass Index (BMI) of 19.0 to 32.0 kg/m2 (inclusive); and a total body weight 
>50.0 kg (110 lbs) and <100.0 kg. 


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Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the 
study: 
1. Subjects who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are the Sponsor employees directly involved in the conduct 
of the study. 
2. Concurrent participation or participation in another clinical trial within at least 5 tissue 
half-lives prior to dosing (calculated from the previous study’s last dosing day). If the 
previous trial involved agents with delayed effects or prolonged metabolism, a 
12 months interval is required.  
3. Evidence or history of clinically relevant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease 
(including drug allergies). This includes any acute or chronic medical or psychiatric 
condition or laboratory abnormality that may increase the risk associated with study 
participation or investigational drug administration or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would make the 
subject inappropriate for entry into this study. 
4. Presence of mitochondrial mutations making subject susceptible to aminoglycoside 
toxicity. 
5. Subjects with any history of ear disease or surgeries, persistent dizziness or persistent 
tinnitus.  
6. Subjects with any abnormality at screening, that indicates the presence of a vestibular 
pathology, conductive hearing loss or balance problem (by an ENT). 
Subjects with audiometry abnormalities in the conventional frequencies (up to 8 kHz) 
results at screening as follows: any pure-tone threshold >55 dB and/or inter-ear 
difference in any frequency of >20 dB. 
Dizziness Handicap Inventory (DHI)-H score >16. Tinnitus Handicap Inventory 
(THI)-H score >14. 
7. History of regular alcohol consumption exceeding 14 drinks/week for females or 
21 drinks/week for males (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of 
hard liquor) within 6 months of screening. 
8. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at 
least 5 min of supine rest. If BP is 140 mm Hg (systolic) or 90 mm Hg (diastolic), the 
BP should be repeated two more times and the average of the three BP values should be 
used to determine the subject’s eligibility. 
9. Screening supine (for 5 minutes) 12-lead ECG demonstrating QTc >450 msec for men 
and >470 msec for women, or a QRS interval >120 msec. If QTc or QRS exceed these 
limits, the ECG should be repeated two more times and the average of the three QTc or 
QRS values should be used to determine the subject’s eligibility.  
10. Subjects with ANY abnormalities in clinical laboratory tests at screening, considered by 
the study physician as clinically relevant. In particular, subjects with alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine and total 
bilirubin 1.5 upper limit of normal will be excluded.  
11. Pregnant or breastfeeding female subjects;  
12. Subjects who donated blood or received blood or plasma derivatives in the three months 
preceding study drug administration.  
13. Unwilling or unable to comply with all scheduled visits, treatment plan, laboratory tests 
and other study procedures and the restrictions described in this protocol. 
14. Known relevant allergy to any drug and/or aminoglycosides.  
15. Subjects with an inability to communicate well with the Investigators and CPU staff 
(e.g., language problem, poor mental development). 


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16. Subjects with visual impairment or inability to read and comprehend the DHI and THI 
scales. 
17. Subjects with any acute medical situation (e.g., acute infection) within 48 hours (h) of 
study start, which is considered of significance by the Investigator. 
Statistical Methods  
No formal sample size was estimated. The number of 9 subjects included in each dose group 
is deemed sufficient to respond to exploratory safety/tolerability and PK purposes. 
Statistical analyses will be performed using SAS® v9.2 or higher (SAS Institute, Cary NC, 
United States of America [USA]), PK parameters calculation will be performed using 
Phoenix 6.2 (Pharsite Corp., USA) or later 
Adverse events will be classified by system-organ classes and preferred terms and then 
summarized by number and percentage of volunteers experiencing AEs. 
Pharmacokinetic parameters of ELX-02 (Cmax, tmax, AUCt, AUC24h, AUC48h, AUC72h, 
AUCinf, t1/2, Vd/F, and CL/F) will be summarized by descriptive statistics by dose group and 
day of administration (sample size, mean, median, standard deviation, CV%, minimum and 
maximum, geometric mean and geometric CV%, when applicable). 
Steady-state achievement will be evaluated by visual inspection of predose (and 1h postdose) 
concentrations figures. 
The following parameters will be calculated based on ELX-02 urine concentrations: Ae of 
ELX-02 (in mass and %dose - fe) for each collection interval, cumulated urinary excretion 
(in %dose) for each collection interval, total excretion (in %dose) and renal clearance (using 
the AUC and Ae for the same time interval). 
For each of the PK parameters Cmax and AUCs, the dose linearity will be assessed using a 
power model, including the log-transformed PK parameters as dependent variables and the 
log-transformed dose, day and dose*day as fixed effects. The slope for log-transformed dose 
(ß) will be estimated with its 90% confidence interval to examine dose proportionality. The 
tmax will be compared between dose groups and days using the appropriate non-parametric 
tests. 
Descriptive statistics will be used to summarize demographics, baseline characteristics, and 
safety data.  
Aggregate study data will be analyzed from all cohorts for the study report, regardless of 
where the cohort was conducted. 
Duration of Clinical 
Phase  
Approximately 12 weeks for each subject including a screening period of up to 6 weeks 
before first dosing, 4 weeks after the first dose and 2 weeks for final safety follow-up. 
 


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Table 1:  Time and Events Schedule 
Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics  
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI)  
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Screen 
Day -42 
to -2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Day -1  
  
 
 
 
X 
X 
 
 
X 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
Day 1 
-180 
min 
 
 
 
X 
Xc 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
15 
min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
0
-
1
2 
h 
 
 
 
 
 
 
 
X 
30 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
45 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
1h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
3h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
6h 
 
 
 
 
 
 
 
X 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
12h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
1
2
-
2
4
h 
X 
 
X 
X 
 
 
 
X 


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ELOXX PHARMACEUTICALS  
CONFIDENTIAL 
Page 19 
Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics  
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI)  
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Day 2 
24h 
 
 
 
 
 
 
X 
 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
2
4
-
4
8
h 
X  
 
X 
X 
 
X 
 
X 
36h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
Day 3 
48 h 
 
 
 
 
X 
 
X 
X 
Xq 
X 
 
 
 
 
 
X 
Xp 
Xp 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
Day 4 
  
 
 
 
 
Xc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
4
8
-
7
2 
h 
X 
X 
X 
X 
 
 
 
X 
Day 7  
  
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
X 
x 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Day 8 
  
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Day 10 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
  
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Day 14 
  
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
X 
x 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Day 15 
  
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Day 17 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Day 18 
  
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Day 21  
  
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
x 
x 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 


Protocol EL-002 
Revised Final 
Version: 29 May 2019 
 
ELOXX PHARMACEUTICALS  
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Page 20 
Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics  
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI)  
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Day 22 
  
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 Day 24 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Xp 
 
X 
 
 
 
 
 
 
 
 
 
 
Day 25 
  
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
  
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Day 28 
  
 
 
 
 
X 
 
X 
X 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
Day 29 
-180 
min 
 
 
 
 
Xc 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
15 
min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
0
-
1
2 
h 
 
 
 
 
 
 
 
X 
30 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
45 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
1 h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
3h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
6h 
 
 
 
 
 
 
 
X 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
12h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
1
2
-
2
4 
h 
X 
 
X 
X 
 
 
 
X 


Protocol EL-002 
Revised Final 
Version: 29 May 2019 
 
ELOXX PHARMACEUTICALS  
CONFIDENTIAL 
Page 21 
Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics  
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI)  
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Day 30 
24h 
 
 
 
 
 
 
X 
 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
2
4
-
4
8 
h 
X 
 
X 
X 
 
X 
 
X 
36h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
Day 31 
48h 
 
 
 
 
 
 
X 
X 
Xq 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
Day 32 
72h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
4
8
-
7
2 
h 
X 
 
 
X 
 
 
 
 
Day 36 
  
 
 
 
 
 
 
X 
X 
Xq 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
AE: Adverse event, CM: Concomitant therapy, HIV: Human Immunodeficiency Virus, HbsAg: Hepatitis B surface antigen, HCVAb: Hepatitis C virus antibody, CPU: 
Clinical Pharmacological Unit, DHI: Dizziness Handicap Inventory, THI: Tinnitis Handicap Inventory. 
a. 
Informed consent to be provided before any study-related assessment. 
b. Including hearing and balance disorders. 
c. 
Weight only to be taken if not already done the previous day. 
d. Vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR), and oral body temperature. Vital parameters will be assessed in supine 
position after at least 5 min. supine rest.  
e. 
A complete physical examination is to be performed at all timepoints except for the 6h postdose assessment on Day 1 and Day 29 when a brief 
examination is to be performed. 
f. 
Biochemistry, hematology, and coagulation. All blood samples for safety assessments should be taken after an overnight fast of at least 8h, except for 
the sample taken at 6h postdose on Day 1 and Day 29. At screening, subjects will be instructed not to eat within 3h before arrival at the CPU. 


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Page 22 
g. Urine pregnancy tests only to be performed for women regardless of childbearing potential. 
h. A single 12-lead ECG will be taken providing QT, QTc, HR, QRS, and PR after 5 minutes supine. 
i. 
Subjects will be scheduled for audiometric and vestibular tests preceded by an ENT physical exam in a specialized department. The auditory and 
vestibular testing will be performed at Screening (to confirm eligibility), and prior to initial dosing to determine a baseline and will include: (1) 
Otoscopy, (2) Immittance audiometry (commonly called tympanometry), (3) Speech Reception Threshold, (4) Pure Tone Audiometry (PTA) with 
frequencies up to 8 kHz if possible (should there be a PTA threshold of ≥15dB, the subject should undergo bone conduction testing), (5) High frequency 
audiometry (HFA) with frequencies up to 16 kHz if possible, (6) Tinnitus Handicap Inventory, (7) Dizziness Handicap Inventory. Follow up testing 
will be performed at Day 3 (-1 day), Day 10 (-2 days), Day 17 (-2 days), Day 24 (-2 days), and EOS (7-11 days after last dosing). The otoscopic exam 
on Day 3, Day 10, Day 17 and Day 24 can be performed 72 hours prior to dosing by a CPU physician. 
j. 
Subjects will come to the CPU for confinement on Day -1, Day 7, Day 14, Day 21, and Day 28. 
k. The predose PK blood sample will be taken in a standardized manner for all subjects, right before study drug administration. 
l. 
During the 0-12h collection period urine will be collected every hour, during the 12-24h collection period every 6h (i.e., 12-18h collection and 18-24h 
collection), and during the 24-48h collection period urine will be collected every 12h (i.e., 24-36h collection and 36-48h collection). Urine gravity 
will be calculated for each collection. The subjects will collect the urine at home (in urine jars) during the 48h-72h collection period. 
m. Creatinine samples will be taken at all timepoints corresponding to renal injury biomarker collection. On days 1-4 and 29-32, samples for renal injury 
biomarkers and creatinine will be taken from urine spot samples at 24hr, 36hr, 48hr and 72hr post dose. 
n. Subjects should consume at least 500 mL of water within 120 minutes before dosing. Subcutaneous (SC) injection (s) in the abdominal wall as per the 
subject’s body weight. The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) of fluids every hour up to 10h 
after dosing. 
o. All blood samples for retention need to be taken after an overnight fast of at least 8h, except for the samples taken at 3h postdose on Day 1 and Day 29. 
p. Subject will return to the ENT specialist for auditory and vestibular tests within 48 hours prior to dosing. The otoscopic exam on Day 3, Day 10, Day 
17 and Day 24 can be performed 72 hours prior to dosing by a CPU physician. 
q. No GFR/MDRD sample/analysis beyond the screening period.  
 
 


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Page 23 
ABBREVIATIONS 
Abbreviation 
Term 
AAA 
American Academy of Audiology 
AE 
Adverse events 
Ae 
Cumulative amount of unchanged drug excreted into urine 
AEOI 
Adverse event of interest 
ALT 
Alanine aminotransferase (also known as glutamate-pyruvate 
transaminase-SGPT) 
ASHA 
American Speech-Language-Hearing Association 
AST 
Aspartate aminotransferase (also known as glutamate-
oxaloacetate transaminase-SGOT) 
AUCt 
Area under the plasma concentration-time curve calculated 
from time of administration to the last quantifiable 
concentration, computed using the linear trapezoidal rule 
AUCinf 
Area under the concentration-time curve from time 0 
extrapolated to infinity  
AUC24h 
Area under the plasma concentration-time curve calculated 
from time of administration to time 24h, computed using the 
linear trapezoidal rule 
AUC48h 
Area under the plasma concentration-time curve calculated 
from time of administration to time 48h (after first dose only), 
computed using the linear trapezoidal rule 
AUC72h 
Area under the plasma concentration-time curve calculated 
from time of administration to time 72h, computed using the 
linear trapezoidal rule 
AVDSMB 
Auditory and Vestibular Data Safety Monitoring Board 
BMI 
Body mass index 
BP 
Blood pressure 
CF 
Cystic fibrosis 
CFTR 
Cystic fibrosis transmembrane conductance regulator 
CL/F 
Apparent plasma clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
Cpredose 
Trough plasma concentration observed at the end of the 
dosing interval (i.e. at each predose starting from second 
dose) 
CPU 
Clinical Pharmacological Unit 
CRF 
Case report form 
CSA 
Clinical study agreement 
CTA 
Clinical trial application 
CTCAE 
Common Terminology Grades for Adverse Events 


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Page 24 
Abbreviation 
Term 
DAIDS 
Division of Aids 
DHI 
Dizziness Handicap Inventory 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid  
DOA 
Drugs of abuse 
DSMB 
Data Safety Monitoring Board  
EDMC 
External Data Monitoring Committee 
EDP 
Exposure during pregnancy 
ECG 
Electrocardiogram 
ENT 
Ear nose and throat 
EOS 
End of study 
EU 
European 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GAG 
Glycosaminoglycans 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HbsAg  
Hepatitis B surface antigen 
HCT 
Hematocrit 
HCV Ab 
Hepatitis C virus antibody 
HED 
Human Equivalent Dose 
HFA 
High Frequency Audiometry 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate  
h,  
Hour, hours 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
Potassium 
kg 
Kilogram 
KIM-1 
Kidney injury molecule-1 
LLOQ 
Lower Limit of Quantification 
LPLV 
Last visit of the last subject in the study 


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Page 25 
Abbreviation 
Term 
LS 
Life Sciences 
MA 
Medical Affairs 
MDRD 
Modification of Diet in Renal Disease  
MPS 
Mucoplysaccharidose type I 
min 
Minute 
mL 
Milliliter 
mmHg 
Millimeter mercury 
MRSD 
Maximum recommended starting dose 
MRT 
Mean residence time 
Mecp2 
Methyl-CpG-binding protein 2  
msec 
Millisecond 
MTD 
 
Maximum tolerated dose 
Na 
Sodium 
NOAEL 
No observed adverse effect level  
ºC 
Degrees centigrade 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OTC 
Over the counter 
PI 
Principal investigator 
PK 
Pharmacokinetics  
PTA 
Pure Tone Audiometry 
Rac 
Accumulation ratio 
RBC 
Red blood cells 
RNA 
Ribonucleic acid 
rRNA 
Ribosome Ribonucleic acid 
RR 
Respiratory Rate 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SRT 
Speech Reception Threshold 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Elimination half-life 
THI 
Tinnitus Handicap Inventory 
tmax 
Time at which Cmax occurs 
tRNA 
Transfer Ribonucleic acid 
USA  
United States of America 
UDS 
Urine drug screen 
Vd/F 
Apparent volume of distribution 
versus 
vs 


















Protocol EL-002 
Revised Final 
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Page 34 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
2.1.1. Primary Objective 
1. To assess the safety and tolerability of multiple ascending subcutaneously (SC) 
administered doses of ELX-02. 
 
2. To study the PK of ELX-02 administered as multiple SC doses. 
2.1.2. Secondary Objectives 
1. To assess whether a maximum tolerated dose (MTD) is attained within the given 
dose range. 
 
2. To assess linearity between ascending SC doses and PK parameters. 
2.2. Endpoints 
2.2.1. Primary Endpoints  
1. Incidence and characteristics of AEs and other changes in safety parameters at 
ascending doses.  
2. Blood and urine PK parameters of ELX-02. 
2.2.2. Secondary Endpoints  
1. Assessment, based on the safety profile, whether dose-limiting toxicity (DLT) and 
MTD are attained within the tested ELX-02 doses range. 
2. Dose linearity of PK parameters within the administered SC doses range. 
 


Protocol EL-002 
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Page 35 
3. STUDY DESIGN 
3.1. Overall Study Design  
This is a Phase 1, randomized, double-blinded, placebo-controlled, third party open, multiple 
dose escalation study to evaluate the safety, tolerability and PK of subcutaneously administered 
ELX-02 in independent consecutive cohorts of healthy subjects. 
The investigational drug, ELX-02, is formulated as a solution for SC injection, containing 
200 mg/mL. The placebo control will consist of a SC injection of normal saline at matching 
volumes.  
The study includes at least 5 cohorts of 9 subjects each (both males and females need to be 
enrolled in each cohort, a significant number of female subjects needs to be enrolled). Subjects 
will be randomized to receive multiple doses of ELX-02 or placebo at a ratio of 2:1 in each 
cohort: Six subjects will receive ELX-02 and three will receive placebo: 
Cohort 1: ELX-02 0.1 mg/kg or placebo SC twice a week for 9 doses; 
Cohort 2: ELX-02 0.3 mg/kg or placebo SC twice a week for 9 doses; 
Cohort 3: ELX-02 1.0 mg/kg or placebo SC twice a week for 9 doses; 
Cohort 4: ELX-02 2.5 mg/kg (100 mg/mL) or placebo SC twice a week for 9 doses; 
Cohort 5: ELX-02 up to 2.5 mg/kg (50 mg/mL) or placebo SC twice a week for 9 doses; 
Cohort 6: ELX-02 2.5 to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
Cohort 7: ELX-02 up to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
Dose escalation to the next cohort will not be performed until after the 14-day observation 
period for the previous cohort, to allow for detection of unanticipated delayed AEs.  
Changes to the planned dose may be made in any cohort, depending on safety and any available 
PK data. The dose will not exceed 5.0 mg/kg. 
The assessments performed are summarized per visit in Table 1. 
The study will comprise the following periods for each subject: 
 A screening period, within 42 days before dosing up to Day -2 (including an ear, nose, and 
throat (ENT) exam with auditory and vestibular assessment up to Day -8). 
 An additional baseline ENT exam with auditory and vestibular assessment will be 
performed between Day -7 and Day -1.  These assessments (screening and baseline) 
can be done on the same day (between Day -7 and Day -1) with 2-3 hrs between the 
2 assessments. 
 An in-house treatment and follow-up period consisting of a predose day (Day -1), dosing 
day (Day 1), and follow-up days (Days 2 and 3). Subjects will be released from the Clinical 
Pharmacological Unit (CPU) approximately 48h after dosing.  
 Subject will return to the ENT specialist for auditory and vestibular tests on Day 3 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 4. 
 An in-house treatment period consisting of a predose day (Day 7) and a dosing day (Day 8).   


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 A return visit for performing audiometric and vestibular tests on Day 10 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 11. 
 An in-house treatment period consisting of a predose day (Day 14) and a dosing day 
(Day 15).  
 A return visit for performing audiometric and vestibular tests on Day 17 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 18. 
 An in-house treatment period consisting of a predose day (Day 21) and a dosing day 
(Day 22).   
 A return visit for performing audiometric and vestibular tests on Day 24 (-1 day). 
 A return visit to the CPU for treatment and testing on Day 25. 
 An in-house treatment and follow-up period consisting of a pre-last dose day (Day 28), 
dosing day (Day 29), and follow-up days (Days 30 and 31). Subjects will be released from 
the CPU approximately 48h after the last dosing.   
 A return visit to the CPU on Day 32. 
 An End-of-Study (EOS) visit will take place 7-10 days after last dosing. The additional 
ENT exam may be performed 7-11 days after last dosing. 
The duration will be approximately 12 weeks for each subject including a screening period of 
up to 6 weeks before first dosing, 4 weeks after the first dose and 2 weeks for final safety 
follow-up. 
3.2.  Progression to Next Cohort and Dose Escalation 
The decision to proceed to a higher dose level will be following the recommendations of both 
the general and auditory and vestibular DSMBs based on the dose-escalation stopping rules 
(see below). The decision will be based on review of the blinded safety data, any available 
blinded PK data, and the results of audiologic tests and questionnaires collected up to the 
DSMB meeting and the recommendations of the AVDSMB following review of the results of 
audiologic tests and questionnaires. The next cohort will be dosed after the DSMB and 
AVDSMB have evaluated the safety data and any available PK data and have recommended 
to escalate. 
More details on the DSMB are provided in Section 8.16. 
The principles of dose escalation, determination of DLT and MTD, are as follows:  
For CTCAE related events, 
 Grade-1 drug-related toxicity will allow dose escalation to the next dose level. 
 Grade-2 drug-related toxicity:  
o Cohort 1: 
If the total number of subjects with this drug-related toxicity does not exceed 
3, dose escalation is allowed to Cohort 2. 
If the total number of subjects with this drug-related toxicity is 4 or more, this 


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will be considered a DLT and dose escalation to Cohort 2 will not be 
authorized. 
o Cohorts 2 and above: 
If this toxicity occurs in up to 1 subject per cohort, dose escalation to the next 
dose level is permitted. 
If this toxicity occurs in 3 subjects per cohort, 6 subjects receiving ELX-02 and 
3 subjects receiving placebo will be added to the current dose level: 
If the number of subjects of the repeated dose level with this drug-related 
toxicity does not exceed 3, dose escalation is permitted.  
If 4 or more subjects of the repeated dose level - have this drug-related toxicity, 
this will be considered a DLT and dose escalation to the next dose level will 
not be authorized. The previous dose level will be determined as the MTD. 
 Grade-3, 4 or 5 drug-related toxicity: if it occurs at any dose level and in any cohort, 
this will be considered a DLT and the previous dose level will be determined as the 
MTD. 
Outside of CTCAE guidelines: 
For abnormalities in HFA, an ototoxic event is defined as the loss of >25 dB averaged at in three 
consecutive frequencies in at least one ear. 
 For a confirmed ototoxic event in HFA in any cohort:  
o If an HFA ototoxic event occurs in 2 subjects receiving ELX-02 in any cohort, 
6 subjects receiving ELX-02 and 3 subjects receiving placebo will be added to 
the current dose level, unless it is determined by the Sponsor and the 
AVDSMB, following a thorough medical review, that the study may resume. 
In this instance additional subjects will not need to be added. 
o If an HFA ototoxic event occurs in ≥3 subjects receiving ELX-02 in any cohort, 
this will be considered a DLT and dose escalation to the next dose level will 
not be authorized. The previous dose level will be determined as the MTD. 
If the criteria for stopping a dose has been met for an individual subject during a cohort, the 
study may be temporarily suspended immediately to allow for further medical evaluation with 
additional assessments of the proported event, as appropriate. If any subject/subjects meet dose 
stopping or significant change criteria, the sponsor, after discussion with PI, may pause the 
study for another careful review of data for all subjects; Study may be resumed for the 
remaining subjects after discussions between the sponsor and site, taking into consideration 
the safety surveillance of the discontinued participants, as well as, the dosed ones. If this 
occurs, the following process will be initiated: 
 Subjects will continue their participation with the same dose in order to assure that all 
subjects receive their entire complement of nine doses per cohort. 
 Subjects who have received the required number of injections for a dose on a dosing 
day prior to study suspension will continue with their next administration, regardless 
of the treatment day, in order to receive their total of 9 doses per cohort. 
 Subjects who did not receive the required number of injections on a dosing day prior 
to study suspension will not need to repeat that dosing day, they will proceed to the 
next administration, regardless of the treatment day, in order to receive their total of 


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nine doses per cohort.  
 
The discontinued subjects who met the significant change or dose stopping criteria  will be 
followed for safety and surveillance audiology tests; the monitoring period will continue 
either until the resolution of the event, such time that  it is determined that changes are 
permanent or the subject is lost to follow-up. The determination for permanency will be 
made by the AVDSMB and does not have a specified time frame. 
 
*Note: The number of subjects with a particular drug-related toxicity reflects those with the 
same preferred term according to the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA). 
**Note: toxicity will be rated according to the Common Terminology Grades for Adverse 
Events (CTCAE)21 grading rules. For adverse events of interest related to Ear and Labyrinth 
disorders, the adjudication committee will assess the grading. 
***Note: specific laboratory grading rules will be specified in the protocol for Kidney injury 
molecule (KIM-1) and clusterin based on the laboratory’s Normal Ranges for these 
parameters. 
****Note: injection site reactions will be assessed according to the Division of Aids (DAIDS) 
criteria (Section 13.1). 
The subsequent cohorts will be dosed at least 14 days following last dosing of the previous 
cohort. 
 
 


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Figure 2: Study Design Scheme 
Cohort 1 
ELX-02 0.1 mg/kg or placebo SC twice a 
week for 9 doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB  
Cohort 2 
ELX-02 0.3 mg/kg or placebo SC twice a 
week for 9 doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB 
Cohort 3 
ELX-02 1.0 mg/kg or placebo SC twice a 
week for 9 doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB 
Cohort 4 
ELX-02 2.5 mg/kg (100 mg/mL) or placebo 
SC twice a week for 9 doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB 
Cohort 5 
ELX-02 up to 2.5 mg/kg (50 mg/mL per 
injection) or placebo SC twice a week for 9 
doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB 
Cohort 6 
ELX-02 2.5 to 5.0 mg/kg or placebo SC 
twice a week for 9 doses 
≥14 days following last dosing of the previous cohort and following advice DSMB and 
AVDSMB 
Cohort 7 
ELX-02 up to 5.0 mg/kg or placebo SC 
twice a week for 9 doses. 
 


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4. SUBJECT SELECTION 
Up to 63 healthy adult subjects will participate in the study at multiple centers: 9 in each cohort 
randomized 2:1 to ELX-02 and placebo. Both males and females need to be enrolled in each 
cohort.  
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.  
Subject eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before subjects are included in the study. 
4.1. Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Be able and willing to provide written Informed Consent indicating that the subject has 
been informed of all pertinent aspects of the study. 
2. Healthy female subjects and male subjects who, at the time of screening, are between the 
ages of 18 and 55 years, inclusive.  
Healthy is defined as no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure (BP) and pulse rate 
measurement, 12-lead electrocardiogram (ECG), and clinical laboratory tests.  
3. 
Female subjects of non-childbearing potential must meet at least one of the following 
criteria: 
 Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological cause; 
post-menopausal status will be confirmed by a serum follicle-stimulating hormone 
level; 
 Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
 Have medically confirmed ovarian failure. 
All other female subjects (including females with tubal ligations) will be considered to be 
of childbearing potential and may be enrolled if they have negative pregnancy tests at 
screening and admission day and agree to use 2 highly effective methods of contraception 
for 14 days before first study drug administration and 28 days after last study drug 
administration. Female subjects of childbearing potential must agree to undergo repeated 
pregnancy tests. For highly effective methods of contraception see Section 6.5.1. 
4. Male subjects must be willing to use 2 highly effective methods of contraception. They 
must agree to use a condom consistently and correctly, during the course of the study until 
28 days after last study drug administration. 
5. Not using any prescription medication and dietary supplements within 30 days or 
5 half-lives (whichever is longer) prior to the first study drug administration, except for 


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contraceptives – nor be taking any over-the-counter (OTC) herbal or medicinal products. 
As an exception, acetaminophen/paracetamol may be used at doses of ≤2 g/day.  
6. Non-smoking and no use of any tobacco or nicotine products (by declaration) for a period 
of at least 6 months prior to screening visit. 
7. Be on no medication with potential to impair renal function (e.g., non-steroidal 
anti-inflammatory [NSAID]s) or with ototoxic potential (e.g., quinine, salicylates, 
aminoglycosides). 
8. Normal renal function (glomerular filtration rate >60 mL/min/1.73m2) based on creatinine 
plasma concentration and the Modification of Diet in Renal Disease (MDRD) equation for 
estimated glomerular filtration rate. Subjects with lower MDRD clearance can be included 
on the condition that they have a normal 24h creatinine clearance (determined by a 24h 
urine collection). 
9. Negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), 
hepatitis C virus antibody (HCV Ab) serology tests at screening. 
10. No history of alcohol or DOA. Negative UDS and serum alcohol test at screening and Day 
-1.  
11. No personal history (or current) or hereditary hearing loss, persistent tinnitus, persistent 
vertigo, persistent imbalance, persistent unsteadiness and no regular exposure to excessive 
noise (such as employment in a factory, music teacher, etc). 
12. Body Mass Index (BMI) of 19.0 to 32.0 kg/m2 (inclusive); and a total body weight 
>50.0 kg (110 lbs) and <100.0 kg. 
4.2. Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the study: 
1. Subjects who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are the Sponsor employees directly involved in the conduct 
of the study. 
2. Concurrent participation or participation in another clinical trial within at least 5 tissue 
half-lives prior to dosing (calculated from the previous study’s last dosing day). If the 
previous trial involved agents with delayed effects or prolonged metabolism, a 12 months 
interval is required.  
3. Evidence or history of clinically relevant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease 
(including drug allergies). This includes any acute or chronic medical or psychiatric 
condition or laboratory abnormality that may increase the risk associated with study 
participation or investigational drug administration or may interfere with the interpretation 
of study results and, in the judgment of the Investigator, would make the subject 
inappropriate for entry into this study. 
4. Presence of mitochondrial mutations making subject susceptible to aminoglycoside 
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5. Subjects with any history of ear disease or surgeries, persistent dizziness or persistent 
tinnitus.  
6. Subjects with any abnormality at screening, that indicates the presence of a vestibular 
pathology, conductive hearing loss or balance problem (by an ENT). 
Subjects with auditory abnormalities in conventional frequencies at screening as follows 
(up to 8 kHz): any pure-tone threshold >55 dB and/or inter-ear difference in any frequency 
of >20 dB. 
Dizziness Handicap Inventory (DHI)-H score >16. Tinnitus Handicap Inventory (THI)-H 
score >14. 
7. History of regular alcohol consumption exceeding 14 drinks/week for females or 
21 drinks/week for males (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard 
liquor) within 6 months of screening. 
8. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at least 
5 min of supine rest. If BP is 140 mm Hg (systolic) or 90 mm Hg (diastolic), the BP 
should be repeated two more times and the average of the three BP values should be used 
to determine the subject’s eligibility. 
9. Screening supine (for 5 minutes) 12-lead ECG demonstrating QTc >450 msec for men and 
>470 msec for women, or a QRS interval >120 msec. If QTc or QRS exceed these limits, 
the ECG should be repeated two more times and the average of the three QTc or QRS 
values should be used to determine the subject’s eligibility.  
10. Subjects with ANY abnormalities in clinical laboratory tests at screening, considered by 
the study physician as clinically relevant. In particular, subjects with alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine and total 
bilirubin 1.5 upper limit of normal will be excluded.  
11. Pregnant or breastfeeding female subjects. 
12. Subjects who donated blood or received blood or plasma derivatives in the three months 
preceding study drug administration.  
13. Unwilling or unable to comply with all scheduled visits, treatment plan, laboratory tests 
and other study procedures and the restrictions described in this protocol. 
14. Known relevant allergy to any drug and/or aminoglycosides.  
15. Subjects with an inability to communicate well with the Investigators and CPU staff (e.g., 
language problem, poor mental development). 
16. Subjects with visual impairment or inability to read and comprehend the DHI and THI 
scales. 
17. Subjects with any acute medical situation (e.g., acute infection) within 48 hours (h) of 
study start, which is considered of significance by the Investigator. 


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4.3. Prohibitions 
The subjects must consume at least 500 mL of water within 120 minutes before dosing. The 
study staff will encourage subjects to drink at least one glass of fluids every hour up to 10h 
after dosing. 
During confinement at the CPU, no food intake in addition to the standard meals and snacks 
provided at the CPU will be allowed. 
Authorization to leave the CPU will be given by the Investigator. 
No blood donation will be allowed until 4 weeks after the last study drug administration. 
Female subjects of childbearing potential and non-vasectomized male subjects having a female 
partner of childbearing potential must agree to the use 2 effective methods of contraception 
throughout the study (for female subjects from 14 days before first study drug administration) 
and until 28 days after the last administration of study drugs, as outlined in Section 4.4. For 
details on the existing data regarding the reproductive toxicity, please see the current 
Investigator Brochure19. 
Information on prohibited therapies can be found in Section 6.1. 
4.4. Lifestyle Guidelines  
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use 2 highly effective 
methods of contraception consistently and correctly for the duration of the active treatment 
period (for female subjects from 14 days before first study drug administration) and for at least 
28 days after the last dose of investigational product.  
Subjects need to affirm that they meet the criteria for correct use of at least 2 of the selected 
methods of contraception. The Investigator or his/her designee will discuss with the subject 
the need to use highly effective contraception consistently and document such conversation in 
the subject’s chart. In addition, the Investigator or his or her designee will instruct the subject 
to call immediately if the selected contraception method is discontinued or if pregnancy is 
known or suspected in the subject or the subject’s partner.  
More details on contraception methods for female and male subjects can be found in 
Section 6.5.1 and Section 6.5.2, respectively. 
4.5. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study administrative structure. 
4.6. Contact Cards 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, at 
a minimum, protocol and investigational compound identifiers, subject study numbers, and 
contact information for the investigational site.  
4.7. Rater Qualifications 
Audiometric and vestibular tests will be performed by an ENT specialist. More details are 
provided in Table 1 and in Section 7.3.6. 


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4.8. Subject Identification 
Each subject who has signed the informed consent will be identified by a unique study 
screening number. Subjects who are dosed will receive an additional Randomization number. 
Subject identification will be confirmed by the study staff at each study visit. 
4.9. Re-Screening of Subjects 
If dosing is not expected to occur within 42 days of initial screening procedure, a re-screening 
visit will be performed to allow subject's participation. Mitochondrial mutations testings will 
not need to be repeated. 
Subjects who completed all screening procedures and were found eligible to participate in the 
study may serve as standbys in their designated cohort. In case a standby subject is not dosed, 
he will be discharged from the CPU but may be invited to participate in another cohort later 
on.  
4.10. Screening Failures 
Subjects who fail to meet the entrance criteria at any stage during the screening period are 
defined as screen failures. All screen failures will be recorded in the Identification and 
screening logs. The reason(s) for screen failure will be documented. The screening log will be 
kept in the Investigators Site File.  
Screen failure subjects will be withdrawn from the study and will not count towards the total 
enrolled or total eligible subjects. 
4.11. Removal, Replacement or Early Withdrawal 
Subjects are free to discontinue their participation in the study at any time and without 
prejudice to further treatment. The Investigator must withdraw any subject from the study if 
that subject requests to be withdrawn, or if it is determined that continuing in the study would 
result in a safety risk to the subject.   
Subjects discontinued or withdrawn from the study after receiving ≤6 doses may be replaced 
upon request from the Sponsor. The subject's participation in this study may be discontinued 
due to the following reasons: 
1. Request by regulatory agency, Sponsor, primary care physician or Investigator. 
2. Subject withdraws consent. 
3. Female subject is pregnant. 
4. Positive UDS and/or serum alcohol test on admission to the CPU on Day -1. If subjects 
have a positive UDS and/or serum alcohol test after Day -1, there continued participation 
will be re-evaluated on a case by case basis. 
5. Adverse event (AE) or Serious Adverse Event (SAE) meeting criteria for drug-related 
event and meeting stopping criteria.  
6. Subject is unwilling or unable to continue the study or is lost-to-follow-up. 
7. Subject is non-compliant with study procedures/study protocol. 
8. Investigator decides that withdrawal from the study is in the best interest of the subject. 


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9. Subject needs medication not allowed in the protocol. 
10. Any clinically significant change in subject’s medical condition. 
11. Subjects may be replaced at the discretion of the Sponsor.  
4.12. Early Study Termination  
The study may be discontinued prematurely at any time and for any reason. Such reasons may 
be any of, but not limited to, the following:  
1. Occurrence of SAEs of an unanticipated nature in accordance with the stopping rules, 
severity, and duration or the unexpected incidence of known SAEs (SUSAR); 
2. Medical or ethical reasons affecting the continued performance of the study 
3. Poor performance or compliance of the site. 
4. Exposure of the subjects to unacceptable health risks. 
5. A regulatory authority decision. 
6. Change in opinion of the IEC. 
7. Following DSMB/AVDSMB recommendation. 
8. ELX-02 safety concerns. 
9. At the discretion of the Sponsor (e.g. decision of the Sponsor to discontinue development 
of ELX-02 at any time). 
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the PI. 
After notification, the PI must contact all participating subjects and the site pharmacy within 
48 hours. As directed by the Sponsor, all study materials must be collected and the database 
must be completed to the greatest extent possible. 


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5. STUDY TREATMENTS  
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33). 
5.1. Allocation to Treatment 
Eligible subjects will be assigned to one of the following administrations:  
 Cohort 1: ELX-02 0.1 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 2: ELX-02 0.3 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 3: ELX-02 1.0 mg/kg or placebo SC twice a week for 9 doses; 
 Cohort 4: ELX-02 2.5 mg/kg (100 mg/mL) or placebo SC twice a week for 9 doses; 
 Cohort 5: ELX-02 up to 2.5 mg/kg (50 mg/mL) or placebo SC twice a week for 9 doses; 
 Cohort 6: ELX-02 2.5 to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
 Cohort 7: ELX-02 up to 5.0 mg/kg or placebo SC twice a week for 9 doses. 
Dose escalation to the next cohort will not be performed until after the 14-day observation 
period for the previous cohort, to allow for detection of unanticipated delayed AEs.  
Changes to the planned dose may be made in any cohort, depending on safety and any available 
PK data. The dose will not exceed 5.0 mg/kg. Additional cohorts and subjects may be added 
to affirm safety at any dose level, at or below the maximum proposed dose level of 5.0 mg/kg 
for the study. 
The investigational drug, ELX-02, is formulated as a solution for SC injection, containing 200 
mg/mL. The placebo control will consist of a SC injection of normal saline at matching 
volumes.  
As subjects are confirmed to be eligible for the study, they will be assigned a single unique 
identifier across the study. 
5.1.1. Randomization and Blinding 
At screening, subjects receive a unique screening number. Subjects who are rescreened will be 
assigned the same screening number they received at first screening but with an additional 
identifier. Subjects who fail screening and are not enrolled will not be included in the database. 
The failure details will be documented in the subjects’ recruitment file. 
Subjects will be assigned to one of the treatment groups. Allocation of each subject to a given 
treatment group will be described in a randomization list prepared prior to study start by the 
CRO using SAS® software (SAS Institute Inc., Cary, NC, United States of America [USA]). 
The randomization will be balanced using randomly permuted blocks across the treatment 
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Based on this randomization code, the study drug will be packaged and labeled. Medication 
code numbers will be preprinted on the study drug labels and assigned as subjects qualify for 
the study and are randomly assigned to treatment or the pharmacist or appropriate qualified 
member of the study staff, who is unblinded to treatment and assigned by the PI, will prepare 
the study drug that corresponds to the assigned subject randomization number. 
Blinding will be achieved by the double-dummy method with placebo identical in appearance. 
The randomization list will be retained by the CRO until the end of the study (database lock). 
One copy of the randomization list will be sent in a sealed envelope to the site pharmacist 
before the start of the study. Another copy will also be sent before the start of the study in a 
sealed envelope to the bioanalytical laboratory responsible for plasma and urine drug 
determination. Upon completion of the study, the monitor needs to check the completeness and 
status of the envelopes and once this is done the monitor can retrieve the envelopes and have 
them destroyed. 
One copy of code breaking envelopes will be made available to the CPU, to be used only in 
case of emergency. An additional copy of code breaking envelopes will be kept at the CRO. 
Upon request, the CRO will provide the code-break information to the CRO for SAE reporting 
purposes. Should a subject experience an AE for which it is necessary to break the blind during 
the study in order to determine the appropriate treatment for the event, the PI or designee will 
call the medical monitor prior to unblinding. The reason for unblinding will be documented in 
the electronic source data (eSource) system. Subjects who are unblinded for any reason during 
their participation in the study will not be replaced and will be withdrawn immediately from 
the study. 
5.1.2. Breaking the Blind  
This will be a double-blinded study; neither the subject nor the Investigators, the study staff 
who are administering the test products and any personnel involved in subjects’ assessment 
and monitoring, will know the treatment assignment. Only the pharmacists responsible for 
preparing the clinical test material and the study un-blinded monitor responsible for 
accountability and, if required, the DSMB members will be un-blinded. 
The pharmacy at the CPU will prepare ELX-02/Placebo dose, according to instructions 
provided in the study's pharmacy manual, based on a prescription issued by the Investigator. 
Treatment allocation will be available to the pharmacy staff in advance. The study drug will 
be appropriately labeled, indicating the date and randomization number.   
The Sponsor is permitted to request unblinding of any subject in association with adverse 
events. In the absence of a medical emergency, the blinded randomization for this trial will not 
be revealed until all data are entered into the database, edits checks are performed, queries 
closed, CRF signed by the PI, and the database is officially locked. 
5.2. Subject Compliance 
ELX-02 or placebo will be administered by the appropriately designated study staff at the 
investigational site, under supervision of the Investigator. 
5.3. Investigational Product Supplies 
ELX-02 will be prepared in accordance with Good Manufacturing Practice (GMP) as required 
by the current Good Clinical Practice (GCP). 




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5.4. Administration 
ELX-02 and matching placebo will be administered to each subject, while confined to bed, by 
a designated study nurse or Investigator. An Investigator must be present during all 
ELX-02/Placebo administrations. 
Subjects should consume at least 500 mL of water within 120 minutes before dosing. 
The drug will be administered as SC injection(s) to the abdominal region around the umbilicus 
or to any area with a significant subcutaneous adipose tissue (e.g. thigh). Injections for each 
subject should be performed sequentially to minimize time lag between injections. Detailed 
instructions on number of injections and injected volume will be specified in the pharmacy 
manual.  
The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) 
of fluids every hour up to 10h after dosing. 
Details of each ELX-02 or matching placebo administration will be recorded. 
The used vials from which the drug was administered to the subjects will be retained for dose 
confirmation. For details on the Study Drug Accountability, refer to the pharmacy manual. 
5.5. Investigational Product Storage  
  
Regular temperature logging of the study drug storage freezer at the CPU should be performed. 
In case a deviation in storage conditions should occur, the CPU must not further dispense the 
affected study drug and notify the Sponsor. 
The Investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label. Site systems must be capable of measuring and documenting (for example, via a log), at 
a minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products). This should be 
captured from the time of investigational product receipt throughout the study. Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be available. The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product. It will not be 
considered a protocol deviation if the sponsor approves the use of the investigational product 
after the temperature excursion. Use of the investigational product prior to sponsor approval 
will be considered a protocol deviation.   


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Specific details regarding information the site should report for each excursion will be provided 
to the site. 
5.6. Investigational Product Accountability  
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  
The Sponsor’s designated site monitor will periodically check the supplies of study drugs held 
by the Investigator or pharmacist to ensure accountability and appropriate storage conditions 
of all study drugs used. 
Unused study drugs must be available for verification by the site monitor during on-site 
monitoring visits. Any discrepancies between returned and expected returned study drugs 
should be explained and documented. All used vials must be stored frozen until the end of the 
study. 
After the last visit of the last subject in the study (LPLV), any unused study drug will be 
returned to the Sponsor or destroyed at the CPU with the Sponsor’s written permission (in this 
case a certificate of destruction will be provided and filed in the electronic Trial Master File 
(eTMF). 
Hazardous materials such as used ampoules, needles, syringes and vials containing hazardous 
liquids, should be disposed of immediately in a safe manner and therefore will not be retained 
for drug accountability purposes. 
5.7. Destruction of Investigational Product Supplies  
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by Eloxx 
Pharmaceuticals, and all destruction must be adequately documented. 


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6. STUDY RESTRICTIONS  
6.1. Concomitant Treatments 
There is no knowledge of cross reaction between ELX-02 and other drugs.  
Use of prescription or nonprescription drugs and dietary supplements within 30 days or 
5 half-lives (whichever is longer) prior to the administration of study drug is prohibited. As an 
exception, 
acetaminophen/paracetamol may be used at doses of 2 g/day and contraception (see section 
6.5.1.). Herbal supplements should be  
discontinued at least 30 days prior to administration of the study drug.  
Since ELX-02 is an aminoglycoside derivative, special care should be placed in avoiding 
concomitant medications which interact with aminoglycosides such as (Gentamicin Product 
Monograph, 2012):  
 Antimicrobials (such as other aminoglycosides, cephalosporins, clindamycin, 
polymyxin B, clindamycin) which may increase the risk of nephrotoxicity and/or 
neuro- or ototoxicity; 
 Cholinergic agents (e.g., neostigmine, pyridostigmine): Gentamicin antagonizes the 
effect of neostigmine and pyridostigmine; 
 Loop diuretics (e.g., furosemide) which increase the risk for ototoxic and nephrotoxic 
effects of aminoglycosides; 
 Neuromuscular blocking agents and opioid-analgesics (e.g,. fentanyl, 
succinylcholine);  
 Anti-neoplastic agents (e.g., carboplatin, cisplatin) which increase the risk of 
nephrotoxicity and/or neurotoxicity; 
 Immunosuppresive agents (e.g., cyclosporine, tacrolimus) which increase the risk of 
nephrotoxicity and/or neurotoxicity;  
 Mannitol which increases the risk of nephrotoxicity and/or neurotoxicity; 
 Magnesium which may increase neuromuscular blockade; 
 Quinine – an agents with ototoxic potential; 
 Salicylates: agents with ototoxic potential; 
 Aminoglycosides; 
 Non-steroidal anti-inflammatory drugs (NSAIDs) which may decrease glomerular 
filtration rate. 
If intake of a concomitant drug should become necessary for any reason during the course of 
the study, the subject is required to inform the Investigator immediately, who will record the 
drug name, its dose and the time of intake. 
6.2. Limit of Noise Exposure 
All subjects will be instructed to minimize excessive noise exposure from screening until the 
completion of the final ENT exams.  


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In addition, subjects will be required to wear silicone earplugs when exposed to louder than 
normal noise. However, this will NOT permit them to attend loud concerts, visit shooting 
range, and so on. 
6.3. Meals and Dietary Restrictions 
 Subjects shall receive standardized meals while staying in-house at the CPU. 
 At least 500 mL water will be consumed within 120 minutes before dosing. The study 
staff will encourage subjects to drink at least one glass (approximately 250 mL) of 
fluids every hour up to 10h after dosing. Non-caffeinated drinks may be consumed ad 
libitum. 
 Food and drinks containing xanthines (coffee, chocolate, tea etc.) will not be permitted 
from 48h before first study drug administration until 48h after last administration. 
 Subjects will abstain from alcohol from 48h before first study drug administration and 
during the dosing period until 48h after last study drug administration. 
 Subjects will abstain from smoking for 6 months prior to the first screening visit until 
48h after the last study drug administration. 
 Subjects will abstain from illicit drug use from the first screening visit until 48h after 
the last study drug administration. 
6.4. Activity 
Subjects will remain in bed for the first 4 hours (h) after dosing on Day 1 and Day 29 (except 
when required to void). After this they may be ambulatory but should not engage in strenuous 
activities (e.g., heavy lifting, weight training, calisthenics, aerobics) until the End of Study 
(EOS) visit.  
6.5. Contraception 
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use 2 highly effective 
methods of contraception consistently and correctly throughout the study (from 14 days before 
first study drug dosing for female subjects) and until 28 days after last study drug 
administration. The Investigator or designee, in consultation with the subject, will confirm that 
the subject has selected an appropriate method of contraception from the permitted list of 
contraception methods (see below). In addition, the Investigator or designee will instruct the 
subject to call immediately if the selected contraception method is discontinued or if pregnancy 
is known or suspected in the subject or the subject’s partner. All this will be documented in the 
subject's source documents. 
6.5.1. Female Subjects 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
 Achieved postmenopausal status, defined as follows: cessation of regular menses for at 
least 12 consecutive months with no alternative pathological or physiological cause; 
post-menopausal status will be confirmed by a serum follicle-stimulating hormone 
(FSH) level; 
 Have undergone a documented hysterectomy and/or bilateral oophorectomy; 


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 Have medically confirmed ovarian failure. 
All female subjects, regardless of childbearing potential, must agree to undergo pregnancy test 
at screening and on D -1, D7, D14, D21 and D28. 
Unless willing to abstain from sexual intercourse for 14 days prior to the first study drug 
administration, and for 28 days after the last dose, all other female subjects (including females 
with tubal ligations) will be considered to be of childbearing potential and must use 2 highly 
effective methods of contraception for two weeks (14 days) before first study drug 
administration and four weeks (28 days) after last dosing. These include: 
 Established use of oral, inserted, injected, implanted or transdermal hormonal methods 
of contraception (provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness). 
 Copper -containing intrauterine device (IUD).  
If the female subject has a vasectomized partner (with absence of sperm in the postvasectomy 
ejaculate), no additional method of contraception is needed. 
6.5.2. Male Subjects 
All sexually active male subjects will be advised of the potential risks involved in transfer of 
and exposure to ELX-02 through semen to their partners. Unless they are abstaining from 
sexual intercourse for 14 days prior to the first study drug administration, and for 28 days after 
the last dose they must agree to use 2 highly effective method of contraception during the 
course of the study until 28 days after last dosing. These include a condom, having undergone 
a vasectomy with absence of sperm in the postvasectomy ejaculate, or having a female partner 
who meets the criteria for non-childbearing potential. 


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7. STUDY PROCEDURES 
7.1. Timing of Assessments 
The timing of assessments is specified below and in Table 1. Allowed time window deviations 
are provided in Section 7.2. 
On days when vital signs and a 12-lead ECG parameters need to be assessed as well as blood 
sampling, the vital signs and 12-lead ECG will be performed before blood sampling, except 
when an indwelling cannula has been placed. 
Screening Period (Visit 1) 
This visit will take place within 42 to 2 days before dosing. Subjects will sign an informed 
consent form and will be assessed for their eligibility to participate in the study. 
The following screening assessments will be performed for each subject: 
 Medical history (including questions relating to hearing and balance disorders). 
 Contraception method. 
 Demographics. 
 Physical examination. 
 Height, Weight, and BMI (calculated as kg/m2). 
 Vital signs: Supine (following at least 5 min of supine rest) BP, heart rate (HR), 
respiratory rate (RR) and oral body temperature.  
 12-lead ECG taken after 5 minutes in a supine position. 
 Blood and urine lab tests (see Section 7.3.9 for more details): 
o Blood and urine safety tests 
o Serology (HIV, HBsAg, HCVAb) 
o Urine drug screen (UDS) 
o Serum alcohol test 
o Blood pregnancy test  
o FSH  
o Urine sample for creatinine and renal injury biomarker testing  
o Blood sample for mitochondrial mutations testing 
 Compliance with inclusion/exclusion criteria. 
 Assessment of AEs and concomitant medications. 


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Screening Visit 2: Auditory and Vestibular Assessments 
During the screening period subjects will undergo auditory and vestibular assessments to 
confirm eligibility (Day -42 to -8). In addition, a baseline exam (PTA and HFA will be 
duplicated) will be performed prior to initial dosing (within 7 days prior to dose). These 
assessments can be done on the same day (between Day -7 and Day -1) with 2-3 hrs between 
the 2 assessments. 
The auditory tests to be performed are outlined in Section 7.3.6.  
In addition, subjects will complete vestibular and tinnitus questionnaires. 
Only subjects having normal test results according to an ENT physician may participate in the 
study. 
Treatment Period 
Day -1 
Subjects will come to the CPU on Day -1 and will be interviewed by study personnel regarding 
concomitant medications and any change in their health status or diet since screening. 
Inclusion/exclusion criteria will be reconfirmed and eligible subjects will undergo the 
following procedures: 
 Physical examination. 
 Weight. 
 Blood and urine safety tests (see Section  7.3.9 for more details). 
The subjects will stay confined till the morning of Day 3. 
The following assessments will be done : 
 UDS. 
 Urine pregnancy test (all women regardless of childbearing potential). 
 Serum alcohol  test.  
 Urine sample for creatinine and renal injury biomarker testing (see Section 7.5.1). 
 Assessment of AEs and concomitant medications.  
Day 1 
Predose 
Inclusion/exclusion criteria will be reconfirmed. 
Prior to drug administration, the following activities will be completed: 
 First morning urine sample for PK determination, for creatinine and renal injury 
biomarkers assessment. 
 Vital signs (supine, BP, HR, RR, and oral temperature) after at least 5 min supine. 
 12-lead ECG taken after 5 minutes in a supine position 
 Assessment of AEs and concomitant medications.  


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 Weight (if not yet taken on Day -1). 
 Subjects will drink at least 500 mL water within 120 minutes before dosing. 
 Blood samples for PK, housekeeping proteins, and retention (a retention sample will 
be taken to assess any potential safety issues e.g., hematology and biochemistry, 
coagulation) will be drawn. The PK blood sample will be taken 180 min before dosing. 
Study Drug administration 
Each subject will receive ELX-02 or Placebo with SC injection as per subject’s body weight 
measured at Day -1 or Day 1 predose, while confined to bed, as described in Section 5.4. Date 
and time of drug administration will be documented.  
Postdose 
 After dosing, subjects will remain confined to bed for four hours (except when required 
to void). They will then be allowed to move freely within the ward but must refrain 
from strenuous physical activity for the duration of the study. 
 Blood samples for PK will be collected at 15 min, 30 min, 45 min, 1h, 3h, 6h, and 12h 
postdose (Section 7.4). 
 Vital signs (supine BP, HR, RR, and oral temperature) will be measured at 30 min, 
45 min, 1h, 3h, and 12h postdose after 5 minutes in a supine position. 
 Brief physical examination at 6h postdose. 
 Blood and urine safety test at 6h postdose. 
 Urine collection for PK during 0-12h hourly UC (each void collected separately) and 
12-24h postdose, 6h intervals UC (cumulative collection 12-18h, and 18-24h postdose). 
 Urine samples for renal injury biomarkers and creatinine (from the last void of the 
0-12h collection) (Section 7.5.1). 
 12-lead ECG recording at 3h, 6h, and 12h postdose taken after 5 minutes in a supine 
position. 
 Assessment of local reaction of injection site(s) 45 min, 6h, and 12h postdose 
(Section 7.3.7). 
 Blood sampling for retention at 3h postdose. 
 AEs assessment and change in concomitant medications. 
 Meals will be served. 
The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) 
of fluids every hour up to 10h after dosing. 
Day 2  
 Vital signs (after 5 minutes in a supine position), BP, HR, RR, and oral temperature 
24h). 
 12-lead ECG (24h) taken after 5 minutes in a supine position. 


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 Assessment of local injection(s) reaction (24h). 


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Blood sample collection: 
o Safety lab tests (24h)  
o PK (24h and 36h) 
o Blood sampling for housekeeping proteins (24h). 
 Urine collection : 
o Urinalysis (24h) 
o Urine PK, 12h intervals (cumulative 24h-36h and 36-48h collection) 
o Renal injury biomarkers and creatinine (24h and 36h urine void)  
 AEs assessment and change in concomitant medications.  
Day 3 (Discharge from CPU) 
Before discharge (at approximately 48 hours after dosing), subjects will undergo the following 
assessments: 
 Last urine collection added to the previous urine collection for PK. 
 Urine samples for renal injury biomarkers, creatinine and general urinalysis (48h urine 
void). 
 Assessment of local injection(s) reaction (48h). 
 Vital signs (supine BP, HR, RR, and oral temperature) after 5 min in a supone position 
(48h) 
 Weight. 
 Physical examination (48h). 
 12-lead ECG (48h) taken after 5 minutes in a supine position 
 Blood samples collection (48h):  
o Safety lab tests (48h) 
o PK (48h) 
o Blood sampling for housekeeping proteins (48h). 
 AEs assessment and change in concomitant medication. 
 Auditory and vestibular assessments (may be performed on Day 2, as well if not 
otherwise possible). 
Subjects will be discharged following satisfactory clinical assessment by the Investigator. Two 
urine jars will be provided to the subject for 48-72h urine collection at home.  
Day 4-Day 11-Day 18 
Subjects will hand over the urine jars to the site personnel (only on Day 4), for the urine PK 
sampling from the collection 48-72h. 
Predose 
 Vital signs (supine BP, HR, RR, and oral temperature). 
 Weight (if not taken at previous day). 


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 Urine samples for creatinine and renal injury biomarkers. 
 AEs assessment and change in concomitant medication. 
 Subjects will drink at least 500 mL water within 120 minutes before dosing. 
 A PK blood sample will be taken 180 min before study drug administration.  
Study drug administration 
Each subject will receive ELX-02 or Placebo with SC injection, while confined to bed, as 
described in Section 5.4. Time and date of drug administration will be documented.  
Postdose 
 Local reaction of injection site (up to 1h postdose). 
 PK blood sample (1h). 
The study staff will encourage the subjects to drink at approximately 250 mL of fluids every 
hour up to 10h after dosing. 
Subjects will remain at the CPU for 2h following study drug administration for safety 
observation. 
Day 10-Day 17-Day 24 
Auditory and vestibular assessments (may be performed on Day 9, Day 16, or Day 23, 
respectively, as well if not otherwise possible). 
Weight (to be assessed in the morning)  
Day 7-Day 14-Day 21 
Subjects will come to the CPU for safety blood/urine sampling  and AE/CM assessments, 
weight and stay confined till the last assessment the day after. 
 UDS on Day 14 
 Serum alcohol on Day 14 
 Blood safety and general urinalysis. 
 AEs assessment and change in concomitant medication. 
 Weight (to be assessed in the morning). 
Day 8-Day 15-Day 22 
Predose 
 Serum alcohol on Day 22 
 Vital signs (supine BP, HR, RR, and oral temperature). 
 Weight (if not taken at previous day). 
 Physical examination. 
 12-lead ECG taken after 5 minutes in a supine position. 


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 Urine samples for creatinine and renal injury biomarkers. 
 Blood sampling for housekeeping proteins. 
 Urine pregnancy test (all women regardless of childbearing potential) 
 Blood sampling for retention. 
 AEs assessment and change in concomitant medication. 
 Subjects will drink at least 500 mL water within 120 minutes before dosing. 
 A PK blood will be taken right before dosing. 
Study drug administration 
Each subject will receive ELX-02 or Placebo with SC injection, while confined to bed. Date 
and time of drug administration will be documented.  
Postdose 
 Assessment of local injection(s) reaction (up to 1h postdose). 
 PK blood sample (1h). 
The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) 
of fluids every hour up to 10h after dosing. 
Subjects will remain at the CPU for 2h following study drug administration for safety 
observation. 
Day 25 
Predose 
 Urine samples for creatinine and renal injury biomarkers. 
 Vital signs (supine BP, HR, RR, and oral temperature). 
 Weight. 
 AEs assessment and change in concomitant medication. 
 Subjects will drink at least 500 mL water within 120 minutes before dosing. 
 A PK blood sample will be taken right before study drug administration.  
Study drug administration 
Each subject will receive ELX-02 or Placebo with SC injection, while confined to bed. Date 
and time of drug administration will be documented.  
Postdose 
The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) 
of fluids every hour up to 10h after dosing. 
 Assessment of local injection(s) reaction (up to 1h postdose). 
 PK blood sample (1h postdose). 


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Day 28 (Check-in) 
Subjects will be admitted to the CPU on Day 28 for safety blood and urine sampling and will 
be interviewed by study personnel regarding concomitant medications and any change in their 
health status or diet since the previous visit.  
 Physical examination. 
 Blood safety and general urinalysis. 
 Weight 
Subjects will stay confined till the morning of Day 31. 
The following assessments will be done : 
 Vital signs (supine BP, HR, RR, and oral temperature) taken after 5 minutes in a supine 
position. 
 Urine pregnancy test (all women regardless of childbearing potential). 
 Urine Drug Screen (UDS). 
 Serum alcohol test. 
 Urine samples for creatinine and renal injury biomarkers. 
 Assessment of AEs and concomitant medications. 
Day 29 
Predose 
Prior to drug administration, the following activities will be completed: 
 First morning urine sample for PK determination, for creatinine, renal injury 
biomarkers assessment. 
 Vital signs (supine BP, HR, RR, and oral temperature) taken after 5 minutes in a supine 
position. 
 12-lead ECG taken after 5 minutes in a supine position. 
 Assessment of AEs and concomitant medications.  
 Weight (if not already taken on Day 28). 
 Subjects will drink at least 500 mL water within 120 minutes before dosing. 
 Blood samples for PK, housekeeping proteins, and retention (a retention sample will 
be taken to assess any potential safety issues e.g hematology and biochemistry, 
coagulation) will be drawn. The PK blood sample will be taken right before study drug 
administration.  
Study Drug administration 
Each subject will receive ELX-02 or Placebo with SC injection, while confined to bed, as 
described in Section 5.4. Date and time of drug administration will be documented.  
Postdose 


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 After dosing, subjects will remain confined to bed for four hours (except when required 
to void). They will then be allowed to move freely within the ward but must refrain 
from strenuous physical activity for the duration of the study. 
 Blood samples for PK will be collected at 15 min, 30 min, 45 min, 1h, 3h, 6h, and 12h 
postdose (Section 7.4). 
 Vital signs (supine BP, HR, RR, and oral temperature) will be measured at 30 min, 
45 min, 1h, 3h, and 12h postdose. 
 Brief physical examination at 6h postdose. 
 Blood and urine safety test at 6h postdose. 
 Hourly Urine collection for PK during 0-12h (each void collected separately) and 12-
24h postdose (cumulative collection in 6h intervals ;  12-18h, and 18-24h postdose). 
 Urine samples for renal injury biomarkers and creatinine (from the last void of the 
0-12h collection) (Section 7.5.1). 
 12-lead ECG recording at 3h, 6h, and 12h postdose taken after 5 minutes in a supine 
position. 
 Assessment of local reaction of injection site(s) 45 min, 6h, and 12h postdose 
(Section 7.3.7). 
 Blood sampling for retention (at 3h postdose). 
 AEs assessment and change in concomitant medications. 
 Meals will be served. 
The study staff will encourage the subjects to drink at least one glass (approximately 250 mL) 
of fluids every hour up to 10h after dosing. 
Day 30  
 Vital signs (supine BP, HR, RR and oral temperature, 24h). 
 12-lead ECG (24h) taken after 5 minutes in a supine position. 
 Blood sample collection: 
o Safety lab tests (24h) 
o PK (24h and 36h) 
o Blood sampling for housekeeping proteins (24h). 
 Urine collection: 
o Urinalysis (24h) 
o PK (12h intervals cumulative 24h-36 and 36-48h) 
o Renal injury biomarkers and creatinine (24h and 36h urine void)  
 AEs assessment and change in concomitant medications.  
 Local reaction of injection site (24h). 
Day 31 (Discharge from CPU) 


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Before discharge (at approximately 48 hours after dosing), subjects will undergo the following 
assessments: 
 Last urine collection added to the previous urine collection for PK. 
 Urine samples for renal injury biomarkers, creatinine and general urinalysis. (48h urine 
void). 
 Assessment of local injection(s) reaction (48h). 
 Vital signs (supine BP, HR, RR, and oral temperature) (48h). 
 Physical examination (48h). 
 12-lead ECG (48h) taken after 5 minutes in a supine position. 
 Blood sampling for safety lab tests (48h). 
 Blood sampling for PK (48h). 
 Blood sampling for housekeeping proteins (48h). 
 AEs assessment and change in concomitant medication. 
Subjects will be discharged following satisfactory clinical assessment by the Investigator. Two 
urine jars will be provided to the subject for 48-72h urine collection at home.  
Day 32  
Subjects come to the CPU in the morning for a 72h PK blood sample. They will hand over the 
urine jars to the site personnel, for the urine PK sampling from the collection 48-72h. The site 
personnel will check if any AE and/or change in concomitant medications occurred. 


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End of Study Visit (Day 36) 
This visit will take place 7-10 days after last dosing. Auditory and vestibular assessments 
may take place 7-11 days after last dosing. 
The following assessments will take place: 
 Physical examination. 
 Assessment of local injection(s) reaction. 
 Vital signs (supine BP, HR, RR, oral temperature). 
 12-lead ECG taken after 5 minutes in a supine position. 
 Blood and urine safety tests. 
 Serology (HIV, HBsAg, HCVAb). 
 Urine pregnancy test (all women regardless of childbearing potential).  
 Urine samples for creatinine and renal injury biomarkers. 
 Serum alcohol test. 
 Blood sampling for housekeeping proteins. 
 AEs assessment and change in concomitant medications. 
 Audiometry tests. 
 Vestibular and tinnitus questionnaires. 
Unscheduled Visit 
An unscheduled visit may take place at any time during the study at the subject's request or as 
deemed necessary by the Investigator due to medical considerations. The date and reason for 
the unscheduled visit will be recorded. AE monitoring and concomitant medication recording 
will be recorded. Other procedures and evaluations will be completed as deemed necessary by 
the Investigator and may include (but not limited to) safety laboratory tests, ECG, vital signs 
and physical examination. 
Handling Subject Withdrawal 
If a subject's participation in the study is prematurely terminated for any reason or fails to 
return for a scheduled visit, every effort should be made to determine the reason. This 
information will be recorded.  
Upon withdrawal from the study, any time after dosing has taken place, all efforts should be 
made to invite the subject to complete the EOS visit. 
If for any reason the subject does not agree to return to the CPU for the above visit, the reason 
and/or efforts made will be recorded. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 


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7.2. Allowed Time Window Deviations 
Allowed time window deviations are (assessments at screening, Day -1, and EOS not 
described here): 
Vital signs  
Day 1 and Day 29:  
predose, and 30 min (± 5 min), 45 min (± 5 min), 1h (± 15 min), 3h (± 
15 min), 12h (± 30 min), 24h (± 1h), 48h (± 1h) postdose. 
On other dosing days, vital signs need to be assessed before dosing. 
Physical examination 
Day 1 and Day 29:  
6h (± 1h), 48h (± 2h) postdose. 
On other dosing days, the physical examination needs to be performed before dosing. 
ECG 
Day 1 and Day 29:  
predose, and 3h (± 15 min), 6h (± 15 min), 12h (± 30 min), 24h (± 1h), 
48h (± 1h) postdose. 
On other dosing days, a 12-lead ECG needs to be taken before dosing. 
Audiometric testing 
The allowed time window deviations for audiometric and vestibular testing during the 
treatment period are Screening (-42 to -8 days), Baseline (-7 to Day -1) (these two tests can 
be performed on the same day) Day 3 (-1 day), Day 10 (-1 day), Day 17 (-1 day), Day 24 
(-1 day), and EOS (7-11 days after last dosing). The otoscopic exam on Day 3, Day 10, Day 
17 and Day 24 can be performed 72 hours prior to dosing. 
Local reaction of injection 
Day 1 and Day 29: 
45 min (± 5 min), 6h (± 15 min), 12h (± 30 min), 24h (± 1h), 48h 
(± 1h) postdose. 
On other dosing days the local reaction of injection needs to be assessed up to 1h post dosing. 
For laboratory samples 
a. Blood samples 
 Safety sampling: Day 1 and Day 29: 6h (± 15 min), 24h (± 15 min), 48h 
(± 30 min). Other safety blood samples will be taken in the morning of Day 7, 
Day 14, Day 21, and Day 28.  
 PK sampling: Day 1 and Day 29: predose, 15 min (± 2 min), 30 min (± 5 min), 
45 min (± 5 min), 1h (± 5 min), 3h (± 15 min), 6h (± 15 min), 12h (± 30 min), 


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24h (± 1h), 36h (± 1h), 48h (± 1h), 72h (± 1h). On other dosing days, the PK 
blood samples will be taken predose and 1h postdose (± 5 min). 
 Housekeeping proteins: Day 1 and Day 29: predose and 24h (± 1h), 48h (± 1h) 
postdose. On other dosing days the sample needs to be taken predose. 
 Blood retention sampling: Day 1 and Day 29 predose and at 3h (± 15 min) 
postdose. On other dosing days the sample needs to be taken predose.  
b.  Urine samples 
 Safety sampling: Day 1 and Day 29: 6h (± 30 min), 24h (± 2h), 48h (± 2h). Other 
safety urine samples will be taken in the morning of Day 7, Day 14, Day 21, and 
Day 28. 
 PK sampling: Day 1 and Day 29: predose and during 0-12h (± 15 min), 12-24h 
(± 15 min), 24-48h (± 15 min), and 48-72h (± 15 min) postdose. And on Day 8, 
11, 15, 18, 22, and 25 for creatinine. 
 Renal injury biomarkers and creatinine sampling: predose and 12h sample from 
last void of the 0-12h collection (± 30 min), 24h (± 2h), 36h (± 2h), 48h (± 2h), 
and 72h (± 2h) postdose. And on Day 8, 11, 15, 18, 22, and 25.  
7.3. Safety Evaluations 
7.3.1. Adverse Events (AEs) 
Adverse events will be collected continuously starting from signing the Informed Consent 
Form (ICF) until EOS visit for randomized subjects.  
Adverse events reported prior to dosing will be considered non treatment emergent. Any new 
systemic effect that occurs between scheduled visits should be brought to the attention of the 
Investigator and recorded in the subject’s files. 
Common Terminology Criteria for Adverse Events (CTCAE21) will be used to determine the 
AE safety profile of ELX-02. For more information refer to Section 8. 
7.3.2. Concomitant Medications 
Use and any changes in concomitant medication will be recorded continuously starting from 
screening until EOS visit. Contraindicated drugs are listed in Section 6.1. 
7.3.3. Vital Signs 
Vital signs (supine BP, HR, RR, and oral temperature) will be measured in supine position 
after at least 5 min of supine rest at the time points specified in Section 7.1 and in Table 1. 
On days when vital signs parameters need to be assessed as well as blood sampling, the vital 
signs will be performed before blood sampling, except when an indwelling cannula has been 
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Changes in vital signs determined by the Investigator to be clinically significant will be noted 
as an AE in the eSource. Such abnormalities will be closely monitored until stabilized or 
resolved. 
7.3.4. Physical Examination 
Complete physical examination will be performed at the time-points specified in Section 7.1 
and in Table 1. 
Significant changes from baseline examination on screening will be recorded as AEs. 
7.3.5. ECG Examination 
A 12-lead ECG (taken after 5 minutes in a supine position) will be performed at the 
timepoints specified in Section 7.1 and in Table 1. 
 
The following values will be collected: QT, QTc, HR, QRS, and PR.  
On days when a 12-lead ECG parameters needs to be assessed as well as blood sampling, the 
vital signs and 12-lead ECG will be performed before blood sampling, except when an 
indwelling cannula has been placed. 
Any ECG abnormality compared to baseline (Day 1 predose) reading determined by the 
Investigator to be clinically significant will be recorded as an AE. Such abnormalities will be 
closely monitored until stabilized or resolved. 
7.3.6. Auditory and Vestibular Assessments 
The following auditory and vestibular tests will take place: 
 
Otoscopy at all visits (the otoscopic exam on Day 3, Day 10, Day 17 and Day 24 can be 
performed 72 hours prior to dosing by a CPU physician) 
 
Tympanometry (Immittance audiometry) at all visits 
 
Speech Reception Threshold (SRT)- will be performed at screening and baseline. At 
follow up visits, SRT will be performed only if there are ASHA significant change 
criteria/reverse ASHA significant change criteria noted in the PTA/HFA exam. 
 
Pure tone audiometry (PTA) with frequencies up to 8 kHz if possible. Should there be 
an air conduction threshold of ≥15 dB, the subject should undergo bone conduction 
testing at that frequency if that threshold is for the frequency is 4 kHz or lower. 
 
High frequency audiometry (HFA) up to 16 kHz if possible.  
 Tinnitus questionnaires (Tinnitus Handicap Inventory) 
 Vestibular questionnaires (Dizziness Handicap) 
 
For all tests, the same equipment should be used, as well as any repeat test to minimize 
technical variability.  
More details can be found in Section 8.4.2. For description of these assessments refer to the 
Auditory and Vestibular Tests Manual. 


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All audiometric findings will be written on an auditory entry form and abnormal findings will 
be sent to the AVDSMB (consisting of a physician and audiologist) when required. The 
AVDSMB will decide if further dosing will occur, taking into account the stopping criteria. 
7.3.7. Local Reaction of Injection Site 
The extent of local reaction on the injection site will be graded according to CTCAE 4.03, 
modified from the Food and Drug Administration (FDA) Guidance for Industry (FDA, 200722) 
and DAIDS criteria (Section 13.1). 
Local reaction will be assessed at the timepoints specified in Section 7.1 and in Table 1. 
7.3.8. Pregnancy Testing 
For female subjects of childbearing potential, a serum or urine pregnancy test (all women 
regardless of childbearing potential) will be performed at the timepoints specified in 
Section 7.1 and in Table 1. 
A negative pregnancy result is required before the subject may receive the investigational 
product. Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected), and at the end 
of the study to confirm the subject has not become pregnant during the study. Pregnancy tests 
may also be repeated as per request of institutional review boards (IRBs)/Independent ethics 
committees (IECs) or if required by local regulations.  
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with ELX-02, the Investigator must submit this information on a pregnancy 
report form to the CRO within 24 h of their knowledge of the event, preferably by fax or by e-
mail. Contact information will be provided in a separate document. 
If a participating s ubject's partner becomes pregnant during the study period, the Investigator 
will request her to sign an informed consent before following up her pregnancy course. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome. The 
Investigator will follow the pregnancy until completion (or until pregnancy termination) and 
notify the Sponsor of the outcome on a follow-up report.   
If the outcome of the pregnancy meets the criteria for an SAE (i.e. ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs. 
More information can be found in Section 8.14. 
7.3.9. Safety Blood and Urine, and Blood Sampling for Retention 
Safety laboratory evaluations and blood sampling for retention will be performed at the 
timepoints specified in Section 7.1 and in Table 1. 
All blood samples for retention need to be taken after an overnight fast of at least 8h, except 
for the samples taken at 3h postdose on Day 1 and Day 29. Processing and storage of the 
samples are detailed in the laboratory manual provided by the Sponsor. 


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All blood samples for safety assessments should be taken after an overnight fast of at least 8h, 
except for the samples taken at 6h postdose on Day 1 and Day 29. At screening subjects will 
be instructed not to eat within 3h before arrival at the CPU. 
The following safety laboratory assessment variables will be analyzed: 
 
 






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For any additional information related to laboratory related procedures, requirements and 
supplies, refer to the Laboratory Manual. 
7.4.2. Urine Collection 
Urine samples, to measure the rate of ELX-02 excretion, will be collected at the timepoints 
specified in Section 7.1 and in Table 1. 
 
₋ 
Day 1: Predose collection (first void in the morning). Urine samples for PK, biomarker, 
and creatinine analysis will be collected. Specific gravity will be calculated for the 
collection. 
₋ 
Day 1 (0-12 hours postdose collection period): Subjects will be encouraged to void as 
frequently as possible (i.e., asked every hour if they can collect urine), and each 
individual sample will be collected separately. Each sample’s weight will be recorded 
individually prior to removing urine for analyses. Specific gravity will be calculated 
for each collection. 
₋ 
Day 1: 12-24 hours postdose collection period. This urine collection period includes all 
voids starting after 12h and includes the first void on the next day (i.e., 24h postdose 
void).  
The urine will be collected every 6h (i.e., 12-18h collection and 18-24h collection). The 
12-18h voids and the 18-24h voids will be collected into separate urine collection 
containers.  
In addition, a single urine collection will be taken 24 hours after dosing using a third 
container (i.e., first morning void of Day 2). All urine containers will be weighed 
individually and the weights will be recorded. Urine samples for urinalysis, biomarker 
and creatinine analysis will be withdrawn from the single 24h urine void. Urine samples 
for PK analysis will be withdrawn from the pooled 12-18h and pooled 18-24h urine 
collection containers. Specific gravity will be calculated for each collection. 
₋ 
Day 2 – Day 3: 24-48 hours postdose collection period. This urine collection period 
includes all voids subsequent to the 24h postdose void and includes the first void on 
the next day (i.e., 48 hours postdose void).  
The urine will be collected every 12h (i.e. 24-36h collection and 36-48h collection). 
The 24-36h voids and the 36-48h voids will be collected into separate urine collection 
containers.  
In addition, a single urine collection will be taken 36 hours after dosing using a third 
container and a single urine collection will be taken 48 hours after dosing using a fourth 
container (i.e. the first morning void of Day 3). All urine containers will be weighed 
individually and the weights will be recorded. Urine samples for urinalysis will be 
withdrawn from the single 48h urine void. Urine samples for biomarker and creatinine 
analysis will be withdrawn from the single 36h and 48h urine void. Urine samples for 
PK analysis will be withdrawn from the pooled 24-36h and pooled 36-48h urine 
collection containers. Specific gravity will be calculated for each collection. 
₋ 
Day 3 – Day 4: 48-72 hours postdose collection period. This urine collection period 
includes all voids subsequent to the 48h postdose void and includes the first void on 
the next day (i.e., 72 hours postdose void).  


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During this collection period, subjects will be at home and collect the urine in urine 
jars (provided by the study site personnel). During this period, voids will be collected 
into a urine collection container. In addition, a single urine collection will be taken 72 
hours after dosing using a second container. Urine samples for biomarker analysis and 
creatinine will be withdrawn from the single 72h urine void. Urine samples for PK 
analysis will be withdrawn from the pooled 48-72h urine collection container. Gravity 
will be calculated for each collection. 
₋ 
Day 29: Predose collection (first void in the morning). Urine samples for PK, 
biomarker, and creatinine analysis will be collected. Specific gravity will be calculated 
for the collection. 
₋ 
Day 29 (0-12 hours postdose collection period): Subjects will be encouraged to void as 
frequently as possible (i.e., asked every hour if they can collect urine), and each 
individual sample will be collected separately. Each sample’s weight will be recorded 
individually prior to removing urine for analyses. Specific gravity will be calculated 
for each collection. 
₋ 
Day 29: 12-24 hours postdose collection period. This urine collection period includes 
all voids starting after 12h and includes the first void on the next day (i.e., 24h postdose 
void).  
The urine will be collected every 6h (i.e., 12-18h collection and 18-24h collection). The 
12-18h voids and the 18-24h voids will be collected into separate urine collection 
containers.  
In addition, a single urine collection will be taken 24 hours after dosing using a third 
container (i.e., first morning void of Day 30). All urine containers will be weighed 
individually and the weights will be recorded. Urine samples for urinalysis, biomarker 
and creatinine analysis will be withdrawn from the single 24h urine void. Urine samples 
for PK analysis will be withdrawn from the pooled 12-18h and pooled 18-24h urine 
collection containers. Specific gravity will be calculated for each collection. 
₋ 
Day 30 – Day 31: 24-48 hours postdose collection period. This urine collection period 
includes all voids subsequent to the 24h postdose void and includes the first void on 
the next day (i.e., 48 hours postdose void).  
The urine will be collected every 12h (i.e. 24-36h collection and 36-48h collection). 
The 24-36h voids and the 36-48h voids will be collected into separate urine collection 
containers.  
In addition, a single urine collection will be taken 36 hours after dosing using a third 
container and a single urine collection will be taken 48 hours after dosing using a fourth 
container (i.e. the first morning void of Day 31). All urine containers will be weighed 
individually and the weights will be recorded. Urine samples for urinalysis will be 
withdrawn from the single 48h urine void. Urine samples for biomarker analysis and 
creatinine will be withdrawn from the single 36h and 48h urine void. Urine samples for 
PK analysis will be withdrawn from the pooled 24-36h and pooled 36-48h urine 
collection containers. Specific gravity will be calculated for each collection. 
₋ 
Day 31 – Day 32: 48-72 hours postdose collection period. This urine collection period 
includes all voids subsequent to the 48h postdose void and includes the first void on 
the next day (i.e., 72 hours postdose void).  


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During this collection period, subjects will be at home and collect the urine in urine 
jars (provided by the study site personnel). During this period, voids will be collected 
into a urine collection container. In addition, a single urine collection will be taken 72 
hours after dosing using a second container. Urine samples for biomarker analysis and 
creatinine will be withdrawn from the single 72h urine void. Urine samples for PK 
analysis will be withdrawn from the pooled 48-72h urine collection container. Specific 
gravity will be calculated for each collection. 
After weighing and removing urine for analyses, the collection containers with remaining urine 
may be discarded. 
If urine cannot be obtained at a certain time interval it will be duly recorded and urine 
will be collected at the next time interval. 
Urine collection will be timed and measured for weight to determine the retained fraction of 
ELX-02 concentration and delay of excretion of the retained fraction and the PK. 
7.4.3. Bioanalysis 
Samples for determination of the concentration of ELX-02 will be analyzed by a qualified 
vendor (Aptuit) under the responsibility of the Sponsor, using a validated analytical method 
(HPLC-MS/MS). Instructions for laboratory processing will be detailed in the laboratory 
manual. 
The laboratory analysis will be carried out following the principles of Good Laboratory 
Practice (GLP) regulations of the Organization for Economic Co-operation and Development 
(OECD). The analytical procedure will be described in a separate analytical protocol. 
Validation data and details of the analytical procedure will be gathered in an analytical report 
that will be attached to or referred to in the Clinical Study Report upon completion of the study. 
Samples that remain after protocol-specific assessments have been performed may be used for 
further exploratory work on pharmacokinetics, metabolites, plasma protein binding, protein 
analysis, and biochemistry. No human DNA or RNA analysis will be performed. 
7.4.4. Pharmacokinetic Parameters 
The following parameters, where appropriate, will be determined for ELX-02, according to the 
definitions and methods of calculation below: 
- 
Cmax and tmax 
Maximum plasma concentration and corresponding time, directly 
obtained from the experimental data of plasma concentration vs time 
curves, without interpolation; 
- 
AUCt 
Area under the plasma concentration-time curve calculated from time 
of administration to the last quantifiable concentration, computed 
using the linear trapezoidal rule; 
- 
AUC24h 
Area under the plasma concentration-time curve calculated from time 
of administration to time 24h, computed using the linear trapezoidal 
rule; 
- 
AUC48h 
Area under the plasma concentration-time curve calculated from  
time of administration to time 48h (after first dose only), computed 
using the linear trapezoidal rule; 


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AUC72h 
Area under the plasma concentration-time curve calculated from  
 
time of administration to time 72h (after first dose only), computed 
using the linear trapezoidal rule; 
 
 
AUCinf 
The area under the plasma concentration-time curve extrapolated to 
 
 
infinity, calculated as AUCt + Clast / z, where Clast is the last  
 
 
 
concentration above the lower limit of quantification (LLOQ; 
- 
Cpredose 
Trough plasma concentration observed at the end of the dosing 
interval (i.e. at each predose starting from second dose); 
- 
C1h 
Plasma concentration observed at 1h postdose at each dosing starting 
from second dose; 
- 
t1/2 
Apparent elimination half-life associated with the terminal rate 
constant (z), calculated as ln2/z; 
- 
Vd/F 
Apparent volume of distribution; 
- 
CL/F 
Apparent plasma clearance; 
- 
Rac 
Accumulation ratio, calculated as AUC72h Day29/AUC72h Day 1. 
Additional pharmacokinetic parameters may be calculated as appropriate.  
The following parameters will be calculated based on ELX-02 urine concentrations: urinary 
excretion (Ae) of ELX-02 (in mass and %dose - fe) for each collection interval, cumulated 
urinary excretion (in %dose) for each collection interval, total excretion (in %dose) and renal 
clearance (using the AUC and Ae for the same time interval).  
7.5. Pharmacodynamics 
7.5.1. Renal Injury Biomarkers   
Urine samples (2 mL) for early markers of renal injury (KIM-1 and clusterin) will be collected 
at the timepoints specified in Section 7.1 and in Table 1. 
Processing and storage of the samples are detailed in the lab manual provided by the Sponsor. 
 
7.5.2. Potential Read-Through of Housekeeping Protein  
Blood samples (2 x 8 mL) for determination of ELX-02 effect on housekeeping proteins will 
be taken at the timepoints specified in Section 7.1 and in Table 1.  
Processing and storage of the samples are detailed in the laboratory manual provided by the 
Sponsor. 
The tubes will be pre-identified with details as follows: 
 Study Number 
 Time Point 
 Sample type (peripheral blood mononuclear cells; PBMC) 
The study staff will complete the following details: 
 Randomization Number 
 Actual date and time of sampling 


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Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to perform 
the test. In these cases, the Investigator will take all steps necessary to ensure the safety and 
well-being of the subject. When a protocol-required test cannot be performed, the Investigator 
will document the reason for this and any corrective and preventive actions that he or she has 
taken to ensure that normal processes are adhered to as soon as possible. The study team will 
be informed of these incidents in a timely fashion. 
7.6. Mitochondrial Mutations Testing 
Blood samples for determination of mitochondrial mutations testing will be taken using tubes 
containing K3EDTA at the timepoints specified in Section 7.1 and in Table 1. One back-up 
sample will be taken. The samples will be shipped ambient within 5 days to the Cidegen 
laboratory in Spain. 
Further details will be specified in a laboratory manual provided by the Sponsor. 
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events 
All observed or volunteered AEs regardless of treatment group suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.  
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
requiring immediate notification to Eloxx Pharmaceuticals or its designated representative. For 
all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE. The Investigator is required to assess causality. For events considered 
related to study drug. follow-up by the Investigator may be required until the event or its 
sequelae resolve or stabilize at a level acceptable to the Investigator, and Eloxx 
Pharmaceuticals concurs with that assessment. 
To assist in the determination of case seriousness, further information may be requested from 
the Investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period 
For SAEs, the active reporting period to Eloxx Pharmaceuticals or its designated representative 
begins from the time that the subject provides informed consent, which is obtained prior to the 
subject’s participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the Investigator becomes aware 
of them; at a minimum, all SAEs that the Investigator believes have at least a reasonable 
possibility of being related to investigational product are to be reported to the sponsor. 


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8.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
 Abnormal test findings; 
 Clinically significant symptoms and signs; 
 Changes in physical examination findings; 
 Hypersensitivity; 
 Drug abuse; 
 Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
 Drug overdose; 
 Drug withdrawal; 
 Drug misuse;  
 Drug interactions; 
 Extravasation; 
 Exposure during pregnancy (EDP); 
 Exposure via breastfeeding; 
 Medication error; 
 Occupational exposure. 
8.4. Adverse Events of Interest 
For this study, Adverse Events of Interest (AEOI) include the following: 
a. Hypersensitivity – graded based on CTCAE21.  
b. Nephrotoxicity – graded based on CTCAE21. Further criteria are described in 
Section 8.4.1. 
c. Ototoxicity – graded based on CTCAE21. Further criteria are described in 
Section 8.4.2. Note: For all adverse events of interest related to Ear and 
Labyrinth disorders, the adjudication committee will assess the grading. 


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Adverse events of interest need to be reported immediatelyto the Sponsor Medical 
Respresentative. The Sponsor will report adverse events of interest to the DSMB and AEOIs 
related to ototoxicity will be reported to the AVDSMB. 
An AEOI report must be completed and sent via fax or email within 24 hours of Investigator’s 
knowledge of the event to the study monitor and Sponsor's representative. 
In case the AEOI is classified as SAE, only the SAE report will be completed and sent to the 
CRO, preferably by fax or by e-mail. Contact information will be provided in a separate 
document. More details are provided in Section 8.21.2. 
8.4.1. Criteria for Nephrotoxicity 
Urine samples (2 mL) for early markers of renal injury (KIM-1 and clusterin) will be used for 
as early indicator. Creatinine will be evaluated for safety determination at specified time-points 
prior to and after study drug administration to detect potential renal injury.  
Grading of any nephrotoxic event shall be based on CTCAE21. 
8.4.2. Criteria for Ototoxicity  
Grading of ototoxicity will be done by the adjudication committee appointed to the study in 
accordance with the CTCAE criteria.  
Additional measures will be described in the Auditory and Vestibular Tests Manual. 
1. Tympanometry 
Abnormalities in tympanometry alone will not determine ototoxicity, but will be used to 
ascertain normal middle ear compliance and the presence of a conductive hearing loss that may 
make interpretation of testing impossible.  
2. Speech Reception Threshold: 
Speech reception threshold (SRT) will be used to determine the reliability of PTA 
measurements.  
3. Pure Tone Audiometry: 
Pure Tone Audiometry will be conducted across the conventional range of frequencies 
(250-8,000 Hz), as well as at high frequencies up to 16,000 Hz. Abnormalities consist of 
decreased responses in consecutive frequencies according to the CTCAE criteria. If there is a 
PTA threshold ≥15 dB for frequencies between 250-4000 Hz, bone conduction will be 
performed at that frequency. (Note: 15dB is within normal limits; bone conduction can only 
be performed at that frequency.) 
4. High Frequency Audiometry 
For high frequencies, a potentially ototoxic event is defined as audiometry testing resulting in 
a threshold shift of >25 dB averaged at 3 contiguous test frequencies in at least one ear. If 
ASHA significant change criteria are met (see below) high frequency audiometry should be 
repeated within 24 hours to confirm the results and the investigator should consult on ASHA 
significant change criteria with Eloxx Pharmaceuticals. 
5. Tinnitus questionnaire (Tinnitus Handicap Inventory). 


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If a subject has a score of a 5 point increase in THI score from baseline accompanied by a shift 
in Grade (eg from Grade 1 to Grade 2), the event will be discussed between the Investigator, 
the medically-qualified sponsor representative and the medically-qualified sponsor 
representative and the adjudication committee to determine if further auditory testing will be 
required. Any findings consistent with drug-induced toxicity leading to tinnitus on formal 
evaluation will be re-evaluated 3 months after initial exam and, if persistent, will be deemed 
permanent. 
6. Vestibular questionnaire (Dizziness Handicap). 
If a subject has a score of 31 or greater on the DHI accompanied by a 5 point increase from 
baseline and an associated shift in category (eg from mild to moderate handicap), the event 
will be discussed between the Investigator, the medically-qualified sponsor representative and 
the adjudication committee to determine if further vestibular testing will be required. Any 
findings consistent with drug-induced vestibular toxicity on formal evaluation will be re-
evaluated 3 months after initial exam and, if persistent, will be deemed permanent. 
For both the PTA and HFA: 
The Significant Change Criteria as defined by American Speech-Language-Hearing 
Association (ASHA) and American Academy of Audiology (AAA) will be used to trigger a 
review when the thresholds are worse by the following criteria: 
 ≥20 dB change at any frequency,  
 ≥10 dB change at any 2 adjacent frequencies, or  
 loss of response at 3 consecutive frequencies where responses were obtained at baseline.   
To be considered significant as an early warning for possible ototoxicity, changes showing a 
worsening meeting the above criteria must replicate 24 hours later with no indication of middle 
ear abnormality.  Subjects serve as their own controls for ototoxic change, which is computed 
relative to baseline measures. 
Abnormal tests should be repeated within 24 hours, preferably immediately (with the exception 
of the questionnaires). For all tests, the same equipment should be used for the screening and 
EOS, as well as any repeat test to minimize technical variability.If any of the tests meet the 
significant change criteria described above, this finding must be considered an ototoxic AE 
(“Adverse Event of Interest”), which must be reported immediately to the the Medical Monitor 
and the Sponsor. The Sponsor will update the DSMB and AVDSMB. 
We define reverse ASHA significant change criteria as an improvement, rather than a 
worsening by the same amount of change. Reverse ASHA significant change criteria will be 
used only as a measure of variability or possible learning effect as the subject becomes more 
experienced in the test procedures. 
All audiometric findings will be written on an auditory entry form and abnormal findings will 
be sent to the AVDSMB (consisting of a physician and audiologist) for review prior to each 
dosing (more details can be found in study administrative structure). The AVDSMB will 
decide if further dosing will occur, taking into account the stopping criteria (refer to Section 
3.2). 


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Grading of any ototoxic event shall be based on CTCAE21. Further details are provided in the 
Auditory and Vestibular Tests Manual. 
8.5. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength. Such 
medication errors occurring to a study participant are to be captured. In the event of medication 
dosing error, the sponsor should be notified immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
 Medication errors involving subject exposure to the investigational product; 
 Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating subject. 
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page. 
8.6. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
 Test result is associated with accompanying symptoms; and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
 Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or 
 Test result is considered to be an AE by the Investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.7. Serious Adverse Events 
A SAE is any untoward medical occurrence at any dose that: 
 Results in death; 
 Is life-threatening (immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 


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 Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions); 
 Results in congenital anomaly/birth defect. 
 Medical and scientific judgment is exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization. However, if it is determined 
that the event may jeopardize the subject or may require intervention to prevent one 
of the other AE outcomes, the important medical event should be reported as 
serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
A serious injury that can cause a serious deterioration in state of health can include: 
 a life-threatening illness, even if temporary in nature; 
 a permanent impairment of a body function or permanent damage to a body 
structure;  
 a condition necessitating medical or surgical intervention to prevent the above 2 
bulleted items 
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization; 
 any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use; 
 fetal distress, fetal death, or any congenital abnormality or birth defects. 
8.8. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
Hospitalization does not include the following: 
 Rehabilitation facilities; 
 Hospice facilities; 


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 Respite care (eg, caregiver relief); 
 Skilled nursing facilities; 
 Nursing homes; 
 Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE 
is not in itself an SAE. Examples include:  
 Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pretreatment laboratory abnormality); 
 Social admission (eg, subject has no place to sleep); 
 Administrative admission (eg, for yearly physical examination); 
 Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol); 
 Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
 Hospitalization for observation without a medical AE; 
 Preplanned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject; 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.9. Severity Assessment 
Severe assessment will be performed per categories specified in the CTCAE guidelines21.  
8.10. Causality Assessment 
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable. An Investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be provided. 
If the Investigator does not know whether or not the investigational product caused the event, 


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then the event will be handled as “related to investigational product” for reporting purposes, 
as defined by the sponsor. If the Investigator's causality assessment is "unknown but not related 
to investigational product," this should be clearly documented on study records.   
In addition, if the Investigator determines that a SAE is associated with study procedures, the 
Investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
Causality of each AE must be assessed according to the WHO-Uppsala Monitoring Center 
(UMC) system for standardized case causality assessment: 
Note: all the assessment criteria per causality should be reasonably complied to. 
Certain: 
 Event or laboratory test abnormality with plausible time relationship to drug intake; 
 Cannot be explained by disease or other drugs;  
 Response to withdrawal plausible (pharmacologically, pathologically);  
 Event definitive pharmacologically or phenomenologically (i.e., an objective and 
specific medical disorder or a recognized pharmacological phenomenon); 
 Rechallenge satisfactory, if necessary. 
Probable/Likely 
 Event or laboratory test abnormality with reasonable time relationship to drug intake;  
 Unlikely to be attributable to disease or other drugs;  
 Response to withdrawal clinically reasonable; 
 Rechallenge not required. 
Possible 
 Event or laboratory test abnormality with reasonable time relationship to drug intake; 
 Could also be explained by disease or other drugs; 
 Information on drug withdrawal may be lacking or is unclear. 
Unlikely 
 Event or laboratory test abnormality with a time to drug intake that makes a 
relationship improbable (but not impossible); 
 Disease or other drugs provide plausible explanations. 
Unrelated 
 It does not follow a reasonable temporal sequence from the administration of the test 
drug; 
 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 test drug. 
8.11. Action Taken Regarding the Study Drugs 
The action taken towards the study drugs must be described as follows: 




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2. An example of environmental exposure would be a case involving direct contact with 
a Eloxx Pharmaceuticals product in a pregnant woman (eg, a nurse reports that she is 
pregnant and has been exposed to chemotherapeutic products). 
3. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.  
If a study subject or study subject’s partner becomes or is found to be pregnant during the study 
subject’s treatment with the investigational product, the Investigator must submit this 
information to the CRO on a pregnancy form. In addition, the Investigator must submit 
information regarding environmental exposure product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage). This must be done irrespective of whether an AE has occurred and within 24 hours 
of awareness of the exposure. The information submitted should include the anticipated date 
of delivery (see below for information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome. The 
Investigator will follow the pregnancy until completion (or until pregnancy termination) and 
notify the CRO and Eloxx Pharmaceuticals of the outcome as a follow-up by forwarding the 
completed pregnancy form B. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless preprocedure test findings are conclusive 
for a congenital anomaly and the findings are reported). 
Follow-up is conducted to obtain general information on the pregnancy and its. The 
Investigator will follow the pregnancy until completion (or until pregnancy termination) and 
notify the CRO and Eloxx Pharmaceuticals of the outcome as a follow-up by forwarding the 
completed pregnancy form B. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless preprocedure test findings are conclusive 
for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
 Spontaneous abortion includes miscarriage and missed abortion; 
 Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the Investigator assesses the infant death as related or 
possibly related to exposure to the investigational product.  
Additional information regarding the exposure during pregnancy (EDP) may be requested by 
the Investigator. Further follow-up of birth outcomes will be handled on a case-by-case basis 


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(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the Investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner. The Investigator must document in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner. 
8.15. Follow-up of Adverse Events 
Subjects who have had an AE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are 
otherwise explained.  
Any newly emergent SAE within 30 days after early discontinuation or study completion, that 
is considered to be related to the test drug or study participation should be recorded and 
reported immediately. The post-study period for the purpose of SAE reporting is until the SAE 
is resolved or stabilized or maximum up to 30 days following last visit of the study. 
Unless decided otherwise, the study will terminate 30 days after last subject has attended the 
End-of Study visit. If additional follow-up of an AE is warranted, it will be documented in the 
as the subject' source data but will not be part of the CRF. The PI is required to report on any 
significant findings to the Sponsor. 
8.16. Independent Data and Safety Monitoring Board (DSMB) 
A DSMB for the study will be formed to review the safety information generated for each 
cohort' subjects upon their completion of all EOS assessments.  
The DSMB will be composed of four independent physicians specialized in relevant medical 
fields who will monitor general events. In addition, a separate Auditory and Vestibular DSMB 
composed of two ENT specialists will monitor and assess events which may be ototoxic in 
nature. The Sponsor's medically qualified representative and the Investigator and/or designee 
may attend the DSMB's open sessions but are not allowed to vote. 
The primary responsibility of the DSMB is to evaluate the safety data collected for all subjects 
in the recently completed cohort and the safe conduct of the study and provides the Sponsor 
with a report summarizing the conclusions of the meeting, and its recommendation whether to 
proceed to the next cohort or otherwise. The decision to proceed to a higher dose level will be 
made by the Sponsor after considering the DSMB's, the advice of the AVDSMB, and the PI’s 
recommendation following the safety assessments and based on the dose-escalation stopping 
rules (Section 3.2). 
Dose escalation will be permitted if the prior dose was well tolerated, if there were no safety 
or tolerability concerns. The next cohort will be dosed at least 14 days after the last dosing in 
the previous group. This window between cohort’s dosing can be extended in case the DSMB 
request for additional information to support its conclusion regarding the previous dose safety 
profile. 
DSMB working procedures will be described in a DSMB charter prior to enrolling the first 
subject. The DSMB will prepare a report of its recommendations and will forward it to the 
Sponsor. The Sponsor will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data that are not endpoints, to regulatory authorities, 
as appropriate. 


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8.17. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the Investigator site file. 
8.18. Withdrawal Due to Adverse Events (See Also the Section on 
Subject Withdrawal) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 
8.19. Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject. In addition, each study subject will be questioned about AEs. 
8.20. Recording of Adverse Events 
All (S)AEs occurring during the clinical investigation must be documented in the eSource 
System. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as “upper respiratory infection”). Investigators must record their opinion concerning the 
relationship of the (S)AE to the study drugs in the source documents and in the eSource 
System]. All measures required for (S)AE management must be recorded in the source 
documents and reported according to Sponsor’s instructions. 
All AEs occurring at any time during the study (including the follow-up period) will be 
followed by the Investigator until satisfactory resolution (e.g., value back to baseline value) or 
stabilization or until final database lock. If necessary, in order to obtain additional information 
to ensure safety to the subject, additional blood and urine samples may be taken at the 
discretion of the Investigator. Certain long-term AEs related to therapy cannot be followed 
until resolution within the setting of this study. In these cases follow-up will be the 
responsibility of the treating physician. 
8.21. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 


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8.21.1. Serious Adverse Event Reporting Requirements 
All SAEs independent of the circumstances or suspected cause must be reported on a SAE 
Form by the Investigator to: 
The CRO within 24h of their knowledge of the event, preferably by fax or by e-
mail. Contact information will be provided in a separate document. 
The SAE form should include a clearly written narrative describing signs, symptoms, and 
treatment of the event, diagnostic procedures, as well as any relevant laboratory data and any 
sequelae, in order to allow a complete medical assessment of the case and independent 
determination of the possible causality.  
Follow-up and outcomes should be reported for all subjects who experience an SAE. 
It is critical that the information provided on the SAE Form matches the information recorded 
in the source documents and in the eSource system for the same event. 
Copies of additional laboratory tests, consultation reports, postmortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and applicable. 
Follow-up reports relative to the subject’s subsequent course must be submitted to the CRO 
until the event has subsided or, in case of permanent impairment, until the condition stabilizes. 
If an SAE occurs, Eloxx Pharmaceuticals is to be notified within 24 hours of Investigator 
awareness of the event by the CRO.  
As noted in the Protocol-Specified SAE section, should an Investigator judge one of the 
identified protocol-specified SAEs to have a causal relationship with the investigational 
product, the event must be reported to the sponsor within 24 hours of Investigator awareness, 
even if that event is a component of the endpoint. 
In particular, if the SAE is fatal or life-threatening, notification to Eloxx Pharmaceuticals must 
be made immediately, irrespective of the extent of available AE information. This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.   
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the AE. 
8.21.2. Nonserious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for 
collection of SAE information is not the same as the AE CRF. Where the same data are 
collected, the forms must be completed in a consistent manner. For example, the same AE term 
should be used on both forms. AEs should be reported using concise medical terminology on 
the CRFs as well as on the form for collection of SAE information. 
8.21.3. Sponsor’s Reporting Requirements to Regulatory Authorities 
Adverse events reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations. 


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The CRO assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
the CRO will also report to the Investigator all SAEs that are unlisted (unexpected) and 
associated with the use of the drug. The Investigator (or the CRO where required) must report 
these events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol, unless otherwise required and documented by the 
IEC/IRB. 
Adverse events reporting, including SUSARs will be carried out in accordance with applicable 
local regulations. 
After termination of the clinical study (determined as LPLV), any unexpected safety issue that 
changes the risks benefit analysis and is likely to have an impact on the subjects who have 
participated in the study, together with proposed actions, will be reported by the Sponsor to 
the competent authority(ies) concerned as soon as possible. 
9. STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP). 
9.1. Sample Size Determination 
No formal sample size was estimated. The number of 9 subjects included in each dose group 
is deemed sufficient to respond to exploratory safety/tolerability and PK purposes. 
Statistical analyses will be performed using SAS® v9.2 or higher (SAS Institute, Cary NC, 
USA), PK parameters calculation will be performed using Phoenix 6.2 (Pharsite Corp., USA) 
or later. 
Descriptive statistics will be used to summarize demographics, baseline characteristics, and 
safety data. 
9.2. Pharmacokinetic Analysis 
Pharmacokinetic parameters of ELX-02 (Cmax, tmax, AUCt, AUC24h, AUC48h, AUC72h, AUCinf, 
t1/2, Vd/F, and CL/F, ) will be summarized by descriptive statistics by dose group and day of 
administration (sample size, mean, median, standard deviation, CV%, minimum and 
maximum, geometric mean and geometric CV%, when applicable). 
Steady-state achievement will be evaluated by visual inspection of predose (and 1h postdose) 
concentrations figures. 
For each of the PK parameters Cmax and AUCs, the dose linearity will be assessed using a 
power model, including the log-transformed PK parameters as dependent variables and the 
log-transformed dose, day and dose*day as fixed effects. The slope for log-transformed dose 
(ß) will be estimated with its 90% confidence interval to examine dose proportionality. The 
tmax will be compared between dose groups and days using the appropriate non-parametric 
tests. 
Plots of individual subject time-course profiles of ELX-02 after the administration will be 
presented by subject and day of administration in linear and semi-logarithmic scales. Figures 
enclosing all subjects for each dose and day of administration will be provided. Mean (SD) 
plasma concentrations obtained for each administration mode and drug dose will be plotted on 


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linear and semi-logarithmic scales. Through (predose and 1h postdose) figures will also be 
presented individually and as average. 
The following parameters will be calculated based on ELX-02 urine concentrations: urinary 
excretion (Ae) of ELX-02 (in mass and %dose - fe) for each collection interval, cumulated 
urinary excretion (in %dose) for each collection interval, total excretion (in %dose) and renal 
clearance (using the AUC and Ae for the same time interval). 
Actual sampling times will be used for PK analysis (when actual sampling times are not 
available, planned times will be used instead). 
PK analysis will be performed on the PK population (i.e. enrolled subjects, with analyzable 
PK data and without relevant deviation interfering with the PK evaluations). The PK 
parameters will be calculated with WinNonlin Phoenix 6.2 (or later) software using 
non-compartmental analysis method. 
Pharmacokinetic calculations will be based on individual subject plasma concentrations over 
time graphs. Samples with plasma concentrations below the LLOQ at early time-points will be 
set to as zero. Plasma concentrations below the LLOQ during the terminal phase will be 
omitted from the analysis. 
9.3. Safety Analysis 
Adverse events will be classified by system-organ classes and preferred terms and then 
summarized by number and percentage of volunteers experiencing AEs. 
Summary tables will be generated for Auditory and Vestibular assessment data. Degree of 
hearing loss, and any abnormalities detected in vestibular assessments will be summarized by 
treatment and time point.   
SRT, pure tone audiometry and tympanometry as measurements of auditory function and the 
ENT physical exam and vestibular assessments, in terms of absolute values and the changes 
from baseline will be summarized by treatment and time point with descriptive statistics. 
Questionnaire data will be summarized, but will not be used to determine study outcomes. 
9.4. Interim Analysis 
No interim analysis is planned for this study but interim blinded PK analyses are planned 
after each cohort.  


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10. ETHICS 
10.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB/EC. All correspondence with the 
IRB/EC should be retained in the Investigator file. Copies of IRB/EC approvals should be 
forwarded to Eloxx Pharmaceuticals. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/EC and Eloxx Pharmaceuticals in writing 
immediately after the implementation. 
An IRB/IEC should safeguard the rights, safety, and well-being of all study subjects. Special 
attention should be paid to studies that may include vulnerable subjects. 
Before the start of the study, the Investigator (or Sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents: 
- 
final protocol and, if applicable, amendments; 
- 
Sponsor-approved ICF (and any updates or any other written materials to be provided 
to the subjects); 
- 
Sponsor-approved subject recruiting materials; 
- 
Investigator Brochure (or equivalent information) and addenda; 
- 
available safety information; 
- 
information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 
- 
Investigator’s current curriculum vitae or other documentation evidencing 
qualifications (unless not required, as documented by the IEC/IRB); 
- 
information regarding funding, name of the Sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects; 
- 
any other documents that the IEC/IRB may require to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full written approval of the 
final protocol and amendments (if any), the ICF(s) and updates (if any), applicable recruiting 
materials, and any other written information to be provided to the subjects, and the Sponsor 
has received a copy of this approval. This approval letter must be dated and must clearly 
identify the IEC/IRB and the documents being approved. 
During the study, the Investigator (or Sponsor where required) will send the following 
documents and updates to the IEC/IRB for its review and approval, where appropriate:  
- 
protocol amendments; 
- 
revision(s) to the ICF and any other written materials to be provided to the subjects; 
- 
new or revised subject recruiting materials approved by the Sponsor; 


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- 
revisions to compensation for study-related injuries or payment to subjects for 
participation in the study; 
- 
Investigator’s Brochure addenda or new edition(s); 
- 
summaries of the status of the study at intervals stipulated in guidelines of the 
IEC/IRB (at least annually); 
- 
reports of AEs that are serious, unlisted, and associated with the IMP; 
- 
new information that may adversely affect the safety of the subjects or the conduct of 
the study; 
- 
deviations from or changes to the protocol to eliminate immediate hazards to the 
subjects; 
- 
report of death of any subjects under the Investigator’s care; 
- 
notification if a new Investigator is responsible for the study at the CPU; 
- 
Development Safety Update Report, Short-Term Study Specific Safety Summary and 
Line Listings, where applicable; 
- 
any other requirements of the IEC/IRB. 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s), except when necessary to eliminate immediate hazard to the study subjects. If a 
deviation from or a change to the protocol was implemented to eliminate an immediate hazard 
to study subjects, then the implemented deviation or change, the reasons for it, and, if 
appropriate, the protocol amendment should be submitted to the IEC/IRB as soon as possible. 
The Investigator (or Sponsor where required) will notify the IEC/IRB about the study 
completion within 90 days after the end of the study (LPLV). 
10.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 
2002), Guidelines for GCP (ICH 1996 and E6 R2 revisions), and the Declaration of Helsinki 
(World Medical Association).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified 
by the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae or other relevant documentation requested by the Sponsor, 
the IRB/IEC, or the regulatory authority(ies). 


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10.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. The use of Subject initials should be avoided. 
When study data are compiled for transfer to Eloxx Pharmaceuticals and other authorized 
parties, subject names, addresses, and other identifiable data will be replaced by a numerical 
code based on a numbering system provided by Eloxx Pharmaceuticals in order to de-identify 
study subjects. The study site will maintain a confidential list of subjects who participated in 
the study, linking each subject’s numerical code to his or her actual identity. In case of data 
transfer, Eloxx Pharmaceuticals will maintain high standards of confidentiality and protection 
of subjects’ personal data consistent with applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP E6 R2, local 
regulatory requirements, and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.   
Potential subjects will be fully informed of the nature of the study and of the risks and 
requirements of the study before any study-related assessment will be carried out. During the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be informed that their participation in the study is voluntary and that 
they may withdraw from the study at any time with no reason given and without penalty or 
loss of benefits to which they would otherwise be entitled. Only subjects who are fully able to 
understand the risks, benefits, and potential AEs of the study, and who provide their consent 
voluntarily will be enrolled in the study. 
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. The consent form that is used must be approved by both the Sponsor 
and the reviewing IEC/IRB.  
Finally, they will be told that the Investigator will maintain a subject identification register for 
the purposes of long-term follow-up if needed and that their records may be accessed by health 
authorities and authorized Sponsor staff without violating the confidentiality of the subject, to 
the extent permitted by the applicable law(s) or regulations. By signing the ICF the subject is 
authorizing such access, and agrees to allow his or her study physician to recontact the subject 
for the purpose of obtaining consent for additional safety evaluations, if needed. 
The language about the study used in the oral and written information, including the ICF, 
should be non-technical and practical and should be understandable to the subject (or the 
subject’s legally acceptable representative). The subject will be given sufficient time to read 
the ICF and the opportunity to ask questions. After this explanation and before entry into the 
study, consent should be appropriately recorded by means of the subject's personally dated 
signature. After having obtained consent, a copy of the ICF must be given to the subject. 
The collection and processing of personal data from subjects enrolled in the study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the study 
drug used in the study. 


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These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must 
be put in place. Sponsor personnel whose responsibilities require access to personal data need 
to agree to keep the identity of the study subjects confidential. 
The informed consent obtained from the subjects includes explicit consent for the processing 
of personal data and for the Investigator to allow direct access to subjects’ original medical 
records for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This 
consent also addresses the transfer of the data to other entities and to other countries. 
10.4. Subject Recruitment 
Advertisements approved by IRBs/ECs and Investigator databases may be used as recruitment 
procedures. 
Eloxx Pharmaceuticals will have an opportunity to review and approve the content of any study 
recruitment materials directed to potential study subjects before such materials are used.  
10.5. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Eloxx Pharmaceuticals should be informed immediately.   
In addition, the Investigator will inform Eloxx Pharmaceuticals immediately of any urgent 
safety measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that the Investigator 
becomes aware of. 


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11. ADMINISTRATIVE REQUIREMENTS 
11.1. Protocol Amendments 
Neither the Investigator nor the Sponsor will modify this protocol without a formal 
amendment. All protocol amendments must be issued by the Sponsor and signed and dated by 
the Investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval nor when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazard to the subjects, in which case an 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the Investigator and IEC/IRB must be provided to 
the Sponsor or his designee. When the change(s) involves only logistic or administrative 
aspects of the study, the IRB (and IEC where required) only needs to be notified. 
11.2. Subject Identification, Enrollment, and Screening Logs 
The Investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by 
the Sponsor site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed 
by the Investigator in the study file. To ensure subject confidentiality, no copies will be made. 
All reports and communications related to the study will identify subjects by initials and/or 
assigned number only. 
The Investigator must also complete a subject screening log which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
11.3. Source Documentation 
This study will utilize an electronic data capturing and information management system that 
will also serve as an eSource system for this study. The system combines all aspects of source 
data capturing with process control and clinical study management. All clinical and laboratory 
data, except those that are paper-based, will be collected directly in the system. The Source 
Document Identification Overview will specify which information will be eSource and which 
will be paper-based. The monitor will check data at the monitoring visits to the CPU. The 
Investigator will ensure that the data collected are accurate, complete, and legible. Data will 
be monitored within LabPas by the study monitor who has only reading rights. Any changes 
required following monitoring will be made by site personnel or the Investigator and will be 
documented with a full audit trail within the system. 
At a minimum, source documentation must be available for the following: subject 
identification, eligibility, and study identification; date of informed consent, dates of visits, 
results of safety and efficacy parameters as required by the protocol, record of all AEs, follow-
up of AEs, concomitant medication, drug receipt/dispensing/return records, study drug 
administration information, laboratory and ECG printouts (if not available digitally), date of 
study completion, and reason for early discontinuation of study drugs or withdrawal from the 
study, if applicable. 
It is recommended that the author of an entry in the (e)Source documents be identifiable. 


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Source data may be directly captured from devices, transferred from third parties (e.g., 
laboratory data), or entered manually into the eSource system in use at the CPU. In such case, 
the majority of the source data will only be available electronically. The remainder of the data, 
captured initially on paper, may be entered retrospectively into the eSource system. 
Following the ICH-GCP guidelines, direct access to (e)Source documentation (medical 
records) must be allowed. 
11.4. Case Report Form Completion 
All source data, except those that are paper-based, will be collected directly into the eSource 
system. Paper-based source data will be manually transcribed to the eSource system. Only the 
data required for the clinical database will be transferred electronically from the eSource 
system to the clinical database. 
11.5. Monitoring 
The monitoring of the study will be done under the responsibility of the Sponsor by the CRO. 
The monitor will perform on-site monitoring visits as frequently as necessary. The monitor 
will record the dates of the visits in a study site visit log that will be kept at the CPU. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data captured in the eSource system for completeness and 
accuracy and perform data source verification to any data that has been captured as paper 
source or entered in the system later on. The nature and location of all source documents will 
be identified to ensure that all sources of original data required to complete the eSource system 
are known to the Sponsor and clinical staff and are accessible for verification by the Sponsor 
site contact. If electronic records are maintained at the investigational site, the method of 
verification must be discussed with the clinical staff. 
Direct access to (e)Source documentation (medical records) must be allowed at all times for 
the purpose of verifying that the data recorded in the eSource system are consistent with the 
original (e)Source data. Findings from this review of the captured data will be discussed with 
the clinical staff. During on-site monitoring visits (notified and agreed upfront with the clinical 
staff), the relevant clinical staff will be available, the (e)Source documentation will be 
accessible, and a suitable environment for review of study-related documents will be provided. 
The monitor will meet with the Investigator on a regular basis during the study to provide 
feedback on the study conduct. 
11.6. Data Management 
Data management of the study will be performed under the responsibility of the Sponsor by 
the CRO. 
After the data entered in the eSource system are released by the Investigator, the data will be 
uploaded into the clinical database to perform cleaning activities. Computerized data cleaning 
checks will be used in addition to manual review, including listings review, to check for 
discrepancies and to ensure consistency and completeness of the data. Queries emerging during 
data cleaning will be generated by the clinical data manager in the eSource system. The 
Investigator or his designee will answer the queries and update the source data, if needed. 
The clinical database will be locked as soon as it is considered clean. Before the clinical 
database will be locked, the study eSource system will be locked by the clinical staff. Only 


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authorized and well-documented updates to the study data are possible after database lock. The 
locked database is used in the final statistical analysis for study reporting. Measures will be 
undertaken to protect subject data handed over by the Investigator to the data management 
department and during inspections against disclosure to unauthorized third parties. Subject 
confidentiality will be maintained at all times. 
11.7. Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study sites, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and by periodic monitoring visits by the Sponsor 
or designate. 
Written instructions will be provided for the collection, preparation, and shipment of plasma 
samples. The Sponsor or his designee will review the eSource system for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; any 
discrepancies will be resolved with the Investigator or designee, as appropriate. After upload 
of the data into the clinical study database, their accuracy verified using appropriate validation 
programs. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, the 
Sponsor will be entitled to audit the facilities used in the clinical and laboratory parts of the 
study, as well as to access all the data files pertaining to the study. Similar procedures may also 
be conducted by agents of any regulatory body, either as part of a national GCP compliance 
program or to review the results of this study in support of a regulatory submission. The 
Investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. 
11.8. On-Site Audits 
Representatives of the Sponsor’s clinical quality assurance department may visit the CPU at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eSource system. 
Subject privacy must, however, be respected. The Investigator and clinical staff are to be 
present and available for consultation during routinely scheduled site audit visits conducted by 
the Sponsor or his designee. 
Similar procedures may also be conducted by agents of any regulatory body, either as part of 
a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The Investigator should immediately notify the Sponsor if they have 
been contacted by a regulatory agency concerning an upcoming inspection. 
11.9. Study Termination 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Eloxx Pharmaceuticals. In addition, Eloxx Pharmaceuticals retains the right to 
discontinue development of the study drug at any time. 
If a study is prematurely terminated or discontinued, Eloxx Pharmaceuticals will promptly 
notify the Investigator. After notification, the Investigator must contact all participating 


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subjects and the site pharmacy within 15 days. As directed by Eloxx Pharmaceuticals, all study 
materials must be collected and the database must be completed to the greatest extent possible. 
In case of an early termination of the study for safety reasons, or temporary halt by the Sponsor, 
the IEC/IRB should be notified within 15 calendar days and should be provided with a detailed 
written explanation for the termination/halt. 
An end-of-study declaration will be submitted to the regulatory authorities and IEC/IRB after 
the complete study has ended. This notification will be submitted within 90 days after the end 
of the study. 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) 
by a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State. 
11.10. Record Retention 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all 
eSource and all paper source documents that support the data collected from each subject, as 
well as all study documents as specified in ICH/GCP Section 8, Essential Documents for the 
Conduct of a Clinical Trial, and all study documents as specified by the applicable regulatory 
requirement(s). The Investigator/Institution will take measures to prevent accidental or 
premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents will be retained 
for a longer period if required according to the applicable regulatory requirements or per 
agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator/Institution as to when these documents no longer need to be retained.  
If the responsible Investigator retires, relocates, or for any other reasons withdraws from his 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor must be notified in writing of the name and address of 
the new custodian. Under no circumstance shall the Investigator relocate or dispose of any 
study documents without having obtained written approval from the Sponsor. 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation related to the study, the Investigator must permit access to such reports. 
11.11. Use of Information and Publication 
11.11.1. Communication of Results by Eloxx Pharmaceuticals 
Eloxx Pharmaceuticals fulfills its commitment to publicly disclose clinical trial results through 
posting the results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European 
Clinical Trials Database (EudraCT), and other public registries in accordance with applicable 
local laws/regulations.  


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In all cases, study results are reported by Eloxx Pharmaceuticals in an objective, accurate, 
balanced, and complete manner and are reported regardless of the outcome of the study or the 
country in which the study was conducted. 
Primary completion date is defined as the date that the final subject was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated. 
The results of the study will be reported in a Clinical Study Report generated under the 
responsibility of the Sponsor. Recruitment performance or specific expertise related to the 
nature and the key assessment parameters of the study will be used to determine a coordinating 
Investigator. 
Clinical narratives may be written for the following events (for example): 
- 
All deaths (irrespective of drug relationship) 
- 
All other SAEs during treatment with the study drugs 
- 
All discontinuations of the study drugs due to AEs (irrespective of drug relationship) 
- 
At the discretion of the team and after statistical analysis of the data, certain 
discontinuations not related to AEs or treatment failure, i.e., related to lost to follow-
up or withdrawal of consent (irrespective of treatment group). 
- 
Any events of special interest explicitly requested by the regulatory agencies 
The coordinating/principal Investigator will sign off the final version of the Clinical Study 
Report. A summary of this final version will be provided to the Investigators, the applicable 
regulatory authorities, and the IECs/IRBs, if required by the applicable regulatory 
requirements, within 1 year after the end of the study (LPLV). 
EudraCT 
Eloxx Pharmaceuticals posts European (EU) Basic Results on EudraCT for all Eloxx 
Pharmaceuticals-sponsored interventional studies that are in scope of EU requirements. EU 
Basic Results are submitted for posting within 1 year of the primary completion date for studies 
in adult populations or within 6 months of the primary completion date for studies in pediatric 
populations. 
11.11.2. Publications by Investigators 
Eloxx Pharmaceuticals supports the exercise of academic freedom and has no objection to 
publication by the PI of the results of the study based on information collected or generated by 
the PI, whether or not the results are favorable to the Eloxx Pharmaceuticals product. However, 
to ensure against inadvertent disclosure of confidential information or unprotected inventions, 
the Investigator will provide Eloxx Pharmaceuticals an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed. 
The Investigator will provide any publication to Eloxx Pharmaceuticals at least 30 days before 
they are submitted for publication or otherwise disclosed.  If any patent action is required to 
protect intellectual property rights, the Investigator agrees to delay the disclosure for a period 
not to exceed an additional 60 days. 


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The Investigator will, on request, remove any previously undisclosed confidential information 
before disclosure, except for any study- or Eloxx Pharmaceuticals product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicenter study, the Investigator agrees that the first publication is to 
be a joint publication covering all study sites, and that any subsequent publications by the PI 
will reference that primary publication. However, if a joint manuscript has not been submitted 
for publication within 12 months of completion or termination of the study at all participating 
sites, the Investigator is free to publish separately, subject to the other requirements of this 
section. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the clinical study agreement (CSA) between 
Eloxx Pharmaceuticals and the institution.  In this section entitled Publications by 
Investigators, the defined terms shall have the meanings given to them in the CSA. 
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues. 
11.12. Registration of Clinical Studies and Disclosure of Results 
The Sponsor will register the existence of a clinical study and disclose its results as required 
by law. 
11.13. Confidentiality 
All study documents are provided by the Sponsor to the Investigator and appointed clinical 
staff in confidence. None of this material may be disclosed to any party not directly involved 
in the study without the Sponsor’s written permission. 
The Investigator must assure that subjects’ anonymity will be maintained. The Investigator 
will keep a separate list with at least the initials, the subjects’ study numbers, names, addresses, 
and telephone numbers. The Investigator will maintain this for the longest period of time 
allowed by his/her own institution and, in any case, until further communication from the 
Sponsor. 


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12. REFERENCES 
1. Moazd and Noller: Rapid chemical probing of conformation in 16 S ribosomal RNA 
and 30 S ribosomal subunits using primer extension, 1986, 187(3):399-416. 
2. Yoshizawa, Fourmy et al.: Structural origins of gentamicin antibiotic action, 1998, 
17(22):6437-48. 
3. Shalev, Rozenberg et al.: Structural basis for selective targeting of leishmanial 
ribosomes: aminoglycoside derivatives as promising therapeutics, 2015, 43(17): 8601–
8613. 
4. Begg and Barclay: A suggested approach to once-daily aminoglycoside dosing, 1995, 
39(6): 605–609. 
5. Rybak, Abate et al.: Prospective evaluation of the effect of an aminoglycoside dosing 
regimen on rates of observed nephrotoxicity and ototoxicity, 1999, 43(7):1549-55. 
6. Croes, Koop et al.: Efficacy, nephrotoxicity and ototoxicity of aminoglycosides, 
mathematically modelled for modelling-supported therapeutic drug monitoring, 2012, 
45(1-2):90-100. 
7. Garreau de Loubresse, Prokhorova et al.: Structural basis for the inhibition of the 
eukaryotic ribosome, 2014, 513(7519):517-22. 
8. Carter, Clemons et al.: Functional insights from the structure of the 30S ribosomal 
subunit and its interactions with antibiotics, 2000, 407(6802):340-8. 
9. Petry, Brodersen et al.: Crystal structures of the ribosome in complex with release 
factors RF1 and RF2 bound to a cognate stop codon, 2005, 123(7):1255-66. 
10. Kondo, Urzhumtsev et al.: Crystal structure of the Homo sapiens cytoplasmic 
ribosomal decoding site complexed with apramycin, 2006, 45(20):3310-4. 
11. Kandasamy J, Atia-Glikin D, Shulman E, Shapira K, Shavit M, Belakhov V, Baasov 
T: Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers 
improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy 
for treatment of genetic diseases caused by nonsense mutations. Journal of medicinal 
chemistry 2012, 55(23):10630-10643. 
12. Shalev and Baasov: When Proteins Start to Make Sense: Fine-tuning Aminoglycosides 
for PTC Suppression Therapy, 2014, 5(8):1092-1105. 
13. Mendell JT, Dietz HC: When the message goes awry: disease producing mutations that 
influence mRNA content and performance. Cell 2001, 107(4):411-414. 
14. Keeling K, Du M, Bedwell DM: Therapies of nonsense-associated diseases. In: 
Nonsense-Mediated mRNA Decay. edn. Edited by Maquat LE. Austin, TX: Landes 
Biosciences; 2006: 121-136. 
15. Hagberg B, Witt-Engerstrom I: Rett syndrome: epidemiology and nosology--progress 
in knowledge 1986--a conference communication. Brain & development 1987, 
9(5):451-457. 


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16. Neufeld EF, Muenzer J. The mucopolysaccharidosis. In: The metabolic and molecular 
bases of inherited disease. edn. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. 
New York: McGraw-Hill; 1995. 
17. Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL. Aminoglycoside 
antibiotics restore dystrophin function to skeletal muscles of mdx mice. The Journal of 
clinical investigation 1999, 104(4):375-381. 
18. Pettit RS. Cystic fibrosis transmembrane conductance regulator-modifying 
medications: the future of cystic fibrosis treatment. Ann Pharmacother 2012, 46(7-
8):1065-1075. 
19. Investigator’s Brochure, Edition June 2017. 
20. Eloxx Study EL-001: A Phase 1a, randomized, double-blinded, placebo-controlled, 
single dose escalation study to evaluate the safety, tolerability and pharmacokinetics 
of ELX-02 in healthy ADULT volunteers, 2016. 
21. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0' Published: 
May 28, 2009 (v 4.03: June 14, 2010), U.S. Department Of Health And Human 
Services,National Institutes of Health, National Cancer Institute. 
22. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. Food and Drug 
Administration, Center for Biologics Evaluation and Research, September 2007. 
 
 


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13. APPENDIX 
13.1. Site Reactions to Injections and Infusions DAIDS Grading Table 
Site Reactions to Injections and Infusions DAIDS Grading Table 
PARAMETER  
GRADE 1 MILD  
GRADE 2 MODERATE  
GRADE 3 SEVERE  
GRADE 4 
POTENTIALLY LIFE-
THREATENING  
Injection Site Pain or 
Tenderness  
Report only one  
Pain or tenderness causing 
no or minimal limitation of 
use of limb  
Pain or tenderness causing 
greater than minimal 
limitation of use of limb  
Pain or tenderness causing 
inability to perform usual 
social & functional 
activities  
Pain or tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization indicated  
Injection Site Erythema 
or Redness 
Report only one  
>15 years of age  
2.5 to < 5 cm in diameter 
OR 6.25 to < 25 cm2 
surface area AND 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities  
≥ 5 to < 10 cm in diameter 
OR ≥ 25 to < 100 cm2 
surface area OR Symptoms 
causing greater than 
minimal interference with 
usual social & functional 
activities  
≥ 10 cm in diameter OR ≥ 
100 cm2 surface area OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR 
Drainage OR Symptoms 
causing inability to perform 
usual social & functional 
activities  
Potentially life-threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or deeper 
tissue)  
Injection Site Induration 
or Swelling  
Report only one  
>15 years of age  
Same as for Injection Site 
Erythema or Redness 
Same as for Injection Site 
Erythema or Redness 
Same as for Injection Site 
Erythema or Redness  
Same as for Injection Site 
Erythema or Redness  
Injection Site Pruritus  
Itching localized to the 
injection site that is 
relieved spontaneously or 
in < 48 hours of treatment  
Itching beyond the 
injection site that is not 
generalized OR Itching 
localized to the injection 
site requiring ≥ 48 hours 
treatment  
Generalized itching 
causing inability to perform 
usual social & functional 
activities  
NA  


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13.2. Dizziness Handicap Inventory 
 
P1.  Does looking up increase your problem? 
o 
Yes 
o 
Sometimes 
o 
No 
E2.  Because of your problem, do you feel frustrated? 
o 
Yes 
o 
Sometimes 
o 
No 
F3.  Because of your problem, do you restrict your travel for business or recreation? 
o 
Yes 
o 
Sometimes 
o 
No 
P4.  Does walking down the aisle of a supermarket increase your problems? 
o 
Yes 
o 
Sometimes 
o 
No 
F5.  Because of your problem, do you have difficulty getting into or out of bed? 
o 
Yes 
o 
Sometimes 
o 
No 
F6.  Does your problem significantly restrict your participation in social activities, such as going 
out to dinner, going to the movies, dancing, or going to parties? 
o 
Yes 
o 
Sometimes 
o 
No 
F7.  Because of your problem, do you have difficulty reading? 
o 
Yes 
o 
Sometimes 
o 
No 
P8.  Does performing more ambitious activities such as sports, dancing, household chores 
(sweeping or putting dishes away) increase your problems? 
o 
Yes 
o 
Sometimes 
o 
No 
E9.  Because of your problem, are you afraid to leave your home without having 
someone accompany you? 
o 
Yes 
o 
Sometimes 
o 
No 
E10. Because of your problem have you been embarrassed in front of others? 
o 
Yes 
o 
Sometimes 
o 
No 
P11.  Do quick movements of your head increase your problem? 
o 
Yes 
o 
Sometimes 
o 
No 
F12.  Because of your problem, do you avoid heights? 
o 
Yes 
o 
Sometimes 
o 
No 
P13.  Does turning over in bed increase your problem? 
o 
Yes 
o 
Sometimes 
o 
No 
F14.  Because of your problem, is it difficult for you to do strenuous homework or yard work? 
o 
Yes 
o 
Sometimes 
o 
No 
E15.  Because of your problem, are you afraid people may think you are intoxicated? 
o 
Yes 
o 
Sometimes 
o 
No 
F16.  Because of your problem, is it difficult for you to go for a walk by yourself? 
o 
Yes 
o 
Sometimes 
o 
No 
P17.  Does walking down a sidewalk increase your problem? 
o 
Yes 
o 
Sometimes 
o 
No 
E18.Because of your problem, is it difficult for you to concentrate 
o 
Yes 
o 
Sometimes 
o 
No 


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F19. Because of your problem, is it difficult for you to walk around your house in the dark? 
o 
Yes 
o 
Sometimes 
o 
No 
E20. Because of your problem, are you afraid to stay home alone? 
o 
Yes 
o 
Sometimes 
o 
No 
E21. Because of your problem, do you feel handicapped? 
o 
Yes 
o 
Sometimes 
o 
No 
E22. Has the problem placed stress on your relationships with members of your family or 
friends? 
o 
Yes 
o 
Sometimes 
o 
No 
E23. Because of your problem, are you depressed? 
o 
Yes 
o 
Sometimes 
o 
No 
F24. Does your problem interfere with your job or household responsibilities? 
o 
Yes 
o 
Sometimes 
o 
No 
P25. Does bending over increase your problem? 
o 
Yes 
o 
Sometimes 
o 
No 
 
DHI Scoring Instructions 
The Subjects will be asked to answer each questions as it pertains to dizziness or unsteadiness problems, specifically
considering their condition during the last month. Questions are designed to incorporate functional (F), physical (P), and
emotional (E) impacts on disability. 
To each item, the following scores can be assigned:  
 
No=0  
 
Sometimes=2 
 
Yes=4  
Scores : 
 
>10 points should be referred to balance specialists for further evaluation. 
 
16-34 points (mild handicap) 
 
36-52 points (moderate handicap) 
 
54 + points (severe handicap) 
 
 






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13.4. Document History 
Summary of Changes: Protocol ELX-02 Dated 8 NOV 2018 to Protocol ELX-02 Dated 
26 February 2019 
Throughout, weight has been added to each time the subject checks into the clinic. 
Check in time to CPU of 7:30 AM has been deleted to accommodate the new CROs 
standards. 
Throughout, description of vital sign and ECG procedure has been clarified to indicate that 
the measurement should be taken after 5 minutes in the supine position. 
Throughout, a(n) highly effective method of contraception has been replaced with 2 highly 
effective methods of contraception. 
Throughout, gravity has been changed to specific gravity. 
Throughout, urine pregnancy test will be performed on all women, regardless of childbearing 
potential. 
Throughout, water consumption prior to dosing has been changed from 500 mL to at least 
500 mL to allow for flexibility. 
Throughout, one glass of water had been clarified to indicate that the volume will be 
approximately 250 mL. 
Throughout, SGS Life Sciences (SGS) has been replaced with “the CRO”, to reflect the 
change in the CRO.  
Phone and FAX numbers for the CRO have been replaced with “contact information will be 
provided in a separate document”, to reflect the change in the CRO. 
Additional minor modifications grammatical, punctuation, and wording modifications have 
been made to provide clarification. 
Section 
Used to Read 
Now Reads 
Rationale for 
Change 
Header 
Date changed 
8 NOV 2018 
26 FEB 2019 
Changed to reflect 
new version 
Title Page 
Investigator: To be 
determined 
Azra Hussaini, MD 
PAREXEL 
International 
Baltimore Early 
Phase Clinical Unit 
New investigator 
added from the US 


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Section 
Used to Read 
Now Reads 
Rationale for 
Change 
Medstar Harbor 
Hospital, 7th floor 
3001 South 
Hanover Street 
Baltimore, MD, 
21225 USA 
Signature of Sponsor 
Representative page 
Ajay Aggarwal, MD 
Greg Williams, 
PhD, Chief 
Operating Officer 
Change in 
personnel at Eloxx 
Signature of 
Investigator 
 
Azra Hussaini, MD  New US 
investigator added 
PROTOCOL 
SUMMARY 
Number of Subjects 
 
 
Up to 63 healthy adult 
subjects will participate in 
the study: 9 in each cohort 
randomized 2:1 to ELX-02 
and placebo. Both males and 
females need to be enrolled 
in each cohort, a significant 
number of female subjects 
need to be enrolled. 
Additional cohorts or 
subjects may be added to 
reaffirm safety of ELX-02.   
Up to 63 healthy 
adult subjects will 
participate in the 
study: 9 in each 
cohort randomized 
2:1 to ELX-02 and 
placebo. Both 
males and females 
need to be enrolled 
in each cohort, a 
significant number 
of female subjects 
need to be enrolled. 
Additional cohorts 
or subjects may be 
added to reaffirm 
safety of ELX-02.   
Changed to correct 
an error 
PROTOCOL 
SUMMARY and 4.1. 
Inclusion Criteria 
Inclusion Criteria #8 
Normal renal function 
(glomular filtration rate >60 
mL/min) based on creatinine 
plasma concentration and the 
Modification of Diet in 
Renal Disease (MDRD) 
equation for estimated 
glomular filtration rate. 
Normal renal 
function 
(glomerular 
filtration rate >60 
mL/min/1.73m2) 
based on creatinine 
plasma 
concentration and 
the Modification of 
Diet in Renal 
Disease (MDRD) 
equation for 
estimated 
glomerular 
filtration rate. 
Correction of 
error, spelling of 
glomerular 
corrected, units 
added 


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Change 
PROTOCOL 
SUMMARY and 4.1. 
Inclusion Criteria 
Inclusion Criteria #12 
Body Mass Index (BMI) of 
19.0 to 30 kg/m2 (inclusive); 
and a toal body weight of 
>50.0 kg (110 lbs) and 
<100.0 kg 
Body Mass Index 
(BMI) of 19.0 to 30 
32 kg/m2 
(inclusive); and a 
toal body weight of 
>50.0 kg (110 lbs) 
and <100.0 kg 
Changed to 
facilitate 
enrollment 
Table 1: Time and 
Events Schedule 
 
7. STUDY 
PROCEDURES 
Additional timepoints 
also added to this 
section 
Urine drugs of abuse 
 
Screening 
Day -1 
Day 28 
Urine drug screen 
Day -1, Day 7, Day 
14, Day 21, and Day 
28. 
(UDS) 
 
Screening 
Day -1 
Day 7 
Day 14 
Day 21 
Day 28 
Change in 
nomenclature 
 
Additional 
timepoints for 
assessment added 
Table 1: Time and 
Events Schedule 
PROTOCOL 
SUMMARY 
7. STUDY 
PROCEDURES 
Change in text also 
added to this section 
Alcohol breath test 
Serum alcohol test 
Day -1, Day 7, Day 
14, Day 21, and 
Day 28. 
 
Test changed at the 
request of the CRO 
Additional 
timepoints for 
assessment added 
Table 1: Time and 
Events Schedule 
Section 6.5.1. Female 
Subjects 
PROTOCOL 
SUMMARY 
7. STUDY 
PROCEDURES 
Change in text also 
added to this section 
Female subjects of non-child 
bearing potential must agree 
to undergo pregnancy test at 
screening. 
All Ffemale 
subjects of non
child bearing 
potential regardless 
of childbearing 
potential, must 
agree to undergo 
pregnancy test at 
screening, and on 
Day -1, Day 7, Day 
14, Day 21, Day 28 
and Day 36. 
Additional 
timepoints for 
assessment added 
 
Table 1: Time and 
Events Schedule 
Footnote i. 
Follow up testing will be 
performed at Day 3 (-1 day), 
Day 10 (-1 day), Day 17 (-1 
day), Day 24 (-1 day), and 
EOS (7-11 days after last 
dosing). 
Follow up testing 
will be performed 
at Day 3 (-1 day), 
Day 10 (-2 days), 
Day 17 (-2 days), 
Day 24 (-2 days), 
Windows changed 
to allow more 
flexibility for CRO 


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Change 
and EOS (7-11 days 
after last dosing). 
STUDY 
ADMINISTRATIVE 
STRUCTURE 
CLINICAL RESEARCH 
ORGANIZATION 
Information will be provided 
in a separate document 
CLINICAL LABORATORY 
ZNA Klinisch Laboratorium 
Campus Middelheim 
Lindendreef 1 
2020 Antwerpen 
Belgium 
EAR, NOSE, AND THROAT 
SPECIALIST 
Guy Cools, MD 
ZNA Department Ear, Nose, 
and Throat (ENT) 
Campus Middelheim 
Lindendreef 1 
2020 Antwerpen 
Belgium 
CLINICAL 
MONITORING 
SGS Life Sciences 
Project Manager: Marthe 
Heylen 
PHARMACOVIGILANCE 
SGS Life Sciences, Medical 
Affairs Department 
BIOMETRICS 
SGS Life Sciences 
Project Manager: Lisbet 
Reynders 
Biostatistician: Bastiaan 
Janssen 
Case Report Form (CRF) 
design, dta management, 
statistics and medical writing 
Section deleted 
Section deleted to 
reflect change in 
CRO, the 
information will be 
provided in a 
separate document 
4. SUBJECT 
SELECTION 
2nd sentence  
Both males and females need 
to be enrolled in each cohort, 
a significant number of 
female subjects need to be 
enrolled. 
Both males and 
females need to be 
enrolled in each 
cohort, a significant 
number of female 
subjects need to be 
enrolled. 
Changed to correct 
an error 


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Change 
4. SUBJECT 
SELECTION 
Section 4.11. 
Removal, 
Replacement or 
Early Withdrawal 
Item #4 
Positive urine drugs of abuse 
and/or alcohol breath test on 
admission to the CPU on 
Day -1. 
Positive urine drugs 
of abuse UDS 
and/or serum 
alcohol breath test 
on admission to the 
CPU on Day -1. If 
subjects have a 
positive UDS 
and/or serum 
alcohol test after 
Day -1, their 
continued 
participation will 
be re-evaluated on 
a case by case 
basis. 
Added to provide 
guidance due to 
the addition of 
drug/alcohol 
sceening tests. 
4. SUBJECT 
SELECTION 
Section 4.11. 
Removal, 
Replacement or 
Early Withdrawal 
Additional stipulation 
added 
 
11. Subjects may be 
replaced at the 
discretion of the 
Sponsor. 
Clarification added 
5. STUDY 
TREATMENTS 
5.4 Administration 
3rd paragraph, 1st 
sentence 
The drug will be 
administered as SC 
injection(s) to the abdominal 
region around the umbilicus 
or to any area with a 
significant subcutaneous 
adipose tissue (e.g. thigh), 
with a maximum of 4 
injections per dosing. 
The drug will be 
administered as SC 
injection(s) to the 
abdominal region 
around the 
umbilicus or to any 
area with a 
significant 
subcutaneous 
adipose tissue (e.g. 
thigh), with a 
maximum of 4 
injections per 
dosing. 
Clarified to 
correctly describe 
dosing options 
6. STUDY 
RESTRICTIONS 
6.3 Meals and 
Dietary Restrictions 
 
- Subjects will 
abstain from 
smoking for 6 
months prior to the 
first screening visit 
until 48h after the 
 


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Change 
Two bullet points have 
been added 
last study drug 
administration. 
- Subjects will 
abstain from illicit 
drug use from the 
first screening visit 
until 48h after the 
last study drug 
administration. 
6. STUDY 
RESTRICTIONS 
6.5.1. Female 
Subjects 
 
All other female subjects 
(including females with tubal 
ligations) will be considered 
to be of childbearing 
potential and must use 1 
highly effective…. 
Unless willing to 
abstain from 
sexual intercourse 
for 14 days prior to 
the first study drug 
administration and 
for 28 days after 
the last dose, 2 1 
highly effective…. 
Modified to 
correct 
inconsistancies 
between sections 
of the protocol 
Abstention has 
been deleted as a 
method of highly 
effective birth 
control due to 
rewording 
6. STUDY 
RESTRICTIONS 
6.5.2. Male Subjects 
New sentence added 
 
Unless they are 
abstaining from 
sexual intercourse 
for 14 days days 
prior to the first 
study drug 
administration and 
for 28 days after 
the last dose…  
Modified to 
correct 
inconsistancies 
between sections 
of the protocol 
Abstention has 
been deleted as a 
method of highly 
effective birth 
control due to 
rewording 
7. STUDY 
PROCEDURES 
7.4.2. Urine Collection 
2nd bullet, 2nd sentence 
AND  
7th bullet, 2nd sentence 
Each sample’s weight will be 
recorded individually prior 
to removing urine for 
analyses cfr. the Time and 
Event Schedule (i.e., 
urinalysis, PK, biomarker, 
and creatinine) 
Each sample’s 
weight will be 
recorded 
individually prior to 
removing urine for 
analyses cfr. the 
Time and Event 
Schedule (i.e., 
urinalysis, PK, 
biomarker, and 
creatinine) 
Deleted to correct 
typographical error 
 


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Original protocol 
Final dated 26 June 2017 
Not applicable (N/A) 
Revised protocol  
Revised final, dated 18 July 
2017 
Following recommendations of the local (Belgian) 
health authorities the following tests/actions were 
added to the previous version of the protocol: 
a. Additional audiometric tests will be 
performed on days before dosing i.e., Day 3 
(-1 day), Day 7 (-1 day), Day 10 (-1 day), 
Day 14 (-1 day), Day 17 (-1 day), Day 21 (- 
day), Day 24 (-1 day), and Day 28 (-1 day). 
b. The audiologist who will perform the 
audiometric tests will write his/her findings 
on an auditory entry form and send 
abnormal results to the adjudication 
committee (consisting of a physician and 
audiologist). The adjudication committee 
will decide if further dosing will occur, 
taken into account the stopping criteria. 
c. The data safety meeting board (DSMB) will 
meet after each cohort and will follow the 
recommendations 
of 
the 
adjudication 
committee. 
Vestibular questionnaires will not be performed on 
Day 15 due to the additional audiometric tests on Day 
14. 
Revised protocol, 
25 Aug 2017 
Revised final, dated 
25 Aug 2017 
Additional urine samples for creatinine safety 
evaluation will be taken at the following timepoints: 
Screening, Day -1, Day 1; 12h postdose, Day 2; 24h 
and 36h postdose, Day 3, Day 4, Day 8, Day 11, 
Day 15, Day 18, Day 22, Day 25, Day 28, Day 29; 12h 
postdose, Day 30; 24h and 36h postdose, Day 31, and 
Day 36 (same urine sampling timepoints as for the 
renal injury biomarkers). The predose urine samples for 
creatinine safety at Day 1 and Day 29 will remain.  
The vital signs at screening will be assessed supine 
following at least 5 min of supine rest instead of after 
standing for 3 min. During the treatment period the VS 
will be assessed following at least 5 min of supine rest 
as well.  
Revised protocol, 
27 Sep 2017 
Revised protocol, 
27 Sep 2017 
Changes to the previous version: 


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 Respiratory rate was added as a vital sign that 
needs to be measured. 
 The amount of blood taken for the analysis of 
the housekeeping proteins per timepoint has 
been changed from ‘2 mL’ to ‘2 x 8mL’. 
 Blood 
samples 
for 
determination 
of 
mitochondrial mutations testing will be taken 
using 2.7 mL tubes (instead of 2.5 mL tubes) 
containing K3EDTA. 
 The total volume of blood that will be drawn 
from each subject has been changed from 
approximately 160 mL for female and 155 mL 
for male subjects into 547 mL for female and 
542 mL for male subjects.  
 Section 7.3.9: the following information was 
added: 
All blood samples for retention need to be taken 
after an overnight fast of at least 8h, except for 
the samples taken at 3h postdose on Day 1 and 
Day 29. Processing and storage of the samples 
are detailed in the laboratory manual provided 
by the Sponsor. 
All blood samples for safety assessments 
should be taken after an overnight fast of at least 
8h, except for the samples taken at 6h postdose 
on Day 1 and Day 29. 
 Section 7.4.2 has been adapted (bold text has 
been added, strike through has been deleted): 
₋ 
Day 1: Predose collection (first void in the 
morning). Urine samples for PK, biomarker, 
and creatinine analysis will be collected. 
Gravity will be calculated for the collection. 
₋ 
Day 1 (0-12 hours postdose collection period): 
Subjects will be encouraged to void as 
frequently as possible (i.e. asked every hour if 
they can collect urine), and each individual 
sample will be collected separately. Each 
sample’s weight will be recorded individually 


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prior to removing urine for analyses cfr. the 
Time and Event Schedule (i.e., urinalysis, 
PK, biomarker, and creatinine). After 
weighing and removing urine for analyses, the 
collection container with remaining urine may 
be discarded. Gravity will be calculated for 
each sample collection. 
₋ 
Day 1: 12-24 hours postdose collection period. 
This urine collection period includes all voids 
starting after 12h and includes the first void on 
the next day (i.e., 24h postdose void).  
The urine will be collected every 6h (i.e., 12-
18h collection and 18-24h collection). The 12-
18h voids and the 18-24h voids All voids 
during this period will be collected into 
separate urine collection containers. In 
addition, a single urine collection will be 
taken 24h after dosing using a third 
container (i.e., first morning void of Day 
2).However, the single 24h void (i.e. first 
morning void of Day 2) will be collected in a 
separate container. All Both urine containers 
will be weighed individually and the sum of 
both weights will be recorded. Urine samples 
for urinalysis and biomarker analysis will be 
withdrawn from the single 24h urine collection. 
Urine samples for PK and creatinine analysis 
will be withdrawn from the pooled 12-18h and 
pooled 18-24h combined, mixed 12 24h urine 
collection 
containers. 
Gravity 
will 
be 
calculated for each sample collection. 
₋ 
Day 2 – Day 3: 24-48 hours postdose collection 
period. This urine collection period includes all 
voids subsequent to the 24h postdose void first 
morning void of Day 2 and includes the first 
void on the next day (i.e., 48 hours postdose 
void).  
The urine will be collected every 12h (i.e. 24-
36h collection and 36-48h collection). All 
voids during this period The 24-36h voids and 
the 36-48h voids will be collected into 
separate one urine collection containers. In 
addition, a single urine collection will be 


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taken 36 hours after dosing using a third 
container and a single urine collection will be 
taken 48 hours after dosing using a fourth 
container (i.e., the first morning void of Day 
3). However, the single 48h void (i.e., first 
morning void of Day 3) will be collected in a 
separate container. Both All urine containers 
will be weighed individually and the sum of 
both the weights will be recorded. Urine 
samples for urinalysis and biomarker analysis 
will be withdrawn from the single 48h urine 
void. Urine samples for biomarker analysis 
will be withdrawn from the single 36h and 
48h urine void. Urine samples for PK and 
creatinine analysis will be withdrawn from the 
combined, mixed pooled 24-36h and pooled 36-
48h urine collection containers. Gravity will be 
calculated for each collection sample. 
₋ 
Day 3 – Day 4: 48-72 hours postdose collection 
period. This urine collection period includes all 
voids subsequent to the 48h postdose void first 
morning void of Day 3 and includes the first 
void on the next day (i.e., 72 48 hours postdose 
void). All voids during this period will be 
collected into one urine collection container. 
During this collection period, subjects will be at 
home and collect the urine in urine jars 
(provided by the study site personnel). During 
this period, voids will be collected into a 
urine collection container. In addition, a 
single urine collection will be taken 72 hours 
after dosing using a second container (i.e., 
the first morning void of Day 4). Urine 
samples for biomarker analysis will be 
withdrawn from the single 72h urine void. 
Urine samples for PK and creatinine analysis 
will be withdrawn from the pooled 48-72h 
urine collection container. Gravity will be 
calculated for each collection sample. 
₋ 
Day 29: Predose collection (first void in the 
morning). Urine samples for PK, biomarker, 
and creatinine analysis will be collected. 
Gravity will be calculated for the collection. 


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₋ 
Day 29 (0-12 hours postdose collection period): 
Subjects will be encouraged to void as 
frequently as possible (i.e. asked every hour if 
they can collect urine), and each individual 
sample will be collected separately. Each 
sample’s weight will be recorded individually 
prior to removing urine for analyses cfr. the 
Time and Event Schedule (i.e., urinalysis, 
PK, biomarker, and creatinine). After 
weighing and removing urine for analyses, the 
collection container with remaining urine may 
be discarded. Gravity will be calculated for 
each sample collection. 
₋ 
Day 29: 12-24 hours postdose collection 
period. This urine collection period includes all 
voids starting after 12h and includes the first 
void on the next day (i.e., 24h postdose void).  
The urine will be collected every 6h (i.e., 12-
18h collection and 18-24h collection). The 12-
18h voids and the 18-24h voids All voids 
during this period will be collected into 
separate urine collection containers. In 
addition, a single urine collection will be 
taken 24h after dosing using a third 
container (i.e., first morning void of Day 
30).However, the single 24h void (i.e. first 
morning void of Day 2) will be collected in a 
separate container. All Both urine containers 
will be weighed individually and the sum of 
both weights will be recorded. Urine samples 
for urinalysis and biomarker analysis will be 
withdrawn from the single 24h urine collection. 
Urine samples for PK and creatinine analysis 
will be withdrawn from the pooled 12-18h and 
pooled 18-24h combined, mixed 12 24h urine 
collection 
containers. 
Gravity 
will 
be 
calculated for each sample collection. 
₋ 
Day 30 – Day 31: 24-48 hours postdose 
collection period. This urine collection period 
includes all voids subsequent to the 24h 
postdose void first morning void of Day 2 and 
includes the first void on the next day (i.e., 48 
hours postdose void).  


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The urine will be collected every 12h (i.e. 24-
36h collection and 36-48h collection). All 
voids during this period The 24-36h voids and 
the 36-48h voids will be collected into 
separate one urine collection containers. In 
addition, a single urine collection will be 
taken 36 hours after dosing using a third 
container and a single urine collection will be 
taken 48 hours after dosing using a fourth 
container (i.e., the first morning void of Day 
31). However, the single 48h void (i.e., first 
morning void of Day 3) will be collected in a 
separate container. Both All urine containers 
will be weighed individually and the sum of 
both the weights will be recorded. Urine 
samples for urinalysis and biomarker analysis 
will be withdrawn from the single 48h urine 
void. Urine samples for biomarker analysis 
will be withdrawn from the single 36h and 
48h urine void. Urine samples for PK and 
creatinine analysis will be withdrawn from the 
combined, mixed pooled 24-36h and pooled 36-
48h urine collection containers. Gravity will be 
calculated for each collection sample. 
₋ 
Day 31 – Day 32: 48-72 hours postdose 
collection period. This urine collection period 
includes all voids subsequent to the 48h 
postdose void first morning void of Day 3 and 
includes the first void on the next day (i.e., 72 
48 hours postdose void). All voids during this 
period will be collected into one urine 
collection container. During this collection 
period, subjects will be at home and collect the 
urine in urine jars (provided by the study site 
personnel). During this period, voids will be 
collected into a urine collection container. In 
addition, a single urine collection will be 
taken 72 hours after dosing using a second 
container (i.e., the first morning void of Day 
32). Urine samples for biomarker analysis 
will be withdrawn from the single 72h urine 
void. Urine samples for PK and creatinine 
analysis will be withdrawn from the pooled 


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48-72h urine collection container. Gravity 
will be calculated for each collection sample. 
Revised protocol 
23 Jan 2018 
Rationale for the amendment: 
During the conduct of the first cohort in this trial, 
audiological testing was performed at baseline, prior to 
each dose and at the end of the study. Bidirectional 
variability was observed inconsistent with ototoxicity, 
which can be attributed to the frequency of testing. 
After querying these results and reviewing them with 
the dedicated, independent, third-party Auditory and 
Vestibular Data Safety Monitoring Board (AVDSMB), 
Eloxx Pharmaceuticals believe that the frequency of 
testing subjects may be contributing to the variability 
by creating learning effects, burdening the site and 
subjects and reducing the careful attention needed for 
these listening tasks. 
 
The frequency of testing causes variability and does not 
safeguard the participating subjects.  Therefore, upon 
the recommendation of the AVDSMB, Eloxx 
Pharmaceuticals 
has 
reduced 
the 
number 
of 
audiological tests during the study to once weekly. 
 
Changes to the previous version (additions are marked 
in bold, deletions are Strikethrough): 
Auditory and vestibular assesments:  
 Addition of baseline ENT exam for eligible 
subjects (in addition to the screening visit to 
confirm eligibility). During the screening 
period subjects will undergo auditory and 
vestibular assessments to confirm eligibility 
(Day -42 to -8). In addition, a baseline exam 
(PTA and HFA will be duplicated) will be 
performed prior to initial dosing (within 7 days 
prior to dose). There must be a minimum of 24 
hours between the screening and baseline ENT 
exams 
 
 The SRT exam will be necessary at screening 
and bassline and for all other study SRT will be 


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performed only upon ASHA significant change 
criteria/ reverse ASHA significant change 
criteria observed in PTA/HFA. 
 Reducing the frequency of the follow up ENT 
at Day 3 (-1 day), Day 10 (-1 day), Day 17 (-1 
day), Day 24 (-1 day) and EOS (7-11 days after 
last dosing). 
 
 Inclusion criteria 11 was changed as follows: 
“No personal history (or current) or hereditary 
hearing loss, persistent tinnitus, persistent 
vertigo, 
persistent 
imbalance, 
persistent 
unsteadiness and no regular exposure to 
excessive noise (such as employment in a 
factory, music teacher, etc). 
 Exclusion creteria 4 was modifed as follows: 
“Presence of mitochondrial mutations making 
subject susceptible to aminoglycoside toxicity 
(A1555G, C1494T, T1095C, A827G, 1 BP 
DEL, 961T, C INS). 
 Exclusion creteria 6 was modifed as follows: 
Subjects with any abnormality at screening, that 
indicates the presence of a vestibular pathology, 
conductive hearing loss or balance problem (by 
an ENT). 
Subjects with audiometry abnormalities in the 
conventional frequencies (up to 8 kHz) results at 
screening as follows: any pure-tone threshold >55 
dB and/or inter-ear difference in any frequency of 
>20 dB. 
 
 Creatinine samples will be taken at all 
timepoints corresponding to renal injury 
biomarker collection. On days 1-4 and 29-
32, samples for renal injury biomarkers and 
creatinine will be taken from urine spot 
samples at 24hr, 36hr, 48hr and 72hr post 
dose. 
 


Protocol EL-002 
Revised Final 
Version: 29 May 2019 
 
ELOXX PHARMACEUTICALS  
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Document 
Version Date 
Summary of Changes and Rationale 
 Protocol Clarifications and Administrative 
changes were added to adjust study 
procedures and personnel changes 
 
 Urine protein and Albumin test were added 
to screening and EOS visits 
Revised Protocol 
15 May 2018 
 Following recommendations of the local 
(Belgium) Health Authorities, a cohort for 
administration of a 5.0 mg/kg dose could be 
implemented in this MAD study after 
satisfactory safety results were obtained for this 
dose in the SAD study. 
Results from the SAD study evaluating the 
ELX-02 5.0 mg/kg and 7.5 mg/kg SC doses 
were added to Section 1.2.2. Given the 
favorable safety profile of the doses, a dose 
cohort of 5.0 mg/kg was added to this MAD 
study. 
 Glomerular filtration rate was only meant to be 
an inclusion criterion and was carried through 
the protocol inadvertently. Use of the eGFR 
estimated by the MDRD equation to monitor 
acute changes in renal function in a normal 
population is not appropriate and not indicated 
because the MDRD equation applies only to 
subjects with a GFR below 60 ml/min, can 
never be used to assess acute renal changes, and 
depends on an equation that smooths out many 
critical parameters. We are measuring serum 
creatinines and KIM-1 and clusterin as 
parameters of renal function. 
Therefore, assessment eGFR estimated by the 
MDRD equation was removed from visits after 
the screening visit. 
 Sponsor address was changed. 
Revised Protocol 
24 September 2018 
 Injection site reactions (ISR) have been 
observed for all cohorts completed to date. The 
completed cohorts and number of ISR are as 
follows: 0.1 mg/kg (2 subjects with 2 ISR), 0.3 
mg/kg (7 subjects with 10 ISR), 1.0 mg/kg (5 
subjects with 41 ISR) and 2.5 mg/kg (7 subjects 


Protocol EL-002 
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Version: 29 May 2019 
 
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Version Date 
Summary of Changes and Rationale 
with 72 ISR). The 0.1 and 0.3 mg/kg cohort ISR 
were of short duration (maximum 2 weeks) 
compared to the 1.0 and 2.5 mg/kg cohorts 
(currently available data indicate ISR lasting up 
to 63 days). The events were generally mild, but 
the cumulative number of events in the 2.5 
mg/kg cohort limit tolerability. The 0.1 and 0.3 
mg/kg cohorts (50 mg/mL) were tolerated 
better then the 1.0 and 2.5 mg/kg doses 
(100mg/mL). In the 2.5 mg/kg cohort, one 
subject had a high frequency hearing change 
that met ASHA criteria. Therefore, an 
additional cohort of 2.5 mg/kg or 1 mg/kg at 
lower concentration (50 mg/mL instead of 100 
mg/mL) is proposed. Adjustment to further 
cohorts may also be proposed depending upon 
the outcome of the repeated cohort.  
 
 Additonal SC injection site locationa are being 
allowed (e.g. thigh)  to spread out the injection 
sites.  
 
 Allowance for screening and baseline ENT 
exams to be performed on the same day to 
minimize subject burden 
 
 
 
Section 
Used to Read 
Now Reads 
Rationale for Change 
Header 
Date changed 
24 SEPT 2018 
8 NOV 2018 
Changed to reflect new 
version 
Cover Page 
A Phase 1, Randomized, 
Double-Blinded, 
Placebo-Controlled, 
Third Party Open, 
Multiple Dose 
Escalation Study to 
Evaluate the Safety, 
Tolerability and 
Pharmacokinetics of 
Subcutaneously 
Administered ELX-02 in 
Independent 
A Phase 1, Randomized, 
Double-Blinded, 
Placebo-Controlled, 
Third Party Open, 
Multiple Dose 
Escalation Single Center 
Study to Evaluate the 
Safety, Tolerability and 
Pharmacokinetics of 
Subcutaneously 
Administered ELX-02 in 
Independent 
Protocol title has 
changed to reflect 
addition of new 
investigator, title has 
been changed 
throughout as 
appropriate 


Protocol EL-002 
Revised Final 
Version: 29 May 2019 
 
ELOXX PHARMACEUTICALS  
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Page 124 
Section 
Used to Read 
Now Reads 
Rationale for Change 
Consecutive Cohorts of 
Healthy Subjects 
Consecutive Cohorts of 
Healthy Subjects 
 
N/A 
US IND Number: 
137391 
US IND Number added 
to expand the study to 
the USA 
 
N/A 
To be determined, 
Investigator, USA 
New investigator to be 
added in the USA 
 
Except as otherwise 
agreed to in writing, by 
accepting or reviewing 
this document, you agree 
to hold this information 
in confidence and not 
copy or disclose it to 
others (except where 
required by applicable 
law, provided prompt 
written information) or 
use it for unauthorized 
purposes. 
Except as otherwise 
agreed to in writing, by 
accepting or reviewing 
this document, you agree 
to hold this information 
in confidence and not 
copy or disclose it to 
others (except where 
required by applicable 
law, provided prompt 
written notice is 
provided to Eloxx 
Pharmaceuticals and an 
opportunity to accord 
confidential treatment to 
the requested disclosable 
information) or use it for 
unauthorized purposes. 
Confidentiality 
statement updated 
Signature of Investigator, 
2nd paragraph 1st 
sentence, text added 
This study will be 
conducted according to 
Good Clinical Practice 
(GCP) and to all 
stipulations, clinically 
and administratively, as 
stated in the protocol, 
including all statements 
as to confidentiality. 
This study will be 
conducted according to 
Good Clinical Practice 
(GCP), local regulations 
and to all stipulations, 
clinically and 
administratively, as 
stated in the protocol, 
including all statements 
as to confidentiality. 
Text added to reflect 
addition of new 
investigator in a new 
venue 
3rd paragraph, 1st 
sentence, text added 
It is agreed that the 
protocol contains all 
necessary information 
required to conduct the 
study as outlined in the 
protocol, and that the 
study will not be 
initiated without the 
approval of the 
Independent Ethics 
Committee (IEC) and 
It is agreed that the 
protocol contains all 
necessary information 
required to conduct the 
study as outlined in the 
protocol, and that the 
study will not be 
initiated without the 
approval of the 
Independent Ethics 
Committee (IEC)/ 
Institutional Review 
Board (IRB) and the 
Text added to reflect 
regulations in a new 
venue 


Protocol EL-002 
Revised Final 
Version: 29 May 2019 
 
ELOXX PHARMACEUTICALS  
CONFIDENTIAL 
Page 125 
Section 
Used to Read 
Now Reads 
Rationale for Change 
the Belgian Ministry of 
Health/FDA. 
Belgian Ministry of 
Health/FDA local health 
authority. 
Additional Signature 
page added 
 
 
Added to accommodate 
new investigator 
PROTOCOL 
SUMMARY 
 
IND Number 137391 
IND Number added 
Number of Subjects 
1st sentence text added 
Up to 63 healthy adult 
subjects will participate 
in the study: 9 in each 
cohort randomized 2:1 to 
ELX-02 and placebo. 
Up to 63 healthy adult 
subjects will participate 
in the study and will be 
recruited at multiple 
clinical centers: 9 in 
each cohort randomized 
2:1 to ELX-02 and 
placebo. 
Clarification added due 
to addition of new 
investigator 
Statistical Methods 
Sentence added to end of 
section 
 
Aggregate study data 
will be analyzed from all 
the cohorts, regardless 
of site where cohort was 
conducted. 
Clarification to data 
pooling was added 
STUDY 
ADMINISTRATIVE 
STRUCTURE 
Sponsor Safety 
Representative: 
Sponsor Medical 
Director: 
Clarification of roles 
CLINICAL 
RESEARCH 
ORGANIZATION 
N/A 
CLINICAL CENTER 
USA 
Information to be added 
to reflect new 
investigator 
5. STUDY 
TREATMENTS 
5.1.2. Breaking the Blind 
3rd paragraph, sentence 
added 
N/A 
The Sponsor is permitted 
to request unblinding of 
any subject in 
association with adverse 
events.   
Added for clarification 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Protocol EL-002 
A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Third Party 
Open, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability 
and Pharmacokinetics of Subcutaneously Administered ELX-02 in 
Independent Consecutive Cohorts of Healthy Subjects 
 
 
Protocol Version and Date: 
Revised Final: 29 May 2019  
Name of Test Drug: 
ELX-02 
Developmental Phase of Study: 
Phase 1b 
Methodology: 
Randomized, Double-Blind, Placebo-Controlled, Third 
Party Open, Multiple Dose Escalation 
Sponsor: 
Eloxx Pharmaceuticals 
950 Winter Street 
Waltham, MA 02451 
Tel: +1 (781) 577-5300 
Analysis Plan Date: 
25 July 2019 
Analysis Plan Version: 
Final Version 1.0 
 
Confidentiality Statement 
 
The information contained herein is confidential and the proprietary property of 
Eloxx Pharmaceuticals and any unauthorized use or disclosure of such information 
without the prior written authorization of Eloxx Pharmaceuticals is expressly prohibited. 
 
 
 
 




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Statistical Analysis Plan, Protocol EL-002 
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TABLE OF CONTENTS 
 
1. 
Information from the Study Protocol ................................................................................ 9 
1.1. 
Introduction and Objectives .................................................................................. 9 
1.1.1. 
Introduction ........................................................................................... 9 
1.1.2. 
Study Objectives .................................................................................... 9 
1.1.3. 
Purpose of this Document ..................................................................... 9 
1.2. 
Study Design ....................................................................................................... 10 
1.2.1. 
Synopsis of Study Design .................................................................... 10 
1.2.2. 
Randomization Methodology .............................................................. 11 
1.2.3. 
Removal, Replacement or Early Withdrawal ...................................... 11 
1.2.4. 
Breaking the Blind .............................................................................. 12 
1.2.5. 
Study Procedures ................................................................................. 12 
1.2.6. 
Efficacy, Pharmacokinetic, and Safety Parameters ............................. 18 
1.2.6.1. Efficacy Parameters ................................................................ 18 
1.2.6.2. Pharmacokinetic Endpoints and Parameters ........................... 18 
1.2.6.3. Safety Endpoints and Parameters ........................................... 18 
2. 
Subject Population .......................................................................................................... 19 
2.1. 
Population Definitions ........................................................................................ 19 
2.2. 
Protocol Deviations ............................................................................................. 19 
3. 
General Statistical Methods ............................................................................................ 20 
3.1. 
Sample Size Justification .................................................................................... 20 
3.2. 
General Methods ................................................................................................. 20 
3.3. 
Computing Environment ..................................................................................... 20 
3.4. 
Baseline Definitions ............................................................................................ 20 
3.5. 
Methods of Pooling Data .................................................................................... 20 
3.6. 
Adjustments for Covariates ................................................................................. 21 
3.7. 
Multiple Comparisons/Multiplicity ..................................................................... 21 
3.8. 
Subpopulations ................................................................................................... 21 
3.9. 
Withdrawals, Dropouts, Lost to Follow-up ......................................................... 21 
3.10. 
Missing, Unused, and Spurious Data .................................................................. 21 
3.11. 
Visit Windows .................................................................................................... 21 
3.12. 
Interim Analyses ................................................................................................. 21 


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4. 
Study Analyses ................................................................................................................ 22 
4.1. 
Subject Disposition ............................................................................................. 22 
4.2. 
Demographics and Baseline Characteristics ....................................................... 22 
4.3. 
Pharmacokinetic Evaluations .............................................................................. 22 
4.3.1. 
PK Concentrations and Parameters ..................................................... 22 
4.3.1.1. Plasma PK Concentrations .................................................................. 22 
4.3.1.2. Plasma PK Parameters ......................................................................... 22 
4.3.1.3. Urine PK Concentrations ..................................................................... 24 
4.3.1.4. Urine PK Parameters ........................................................................... 24 
4.3.2. 
Dose Proportionality Assessment ........................................................ 24 
4.3.3. 
Pharmacokinetic Data Reporting ......................................................... 25 
4.4. 
Safety Analyses ................................................................................................... 26 
4.4.1. 
Study Drug Exposure .......................................................................... 27 
4.4.2. 
Adverse Events .................................................................................... 27 
4.4.3. 
Adverse Events of Interest and Injection Site Reactions ..................... 28 
4.4.4. 
Laboratory Data ................................................................................... 28 
4.4.5. 
Vital Signs and Physical Examination ................................................. 28 
4.4.6. 
Auditory and Vestibular Assessments ................................................. 29 
4.4.6.1. Otoscopy .............................................................................................. 29 
4.4.6.2. Pure Tone Audiometry and High Frequency Audiometry .................. 29 
4.4.6.3. Speech Reception Threshold ............................................................... 29 
4.4.6.4. Tympanometry .................................................................................... 30 
4.4.6.5. Tinnitus Handicap Inventory Questionnaire ....................................... 30 
4.4.6.6. Dizziness Handicap Inventory Questionnaire ..................................... 30 
4.4.7. 
Electrocardiogram ............................................................................... 31 
4.4.8. 
Renal Injury Biomarkers ..................................................................... 31 
4.4.9. 
Concomitant Medications .................................................................... 31 
5. 
Changes to Planned Analyses ......................................................................................... 32 
6. 
References ...................................................................................................................... 33 


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Statistical Analysis Plan, Protocol EL-002 
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TABLES INCLUDED IN THE TEXT 
Table 1 
 Schedule of Assessments ................................................................................... 13 


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Statistical Analysis Plan, Protocol EL-002 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
Ae 
Amount excreted 
Ae24h 
Amount excreted from time = 0 to 24 hours post-dose (also Ae48h, 
Ae72h, etc.) 
AEOI 
Adverse Events of Interest 
ASHA 
AUC 
American Speech-Language-Hearing Association 
Area under the concentration-time curve 
AUCt 
Area under the concentration-time curve calculated to the last non-
BLQ concentration 
AUC24h 
Area under the concentration-time curve calculated to 24 hours post-
dose (also AUC48h, AUC72h, etc.) 
AUCinf 
Area under the concentration-time curve extrapolated to infinity 
%AUCextrap 
Percent AUC extrapolated to infinity from last observer non-BLQ 
concentration. 
AVDSMB 
Auditory and Vestibular Data Safety Monitoring Board 
BLQ 
Below the Lower limit of Quantification 
C0h 
Plasma concentration at time = 0 h (predose) 
C1h 
Plasma concentration at time 1 hour 
CL/F 
Apparent plasma clearance, uncorrected for fraction absorbed 
CLR 
Apparent renal clearance 
Clast 
Last observed non-BLQ concentration 
Cmax 
Peak plasma concentration 
CPU 
Clinical Pharmacological Unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variance 


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Abbreviation 
Definition 
DAIDS 
dB HL 
DHI 
DLT 
DSMB 
ECG 
eCRF 
fe 
fe24h 
HFA 
ISR 
KIM-1 
λz 
MedDRA 
MTD 
PK 
PT 
PTA 
Rac(AUC) 
Rac(Cmax) 
Rmax 
SAE 
SAP 
Division of Acquired Immunodeficiency Syndrome 
Decibels in Hearing Level 
Dizziness Handicap Inventory 
Dose Limiting Toxicity 
Data Safety Monitoring Board 
Electrocardiogram 
Electronic Case Report Form 
Excreted fraction (fraction of administered dose excreted) 
Fraction of the dose excreted from time = 0 to 24 hours postdose 
(also fe48h, fe72h, etc.) 
High Frequency Audiometry 
Injection Site Reaction 
Kidney Injury Molecule-1 
Terminal elimination rate constant 
Medical Dictionary for Regulatory Affairs 
Maximum Tolerated Dose 
Pharmacokinetic 
Preferred Term 
Pure Tone Audiometry 
Accumulation ratio (by AUC) 
Accumulation ratio (by Cmax) 
Maximum amount excreted in a collection interval 
Serious Adverse Event 
Statistical Analysis Plan 


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Abbreviation 
Definition 
SC 
SD 
SOC 
SRT 
TEAE 
THI 
TLF 
tmax 
t½ 
tlast 
tRmax 
UDS 
Vd/F 
WHO 
Subcutaneous 
Standard Deviation 
System Organ Class 
Speech Reception Threshold 
Treatment-Emergent Adverse Event 
Tinnitus Handicap Inventory 
Tables, Listings, and Figures 
Time at which Cmax occurs 
Elimination half-life 
Time from dose when Clast occurs 
Time when maximum amount is excreted 
Urine Drug Screen 
Apparent volume of distribution, uncorrected for fraction absorbed 
World Health Organization 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
ELX-02, characterized as a eukaryotic ribosomal selective glycoside (ERSG), is a small 
molecule, new chemical entity being developed by Eloxx Pharmaceuticals for the treatment of 
genetic diseases caused by nonsense mutations. Nonsense mutations generating premature 
termination codons account for approximately one third of all genetic diseases. Nonsense 
mutations are a genetic mutation in a deoxyribonucleic acid (DNA) sequence that results in a 
shorter, unfinished protein product. Consequently, most nonsense mutations result in 
nonfunctional proteins (Mendell, 2001; Keeling, 2006). Examples of genetic diseases where 
nonsense mutations are part of their phenotype include Rett syndrome, Mucopolysaccharidosis 
type I (Hurler syndrome), Duchenne muscular dystrophy, and cystic fibrosis. 
Across a series of pharmacology studies, the translational read-through capabilities of ELX-02 
have been tested in in vitro cell models and in in vivo animal models. ELX-02 induced 
expression of functional proteins with pharmacodynamic and behavioral effects with a 
satisfactory window of safety in several cellular and animal models of genetic disease caused by 
nonsense mutations, including, cystic fibrosis (CF) and cystinosis. More information on ELX-02 
can be found in the Investigator’s Brochure. 
Eloxx Pharmaceuticals has completed two Phase 1a, single-center, randomized, double-blinded 
placebo-controlled single ascending dose studies in healthy human subjects. After single 
subcutaneous (SC) administration, ELX-02 was generally well tolerated at doses ranging from 
0.3 to 7.5 mg/kg without severe or serious drug-related adverse events (AEs). The mean terminal 
apparent half-life ranged between 2 and 8 hours. AUCinf showed dose linearity and Cmax 
approximate proportionality. 
This multicenter study was initiated to assess the safety, tolerability and pharmacokinetics (PK) 
of ELX-02 in healthy human subjects receiving multiple escalating doses (ranging from 0.1 to 
5.0 mg/kg) via SC injection(s) in a randomized, double-blinded, placebo-controlled design.  
1.1.2. 
Study Objectives 
The primary objectives of this study are: 
• To assess the safety and tolerability of multiple ascending SC administered doses of 
ELX-02 
• To study the PK of ELX-02 administered as multiple SC doses 
The secondary objectives of this study are: 
• To assess whether a maximum tolerated dose (MTD) is attained within the given dose 
range 
• To assess dose proportionality of exposure parameters (Cmax and AUC) 
1.1.3. 
Purpose of this Document 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 


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the clinical study report for this study. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a Phase 1, randomized, double-blind, placebo-controlled, third party open (i.e. 
pharmacist), multiple dose escalation study to evaluate the safety, tolerability and PK of SC 
administered ELX-02 in independent consecutive cohorts of healthy subjects. 
The investigational drug, ELX-02, is formulated as a solution for SC injection, containing 
200 mg/mL. The placebo control will consist of a SC injection of normal saline at matching 
volumes. 
The study is designed to include at least 5 cohorts of 9 subjects each, including both males and 
females. Subjects will be randomized to receive multiple doses of ELX-02 or placebo at a ratio 
of 2:1 in each cohort; 6 subjects will receive ELX-02 and 3 will receive placebo for a total of up 
to 63 subjects. Study drug will be administered SC twice a week for 9 doses and dose levels 
planned in the protocol for each cohort are described below: 
• Cohort 1: ELX-02 0.1 mg/kg or placebo 
• Cohort 2: ELX-02 0.3 mg/kg or placebo 
• Cohort 3: ELX-02 1.0 mg/kg or placebo 
• Cohort 4: ELX-02 2.5 mg/kg or placebo 
• Cohort 5: ELX-02 up to 2.5 mg/kg or placebo 
• Cohort 6: ELX-02 2.5 to 5.0 mg/kg or placebo 
• Cohort 7: ELX-02 up to 5.0 mg/kg or placebo 
Dose escalation to the next cohort will not be performed until 14 days after the last subject’s last 
dose in the previous cohort, to allow for detection of unanticipated delayed AEs. 
The decision to proceed to a higher dose level will be following the recommendations of both the 
general Data Safety Monitoring Board (DSMB) and the Auditory and Vestibular Data Safety 
Monitoring Board (AVDSMB) based on the dose-escalation stopping rules. The DSMB and 
AVDSMB recommendation to proceed to a higher dose will be based on review of the blinded 
safety data, any available blinded PK data, and the results of audiologic tests and questionnaires. 
The next cohort will be dosed after the DSMB and AVDSMB have evaluated the available data 
and have recommended to escalate. 
The principles of dose escalation, determination of dose limiting toxicity (DLT) and MTD, are 
detailed in Protocol Section 3.2.  
Study duration will be approximately 12 weeks for each subject including a screening period of 
up to 6 weeks, treatment period of 4 weeks, and 2 weeks for final safety follow-up. Subjects will 
receive in-patient treatment in the Clinical Pharmacological Unit (CPU) for approximately 8 
days throughout the treatment period. 
At the time this SAP was written, five doses have been investigated and two of the dose levels 
involved two different dilution schemes (different concentrations being injected), for a total of 


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seven cohorts. The final doses (ELX-02 injection solutions) administered in the study are 
summarized below: 
• Cohort 1: ELX-02 0.1 mg/kg (50 mg/mL) or placebo 
• Cohort 2: ELX-02 0.3 mg/kg (50 mg/mL) or placebo 
• Cohort 3: ELX-02 1.0 mg/kg (100 mg/mL) or placebo 
• Cohort 4: ELX-02 2.5 mg/kg (100 mg/mL) or placebo 
• Cohort 5: ELX-02 1.0 mg/kg (50 mg/mL) or placebo 
• Cohort 6: ELX-02 2.5 mg/kg (50 mg/mL) or placebo 
• Cohort 7: ELX-02 5.0 mg/kg (50 mg/mL) or placebo. 
1.2.2. 
Randomization Methodology 
Subjects who complete the study screening assessments and meet all eligibility criteria will be 
randomly assigned to receive either ELX-02 or placebo in a 2:1 ratio within each cohort. Within 
each cohort, up to 6 subjects will be randomized to receive ELX-02 and up to 3 subjects will be 
randomized to receive placebo for a total of up to 63 subjects. Treatment arm codes will be 
generated using a permuted block design. Each block will assign a 2:1 random allocation of 
ELX-02 or placebo using SAS® software. Each eligible subject will be assigned a unique on-
study identification number. Two separate randomization schedules were created, one by SGS 
for Cohorts 1-6 and the other by Parexel for Cohort 7, as two separate EDC databases were 
created and used by these two vendors. 
1.2.3. 
Removal, Replacement or Early Withdrawal 
The Sponsor reserves the right to prematurely discontinue the study at any time for any reason. 
Subjects are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any subject from the study if that subject 
requests to be withdrawn, or if it is determined that continuing in the study would result in a 
safety risk to the subject. Subjects discontinued or withdrawn from the study after receiving ≤6 
doses may be replaced upon request from the Sponsor. The subject's participation in this study 
may be discontinued due to the following reasons: 
• Request by regulatory agency, Sponsor, primary care physician or Investigator 
• Subject withdraws consent 
• Female subject is pregnant 
• Positive Urine Drug Screen (UDS) and/or serum alcohol test on admission to the CPU on 
Day -1. If subjects have a positive UDS and/or serum alcohol test after Day -1, their 
continued participation will be re-evaluated on a case by case basis 
• AE or Serious Adverse Event (SAE) meeting criteria for drug-related event and meeting 
stopping criteria described in Protocol Section 3.2. 
• Subject is unwilling or unable to continue the study or is lost-to-follow-up 
• Subject is non-compliant with study procedures/study protocol 
• Investigator decides that withdrawal from the study is in the best interest of the subject 
• Subject needs medication not allowed in the protocol 


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• Any clinically significant change in subject’s medical condition 
• Subjects may be replaced at the discretion of the Sponsor 
1.2.4. 
Breaking the Blind 
Breaking the blind is expressly forbidden except in the event of a medical emergency where the 
identity of the study drug must be known in order to properly treat the subject. If breaking the 
blind is required because of a medical emergency, the treatment identity for the unblinded 
subject will only be revealed by the qualified designee with approval from the Sponsor’s Medical 
Monitor or designee. Subjects who are unblinded for any reason during their participation in the 
study will not be replaced and will be withdrawn immediately from the study. 
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered into the database, edits checks are performed, queries closed, 
electronic case report forms (eCRFs) signed by the principal investigator, and the database is 
officially locked. 
The bioanalytical scientists and pharmacokineticists will be unblinded to treatment arm prior to 
database lock by having access to individual subject ELX-02 concentration data. The blind will 
be maintained to the clinical study team by transmitting only blinded PK summary tables and 
figures to the DSMB and the AVDSMB, and therefore there is no possibility of revealing 
individual subject treatment assignment. 
1.2.5. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 


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Statistical Analysis Plan, Protocol EL-002 
25 July 2019, Final Version 1.0 
13  
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Table 1 
 
Schedule of Assessments 
Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics 
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI) 
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Screen  
Day -42 
to -2  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
Xi 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Day -1 
 
 
 
 
X 
X 
 
 
X 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
Day 1 
-180 
min 
 
 
 
X 
Xc 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
15 min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
0 
- 
1 
2 
h 
 
 
 
 
 
 
 
X 
30 min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
45 min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
1h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
3h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
6h 
 
 
 
 
 
 
 
X 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
12h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
1 
2 
- 
2 
4 
h 
X 
 
X 
X 
 
 
 
X 


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Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics 
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI) 
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Day 2 
24h 
 
 
 
 
 
 
X 
 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
2 
4 
- 
4 
8 
h 
X 
 
X 
X 
 
X 
 
X 
36h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
Day 3 
 
 
 
 
 
X 
 
X 
X 
Xq 
X 
 
 
 
 
 
X 
Xp Xp 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
Day 4 
 
 
 
 
 
Xc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
4 
8 
- 
7 
2 
h 
X 
X 
X 
X 
 
 
 
X 
Day 7 
 
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Day 8 
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Day 10 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Day 11 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
Day 14 
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Day 15 
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Day 17 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Day 18 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Day 21 
 
 
 
 
X 
 
 
 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Day 22 
 
 
 
 
Xc 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 


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Statistical Analysis Plan, Protocol EL-002 
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Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics 
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI) 
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
Day 24 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xp Xp 
 
X 
 
 
 
 
 
 
 
 
 
 
Day 25 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Day 28 
 
 
 
 
 
X 
 
X 
X 
Xq 
X 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
Day 29 
-180 
min 
 
 
 
 
Xc 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
15| 
min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
0 
- 
1 
2 
h 
 
 
 
 
 
 
 
X 
30 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
45 
min 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
1 h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
3h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
6h 
 
 
 
 
 
 
 
X 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
12h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
1 
2 
- 
2 
4 
h 
X 
 
X 
X 
 
 
 
X 
Day 30 
24h 
 
 
 
 
 
 
X 
 
Xq 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 


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Statistical Analysis Plan, Protocol EL-002 
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Day in 
Study 
Hours Postdose 
Informed consenta 
Demographics 
Medical historyb 
Inclusion/exclusion criteria 
Weight 
Height, body mass index 
Vital signsd 
Physical examinatione 
Blood safety lab testsf 
General urinalysis 
HIV, HbsAg, HCVAb 
Blood pregnancy + FSH (females) 
Urine pregnancy (females)g 
Urine drug screen (UDS) 
Serum alcohol test 
12-lead ECGh 
Audiometric testingi 
Vestibular Questionnaires (DHI, THI) 
Confinement to CPUj 
Discharge from CPU (2 hr after administration) 
Blood PKk 
Urine collection for PKl 
Urine collection for creatinine m 
Dosingn 
Local reaction of injection site 
Urine for renal injury biomarkersm 
Blood samples for retentiono 
Blood for housekeeping proteins 
Sample for mitochondrial mutations testing 
AE and CM monitoring 
 
36h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
2 
4 
- 
4 
8 
h 
X 
 
 
X 
 
 
 
X 
Day 31 
 
 
48h 
X 
X 
Xq 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Day 32 
 
 
72h 
 
 
 
 
 
 
 
 
 
 
X 
4 
8 
- 
7 
2 
h 
X 
 
X 
 
 
Day 36 
X 
X 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE: Adverse event, CM: Concomitant therapy, HIV: Human Immunodeficiency Virus, HbsAg: Hepatitis B surface antigen, HCVAb: Hepatitis C virus antibody, CPU: Clinical 
Pharmacological Unit, DHI: Dizziness Handicap Inventory, THI: Tinnitis Handicap Inventory. 
a  Informed consent to be provided before any study-related assessment. 
b  Including hearing and balance disorders. 
c  Weight only to be taken if not already done the previous day. 
d  Vital signs include heart rate (HR), blood pressure (BP), respiratory rate (RR), and oral body temperature. Vital parameters will be assessed in supine position after at least 5 min. supine 
rest. 
e  A complete physical examination is to be performed at all timepoints except for the 6h postdose assessment on Day 1 and Day 29 when a brief examination is to be performed. 
f  Biochemistry, hematology, and coagulation. All blood samples for safety assessments should be taken after an overnight fast of at least 8h, except for the sample taken at 6h postdose on 
Day 1 and Day 29. At screening, subjects will be instructed not to eat within 3h before arrival at the CPU. 
g  Urine pregnancy tests only to be performed for women regardless of childbearing potential. 
h  A single 12-lead ECG will be taken providing QT, QTc, HR, QRS, and PR after 5 minutes supine. 
i  Subjects will be scheduled for audiometric and vestibular tests preceded by an ENT physical exam in a specialized department. The auditory and vestibular testing will be performed at 


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Screening (to confirm eligibility), and prior to initial dosing to determine a baseline and will include: (1) Otoscopy, (2) Immittance audiometry (commonly called tympanometry), (3) 
Speech Reception Threshold, (4) Pure Tone Audiometry (PTA) with frequencies up to 8 kHz if possible (should there be a PTA threshold of ≥15dB, the subject should undergo bone 
conduction testing), (5) High frequency audiometry (HFA) with frequencies up to 16 kHz if possible, (6) Tinnitus Handicap Inventory, (7) Dizziness Handicap Inventory. Follow up 
testing will be performed at Day 3 (-1 day), Day 10 (-2 days), Day 17 (-2 days), Day 24 (-2 days), and EOS (7-11 days after last dosing). The otoscopic exam on Day 3, Day 10, Day 17 
and Day 24 can be performed 72 hours prior to dosing by a CPU physician. 
j  Subjects will come to the CPU for confinement on Day -1, Day 7, Day 14, Day 21, and Day 28. 
k  The predose PK blood sample will be taken in a standardized manner for all subjects, right before study drug administration. 
l  During the 0-12h collection period urine will be collected every hour, during the 12-24h collection period every 6h (i.e., 12-18h collection and 18-24h collection), and during the 24-48h 
collection period urine will be collected every 12h (i.e., 24-36h collection and 36-48h collection). Urine gravity will be calculated for each collection. The subjects will collect the urine 
at home (in urine jars) during the 48h-72h collection period. 
m  Creatinine samples will be taken at all timepoints corresponding to renal injury biomarker collection. On days 1-4 and 29-32, samples for renal injury biomarkers and creatinine will be 
taken from urine spot samples at 24hr, 36hr, 48hr and 72hr post dose. 
n  Subjects should consume at least 500 mL of water within 120 minutes before dosing. Subcutaneous (SC) injection (s) in the abdominal wall as per the subject’s body weight. The study 
staff will encourage the subjects to drink at least one glass (approximately 250 mL) of fluids every hour up to 10h after dosing. 
o  All blood samples for retention need to be taken after an overnight fast of at least 8h, except for the samples taken at 3h postdose on Day 1 and Day 29. 
p  Subject will return to the ENT specialist for auditory and vestibular tests within 48 hours prior to dosing. The otoscopic exam on Day 3, Day 10, Day 17 and Day 24 can be performed 72 
hours prior to dosing by a CPU physician. 
q  No GFR/MDRD sample/analysis beyond the screening period. 


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1.2.6. 
Efficacy, Pharmacokinetic, and Safety Parameters 
1.2.6.1. 
Efficacy Parameters 
This study does not assess efficacy. 
1.2.6.2. 
Pharmacokinetic Endpoints and Parameters 
The primary PK endpoint is to characterize plasma and urine PK of ELX-02. 
The secondary PK endpoint is to determine the dose proportionality of plasma ELX-02 exposure 
across the administered SC dose range. 
The PK parameters that will be calculated are provided in Section 4.3. 
1.2.6.3. 
Safety Endpoints and Parameters 
The primary safety endpoint is to characterize the incidence of AEs and other changes in safety 
parameters at ascending doses. 
The secondary safety endpoint is to assess, based on the safety profile, whether dose-limiting 
toxicity (DLT) and MTD are attained within the tested ELX-02 dose range. 
Safety evaluations performed during the study include auditory and vestibular assessments, 
questionnaires, ear, nose and throat physical examinations, measurement of vital signs, 12-lead 
electrocardiograms (ECGs), clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis, and coagulation), and monitoring of AEs (including adverse events of interest 
(AEOIs), injection site reactions (ISRs), and treatment discontinuations due to AE), DLTs, and 
concomitant medications. 


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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• Pharmacokinetic (PK) Population: All subjects who are randomized, receive any 
amount of study drug, have at least 1 evaluable PK assessment, and have no relevant 
deviation interfering with the PK evaluations. 
• Safety Population: All subjects who are randomized and receive any amount of study 
drug. 
The PK population is the primary population for the analysis of PK parameters. The safety 
population is the primary population for the analysis of safety parameters. 
2.2. 
Protocol Deviations 
Protocol deviations will be presented in a data listing.


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
No formal sample size estimations were performed. The planned sample size of 9 subjects per 
dose group with a total of up to 63 subjects was considered sufficient to address the safety, 
tolerability and PK objectives of this study. 
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
drug which is designated as Day 1. The preceding day is Day -1, the day before that is Day -2, 
etc. 
All output will be incorporated into Microsoft Word RTF or Adobe Acrobat PDF files, sorted 
and labeled according to the International Council on Harmonisation (ICH) recommendations, 
and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, PK, and safety parameters. 
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented. For 
continuous variables, the number of subjects, mean, median, standard deviation (SD), minimum, 
and maximum values will be presented. 
Summary tabulations for general and safety analyses will be presented by treatment and dose 
(including placebo, all dose levels and all ELX-02) and separately by concentration (including 
Cohorts 3, 4, 5 and 6). Placebo will be pooled across cohorts and presented in one column. A 
total column for those receiving ELX-02, regardless of dose, will also be included. The placebo 
and the total columns will not be included in the summary tabulations for PK analyses. 
Figures for PK concentrations will be presented by cohort and figures for PK parameters will be 
presented by dose. If differences in PK parameters (AUC, Cmax, t1/2) between final diluted 
injection concentrations are observed in the “by concentration” summary tables, figures for PK 
parameters will be presented by cohort. Details for figure presentation are described in Section 
4.3.3. 
All data listings will be presented by cohort. 
3.3. 
Computing Environment 
All statistical analyses will be performed using SAS version 9.4, unless otherwise noted. PK 
parameters will be derived using Phoenix WinNonlin version 8.0 or higher. Medical history and 
AEs will be coded using Medical Dictionary for Regulatory Affairs (MedDRA) version 20.1. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary version 20170901 (Enhanced) Format B3. 
3.4. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
3.5. 
Methods of Pooling Data 
Data will be pooled across study sites within each treatment group (ELX-02 or placebo). Data 
will be pooled across cohorts for the placebo group. 


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3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
3.7. 
Multiple Comparisons/Multiplicity 
Analyses will not be adjusted for multiple comparisons for this early phase study in healthy 
subjects with a primary objective of assessing safety, tolerability, and PK.  
3.8. 
Subpopulations 
No analyses of subject subgroups are planned. 
3.9. 
Withdrawals, Dropouts, Lost to Follow-up 
Subjects discontinued or withdrawn from the study after receiving ≤6 doses may be replaced 
upon request from the Sponsor. 
3.10. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points, other than 
described in this section. All data recorded on the eCRF will be included in data listings. 
When tabulating AE data, partial dates will be handled as follows. If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment. In this case, in order to conservatively report the event as treatment-
emergent, the onset date will be assumed to be the date of first dose. If the onset day and month 
are both missing, the day and month will be assumed to be January 1, unless the event occurred 
in the same year as the study treatment. In this case, the event onset will be coded to the date of 
first dose in order to conservatively report the event as treatment-emergent. A missing onset date 
will be coded as the date of first dose. If the resulting onset date is after a reported date of 
resolution, the onset date will be set equal to the date of resolution. Imputation of partial dates is 
used only to determine whether an event is treatment-emergent; data listings will present the 
partial date as recorded in the eCRF. 
Missing AE severities will not be imputed and will be considered missing in any tabulations of 
AE severity. When relation of AE to the study drug is missing, the AE will be considered 
“related” to study drug. 
When tabulating concomitant medications, if an end date is missing or the medication is ongoing 
at the time of first dose, the medication will be considered concomitant. 
All final PK parameters will be calculated based on actual time from dose. Interim PK parameters 
may be calculated based upon scheduled time if actual time data are not yet available. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the nominal visit as recorded in the eCRF even if the assessment is outside of the 
visit window. In data listings, the relative day of all dates will be presented (see Section 3.2). 
3.12. 
Interim Analyses 
No formal interim analyses are planned for this study. Interim blinded PK analyses are planned 
after each cohort from Cohort 1 through Cohort 6. Safety data will be assessed by the DSMB and 
AVDSMB in a blinded manner at the end of each cohort up to Cohort 6.  
 


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
Subject disposition will be tabulated and will include the number of subjects randomized to 
each treatment (ELX-02 or placebo), the number dosed with each treatment, and the number in 
each analysis population by treatment and dose and separately by concentration. The frequency 
and percentage of subjects who prematurely discontinue from the study, along with the 
primary reason for discontinuation, will also be summarized. 
A by-subject data listing of study completion information including the primary reason for 
premature discontinuation will be presented by cohort. 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented by treatment and 
dose and separately by concentration. The number and percentage of subjects in each race and 
sex will be tabulated. Age, baseline height, baseline weight, and body mass index (BMI) will 
be summarized using descriptive statistics (number of subjects, mean, SD, median, minimum, 
and maximum). Medical history will also be tabulated. 
Demographic and baseline characteristics including alcohol and stimulating beverage 
consumption, tobacco use, UDS, and serology (HIV, HBsAg, HCVAb) for each subject will 
be provided in data listings by cohort.  
4.3. 
Pharmacokinetic Evaluations 
Cohorts 1-6 blinded interim PK analyses for dose escalation recommendations by the DSMB 
and the AVDSMB will be the responsibility of SGS. Derivation of PK parameters for Cohorts 
1-7 final analyses will be the responsibility of Early Phase QCD Team, Parexel International. 
For Cohorts 1-6 blinded interim analysis, the clinical team will remain blinded in that only 
summary tables and figures generated by the SGS team will be shared with the DSMB and the 
AVDSMB and no subject level data will be shared with the study team. Pharmacokinetic 
parameters will be calculated by noncompartmental analysis methods from the concentration-
time data using Phoenix® WinNonlin® version 8.0 or higher.  
Generation of PK tables, listings, and figures (TLFs) for the final clinical report will be the 
responsibility of Early Phase Biostatistics team, Parexel International. 
Pharmacokinetic parameters will be generated using the PK population. 
4.3.1. 
PK Concentrations and Parameters 
4.3.1.1. 
Plasma PK Concentrations 
Blood samples to determine ELX-02 concentrations in plasma will be drawn on Day 1 and Day 
29 at the following nominal time points: 
• Predose, 15 min (± 2 min), 30 min (± 5 min), 45 min (± 5 min), 1h (± 5 min), 3h (± 15 
min), 6h (± 15 min), 12h (± 30 min), 24h (± 1h), 36h (± 1h), 48h (± 1h), 72h (± 1h).  
and on Days 4, 8, 11, 15, 18 and 22 at the following nominal timepoints: 
• Predose and 1h postdose (± 5 min). 
4.3.1.2. 
Plasma PK Parameters 
All final PK parameters will be calculated based on actual time from dose. Interim PK 


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parameters may be calculated based upon scheduled time if actual time data are not yet 
available. All values below the lower limit of quantification (BLQ) predose and in the 
absorption phase prior to the first quantifiable concentration will be substituted by zeros. All 
BLQ values occurring after the first quantifiable concentration will be treated as missing when 
calculating PK parameters.  
The following plasma PK parameters will be determined for ELX-02, as appropriate, according 
to the definitions and methods of calculation below: 
• Cmax: Maximum plasma concentration directly obtained from the experimental data of 
plasma concentration vs time curves, without interpolation (Day 1 and Day 29). 
• tmax: Time corresponding to maximum plasma concentration, directly obtained from the 
experimental data of plasma concentration vs time curves, without interpolation (Day 1 
and Day 29). 
• AUCt: Area under the plasma concentration-time curve calculated from time of 
administration to the last quantifiable concentration, computed using the linear 
trapezoidal rule (Day 1 and Day 29). 
• AUC24h: Area under the plasma concentration-time curve calculated from time of 
administration to time 24h, computed using the linear trapezoidal rule (Day 1 and Day 
29). 
• AUC48h: Area under the plasma concentration-time curve calculated from time of 
administration to time 48h computed using the linear trapezoidal rule (Day 1 and Day 
29). 
• AUC72h: Area under the plasma concentration-time curve calculated from time of 
administration to time 72h, computed using the linear trapezoidal rule (Day 1 and Day 
29). 
• %AUCextrap: Percent AUC extrapolated to infinity from last observed non-BLQ 
concentration. 
• AUCinf: The area under the plasma concentration-time curve extrapolated to infinity, 
calculated as AUCt + Clast / λz, where Clast is the last concentration above the lower limit 
of quantification (LLOQ) (Day 1 and Day 29). If %AUCextrap is greater than 20%, the 
AUC value will be flagged in TLFs, footnoted, and not included in the calculation of 
summary statistics. 
• C0h: Plasma concentration observed at predose at each dosing  
• C1h: Plasma concentration observed at 1h postdose at each dosing. 
• Clast: Last observed non-BLQ concentration. 
• Tlast: Time from dose when Clast occurs. 
• t½: Apparent elimination half-life associated with the terminal rate constant (λz), 
calculated as ln2/λz (Day 1 and Day 29). 
• λz: Terminal elimination rate constant is calculated using clearance (CL/F) and volume 
of distribution (Vd/F) (λz = (CL/F)/V). 
• Vd/F: Apparent volume of distribution (Day 1 and Day 29). Vd/F (or Vz) will be 
calculated based on terminal phase using the equation “Dose/λz.AUCinf”, uncorrected 


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for fraction absorbed. 
• CL/F: Apparent plasma clearance, uncorrected for fraction absorbed (Day 1 and Day 
29). 
• Rac(AUC): Accumulation ratio, calculated as AUC72h Day29/AUC72h Day 1. 
• Rac(Cmax): Accumulation ratio, calculated as Cmax Day29/Cmax Day 1. 
Additional pharmacokinetic parameters may be calculated as appropriate.  
4.3.1.3. 
Urine PK Concentrations 
Urine samples to determine ELX-02 concentrations in urine will be collected at the following 
intervals on Day 1 and Day 29:  
• Predose and during the following post-dose intervals:  
- 
hourly during 0-12h (± 15 min) time period, (0-1h, 1-2h, 2-3h, 3-4h, 4-5h, 5-6h, 
6-7h, 7-8h, 8-9h, 9-10h, 10-11h, and 11-12h)  
- 
6-hourly pooled in 12-24h (± 15 min) time period, (12-18h and 18-24h) 
- 
12-hourly pooled after 24h up to 72h, (24-36h, 36-48h, 48-60h and 48-72h). 
• Urine will be pooled in each interval (1, 6 or 12-hour interval), volume measured, and an 
aliquot will be processed to determine ELX-02 concentration. 
4.3.1.4. 
Urine PK Parameters 
The following urinary PK parameters will be calculated: 
• Ae: Amount excreted in urine in an interval: 0-1h, 1-2h, 2-3h, 3-4h, 4-5h, 5-6h, 6-7h, 7-
8h, 8-9h, 9-10h, 10-11h, 11-12h, 12-18h, 18-24h, 24-36h, 36-48h, 48-60h, and 60-72h on 
Day 1 and Day 29. Cumulative amount excreted will also be calculated, i.e. Ae12h, Ae24h, 
Ae48h, Ae72h . 
• Rmax: Maximum amount excreted in urine in a collection interval. 
• tRmax: Time when maximum amount is excreted in urine. This will be mid-point of the 
collection interval. 
• Fe: Percent of dose excreted in urine on Day 1 and Day 29 (Ae(t)/dose*100), where t = 12, 
24, 48, 72 (will be shown as Fe12h, Fe24h, Fe48h, Fe72h). 
• CLR: Renal clearance on Day 1 and Day 29 (CLR = Ae72h / plasma AUC72h). If Ae72h or 
AUC72h is not available, CLR will be calculated based on data up to 48 hours. 
4.3.2. 
Dose Proportionality Assessment 
Differences in PK profiles between final diluted injection concentrations (50 vs 100 mg/mL) will 
be explored using the figures (Section 4.3.3) and the “by concentration” tables. AUC and Cmax 
will be evaluated using the ratio with its 90% confidence interval to compare Cohort 3 vs 5 and 
Cohort 4 vs 6. The elimination half-life, t1/2, will be evaluated using the Kruskal-Wallis test. If 
no apparent differences in the PK profiles and PK parameters between the injection 
concentrations are observed, the PK data from two different cohorts with the same dose will be 
pooled together for assessing dose proportionality. Otherwise, dose proportionality will be 
assessed using the data from Cohorts 1, 2, 5, 6, and 7 in which the lower diluted injection 
concentration (50 mg/mL) was administered. 


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Dose proportionality will be assessed using a power model separately on Day 1 and Day 29, 
including the log-transformed PK parameters (Cmax, AUCt, and AUCinf) as the dependent 
variables and the log-transformed dose as the fixed effect. Individual PK values will be used to 
perform a least-squares linear regression analysis, using the formula: 
logpkvar=A + ß×logdose, where: 
• ‘logpkvar’ represents the natural log transformed Cmax, AUCt, and AUCinf. 
• ‘logdose’ represents the natural log transformed dose.  
The slope for log-transformed dose (ß) will be estimated with its 90% confidence interval to 
examine dose proportionality. The PROC REG procedure will be used in SAS in the following 
data step: 
PROC REG DATA=pkparam alpha=0.10; MODEL log_pkvar = log_dose / CLB; RUN; 
The tmax will be compared between dose groups and days (Days 1 and 29) using the Kruskal-
Wallis one-way analysis of variance (ANOVA). P-values based on the Kruskal-Wallis test will 
be presented. 
Additional statistical analysis may be performed. If applicable, steady state will be informally 
assessed via a visual inspection of the figures of predose and 1-hour postdose plasma 
concentrations vs time (day). 
4.3.3. 
Pharmacokinetic Data Reporting 
Tables: 
All plasma and urinary PK concentrations will be summarized by dose, final diluted injection 
concentration, day, and timepoint using descriptive statistics (number of subjects, mean, SD, 
median, coefficient of variance [CV%], minimum and maximum). All PK concentration and 
descriptive statistic values will be reported to 3 decimal places.  
All plasma and urinary PK parameters will be summarized by dose, final diluted injection 
concentration, and day using descriptive statistics (number of subjects, mean, SD, median, 
CV%, minimum and maximum, geometric mean, and geometric CV%). All PK parameters 
and descriptive statistic values will be reported to 3 decimal places, with the exception of the 
individual tmax values, which will be reported to 2 decimal places. Footnotes will include 
information on parameters not included in summaries and the reasons for not including.  
All BLQ, zero, and missing values of PK parameters will not be included in concentration and 
parameters summary calculations. If the number of non-BLQ, non-zero, and non-missing 
values are less than 3 in a summarization group, summary statistics will not be calculated. 
Listings: 
Individual plasma PK sample collection times will be listed by cohort, and will include details 
about subject number, cohort, dose, day, nominal sample time point, actual sample time point 
and concentration in the PK population. If any subjects are excluded from the PK population, a 
separate listing will be produced for these subjects if PK parameters are calculable. 
Individual urine PK sample collection times will include details about subject number, cohort, 
dose, scheduled urine collection interval, actual start and end time of urine collection interval, 
urine volume collected in the urine collection interval, and concentration in the PK population.  
All values will be reported to 3 decimal places, with the exception of the individual tmax values, 


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which will be reported to 2 decimal places.  
All BLQ concentrations or missing data will be labeled as such in the concentration data 
listings. 
Figures: 
Plasma PK concentration and PK parameter figures: 
• Subject profile for plasma concentration-time will be presented graphically on a linear 
and semi-log scale for the PK population (overlaid Day 1 and Day 29, including C0h and 
C1h on each scheduled day between Day 1 and Day 29). 
• Grouped individual plasma concentration versus nominal time will be presented 
(Spaghetti Plots) on the linear and semi-log for the PK population (by cohort, separate 
Day 1 and Day 29 plots).  
• Arithmetic mean (±SD) plasma concentration vs nominal time profiles will be presented 
graphically on a linear and semi-log scale (no SD for semi-log plot) for the PK 
population (by cohort, separate Day 1 and Day 29 plots, all cohorts on one plot).  
• Grouped individual predose and 1h postdose plasma concentration vs nominal time 
from Day 1 through Day 29 will be presented (Spaghetti Plots) on the linear and semi-
log scale for the PK population (by cohort). 
• Mean (±SD) predose and 1h postdose plasma concentration vs nominal time from Day 
1 through Day 29 will be presented on the linear and semi-log scale (no SD for semi-
log plot) for the PK population (by cohort). 
• Additional PK plots (by dose): Day 1 and Day 29 where applicable Cmax, tmax, t½, 
AUC24h, Cl/F, Vd/F vs dose. 
Urine PK parameter figures: 
• 
Subject profile for amount excreted over time will be presented graphically on a linear 
and semi-log scale for the PK population (overlaid Day 1 and Day 29). A dashed line 
representing individual subject dose will be included on each plot. 
• 
Grouped individual amount excreted versus nominal time will be presented (Spaghetti 
Plots) on the linear and semi-log for the PK population (by cohort, separate Day 1 and 
Day 29 plots). 
• 
Arithmetic mean (±SD) amount excreted vs nominal time profiles will be presented 
graphically on a linear and semi-log scale (no SD for semi-log plot) for the PK 
population (by cohort, separate Day 1 and Day 29 plots, all cohorts on one plot). 
• 
Additional urine PK plots (by dose), including but not limited to plasma CL/F vs CLR, 
may be included as appropriate. 
Details of any deviations from the planned analysis will be documented in the PK report. 
4.4. 
Safety Analyses 
All safety tabulations will be presented by treatment and dose and separately by concentration 
for all subjects in the Safety population. 
If warranted, additional analyses of safety versus PK exposure (eg, AUC and Cmax) may be 
explored. 


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4.4.1. 
Study Drug Exposure 
Study drug exposure will be calculated as the number of days subjects were administered 
study drug, as determined below, using descriptive statistics. 
Duration of Study Drug Exposure (days) = (Date of last dose – Date of first dose) + 1 
Dose intensity will be computed using the following definition and summarized by treatment 
and dose and separately by concentration: 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼=
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 
Relative dose intensity will be computed using the following definition and summarized by 
treatment and dose and separately by concentration: 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝐷𝐷𝐷𝐷𝐷𝐷𝑒𝑒 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 (%) =
(𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷/𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷)
(𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷/𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷) ∗100 
Percent compliance will be summarized for each subject as: 
Percent Compliance (%) = 
Number of Injections Received 
* 100 
Number of Injections Expected 
The number of injections expected is the number defined in the protocol (9 total injections 
per subject). The number of expected injections for any subject who withdraws or dies prior 
to completing all scheduled doses will be counted up to the date of withdrawal or death. 
Duration of study drug exposure, number of doses received, dose intensity, relative dose 
intensity, and percent compliance for each subject will be listed by cohort. 
4.4.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system and displayed in tables and data 
listings using system organ class (SOC) and preferred term (PT). AEs will be presented by 
severity (mild, moderate, or severe). 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE occurring after the first dose of study 
medication. Adverse events reported prior to dosing will be considered non treatment-
emergent.  
The number and percentage of subjects as well as the number of events for each particular 
treatment-emergent AE (TEAE) will be summarized by treatment and dose, concentration, 
SOC, and PT for the following: TEAEs, TEAEs assessed by the Investigator as related to 
treatment, severe TEAEs, serious TEAEs, TEAEs leading to permanent study drug 
discontinuation, TEAEs leading to temporary discontinuation, TEAEs leading to dose 
reduction, TEAEs by maximum severity, and TEAEs by relationship to study drug. 
In these tabulations for the number and percentage of subjects, each subject will contribute 
only once (i.e., the most related occurrence or the most intense occurrence) to each of the 
incidence rates for a given SOC or PT in the descriptive analysis, regardless of the number of 
episodes.  
For tabulations that include classification by relationship to study treatment, AEs with missing 
relationship will be considered related to study drug. For tabulations that include classification 


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by severity, AEs with missing severity will be included in a category for missing. 
All AEs occurring on-study will be listed in by-subject data listings by cohort. 
By-subject data listings will also be provided for the following: subject deaths, SAEs, 
severe TEAEs, TEAEs leading to treatment discontinuation, and TEAEs leading to dose 
reduction.  
4.4.3. 
Adverse Events of Interest and Injection Site Reactions 
Treatment-emergent AEOIs, defined per-protocol as hypersensitivity, nephrotoxicity, and 
ototoxicity, will be assessed. AEOIs, searched by the following standardized MedDRA queries 
(SMQs), will be summarized by PT: Hypersensitivity, Hearing and Vestibular Disorders, and 
Acute Renal Failure, as appropriate. The number and percentage of subjects with at least one 
AEOI as well as the number of AEOIs will be presented by treatment and dose and separately by 
concentration.  
ISRs, defined per-protocol as pain or tenderness, erythema or redness, induration or swelling, 
and pruritus, and assessed by the investigators according to the Division of Acquired 
Immunodeficiency Syndrome (DAIDS) Criteria as described in Protocol Section 13.1 will be 
summarized by grade at each timepoint.  
ISRs reported as spontaneous AEs that are coded with the high-level term (HLT) “Injection site 
reactions” will also be analyzed. The number and percentage of subjects with at least one ISR as 
well as the number of ISR events will be presented by treatment and dose and separately by 
concentration. The duration of each reported ISR will be derived using the AE dataset. The 
average duration of ISRs per subject will be summarized by treatment and dose and separately 
by concentration.  
All AEOIs and ISRs occurring on-study as well as the duration of each observed ISR will be 
listed in by-subject data listings by cohort. 
4.4.4. 
Laboratory Data 
Clinical laboratory values will be expressed in Système International (SI) units. 
The actual value and change from baseline (Day 1) to each on-study evaluation will be 
summarized for each clinical laboratory parameter, including hematology, clinical chemistry, 
urinalysis, and coagulation and presented by treatment and dose and separately by concentration. 
In the event of repeat values, the last non-missing value per study day/time will be used. 
Laboratory results recorded at unscheduled visits will not be tabulated. 
Severity of clinical laboratory measurements will be determined using Common Terminology 
Criteria for Adverse Events (CTCAE) criteria when available. 
Shift tables of change in CTCAE grade of laboratory parameters from baseline to worst value and 
from baseline to last value on study will be presented. Both scheduled and unscheduled visits will 
be included in shift tables. 
All laboratory data will be provided in by-subject data listings, including results of pregnancy 
tests, alcohol tests, and serology. A subset listing will be presented for all laboratory values with 
CTCAE grade ≥3.  
4.4.5. 
Vital Signs and Physical Examination 
The actual value and change from baseline to each on-study evaluation will be summarized for 


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vital signs, including blood pressure (systolic/diastolic), heart rate, body temperature, and 
respiratory rate and presented by treatment and dose and separately by concentration. 
Vital sign measurements and all physical examination findings will be presented in by-subject 
data listings by cohort. 
4.4.6. 
Auditory and Vestibular Assessments 
Audiometric and vestibular tests will be performed at Screening, Baseline, Day 3, Day 10, Day 
17, Day 24 and end of study (EOS). 
4.4.6.1. 
Otoscopy 
The number and percentage of subjects with otoscopic examination results (normal, abnormal, 
not done) for each ear will be summarized by visit, treatment and dose, and separately by 
concentration. 
Otoscopic examination results for each ear and comments will be listed by cohort, subject and 
visit. 
Use of hearing aid and regular/history of excessive noise exposure will be provided in by-subject 
data listings. 
4.4.6.2. 
Pure Tone Audiometry and High Frequency Audiometry 
Air conduction pure tone audiometry (PTA) will be conducted across the conventional range of 
frequencies (0.25, 0.5, 1, 2, 3, 4, 6, 8 kHz), as well as at high frequencies (10, 12, 14, 16 kHz). If 
there is a PTA threshold ≥15 decibels in hearing level (dB HL) for frequencies between 0.25 - 4 
kHz, bone conduction will be performed at that frequency. 
PTA/High Frequency Audiometry (HFA) threshold and change from baseline in PTA/HFA 
threshold for each ear at each frequency will be summarized descriptively (n, mean, SD, median, 
min, median, max) at each visit by treatment and dose, and separately by concentration. 
Mean (±SD) changes from baseline in PTA/HFA threshold by dose will be plotted across all 
visits for each ear at each frequency. 
For conventional frequencies (0.25 - 8 kHz) and HFA (10 - 16 kHz), the Significant Change 
Criteria as defined by American Speech-Language-Hearing Association (ASHA) and American 
Academy of Audiology (AAA) are when the thresholds worsen by the following criteria:  
1. ≥ 20 dB change at any frequency, 
2. ≥ 10 dB change at any 2 adjacent frequencies, or 
3. loss of response at 3 consecutive frequencies where responses were obtained at baseline. 
The number and percentage of patients with significant change relative to baseline across the 
conventional frequencies (yes, no) and significant change relative to baseline at the high 
frequencies (yes, no) will be summarized for each ear by visit, treatment and dose, and separately 
by concentration. 
PTA and HFA data for each subject will be listed by cohort. 
4.4.6.3. 
Speech Reception Threshold 
Speech reception threshold (SRT) will be performed at screening and baseline. At follow up 
visits, SRT will be performed only if there are ASHA significant change criteria/reverse ASHA 
significant change criteria noted in the PTA/HFA exam. 




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• 36-52 points (moderate handicap) 
• 54 + points (severe handicap) 
Individual questions and total scores for the DHI will be provided in by-subject data listings by 
cohort. 
4.4.7. 
Electrocardiogram 
Actual values and change from baseline to each on-study evaluation will be summarized for 
the following ECG results, heart rate, PR, QRS, QT, QTcB, and QTcF intervals. 
ECG data for each subject will be provided in by-subject data listings. 
4.4.8. 
Renal Injury Biomarkers 
Renal injury biomarkers include KIM-1 and clusterin in urine. Renal injury biomarkers will be 
normalized by urine creatinine and computed using the following definition:  
Renal Injury Biomarker / Urine Creatinine. 
Actual value and changes from baseline in each of the renal injury biomarkers normalized by 
urine creatinine will be summarized descriptively at each timepoint by treatment and dose, and 
separately by concentration. 
Renal injury biomarkers, urine creatinine and normalized renal injury biomarkers for each subject 
at each timepoint will be provided in data listings by cohort.  
4.4.9. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary. Results will be 
tabulated by anatomic therapeutic class (ATC), PT, treatment and dose, and separately by 
concentration. 
Concomitant medications will be tabulated, where any medications that were not discontinued 
prior to the first dose of study medication will be included. 
The use of concomitant medications will be included in a by-subject data listing by cohort. 


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5. 
CHANGES TO PLANNED ANALYSES 
The study secondary objective remains unchanged, but the wording has been clarified to be 
more precise from “to assess linearity between ascending SC doses and PK parameters” to “to 
assess dose proportionality of exposure parameters (Cmax and AUC)”. Subsequently, it is 
clarified furthermore in Section 4.3.2 that the dose proportionality will be assessed using a 
power model separately on Day 1 and Day 29, including the log-transformed PK parameters as 
dependent variables and the log-transformed dose as the fixed effect. The protocol specified 
fixed effects of day and dose*day are not required for the model that is performed separately on 
each individual day and therefore are excluded from the power model. 


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6. 
REFERENCES 
Keeling K, Du M, Bedwell DM: Therapies of nonsense-associated diseases. In: Nonsense-
Mediated mRNA Decay. edn. Edited by Maquat LE. Austin, TX: Landes Biosciences; 2006: 
121-136. 
Mendell JT, Dietz HC: When the message goes awry: disease producing mutations that influence 
mRNA content and performance. Cell 2001, 107(4):411-414.