Clinical trial NCT05298306
Conditions: Radiculopathy Lumbar
Sponsor: Lateral Pharma Pty Ltd
Start date: 2022-05-17; Completion date: 2023-06-16
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study consists of two parts. Part A will evaluate the safety and tolerability of intravenous LAT8881 in healthy volunteers using an ascending dose schedule. Part B will evaluate the analgesic efficacy of a single intravenous dose of LAT8881, compared with placebo, in patients with lumbar radicular pain.

Healthy volunteers are not accepted for Part B.

Detailed description:
Part A of this study is a double-blind, randomized, placebo-controlled, single ascending dose study of intravenous administration of LAT8881 over 5 minutes in healthy volunteers. Each participant has three treatment days, 1 infusion per dosing day, on Days 1, 4 and 7 as well as two short visits for safety blood sampling on Days 3 and 6. Subjects in Part A are randomized to receive placebo and LAT8881 according to the following treatment sequences. Two subjects are allocated to each treatment sequence, a total of eight subjects overall.

0.8 mg/kg/1.2 mg/kg/1.8 mg/kg;

0.8 mg/kg/1.2 mg/kg/Placebo;

0.8 mg/kg/Placebo/1.8 mg/kg;

Placebo/1.2 mg/kg/1.8 mg/kg.

Part B of this study is is a placebo-controlled randomized double blind cross-over safety and efficacy study of LAT8881 in up to 20 patients with lumbar radicular pain. Participants will be randomly assigned to one of two groups, to receive either LAT8881 then placebo or placebo then LAT8881. Participants will receive either a single dose of LAT8881 \[the Maximum Tolerated Dose from Part A of the study\] or placebo via intravenous administration over 5 minutes on two consecutive days.

Arms: arm 1: In Part A, LAT8881 will be given as a single intravenous infusion on separate days at doses of 0.8, 1.2 and 1.8 mg/kg.

In Part B, LAT8881 will be given as a single intravenous infusion. The dose will be determined from the results of Part A. arm 2: Matching placebo will be given as a single intravenous infusion in Part A and Part B
Interventions: intervention 1: LAT8881 intervention 2: Placebo
Intervention descriptions: intervention 1: In Part A, LAT8881 will be given as a single intravenous infusion at doses of 0.8, 1.2 and 1.8 mg/kg.

In Part B, a single intravenous infusion of LAT8881 will be given, the dose to be determined by the results in Part A intervention 2: Matching placebo'given as a single intravenous infusion at all dose levels

Protocol documents:
Prot_000.pdf: 
Protocol No. LAT-NP-002 
 
 
 
LAT-NP-002 Protocol Version 5.0, Dated 03FEB2023 
 
Page 1 of 56 
OFFICIAL 
  
 
 
 
 
 
PROTOCOL TITLE:  
  
A Two-part Proof-of-Concept Study Assessing the Safety 
 
  
and Efficacy of LAT8881 in Lumbar Radicular Pain. 
 
 
Protocol Number: 
 
 
LAT-NP-002 
 
NCT Number  
 
 
NCT05298306 
 
Development Phase:   
 
Phase 1b 
 
Document Version:  
 
Protocol Version 5.0 dated 03FEB2023 
 
Sponsor: 
 
 
 
Lateral Pharma Pty Ltd 
 
 
 
 
 
14/114 William St 
 
 
 
 
 
Melbourne, Vic 3000, Australia 
 
 
 
 
 
Phone: +61 (0)400 151 490 
 
 
 
 
 
Email: dk@lateral-pharma.com 
 
Coordinating Principal Investigator:  Prof. Guy Ludbrook 
 
 
 
 
 
PARC Clinical Research 
 
 
 
 
 
Royal Adelaide Hospital 
 
 
This clinical study will be performed in compliance with Good Clinical Practice (GCP) guidelines, 
includingarchiving of essential documents. 
 
Confidentiality statement 
All information relating to the investigational product, Investigator’s Brochure, Study Protocol, Case Report 
Forms and any information and results developed during, or arising from the study, is considered confidential 
and proprietary information of Lateral Pharma Pty Ltd (‘Confidential Information’). This Confidential 
Information shall remain the sole property of Lateral Pharma Pty Ltd and shall not be disclosed to others 
without prior written consent from Lateral Pharma Pty Ltd and shall not be used except in the performance of 
this study. 
 
 


Protocol No. LAT-NP-002 
 
 
 
LAT-NP-002 Protocol Version 5.0, Dated 03FEB2023 
 
Page 2 of 56 
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1. Contents 
1. 
Contents ........................................................................................................................ 2 
1.1. General Study Information ..................................................................................... 7 
1.2. List Of Abbreviations.............................................................................................. 8 
2. 
PROTOCOL SYNOPSIS ................................................................................................ 9 
3. 
SCHEDULE 1 OF OBSERVATIONS AND PROCEDURES PART A ............................ 16 
4. 
SCHEDULE 1 OF OBSERVATIONS AND PROCEDURES PART B ............................ 17 
5. 
INTRODUCTION ......................................................................................................... 19 
5.1. Background ......................................................................................................... 19 
5.2. Findings From Nonclinical and Clinical Studies .................................................... 20 
6. 
STUDY OBJECTIVES.................................................................................................. 25 
6.1. Hypothesis ........................................................................................................... 25 
6.2. Primary Objective ................................................................................................ 25 
6.3. Secondary Objectives .......................................................................................... 25 
6.4. Experimental Objectives ...................................................................................... 25 
7. 
STUDY DESIGN .......................................................................................................... 26 
7.1. Overall design...................................................................................................... 26 
7.2. Justification of Study Design ................................................................................ 26 
7.3. Sample Size ........................................................................................................ 26 
7.4. Justification of Dose............................................................................................. 27 
8. 
STUDY POPULATION ................................................................................................. 27 
8.1. Inclusion Criteria .................................................................................................. 27 
8.2. Exclusion Criteria ................................................................................................. 28 
8.3. Screen Failures ................................................................................................... 30 
9. 
STUDY PROCEDURES ............................................................................................... 30 
9.1. Recruitment ......................................................................................................... 30 
9.2. Informed Consent ................................................................................................ 30 
9.3. Screening ............................................................................................................ 31 
9.4. Randomisation..................................................................................................... 31 
9.5. Follow Up ............................................................................................................ 31 
9.6. ASSESSMENTS .................................................................................................. 31 
9.6.1. 
Demography ................................................................................................ 31 
9.6.2. 
Physical Exam ............................................................................................. 31 
9.6.3. 
Medical History ............................................................................................ 32 
9.6.4. 
Sciatic Pain Assessment and History for Part B ........................................... 32 
9.6.5. 
Prior and Concomitant Medications ............................................................. 32 
9.6.6. 
Vital Signs .................................................................................................... 32 
9.6.7. 
Electrocardiograms ...................................................................................... 32 
9.6.8. 
Average Daily Pain Scores (NRS) for Part B ................................................ 32 
9.6.9. 
Clinical Safety Blood and Urine .................................................................... 33 
9.6.10. 
Urinalysis ..................................................................................................... 33 
9.6.11. 
Urine Drug Screen ....................................................................................... 34 
9.6.12. 
Pregnancy Screen ....................................................................................... 34 
9.6.13. 
Alcohol Breath Test ...................................................................................... 34 
9.6.14. 
CT or MRI Imaging ....................................................................................... 34 
9.6.15. 
Pain assessment (VAS), Patient General Impression of Change (PGIC) and 
Bang Binding Index Assessment (Part B  only) ............................................................ 35 
9.6.16. 
PK and PD Sampling ................................................................................... 35 
9.6.17. 
Mechanical QST assessment using Von Frey Aesthesiometer   (Part B only)
 
 
 .................................................................................................................... 35 


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10. INVESTIGATIONAL PRODUCT (IP) DISPENSING AND ACCOUNTABILITY ............. 36 
11. Administration .............................................................................................................. 36 
12. Investigational Product Compliance ............................................................................. 37 
13. COVID-19 CONSIDERATIONS AND CONTINGENCY PLANNING ............................. 37 
14. BLINDING, PACKAGING AND SHIPPING ................................................................... 37 
14.1. Method for assigning subject study number ......................................................... 37 
15. UNBLINDING ............................................................................................................... 38 
16. SAFETY ASSESSMENTS ........................................................................................... 38 
16.1. Pregnancy Testing ............................................................................................... 38 
17. WITHDRAWAL ............................................................................................................ 38 
17.1. Replacement of participants ................................................................................ 39 
17.2. General Considerations for Stopping Criteria ....................................................... 39 
18. PROHIBITIONS AND RESTRICTIONS IN THE STUDY .............................................. 40 
18.1. Prohibited medications ........................................................................................ 40 
18.2. Contraception ...................................................................................................... 40 
19. Study Oversight ........................................................................................................... 41 
19.1. Suspension or premature termination of the study ............................................... 41 
19.2. Continuation on to Part B ..................................................................................... 42 
20. ADVERSE EVENTS .................................................................................................... 42 
20.1. Adverse event...................................................................................................... 42 
20.2. Adverse drug reaction/Suspected adverse (drug) reaction................................... 42 
20.3. Suspected unexpected serious adverse reactions ............................................... 42 
20.4. Causality .............................................................................................................. 42 
20.5. Severity (Intensity) of adverse event .................................................................... 43 
20.6. Serious adverse event ......................................................................................... 43 
20.7. Recording of adverse events ............................................................................... 44 
20.7.1. 
Clinical lab abnormalities and other abnormal assessments ........................ 44 
20.8. Reporting of serious adverse events .................................................................... 44 
20.9. Follow-up of adverse events and serious adverse events .................................... 45 
21. STATISTICAL ANALYSIS ............................................................................................ 45 
21.1. General considerations ........................................................................................ 45 
21.2. Analysis populations ............................................................................................ 46 
21.2.1. 
Full Analysis Set .......................................................................................... 46 
21.2.2. 
Per protocol population ................................................................................ 46 
21.2.3. 
Safety population ......................................................................................... 46 
21.2.4. 
PK and PD population .................................................................................. 46 
21.2.5. 
Participant disposition .................................................................................. 46 
21.3. Analysis of safety data ......................................................................................... 47 
21.3.1. 
Extent of exposure ....................................................................................... 47 
21.3.2. 
Adverse events ............................................................................................ 47 
21.3.3. 
Clinical laboratory evaluations...................................................................... 47 
21.3.4. 
Other safety measures ................................................................................. 47 
21.4. Analysis of pharmacokinetic data ........................................................................ 47 
21.5. Analysis of efficacy data (Part B only) .................................................................. 48 
21.6. Analysis of exploratory endpoints ........................................................................ 48 
21.7. Planned Interim Analyses .................................................................................... 48 
22. STUDY MANAGEMENT .............................................................................................. 49 
22.1. Regulatory compliance and ethical conduct ......................................................... 49 
22.2. Ethics Committee review ..................................................................................... 49 
22.3. Informed consent process ................................................................................... 49 
22.4. Protocol amendments .......................................................................................... 49 
22.5. Protocol deviations .............................................................................................. 50 


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23. QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 51 
23.1. Training of staff .................................................................................................... 51 
23.2. Study monitoring .................................................................................................. 51 
23.3. Data management and quality control ................................................................. 51 
23.4. Audits and inspections ......................................................................................... 52 
24. DOCUMENTATION, RECORD ACCESS AND ARCHIVING ........................................ 52 
24.1. Maintenance of essential documents/supplements at study site during the study 52 
24.2. Data protection .................................................................................................... 52 
24.3. Data retention & archiving ................................................................................... 53 
25. STUDY ADMINISTRATION ......................................................................................... 54 
25.1. Study agreements ............................................................................................... 54 
25.2. Confidentiality ...................................................................................................... 54 
25.3. Insurance ............................................................................................................. 54 
25.4. Reporting ............................................................................................................. 54 
25.5. Publication policy ................................................................................................. 55 
26. REFERENCES ............................................................................................................ 56 
 


Protocol No. LAT-NP-002 
 
 
 
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SPONSOR (S) SIGNATURE PAGE 
 
The signature below constitutes approval of this protocol. This study will be conducted in 
compliance with the clinical study protocol (and amendments), International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines for current Good Clinical Practice (GCP) and applicable regulatory requirements 
 
 
Authorised by: 
 
 
 
 ________________________  _____________________________  
 ____________________  
 Name 
 Signature 
 Date 
 


Protocol No. LAT-NP-002 
 
 
 
LAT-NP-002 Protocol Version 5.0, Dated 03FEB2023 
 
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INVESTIGATOR (S) SIGNATURE PAGE 
 
I have read this protocol and agree that it contains all necessary details for carrying out the 
study as described. I will conduct this protocol as outlined herein, according to the ethical 
principles that have their origin in the Declaration of Helsinki, International Conference on 
Harmonization (ICH) guidelines for Good Clinical Practice (GCP) and applicable laws, rules 
and regulatory requirement(s).  
 
I agree to obtain the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval of the protocol and informed consent prior to the start of the study.  
 
I agree to obtain formal written informed consent in accordance with applicable federal and 
local regulations and international guidelines from all participants prior to their entry into 
the study.  
 
I have received and reviewed the Investigator’s Brochure including the potential risks and 
side effects of the product and instructions for use.  
 
I agree to report to the Sponsor any adverse events that occur during the study in 
accordance with the ICH GCP guideline and the protocol.  
 
I agree to ensure that all associates, colleagues, and employees assisting me with the 
conduct of the study are informed of their responsibilities in meeting the above 
commitments and the commitments set forth in the Investigator’s Agreement.  
 
I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with the ICH GCP guideline, and federal and local requirements.  
 
I understand that the study may be terminated, or enrolment suspended at any time by the 
Sponsor, with or without cause, or by me if it becomes necessary to protect the best interests 
of the study participants. 
 
 
_______________________   __________________________  
 ___________________  
 Name 
 Signature 
Date 
 


Protocol No. LAT-NP-002 
 
 
 
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1.1. General Study Information 
 
 
Study Monitor: 
 
 
Southern Star Research 
 
 
 
 
 
Level 1, 1 Merriwa Street,  
 
 
 
 
 
Gordon NSW 2072 Australia 
 
 
 
 
 
Postal: PO Box 52, Gordon NSW 2072 Australia 
 
 
 
 
 
Contact Phone: + 61 2 9011 6266 
 
 
 
 
 
Contact Email: info@southernstarresearch.com 
 
Sponsor medical representative 
Southern Star Research 
 
 
 
 
 
Level 1, 1 Merriwa Street,  
 
 
 
 
 
Gordon NSW 2072 Australia 
 
 
 
 
 
Postal: PO Box 52, Gordon NSW 2072 Australia 
 
 
 
 
 
Phone: +61 2 9011 6266 
 
 
 
 
 
Email: jmarjason@southernstarresearch.com 
 


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1.2. List Of Abbreviations 
AST 
Aspartate aminotransferase 
BCC  
Basal Cell Carcinoma  
BMI 
CK 
COVID-19 
CPI 
CRF 
CT 
Body mass index 
Creatinine Kinase 
Novel Coronavirus (Sars-Cov-2) 
Coordinating Principal Investigator 
Case Report Form  
Computed Tomography 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
EDC 
FAS 
Electronic Case Report Form 
Electronic Data Capture 
Full Analysis Set 
FBC 
Full Blood Count 
MSU 
MTD 
NHMRC 
OTC 
PGIC 
PICF 
PD 
PK 
PP 
QST 
Mid-Stream Urine 
Maximum Tolerated Dose 
National Health and Medical Research Council  
Over The Counter 
Patients General Impression of Change 
Patient Information and Consent Form 
Pharmacodynamic 
Pharmacokinetics 
Per Population 
Quantitative Sensory Test 
ULN 
Upper Limit of normal 


Protocol No. LAT-NP-002 
 
 
 
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2. PROTOCOL SYNOPSIS 
Title 
A Two-part Proof-of-Concept Study Assessing the Safety and Efficacy of 
LAT8881 in Lumbar Radicular Pain. 
Short Title 
LAT-NP-002 
Sponsor 
Lateral Pharma Pty Ltd 
Protocol Number 
LAT-NP-002 
Study Phase 
1b 
Primary Objective 
Part A: 
Evaluate the safety and tolerability of intravenous LAT8881 using an 
ascending dose schedule  
Part B: 
Evaluate the analgesic efficacy of LAT8881 in patients with lumbar radicular 
pain 
Secondary 
Objective(s) 
Part A: 
Evaluate the plasma concentrations and the PK properties of LAT8881 
administered as an IV injection in healthy participants using a dose escalating 
design 
Establish the dose regimen for Part B of the study 
Part B: 
Evaluate the effect of Intravenous LAT8881, compared with placebo, on VAS 
pain scores at rest 
Confirm the safety of IV LAT8881 in participants with lumbar radicular pain 
Exploratory 
Objectives 
Part A:  
Collect blood samples to investigate a pharmacodynamic assay and/or 
biomarkers of LAT8881 activity 
Part B: 
Evaluate mechanical Quantitative Sensory Test (QST) assessment on affected 
lower limb using Von Frey Aesthesiometer on two occasions, once prior to 
dosing and once post dosing. 
Evaluate the effect of Intravenous LAT8881, compared with placebo, on VAS 
pain scores during straight-leg raise nerve stretch 
Collect blood samples to investigate (and possibly validate) a 
pharmacodynamic assay and/or biomarkers of LAT8881 activity 
Primary Endpoints Part A  
Safety and Tolerability  
• Incidence, severity, and causality of AEs  
• Incidence and severity of clinical laboratory abnormalities  
• Change from baseline in vital signs (BP, temperature, respiratory rate, 
and heart rate)  
• Change from baseline in 12-lead ECG parameters  
 


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Part B: the change in pain from baseline during and after each infusion on a 
VAS 0-10 numerical rating scale of “pain now” with measures taken as the 
infusion starts and at 15 minute intervals for the first hour, then every thirty 
minutes for an additional two hours, then hourly until 6 hours from infusion 
commencement 
Secondary 
endpoints 
Part A:  
• Pharmacokinetic profile 
Part B:  
• Comparison of radicular “pain now” scores as peak change from 
baseline and area under the curve comparing the two arms over the 
full six hours  
• Comparison of Patients general impression of change between dosing 
arms 
• Adverse event rates in each dosing arm 
Exploratory 
endpoints 
Part A: 
• Pharmacodynamic assay and/or biomarkers of LAT8881 activity. 
Part B: 
• Mechanical QST assessment using Von Frey Aesthesiometer 
• Evaluate the effect of Intravenous LAT8881, compared with placebo, 
on VAS radicular pain scores during straight-leg raise nerve stretch  
• Bang Binding Index assessment, whereby participant will be asked to 
record which dosing occasion they believe they got the active IP. 
• Pharmacodynamic assay and/or biomarkers of LAT8881 activity. 
Study Design 
Part A:  
This is a double-blind, randomized, placebo-controlled, single ascending dose 
study within 8 healthy volunteers of intravenous administration of LAT8881 
over 5 minutes.  
Part A of the Study will enrol 8 participants, each participant has three 
treatment days, 1 infusion per dosing day on days 1, 4 and 7 as well as two 
short visits for safety blood sampling on Day 3 and 6. The 8 subjects will be 
split into two groups of 4 subjects each (3 IMP and 1 placebo), with the two 
groups dosed a few days apart.  
Participants arrive on the morning of treatment day, receive a single infusion, 
leave that afternoon (no overnight stay). Participants will be dosed at 
staggered intervals as determined by PI. . 
Treatments are on Days 1 (0.8 mg/kg), Day 4 (1.2 mg/kg) and Day 7 (1.8 mg/kg) 
or placebo to allow sufficient washout and consideration of any safety 
observed following each dosing day. Day 3 and 6 safety blood results must be 
review prior dosing on the following day.  
Participants will fast for 8 hours pre-dose and 4 hours post dose for each 
dosing occasion.  


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Participants are randomised, so on each treatment day per group, 3 
participants receive LAT8881 and 1 receive placebo (different participants to 
receive placebo each treatment day) 
Participants will remain at the clinic until 6 hours post-infusion in order to 
collect blood samples for PK analysis and for review of safety and tolerability. 
Safety assessments will be reviewed in a clinic exit visit 7 days after the last 
infusion. 
Part B:  
This is a placebo-controlled randomized double blind cross-over safety and 
efficacy study of LAT8881.  
Participants will be randomized into two groups and will receive either a 
single 1.8 mg/kg dose of LAT8881  or placebo via intravenous administration 
over 10 minutes on two consecutive days.  
Participants will be randomly assigned to one of two groups, active then 
placebo or placebo then active.  
After passing screening, participants will be admitted for two nights: 
1. A study staff member will contact the participant for 3 consecutive 
days the week prior to obtain a verbal pain score out of 10 to confirm 
that their mean resting radicular pain meets the study inclusion 
criteria (pain score on each of the 3 days must be ≥3) 
2. The participant will arrive the evening prior to dosing, and will 
complete a final review of inclusion/exclusion criteria.  
3. Baseline assessments will be completed on the first day of dosing 
prior to IMP administration 
4. The participant will then receive their first dose.  
5. Collection of blood samples for PK/ PD analysis and assessments for 
review of safety, tolerability and efficacy are listed in the Schedule of 
Assessments. 
The participants will stay overnight.  
If the PK from the Part A demonstrates elimination in < 6 hours (assessed by 
concentration below LOQ of assay),  
6. the following morning the participants will cross-over and receive 
their second dose.  
7. Collection of blood samples for PK analysis and assessments for 
review of safety, tolerability and efficacy are listed in the Schedule of 
Assessments. 
8. Participants will remain at the clinic until 6 hours post the second 
infusion and then may be discharged.  
At the discretion of the Investigator and in consultation with the Study 
Sponsor, the requirement for subjects to be admitted to the clinic from the 
evening before Day 1 through to discharge at the end of Day 2 can be 
waived. In such circumstances, items 1 through 8 above will still apply, with 
the following modification to item #2: 


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- 
During the morning of Day 1 the following will be undertaken prior to 
dosing: a) a complete final review of inclusion/exclusion criteria, b) a 
written account of the activities the participant undertook on Day 0. 
- 
Prior to dosing on Day 2, a written account of the activities the 
participant undertook after discharge at the end of Day 1. 
Safety assessments will be reviewed 7 days after the last infusion by clinic 
exit visit. 
Participants will fast for 8 hours pre-dose and 4 hours post dose for each 
dosing occasion.  
 
Sample Size (by 
treatment group) 
Part A: 8 healthy participants 
Part B: Up to 20 participants with a history of lumbar radicular pain 
Inclusion Criteria 
Participants who meet all the following inclusion criteria may be included in 
the study: 
1. Male or female healthy participants, aged 18-49 years inclusive at 
screening; 
2. Body mass index (BMI) of ≥ 19.0 kg/m2 to ≤ 32.0 kg/m2 at screening; 
3. The participant must voluntarily provide written informed consent 
prior to any study procedures being performed and is willing and able 
to comply with procedures required in this protocol. 
4. A female participant is eligible to participate if she is not pregnant, 
not breastfeeding, and at least 1 of the following conditions applies:  
a. Not of childbearing potential, defined as surgically sterile 
(documented hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy) or postmenopausal (no menses for 
12 months without an alternative medical cause. A high 
follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy; however, in 
the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient); 
b. Of childbearing potential and agrees to use a highly effective 
method of contraception consistently during the treatment 
period and for at least 60 days following completion of study. 
c. A male participant with a female partner of childbearing 
potential is eligible to participate if he agrees to use highly 
effective contraception during the treatment period and for at 
least 60 days after the last dose of study treatment and 
refrains from donating sperm during this period; 
5. Females of childbearing potential must have a negative pregnancy 
test at screening (serum) and Day 1 (urine). 
6. Willing to be tested for SARS-CoV-2 infection if requested 
7. Agree to adhere to the current state and national advice regarding 
minimizing exposure to severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) from the first Screening visit until the 


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EOS/ETV. A SARS-CoV-2 Test will be taken if clinically indicated and in 
line with local processes. 
For Part B of the study, the following criteria is in addition to criteria 3-7:  
8. Male or female participants with sciatic  pain, aged 18 years and 
above  
9. Body mass index (BMI) of ≥ 19.0 kg/m2  
10. Presenting with a history of sciatic pain, radiating into a lower limb, of 
lancinating, burning, stabbing or electric quality, of duration of more 
than 3 months. 
11. Pain scores (VAS) for average daily leg pain at rest at the relevant nerve 
root of a mean of ≥4/10 and ≤9/10 for 3 days during the week prior to 
treatment, with a minimum of >3/10 on any day.   
12. Demonstration of disc herniation within 6 months by CT or MRI at a 
segmental level consistent with the clinical features. 
13. The site of disc herniation must affect L1-2, L2-3, L3-4, L4-5 or L5-S1. 
14. The patient is willing to keep all analgesic medication and other 
therapy 
usage 
[such 
as 
physiotherapy, 
acupuncture, 
or 
transcutaneous electrical nerve stimulation (TENS)] stable or 
decreased in the week prior to, and a week after, IP administration. 
15. The patient is in good general health, with the exception of the 
presenting condition under study, as determined by medical and 
psychiatric history, physical examination, ECG, serum chemistry and 
hematology, urinalysis and serology. 
 
Exclusion Criteria 
 Any of the following will exclude potential participants from both parts of 
the study: 
1. History or evidence of a clinically significant disorder (including 
psychiatric), condition, or disease that, in the opinion of the 
investigator and medical monitor or designee, would pose a risk to 
participants safety or interfere with the study evaluation, procedures, 
or completion; 
2. History or presence of conditions known to interfere with the 
distribution, metabolism, or excretion of drugs; 
3. Unwillingness to abstain from alcohol from 24 hours prior to 
investigational product administration, during confinement in the 
study site until discharge from the confinement period. 
4. A positive urine drug screen or alcohol breath test at screening; 
unless prescribed medication therapy for participants enrolled in Part 
B 
5. History of surgery or major trauma within 12 weeks of screening, or 
surgery planned during the study; 
6. Has any local skin infection that could compromise the injection site 
or have insufficient venous access. 
7. History of significant neurological diseases, including stroke, TIAs, 
seizures, and vascular malformations.  
8. Positive screen for human immunodeficiency virus (HIV), hepatitis B 
virus surface antigen (HBsAg) or hepatitis C virus antibody (HCV); 


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9. Treatment with any investigational product within 30 days or 5 half-
lives (whichever is longer) prior to baseline visit, or concurrent 
participation in a clinical study with an investigational product or 
device; 
10. Use of prescription or over the counter medications within 14 days of 
investigational product administration and during the study, with the 
exception of current medications provided the dose has been stable 
for at least 14 days, contraceptive medications, paracetamol, oral 
non-steroidal anti-inflammatory agents and vitamins or other 
medications that, in the opinion of the investigator, will not pose a 
risk to participants safety or interfere with the study evaluation, 
procedures or completion; 
11. History of cancer, with the exception of successfully treated non-
metastatic basal cell and squamous cell carcinoma; 
12. Treatment involving chemotherapy or the known possibility of 
chemotherapy in the future 
13. Participant has a known history of active or latent TB, except 
documented and complete adequate treatment of TB; 
14. Has clinically significant  laboratory abnormality as determined by the 
investigator deemed clinically significant by the investigator; inclusive 
of Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≥ 1.5 × the upper limit of normal (ULN)  
15. Has a history of substance abuse in the past 5 years or as determined 
by PI. 
16. Is unwilling to refrain from donating blood products or plasma within 
30 days prior to or post the study drug administration.  
17. Patient has a documented history of allergy or intolerance to 
components of the study drug. 
For Part B of the study, the following criteria is in addition to criteria 1-18:  
18. Has a history of significant pain unrelated to disc herniation that, in 
the opinion of the investigator, would significantly compromise 
assessment of leg radicular pain. 
19. Has radiological evidence of foraminal stenosis or of clinically 
significant spinal stenosis . 
20. Has had lumbar back surgery related to the specific disc(s). 
21. Has received an epidural corticosteroid injection within 3 months of 
screening. 
22. Has an ongoing worker’s compensation claim, disability claims, or 
litigation related to any pain problem. 
23. Has a history of chronic infection, including TB, Hep.B, Hep.C, or HIV. 
24. Has a history of demyelinating disease such as Multiple Sclerosis, 
Neuromyelitis Opticia, or Optic Neuritis. 
25. Has significant spinal stenosis or spondylolisthesis (Grade 2 or 
higher). 
26. Has a history of diabetic neuropathy or peripheral neuropathy in the 
lower extremities. 


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Investigational 
Product 
LAT8881 is administered via an infusion pump at a constant rate. The 
LAT8881 formulation will be presented in a pre-filled syringe containing the 
following: 
- 
LAT8881 10 mg/ml (active) 
- 
DSPE-PEG2000 20 mg/ml (Buffer) 
- 
Mannitol 47 mg/ml (Tonicity) 
- 
Sodium Hydroxide 0.33 mg/ml (Buffer) 
The placebo formulation will be presented as above but without the 
LAT8881 active. 
Dosage Regimen 
Part A:  
LAT8881 (or placebo) is administered at a dose of 0.8 mg/kg, 1.2 mg/kg and 
1.8 mg/kg via an infusion pump at a constant rate over 5 minutes. 
 
Part B:  
LAT8881 (or placebo) is administered at a dose of 1.8 mg/kg via an infusion 
pump at a constant rate over 10 minutes. 
Duration of 
Treatment 
Part A:  
Three single doses of LAT8881 or placebo (Day 1, Day 4 and Day 7) 
Part B:   
Two single doses, one of LAT8881 and one of placebo over two dosing 
occasions.  
Statistical 
Methods 
A maximum of 8 participants in Part 1 and 20 participants in Part 2 will be 
randomised to the trial, to achieve a sample size of up to 28 participants 
completing all study interventions. There will be an interim analysis after at 
least 10 participants in Part B complete the Study Per Protocol. 
 
 
 


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3. SCHEDULE 1 OF OBSERVATIONS AND PROCEDURES PART A 
Procedure 
Day 
-30 to -2 
Day 1/Day 4/Day 7 (hours) 
Day 3/ 6 
Day 
14/ 
ETV 
Screening 
Pre-
Dose 
Dose 
 
5 
min 
 
0.25 
 
0.5 
 
1 
 
1.5 
 
2 
 
2.5 
 
3 
 
4 
 
6 
Discharge 
Day 
prior 
dosing 5 
+/- 2 
day 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, height, 
weight 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical exam 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
× 
Pregnancy test (WOCBP)ͣ 1  
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
× 
Urine drug screen, Urinalysis and  
 Alcohol breath test2 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Test 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C screening 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
× 
 
 
 
 
 
 
 
 
 
 
 
 
x 
× 
12-lead ECG  
× 
× 
 
 
 
 
 
 
× 
 
 
× 
 
 
× 
Vital signs  
× 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
Spot pulse oximetry 
× 
× 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
Randomization 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose administration 4 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
Concomitant medication review 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
PK6 
 
× 
 
× 
× 
× 
× 
 
× 
 
 
x 
x 
 
 
PD6 
 
x 
 
x 
x 
x 
x 
 
x 
 
 
x 
x 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
 
*# Participants who withdraw early from the study will be encouraged to return to the clinic for an ETV assessment. 
* Participants may require an unscheduled visit to address safety issues and/or for any additional PK and/or PD sample collection as required. 
1 All WOCBP will have a serum pregnancy test at Screening and at the ETV visit, if applicable. Urine pregnancy tests will be performed for WOCBP at all other specified subsequent visits. If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
2. Urine Drug Screen and Alcohol Breath Test will be performed in clinic. A urine dipstick will be completed at all visit. In the event of positive Leukocytes and/or nitrates that urine sample will be sent to the local 
labortaotry for a microscopic examination.  


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3. SARS-CoV-2 Test will be taken if clinically indicated and in line with local processes.  
4. All participants will fast 8 hours prior and 4 hours after the study drug administration  
5. Samples must be taken with enough time that results are available prior to planned IP dosing on the following morning.  
6. Pre-dose, 5 ± 1 min, 15 ± 2 min, 30 ± 2 min, 60 ± 5 min, 2 h ± 10 min, 4h ± 20 min, 6h ± 30 min post-dose. 
4. SCHEDULE 1 OF OBSERVATIONS AND PROCEDURES PART B 
Procedure 
Day 
-30 to -2 
Day 1/Day 2 
(hours) 
 
Day 9/ ETV 
Screening 
Pre 
Dose 
Dose 
5min 
10 
min 
15 
min 
20 
min 
30 
min 
45 
min 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
 
6 
 
+/- 1 day 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, height, 
weight 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
exam 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
MRI or CT if >6mths 6 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sciatic Pain History 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 Day NRS Pain Scores 5 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)ͣ 1 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
Urine drug screen, Urinalysis 
and Alcohol breath test2 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Test 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C 
screening 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
× 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
12-lead ECG 
× 
× 
 
 
 
 
 
 
 
 
 
× 
 
 
 
× 
 
× 
 
Vital signs 
× 
× 
 
 
 
 
 
 
 
× 
 
× 
 
× 
 
× 
× 
× 
 
Spot pulse oximetry 
× 
× 
 
 
 
 
 
 
 
× 
 
× 
 
× 
 
× 
× 
× 
 
Pain scores (VAS) 
 
× 
 
 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 


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Provocation Assessment with 
VAS 
 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Patient General Impression of 
Change 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
QST (von Frey) 7 
 
× 
 
 
 
 
 
 
 
 
 
× 
 
 
 
× 
 
 
 
Randomization 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose administration 4 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review 
 
 
 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
PK Sampling8 
 
X 
 
x 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
x 
 
PD Sampling8  
 
x 
 
x 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
x 
 
Concomitant medication 
review 
 
 
 
× 
x 
Bang Binding Index 
assessment 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
Discharge 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
 
*# Participants who withdraw early from the study will be encouraged to return to the clinic for an ETV assessment. 
* Participants may require an unscheduled visit to address safety issues and/or for any additional PK and/or PD sample collection as required. 
1 All WOCBP will have a serum pregnancy test at Screening and at the ETV visit, if applicable. Urine pregnancy tests will be performed for WOCBP at all other specified subsequent visits. If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
2. Urine Drug Screen and Alcohol Breath Test will be performed in clinic. A urine dipstick will be completed at all visit. In the event of positive Leukocytes and/or nitrates that urine sample will be sent to the local 
labortaotry for a microscopic examination.  
3. SARS-CoV-2 Test will be taken if clinically indicated and in line with local processes.  
4. All participants will fast 8 hours prior and 4 hours after the study drug administration 
5. Staff to contact the participant for 3 consecutive days during the week prior to dosing for documentation of daily pain scores 
6. Not required if participant has current imaging available within the last 6 months 
7. Mechanical Quantitative Sensory Test (QST) assessment using Von Frey Aesthesiometer will be completed by trained staff members  
8. Pre-dose, 5 (mid infusion) , 10 (end of infusion) ± 1 min, 20 ± 1 min, 30 ± 2 min, 45 min ± 5 min, 60 min ± 5 min, 6h ± 30 min from the start of the infusion of the dose. 
9. Completed 6 hours post dose on Day 2 only 
 


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5. INTRODUCTION 
5.1. Background  
Neuropathic pain 
Neuropathic pain (NP) is defined as pain caused by a lesion or disease of the somatosensory 
nervous system.2 The damage may be located either centrally or peripherally. Examples of 
central neuropathic pain include pain in Multiple Sclerosis or Parkinson’s disease and pain 
after a stroke; examples of peripheral neuropathic pain include painful diabetic neuropathy, 
phantom limb pain, post-herpetic neuralgia, chemotherapy induced polyneuropathy, and 
trigeminal neuralgia. 
 
The symptoms of peripheral neuropathic pain vary, depending upon the type of nerves that 
are damaged. Typical descriptions of the pain include shooting, stabbing, electric shock, 
burning, tingling, tight, numbness, prickling, itching and a sensation of pins and needles. 
Symptoms may also include allodynia, hyperalgesia, anaesthesia dolorosa, with sensory gain 
or loss. The impact of neuropathic pain on both the individual and on society is substantial. 
In addition to the morbidity associated with the pain itself, patients with neuropathic pain 
have a decreased quality of life, increased use of healthcare resources, increased 
absenteeism and decreased productivity at work. 
 
The development of validated questionnaires for neuropathic pain has enabled better 
assessment of its prevalence in the general population. A recent systematic review of 
epidemiological studies of neuropathic pain estimated that the prevalence of pain with 
neuropathic characteristics ranged from 7- 10%.3 This is likely to increase as the population 
ages, when there will be an increased incidence of risk factors for neuropathic pain, such as 
diabetes, cancer and cancer chemotherapy. 
 
The treatment of neuropathic pain is challenging as it is generally not possible to alleviate 
the cause of the pain. Rather, therapy focuses on treating the symptoms. Non-
pharmacological treatments, such as physical exercise, cognitive behavioural therapy and 
meditation have been proposed but there is only weak evidence for the efficacy of such 
approaches.4 Pharmacological therapy is the mainstay of treatment. A recent review of 229 
randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain 
by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association 
for the Study of Pain (IASP) recommended gabapentin, gabapentin extended 
release/enacarbil, pregabalin, duloxetine, venlafaxine and tricyclic antidepressants as first 
line therapy.5 However, it was found that outcomes with these agents were generally only 
modest, with 4 to 10 patients requiring active treatment for a 50% reduction in pain, 
compared with placebo treatment. Moreover, many of these therapies have side effects, 
such as somnolence, dizziness, motor imbalance and cognitive impairment, which restrict a 
patient’s activities and diminish their quality of life.6 
 
There is clearly an unmet need for more effective therapies to treat neuropathic pain. 
LAT8881 has a different mechanism of action to current therapies and has shown promising 
activity in animal models of neuropathic pain. It also has a good pre-clinical and clinical 


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safety record. This is the first clinical study to investigate this compound (by intravenous 
dosing) in neuropathic pain. 
 
LAT8881 
LAT8881 (Tyr-hGH177-191) is a 16 amino acid peptide fragment based on the C-terminus of 
human-growth hormone (hGH177-191) with an additional tyrosine at the N-terminus. It was 
initially developed for the treatment of obesity, (known during that time as AOD9604), but 
Phase 2 clinical studies did not show a statistically significant weight loss in obese subjects 
and development for this indication was discontinued. 
Subsequent to these clinical trials in obesity, LAT8881 was successfully investigated in a 
variety of animal models of neuropathic pain:  
• An analgesic effect was demonstrated in a number of in vivo preclinical studies after 
administration of LAT8881 at doses ranging from 1.0 to 10 mg/kg, including when 
administrered intravenously, orally and subcutaneously .  
• In vitro electrophysiological studies suggested that LAT8881 inhibits neuronal activity 
in a manner consistent with a reduction in pain signalling.  
• Mechanism of action studies identified the target of LAT8881 to be LANCL1, an inner 
cell-membrane hub protein ubiquitously expressed but high in the nervous system, 
respiratory tissue, and testis, known to be involved in protection from cell stressors 
by engaging several pathways (such as AKT/mTORC, Eps8, GSH, and de-
ubiquitination)7 but, until now, not known as a potential therapeutic target for the 
treatment of neuropathic pain. 
The proposed repurposing of LAT8881 as a treatment for neuropathic pain via a novel and 
unique mechanism is underpinned by the preclinical and clinical safety data obtained when it 
was investigated as an obesity treatment, as detailed in the study Investigational brochure.  
5.2. Findings From Nonclinical and Clinical Studies 
A comprehensive nonclinical safety program with LAT8881 was completed prior to the 
initiation of the obesity clinical program:  
• Conventional repeat-dose studies were undertaken in rats and monkeys, with 
LAT8881 administered intravenously on a daily basis for 28 consecutive days in both 
species and orally for 26 and 39 weeks in the rat and monkey respectively. Maximum 
doses were 10 mg/kg/day to both rat and monkey when given intravenously and 100 
mg/kg/day in the rat and 50 mg/kg/day in the monkey when given orally. No 
concerning toxicities were observed.  
• Following review of studies to assess genotoxic potential, it was concluded that 
LAT8881 does not pose a genotoxic risk for humans under therapeutic conditions.  
• Reproductive studies were undertaken in rats and rabbits, at doses up to 50 
mg/kg/day (rabbit) and 100 mg/kg/day (rat). No effect on reproduction was observed 
in these studies.  
Six clinical studies have been completed with LAT8881 in healthy volunteers and in healthy 
obese subjects. The product was well tolerated when given intravenously in the first two 
clinical studies and orally in the next four studies. When the studies are described in this 


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Protocol, the emphasis is on the safety outcomes, as weight loss was not an objective of the 
neuropathic pain study. These studies are described below and in greater detail in the body 
of this protocol: 
• The first clinical study with LAT8881 was a placebo-controlled Phase I study conducted 
in 2001 (METAOD001). LAT8881 was administered intravenously to healthy male 
volunteers in single doses ranging from 25 to 400 μg/kg. Each subject was randomised 
to receive active drug on three occasions and placebo on another. The number of 
subjects per LAT8881 dose ranged from 4 to 10. LAT8881 was well tolerated over the 
dose range. There were no clinically significant adverse events (AEs), or significant 
abnormalities in vital signs, safety laboratory tests or electrocardiograms (ECGs) 
during the study. The most common treatment-related AEs were fatigue, headache 
and dizziness, with no apparent relationship to dose.   
• The second study (METAOD002) was a Phase IIa, double-blind placebo-controlled  
4  4 Latin Square design study in which 23 healthy clinically obese males participated. 
LAT8881 was administered as an intravenous infusion in single doses of 25, 50 and 100 
μg/kg. Each subject was randomised to receive active drug on three occasions and 
placebo on another. LAT8881 was well tolerated over the dose range: there were no 
study drug-related withdrawals, serious AEs, clinically significant AEs, or changes of 
clinical significance in vital signs, safety laboratory tests, or ECGs during the study. One 
subject reported severe chest pain, considered possibly related to treatment, after 50 
μg/kg, but not after other doses. The most common related adverse event was mild 
or moderate euphoria. This was not observed after placebo. 
• The first study with the oral LAT8881 formulation was a single dose, double-blind, 
placebo-controlled, 4  4 Latin Square designed study to evaluate safety, tolerability 
and pharmacodynamic endpoints in healthy, clinically obese males (METAOD003). The 
study was completed with each of 15 subjects receiving three oral doses (capsule 
formulation) of LAT8881 (9, 27 and 54 mg) and placebo. In addition, one subject 
received LAT8881 at all doses (not placebo) and another subject received LAT8881 (9 
mg and 54 mg only). 
LAT8881 was well tolerated over this dose range. There was one SAE, considered 
unrelated to treatment (hospitalisation for bronchial pneumonia). Two subjects 
withdrew because of AEs, these were not considered related to treatment. There were 
no clinically significant AEs, or changes of clinical significance in vital signs, safety 
laboratory tests or ECGs during the study. The most common treatment-related AEs 
were headache and diarrhoea. All AEs were mild or moderate, except for severe 
diarrhoea in one subject and the bronchiolitis noted above. 
• The next study to be conducted was designed to assess the safety of multiple daily 
oral dosing of LAT8881 (METAOD004) in healthy, clinically obese male volunteers. This 
study was a double-blind, placebo-controlled, dose escalation study with 3 cohorts, 
each of 12 subjects. Subjects in each cohort were randomised, so that 9 received 
active study drug (9, 27 or 54 mg LAT8881, capsule formulation) and 3 received 
placebo. Treatment at each dose was daily for 7 days. Dose escalation was approved 
by the sponsor after a safety review of the previous cohort. 


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LAT8881 was well tolerated over the oral dose range. There were no withdrawals from 
the study, serious adverse events (SAEs), clinically significant AEs, or changes of clinical 
significance in vital signs, safety laboratory tests or ECGs during the study. There were 
no observable trends in the incidence of AEs between the 9 mg and 27 mg LAT8881 
and placebo treatment groups. The highest dose administered (54 mg) was associated 
with an increased incidence of events involving the digestive system (diarrhoea, 
dyspepsia, flatulence, nausea and eructation) and general body symptoms of 
abdominal pain and headache. All were all of mild to moderate intensity. No anti-
LAT8881 antibodies were detected in sera collected from subjects treated with 
LAT8881 for 7 days.  
• A Phase IIb study was then conducted in 300 healthy clinically obese subjects 
(METAOD005). This was a double-blind, randomised, placebo-controlled parallel 
group study carried out in five centres in Australia. After a 2 week placebo run-in 
period, 300 subjects were randomised to receive capsules of placebo or LAT8881 (1, 
5, 10, 20 or 30 mg), once daily for 12 weeks.  
LAT8881 was well tolerated over the dose range. There were no changes of clinical 
significance in vital signs or safety laboratory tests during the study. Some abnormal, 
clinically significant ECG recordings were recorded, but these did not show a dose-
relationship and, when such information was available, were classified as mild and 
unrelated. The incidence and severity of adverse events was similar in all dose groups 
and placebo. Five patients reported at least one SAE, none of which was considered 
to be related to study medication. There were 10 withdrawals from treatment 
because of AEs, only one of which was considered related to treatment (depression). 
The most common treatment-related AEs were headache and gastrointestinal 
symptoms (abdominal distention, abdominal pain, constipation, diarrhoea and 
flatulence). All related AEs were of mild to moderate severity, except in three subjects 
who each had one severe related symptom (itchy skin, headache or diarrhoea). No 
antibodies to LAT8881 were detected in sera collected throughout the treatment 
period.  
Evaluation of weight loss in the METAOD005 study suggested a non-linear bimodal 
dose response and the final clinical study (METAOD006) was conducted at lower doses 
of LAT8881 (0.25, 0.5 and 1 mg). The safety data from this final study is of limited 
significance to the neuropathic pain study because of these low doses. 
• METAOD006 was a Phase IIb randomised, double-blind, placebo-controlled study in 
obese adults to assess the safety, tolerability and effect on body weight of LAT8881, 
in combination with a diet and exercise program. The study consisted of a four-week 
single-blind placebo run-in period, followed by 24 weeks of LAT8881 tablets once per 
day. A total of 534 subjects were enrolled in the study, 502 were randomised at the 
end of the 4-week placebo run-in period and all 502 subjects were included in the 
safety analysis.  
The incidence of AEs was similar between groups. There were 18 SAEs reported, two 
of which were considered related to treatment (syncope after placebo and after 0.25 
mg). Fourteen subjects withdrew from treatment because of AEs, two (fatigue, itchy 
skin) were considered related to treatment. The most common related AEs were 


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OFFICIAL 
headache, dysgeusia, diarrhoea, nausea and increased gamma glutamyl transferase, 
with no clear dose relationship. All were mild to moderate severity.  
Overall, it was concluded that LAT8881 displayed a good safety and tolerability profile 
in this study that was indistinguishable from placebo. However, there were no 
statistically significant changes in weight loss in any treatment group, and it was 
decided to discontinue the clinical program. 
A further two clinical studies were conducted with 30 mg oral capsules, one in peripheral 
neuropathic pain, the other in acute migraine: 
• LAT-NP-001 was a randomised, placebo-controlled, double-blind, crossover, phase IIa 
study to investigate the efficacy and safety of oral LAT8881 in neuropathic pain (post-
herpetic neuralgia or diabetic neuropathy). After a one-week baseline period, subjects 
were randomised to receive LAT8881 30mg or placebo capsules twice daily for four 
weeks, followed by a washout period of two weeks, a second baseline period of one 
week, and then crossover to receive the other treatment for four weeks. A total of 48 
subjects completed both treatment periods. 
LAT8881 was well tolerated in subjects with neuropathic pain due to PHN or DPN, but 
did not reduce the pain or associated symptoms under the conditions of the study 
• LAT-MIG-001 was a randomised, placebo-controlled, double-blind, crossover Phase IIa 
proof of concept study to investigate the efficacy and safety of oral LAT8881 in acute 
migraine. A total of 16 subjects were randomised to receive 2 capsules of 30 mg IMP 
(LAT8881 60 mg or placebo), to be taken at the onset of a migraine of moderate to 
severe intensity. After treatment the subjects returned to the clinic for re-evaluation 
and crossover to the second treatment.  
LAT8881 was well tolerated in subjects with migraine, but it did not reduce migraine 
pain significantly compared to placebo under the conditions of the study. 
Given the following observations, it is a reasonable to assume that the failure to reduce the 
symptoms of pain in clinical studies is due to a lack of systemic exposure to LAT8881 from oral 
dosing: (i) the extensive supporting nonclinical data in neuropathic pain models, (ii) no 
detectable levels of LAT8881 were measured within the blood of a subset of patients in  
LAT-NP-001 that were included within a pharmacokinetic sub-study, and (iii) the oral 
bioavailability of LAT8881 is estimated to be less than 1%.  
The preclinical and clinical data with LAT8881 available to date do not suggest any significant 
safety concerns. There are no established SAEs associated with administration of LAT8881, 
and no pattern of severe, related AEs. There is some evidence of a small increase in mild 
gastrointestinal disorders in one of the oral trials. Some mild ECG changes were noted after 
LAT8881 in two studies (METAOD005 and METAOD006) but not in the other four studies. Only 
one of these ECG changes was considered possibly related to treatment (a subject in Study 
METAOD006 who had a mild ectopic supraventricular rhythm after 0.5 mg LAT8881). 
 
 


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Sciatica, a subtype of neuropathic pain, is also referred to as radicular pain, which is defined 
as pain radiating from the lower back to one or both buttocks or legs. The condition occurs 
when either disc injury or compression of spinal nerve roots, or both, leads to irritation, 
inflammation, and nerve injury with resultant radicular pain and associated neuropathologic 
changes.  
 
In general, sciatica is a self-limiting condition with up to 80% of patients recovering within 8 
weeks of onset and up to 95% of patients recovering within 1 year. It is recommended that 
treatment for patients with sciatica should be conservative in nature for the first 6 weeks 
after symptom onset. 
 
Patients with sciatica are often initially treated with rest and oral analgesics, which include 
nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. However, these may have 
limited effectiveness initially, and/or on perisistent pain. Further, prolonged opioid use is 
associated with undesirable sequelae, both on the patient (tolerance, dependence) and in 
the community (diversion risk). Alternate treatments for persistent neuropathic pain, such 
as gabapentinoids and antidepressants, have limited efficacy, or poorly tolerated side 
effects, or both. The use of epidural steroids is relatively common, but has not been 
convincingly shown to provide sustained benefit, and conveys the risks of an invasive 
procedure.  Surgical options are also invasive, and outcomes are often poor in terms of 
improved pain. Based on the positive findings for neuropathic pain in pre clinical studies 
further examination of this study in participants with neuropathic pain is indicated. 


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6.  STUDY OBJECTIVES 
6.1. Hypothesis 
When administered as an IV infusion at a dose of 0.8 mg/kg to 1.8 mg/kg as determined in 
Part A , LAT8881 reduces neuropathic pain in subjects with lumbar radicular pain, with peak 
pain relief achieved within six  hours post-dose, and with no dose limiting side effects.  
6.2. Primary Objective 
Part A:  
• Evaluate the safety and tolerability of intravenous LAT8881 using an ascending dose 
schedule  
Part B:  
• Evaluate the analgesic efficacy of LAT8881 in patients with lumbar radicular pain 
6.3. Secondary Objectives 
Part A:  
• Evaluate the plasma concentrations and the PK properties of LAT8881 administered 
as an IV injection in healthy participants using a dose escalating design 
• Establish the dose regimen for Part B of the study 
Part B:  
• Evaluate the effect of Intravenous LAT8881, compared with placebo, VAS pain scores 
at rest 
• Confirm the safety of LAT8881 in participants with lumbar radicular pain 
6.4. Experimental Objectives 
Part A: 
• Collect blood samples to investigate (and possibly validate) a pharmacodynamic 
assay and/or biomarkers of LAT8881 activity 
Part B:  
• Evaluate mechanical Quantitative Sensory Test (QST) assessment on affected lower 
limb using Von Frey Aesthesiometer on two occasions, once prior to dosing and once 
post dosing. 
• Evaluate the effect of Intravenous LAT8881, compared with placebo, VAS pain scores 
at during straight-leg raise nerve stretch 
• Bang Binding Index assessment, whereby participant will be asked to record which 
dosing occasion they believe they got the active IP. 
• Collect blood samples to investigate (and possibly validate) a pharmacodynamic 
assay and/or biomarkers of LAT8881 activity 
 
 


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7.  STUDY DESIGN 
7.1. Overall design 
LAT-NP-002 consists of two parts. 
 
Part A:  
A Double blind, Randomized Cross-over Placebo-controlled Pharmacokinetic, Safety and 
Tolerability Study of Ascending doses of LAT8881 in Healthy Participants to determine the 
dose level for Part B. 
 
Part B:  
A Randomized Placebo-controlled Double-blind Cross-over Proof-of-Concept safety and 
efficacy study of LAT8881 in participants with lumbar radicular pain 
 
At the conclusion of Part A of the study, safety data and PK data will be collated and 
presented to HREC along with the justification for dose level and dose interval for Part B, 
noting that a different cohort of subjects will commence Part B. 
7.2. Justification of Study Design 
The study has been designed to look for a Maximum tolerated IV dose of LAT8881 in healthy 
participants followed by assessment of this dose to treat lumbar radicular pain.   
 
Part A:  
• Confirm the maximum tolerated dose within the target dose range 
• Characterise the pharmacokinetic (PK) profile of LAT8881 and of its metabolites 
• Seek to validate a pharmacodynamic (PD) marker and identify a PK/PD relationship 
to guide dosing in future efficacy studies. 
Part B: 
• Demonstrate proof-of-concept that LAT8881 can reduce pain in patients with lumbar 
radicular neuropathy – acute pain relief design allows for the limitations imposed by 
requiring an IV infusion of investigational product 
• Further validate the PK/PD relationship through association with pain relief in  
neuropathic pain subjects 
• Post-hoc analysis of subjects who demonstrate a clinical response to the treatment 
will inform future clinical work and the optimal target product profile. 
7.3. Sample Size 
No formal statistical sample size estimation has been performed due to the exploratory 
nature of this study. Rather the sample size is based on clinical and practical considerations: 
 
 


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• Part A follows a dose escalation design where 8 subjects will be dosed on each of 
three occasions with an increased dose (6 subjects) or placebo (2 subjects). The 8 
subjects will be split into a maximum of two groups of 4 subjects each (3 IMP and 1 
placebo), with the groups dosed at least a few days apart. The MTD will be the 
highest dose level at which no more than 1 of 6 subjects on active dose experience a 
dose-limiting toxicity. 
• In Part B of the study, a proof-of-concept, the sample size will be expanded up to 
n=20 based on the PI’s experience from design and management of lumbar radicular 
pain subjects. 
Overall, a total of 8 subjects (healthy volunteers) are planned for Part A of this study, and up 
to 20 subjects with lumbar radicular pain are planned to be enrolled in Part B. 
7.4. Justification of Dose  
The proposed starting dose was calculated based on the no-observed-adverse-effect level in 
previous clinical trials. 
8.  STUDY POPULATION 
8.1. Inclusion Criteria 
Participants who meet all the following inclusion criteria may be included in the study: 
1. Male or female healthy participants, aged 18-49 years inclusive at screening; 
2. Body mass index (BMI) of ≥ 19.0 kg/m2 to ≤ 32.0 kg/m2 at screening; 
3. The participant must voluntarily provide written informed consent prior to any study 
procedures being performed and is willing and able to comply with procedures 
required in this protocol. 
4. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies:  
a. Not of childbearing potential, defined as surgically sterile (documented 
hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or 
postmenopausal (no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy; however, in the 
absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient); 
b. Of childbearing potential and agrees to use a highly effective method of 
contraception consistently during the treatment period and for at least 60 
days following completion of study. 
c. A male participant with a female partner of childbearing potential is eligible 
to participate if he agrees to use highly effective contraception during the 
treatment period and for at least 60 days after the last dose of study 
treatment and refrains from donating sperm during this period; 


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5. Females of childbearing potential must have a negative pregnancy test at screening 
(serum) and Day 1 (urine). 
6. Willing to be tested for SARS-CoV-2 infection if requested 
7. Agree to adhere to the current state and national advice regarding minimizing 
exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the 
first Screening visit until the EOS/ETV. A SARS-CoV-2 Test will be taken if clinically 
indicated and in line with local processes. 
 
For Part B of the study, the following criteria is in addition to criteria 3-7:  
8. Male or female participants with  sciatic pain, aged 18 years or over; 
9. Body mass index (BMI) of ≥ 19.0 kg/m2  
10. Presenting with a history of  sciatic pain, radiating into a lower limb, of lancinating, 
burning, stabbing or electric quality, of duration of more than 3 months. 
11. Pain scores (VAS) for average daily leg pain at rest at the relevant nerve root of a mean 
of ≥4/10 and ≤9/10 for 3 days during the week prior to treatment, with a minimum of 
>3/10 on any day.   
12. Demonstration of disc herniation within 6 months by CT or MRI at a segmental level 
consistent with the clinical features. 
13. The site of disc herniation must affect L1-2, L2-3, L3-4, L4-5 or L5-S1. 
14. The patient is willing to keep all analgesic medication and other therapy usage [such 
as physiotherapy, acupuncture, or transcutaneous electrical nerve stimulation (TENS)] 
stable or decreased in the week prior to, and a week after, IP administration. 
15. The patient is in good general health, with the exception of the presenting condition 
under study, as determined by medical and psychiatric history, physical examination, 
ECG, serum chemistry and hematology, urinalysis and serology. 
8.2. Exclusion Criteria 
Any of the following will exclude potential participants from both parts of the study: 
1. History or evidence of a clinically significant disorder (including psychiatric), 
condition, or disease that, in the opinion of the investigator and medical monitor or 
designee, would pose a risk to participants safety or interfere with the study 
evaluation, procedures, or completion; 
2. History or presence of conditions known to interfere with the distribution, 
metabolism, or excretion of drugs; 
3. Unwillingness to abstain from alcohol from 24 hours prior to investigational product 
administration, during confinement in the study site until discharge from the 
confinement period. 
4. A positive urine drug screen or alcohol breath test at screening; unless prescribed 
medication therapy for participants enrolled in Part B 
5. History of surgery or major trauma within 12 weeks of screening, or surgery planned 
during the study; 
6. Has any local skin infection that could compromise the injection site or have 
insufficient venous access. 
7. History of significant neurological diseases, including stroke, TIAs, seizures, and 
vascular malformations.  


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8. Positive screen for human immunodeficiency virus (HIV), hepatitis B virus surface 
antigen (HBsAg) or hepatitis C virus antibody (HCV); 
9. Treatment with any investigational product within 30 days or 5 half-lives (whichever 
is longer) prior to baseline visit, or concurrent participation in a clinical study with an 
investigational product or device; 
10. Use of prescription or over the counter medications within 14 days of investigational 
product administration and during the study, with the exception of current 
medications provided the dose has been stable for at least 14 days, contraceptive 
medications, paracetamol, oral non-steroidal anti-inflammatory agents and vitamins 
or other medications that, in the opinion of the investigator, will not pose a risk to 
participants safety or interfere with the study evaluation, procedures or completion; 
11. History of cancer, with the exception of successfully treated non-metastatic basal 
cell and squamous cell carcinoma; 
12. Treatment involving chemotherapy or the known possibility of chemotherapy in the 
future 
13. Participant has a known history of active or latent TB, except documented and 
complete adequate treatment of TB; 
14. Has clinically significant  laboratory abnormality as determined by the investigator 
deemed clinically significant by the investigator; inclusive of Alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≥ 1.5 × the upper limit 
of normal (ULN)  
15. Has a history of substance abuse in the past 5 years or as determined by PI. 
16. Is unwilling to refrain from donating blood products or plasma within 30 days prior 
to or post the study drug administration.  
17. Patient has a documented history of allergy or intolerance to components of the 
study drug. 
For Part B of the study, the following criteria is in addition to criteria 1-18:  
18. Has a history of significant pain unrelated to disc herniation that, in the opinion of 
the investigator, would significantly compromise assessment of leg radicular pain. 
19. Has radiological evidence of foraminal stenosis or of clinically significant spinal 
stenosis . 
20. Has had lumbar back surgery related to the specific disc(s). 
21. Has received an epidural corticosteroid injection within 3 months of screening. 
22. Has an ongoing worker’s compensation claim, disability claims, or litigation related 
to any pain problem. 
23. Has a history of chronic infection, including TB, Hep.B, Hep.C, or HIV. 
24. Has a history of demyelinating disease such as Multiple Sclerosis, Neuromyelitis 
Opticia, or Optic Neuritis. 
25. Has significant spinal stenosis or spondylolisthesis (Grade 2 or higher). 
26. Has a history of diabetic neuropathy or peripheral neuropathy in the lower 
extremities. 
 


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8.3. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may  
be rescreened once at the discretion of the Investigator.  
A minimal set of information will be collected on all screen failures who were never chosen 
for participation: demography, screen failure details and eligibility criteria. 
 
PART A: Evaluate the safety and tolerability of multiple ascending single doses of LAT8881 
 
 
 
 
 
 
 
 
 
PART B: Evaluate the efficacy of Lat8881 in participants with lumbar radicular pain. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.  STUDY PROCEDURES 
9.1. Recruitment 
Participants will be recruited from the PARC Clinical Research database along with advertsing 
for Part B of the study. 
9.2. Informed Consent 
Potential participants will be provided with the Participant Information and Consent Form 
(PICF) and given adequate opportunity to read this document, consult with anyone they wish, 
and to ask questions of the study team, before deciding whether or not to take part. A signed 
consent form will be obtained from each participant prior to performing any study-specific 
procedures, including screening activities. Informed Consent must only be received by study 
Part A
Healthy 
Participants
Screening
Day 1 
0.8mg/kg
or Placebo
Day 4 
1.2mg/kg
or Placebo
Day 7 
1.8mg/kg
or Placebo
FollowUp/ETV 
7 days ±2
Randomised, placebo controlled ascending dose. 
Data safety review, decision on dose for Part 2. 
Blood Sampling Visit also required on Day 3 and 6  
Part B  
Sciatic Pain 
Participants 
Screening 
Day 1 
Day 2 
Follow Up/ETV 7 
days ±2 
LAT8881  
1.8mg/kg 
or  
Placebo 
2 night observation (unless waived by Investigator) 
LAT8881 
1.8mg/kgor  
Placebo 
Randomised, crossover 


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team members designated to this duty on the site Delegation Log. In most cases, the Site 
Principal Investigator or sub Investigators will be responsible for receiving Informed Consent 
for the study. The original copy of the PICF will be retained in the Investigator Site File and a 
copy will be provided to the participant. The date of consent, as well as document version 
and date will be recorded on the Electronic Data Capture (EDC).  
9.3. Screening 
For Part A, the screening visit must occur no more than 60 days prior to dosing. 
 
For Part B. the screening visit must occur no more than 28 days prior to dosing. 
 
For Part B; if the investigator deems appropriate the screening assessments may be split over 
two vists with Informed Consent Form, Medical History, Sciatic Pain Review and CT or MRI 
completed prior to additional assessments.  
9.4. Randomisation 
The results of all assessments conducted in the screening visit will be recorded in the EDC and 
must be reviewed by the Site Principal Investigator to confirm eligibility prior to randomising 
a patient to the study.  Once the Site PI confirms participant eligilibity for the trial, the 
participant will undergo randomisation.   
 
The methodology for assigning study numbers is discussed in section 14.1 below.  
9.5. Follow Up 
Participants will be requested to complete a Follow-Up Visit 1 week after the end of the 
treatment period (Day 14 for Part A and Day 9 for Part B). The focus of this visit will be 
completion of safety assessment and monitoring of AE’s and Concomitant medications.  
9.6. ASSESSMENTS  
9.6.1.  Demography 
Collection of the participants details including initials, gender, age, race, ethnicity 
9.6.2. Physical Exam 
A complete physical examination will include, at a minimum, assessments of the General 
Appearance, HEENT, Neck (incl Thyroid), Cardiovascular, Respiratory, Gastrointestinal, Renal, 
Neurological, Musculoskeletal, and Skin. Height and weight will also be measured and 
recorded at the Screening Visit.  
 
A Symptom Directed Physical Exam will be performed if necessary at the Day 7 Follow Up 
and/or ETV.  


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9.6.3. Medical History 
A complete medical history will be reviewed at Screening and will include evaluation for 
past or present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, metabolic, lymphatic, hematologic, immunologic, dermatologic, psychiatric, 
genitourinary and surgical history or any other diseases or disorders (including cancer). 
9.6.4. Sciatic Pain Assessment and History for Part B 
In addition to the physical exam assessment of sciatic pain and history will occur at the 
screening visit for participant in Part B.  
 
Special attention will required during the examination of the lower back and neurologic 
assessment of the lower limbs. This will particularly seek to determine motor function in the 
affected leg and will assess and record any sensory change that might coincide with the 
dermatomal representation of the affected nerve root. Assessment will include straight leg 
raise and qualities of pain in affected leg.  
9.6.5. Prior and Concomitant Medications 
Prior medications are those medications that are initiated and stopped prior to first study 
drug administration, while concomitant medications are medications taken at least once after 
first study drug administration. All medications stopping on the same day as first study 
treatment will be considered as concomitant medications. SARS-Cov-2 vaccination is 
acceptable, if > 2 week prior to dosing.  
9.6.6. Vital Signs  
Vital signs include blood pressure, heart rate, pulse oximetry, temperature, and respiratory 
rate (in semi supine or supine position after a 5-minute rest). Vital signs will be collected at 
the timpoints in Schedule 1 and 2. 
9.6.7. Electrocardiograms  
Electrocardiogram values will be summarized at each protocol scheduled time point. In 
addition, a frequency tabulation of ECG results (Normal, Abnormal Not Clinically Significant 
or Abnormal Clinically Significant) will be presented at each protocol scheduled time point.  
 
9.6.8. Average Daily Pain Scores (NRS) for Part B 
Study staff will contact the participant at the same time each day for 3 consecutive days 
during the week prior to Day 1 to obtain the participants average leg pain scores for the 
preceding 24 hours. Pain scores need to be at least ≥ 3/10 each day however the 3 day 
mean must meet the inclusion criteria of between ≥ 4/10 and ≤ 9/10.  
 
 


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9.6.9. Clinical Safety Blood and Urine 
 
Urinalysis, Urine Drug Screen and Pregnancy testing will occur at Screening, prior to each 
dosing occasion and Follow up visit or ETV, if applicable.  
For Part A only, Local laboratory Clinical Safety Blood results from samples taken on Day 3 
and 6 are required to be available and reviewed by PI/ designee prior to dosing occasions 2 
and 3. 
 
The following bloods will be performed via a locally contracted pathology laboratory (local 
laboratory): 
Laboratory Tests  
Parameters 
 
Hematology  
Haemoglobin  
Red blood cell count (RBC)  
Red cell distribution width 
(RCD)  
Haematocrit/Packed cell 
volume (PCV)  
RBC Indices:  
Mean cell volume 
(MCV)  
Mean corpuscular 
haemoglobin (MCH)  
Mean platelet volume 
(MPV)  
Platelets  
White blood cell 
(WBC) count with 
Differential:  
Neutrophils  
Lymphocytes  
Monocytes  
Eosinophils  
Basophils  
Clinical 
Chemistry  
  
Sodium  
Potassium  
Chloride  
Bicarbonate  
Anion Gap  
Urea  
Creatinine  
Albumin  
Alkaline phosphatase 
(ALP)  
Gamma-glutamyl 
transferase (GGT)  
Alanine 
Aminotransferase 
(ALT)  
Creatinine Kinase  
eGFR  
Uric acid  
Glucose (non-fasting) 
Calcium  
Ionised Calcium  
Phosphate  
Total Protein  
Globulin  
Bilirubin  
Aspartate 
Aminotransferase 
(AST)  
Lactate 
dehydrogenase (LD)  
Routine Urinalysis 
(if positive urine 
dipstick)  
Bilirubin, Specific gravity, pH, Nitrate, Protein, 
Leucocyte esterase, Blood, Ketones, Glucose, 
Urobilinogen.  
Microscopic 
examination (if blood 
or protein is 
abnormal)  
Pregnancy testing  
Highly sensitive serum  
FSH 
FSH for confirmation of post memopausal status 
Other Tests  
Serology: (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)  
9.6.10. 
Urinalysis  
A urinalysis test (dipstick) will be performed for each participant. Urinary analysis will be 
performed at Screening and other times according to the timepoints listed in Schedule 1 and 
2 .If abnormality is noted for nitrite or leukocyte esterase (and at the discretion of the 


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Investigator) a microscopic examination of RBC, WBC, bacteria and casts will be performed 
by the local laboratory. 
Macroscopic urinalysis parameters to be tested are: 
• pH (PH) 
• Specific Gravity (SPGRAV) 
• Creatinine (CREATININE) 
• Protein (PROT) 
• Glucose (GLUC) 
• Ketones (KETONES) 
• Total Bilirubin (BILI) 
• Occult Blood (OCCBLD) 
• Nitrite (NITRITE) 
• Urobilinogen (UROBIL) 
• Leukocytes (WBC) 
9.6.11. 
Urine Drug Screen 
A Urine drug screen will be performed at screening and other times according to the study 
schedule.  
Urine drug screen to include at minimum:  
• Amphetamines 
• Barbiturates 
• Cocaine 
• Opiates 
• Cannabinoids 
• Benzodiazepines 
A positive drug screen will result in exclusion from the study unless there is documentation 
of a stable dose of prescribed medication therapy for participants enrolled in Part B.  
9.6.12. 
Pregnancy Screen 
All WOCBP will have a serum pregnancy test at Screening and at the ETV visit, if applicable. 
Urine pregnancy tests will be performed pre-dose for WOCBP at all other specified 
subsequent visits. Urine pregnancy tests may be performed in the clinic using a human 
chorionic gonadotropin (hCG) pregnancy test. 
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
9.6.13. 
Alcohol Breath Test 
An alcohol breath test will be performed at screening and other times according to the 
study schedule. A negative result is required for entry and continuation in the study.  
9.6.14. 
CT or MRI Imaging 
Part B only: Assess the radiological validation of the herniated disc (MRI or CT Scan within 
the last 6 months). If an MRI or CT scan does not exist, it is important to order this 


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investigation for review prior to administration of the IMP to fulfil necessary validation of 
entry criteria. MRI is the preferred imaging report unless not appropriate due to metal 
implants.  
9.6.15. 
Pain assessment (VAS), Patient General Impression of 
Change (PGIC) and Bang Binding Index Assessment (Part B  only)  
Pain Assessments will be completed using a Visual Analogue Scale (VAS). VAS scores  will be 
collected at the timepoints in Schedule 2.  
The Patient General Impression of Change will be collected at the timepoints in Schedule 2.  
Bang Binding Index Assessment will be collected at the timepoints in Schedule 2 
9.6.16. 
PK and PD Sampling 
PK and PD sample analysis will be performed using validated or fit-for-purpose methods as 
outlined in the Laboratory Manual. 
 
The Sponsor will supply complete written instructions for handling, processing, storage, and 
shipping of samples prior to study initiation. 
 
Pharmacokinetic and Pharmodynamic samples will be taken at the timepoints in schedule 1 
and 2. The samples will be sent to a certified Central Laboratory for analysis.  
 
Blood samples for plasma PK and PD will be obtained at the following time points:  
Part A: Predose, 5, 15, 30 minutes, 1, 2, 4 and 6 hours post IV injection. 
Part B: Predose, 5, 10, 20, 30, 45 minutes, 1 and 6 hours from the start of the IV infusion. 
Collecting 4 mLs in a K2EDTA tube for the PK sample and 8mls for the PD Samples.  
 
The PK Population will include all randomized participants who received LAT8881, with 
exploitable PK data and without relevant deviations interfering with the PK evaluations.  
The PK Population will be used for the summaries and analyses of all PK data.  
9.6.17. 
Mechanical QST assessment using Von Frey Aesthesiometer 
  
(Part B only) 
Evalutate mechanical Quantitative Sensory Test (QST) assessment to detect sensory changes 
to light touch on affected and non-affected dermatomes using von Frey Aesthesiometer on 
six occasions, once prior to dosing and once 2 hours and 4 hours post dosing. This will occur 
for each dosing occasion. 
QST measurements will be completed by staff trained on performance of this test.  
 


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10. INVESTIGATIONAL PRODUCT (IP) DISPENSING AND ACCOUNTABILITY  
LAT8881 will be stored and handled by the pharmacist(s) according to study Pharmacy Manual (provided 
by the Sponsor or its designee), the pharmacy’s standard operating procedures, applicable laws, and 
regulatory requirements.  
 
The investigator or designee must confirm appropriate temperature conditions have been maintained 
during transit for all investigational product received and any discrepancies are reported and resolved 
before use of the investigational product.  
 
Only participants enrolled in the study may receive investigational product and only authorized site staff 
may supply or administer investigational product. All investigational product must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.  The investigator is 
responsible for investigational product accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). Further guidance and information for the final disposition of 
unused investigational products are provided in the Study Pharmacy Manual. 
 
11. Administration  
Part A:  
LAT8881 is administered at a dose of 0.8 mg/kg, 1.2 mg/kg and 1.8 mg/kg via an infusion pump at a 
constant rate over 5 minutes. The LAT8881 formulation will be presented in a polypropylene luer lock 
syringe containing the following: 
 
- 
LAT8881 10 mg/ml (active) 
- 
DSPE-PEG2000 20 mg/ml (Buffer) 
- 
Mannitol 47 mg/ml (Tonicity) 
- 
Sodium Hydroxide 0.33 mg/ml (Buffer) 
 
Part B:  
LAT8881 is administered at a dose of 1.8 mg/kg via an infusion pump at a constant rate over 10 minutes.  
 
The placebo formulation will be presented as above but without the LAT8881 active.  
 
To minimise potential local infusion site irritation or reaction, the LAT8881 infusion will be administered in 
line with a continuous infusion of 5% Dextrose Solution (50 g of glucose in water for injection, or 
equivalent). The dextrose solution infusion will commence approximately 30 minutes pre-dose and 
continue until the participant ceases fasting.  
The rate of dextrose solution will be 80mls/hr. The IV dosing/ Normal Saline infusion cannula will be 
inserted into the opposite arm to the PK sampling IV Cannula to avoid any dilution of the PK samples.  
 
Further details on the administration process can be found in the Pharmacy Manual. 
 


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12. Investigational Product Compliance  
The participant will receive investigational product directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents. The dose of investigational product and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person administering 
the investigational product. 
 
13. COVID-19 CONSIDERATIONS AND CONTINGENCY PLANNING 
Information regarding COVID-19 risk and considerations is included in the PICF, to ensure that study 
participants are cogniscent of the potential impact on the study and schedule. All participating sites must 
confirm that they are compliant with local infection control policies related to COVID-19.  
 
14. BLINDING, PACKAGING AND SHIPPING 
The IP for all sites will be manufactured and packaged by a contracted certified pharmacy. Treatment packs 
will be shipped to study sites on completion of a remote Site Initiation Visit (SIV).  
 
IP will be labelled with:  
• Study Protocol Number 
• Randomisation number and participant details 
• Instructions for Storage 
• Instructions for Use 
All participant-facing study personnel, including the CPI, Site PIs, and site study teams (including central 
coordinating team), will be blinded to treatment allocation until data collection is completed for all 
participants and the database is locked.  
 
To maintain blinding for participant-facing study personnel, the study drug and placebo will be presented in 
identical sized syringes with clear liquid, and the packaging will also be identical for both study drug and 
placebo. Treatment allocation will not be discernable by differences in appearance. The study interventions 
do not differ across the treatment groups, and study SOPs guiding data collection, particularly participant-
reported data, assist with reducing risk of inadvertent unblinding and discourage speculation regarding 
treatment allocation. 
14.1. 
Method for assigning subject study number  
At screening, each subject will, in chronological order, be allocated a unique Screening Number (Subject 
ID).  
At randomisation on Day 1, the subject will be manually assigned a unique Randomisation Number, which 
will be allocated in ascending order according to their chronological order of inclusion in the study. 
Confirmation of the randomisation number allocated to each subject will be documented in the drug 
accountability records and recorded in the CRF. 
 
For Part A, randomisation will be employed is to identify subjects have placebo on the three treatment 
days.  For Part B, randomisation is to identify the treatment sequence.  


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The Subject ID number will be used to identify the subject throughout the study period and on all study-
related documentation. 
 
15. UNBLINDING  
Blinding of treatment assignment is critical to the integrity of this clinical study.  In the event of a medical 
emergency or pregnancy in an individual participant in which knowledge of the IP is critical to the 
participant’s management, the blind for that participant may be broken. The participant’s safety takes 
priority over any other considerations in determining if a treatment assignment should be unblinded. 
 
If a decision is made to unblind a participant, the Site PI will access to an envelope containing the unblinding 
information. For any participant unblinded and/or withdrawn from the study, the appropriateness and 
requirements for further monitoring blood tests and urine tests as per the Study Schedule following 
emergency unblinding will be decided by the Site PI. This will depend on the clinical circumstances 
surrounding unblinding. 
 
Any request to unblind a participant for non-emergency purposes should be discussed with the Sponsor. 
 
16. SAFETY ASSESSMENTS 
Safety bloods will be performed at each study timepoint, and any early termination visit. Participants will 
undergo physical examination at study visits, as described in the Schedule of Events. AEs will be identified 
via: 
• Participant report 
• Observations (e.g. vital signs, physical examination) 
• UA via dipstick 
• 
Safety blood tests (and MSU, if applicable) 
• 
Fasting pre-dose and in the immediate post dose period  
16.1. 
Pregnancy Testing 
WOCBP must have a negative serum pregnancy test (βHCG) at screening and a negative urine pregnancy test 
prior to dosing on each occasion.  
Participants who are pregnant or breastfeeding are excluded from the study. Participants who return a 
positive urine pregnancy test at any study visit will be discontinued from study drug and a serum pregnancy 
test conducted.  If the serum pregnancy test is also positive, the patient will be discontinued from the study 
and an early termination visit will be undertaken.   
17. WITHDRAWAL 
Participants will be informed that they are free to withdraw from the study. 
The CPI may discontinue the study drug and/or withdraw a participant from the study if, in the Investigator’s 
opinion, it is not in the best interest of the participant to continue the study, or the participant demonstrates 
a consistent pattern of non-compliance with study procedures. Site PIs should discuss with the CPI any 
participant cases where withdrawal should be considered. 
 


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Patients withdrawing from the study early should be strongly encouraged to perform the early termination 
visit as soon as possible following the last dose of study drug and the Follow-Up visit should be performed 7 
days (+/- 2 days) after the last dose of study drug is taken.  If the participant does not want to return to the 
clinic for the Early Termination or Follow-up visit, a phone call visit should be made to collect as much 
information as possible.   
 
17.1. 
Replacement of participants 
In Part A, a subject who is withdrawn from the Study before Day 4 (the second dose) for any reason other 
than a dose limiting toxicity will be replaced. A subject who has withdrawn after Day 4 is completed will not 
be replaced. This will ensure that two subjects take placebo at end dose level.  
 
In Part B, a subject who is withdrawn from the Study before completion of Day 1 (the first dose) for any 
reason other than a dose limiting toxicity will be replaced. A subject who has withdrawn after Day 1 dosing 
is completed will, if possible, be replaced at the discresion of the sponsor and the Investigator. 
 
Replaced subjects will take the same treatment as the original subject that is being replaced. 
 
A termination case report form (CRF) page should be completed for every subject who received study 
medication whether or not the subject completed the study. The reason for any early discontinuation from 
the study will be indicated on this form.  
 
17.2. 
General Considerations for Stopping Criteria  
For Part A of the Study: 
• If 1 or more participants exhibits an SAE, or a significant AE, that is determined to be related to the 
study drug,(ie Serious Adverse Reaction or a Suspected Unexpected Severe Adverse Reaction) the 
study will be halted. No further dosing, dose escalation or inclusion of any further participants at the 
same dose will occur without recommendation by the Data Safety Monitoring Committee (DSMC) as 
per the agreed DSMC charter. 
• If 2 or more participants exhibit a moderate AE determined to be related to the study drug in the 
same system organ class (SOC, e.g., immune or gastrointestinal system, no further dosing, dose 
escalation or inclusion of any further participants at the same dose will occur without 
recommendation by the DSMC.  
• If any participant exhibits a mild or moderate AE that in the Investigator’s opinion may be an allergic 
reaction the study may be halted. No further dosing, dose escalation or inclusion of any further 
participants at the same dose will occur without recommendation by the DSMC.  
For Part B of the Study: 
• If 1 or more participants exhibits an SAE, or a significant AE, that is determined to be related to the 
study drug (i.e. aSerious Adverse Reaction or a Suspected Unexpected Severe Adverse Reaction) the 
study will be halted. No further dosing will occur without recommendation by the DSMC. 
• If 2 or more participants exhibit a moderate AE determined to be related to the study drug in the 
same system organ class (SOC, e.g., immune or gastrointestinal system), the study will be halted. No 
further dosing, will occur without recommendation by the DSMC. 


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• If any participant exhibits a mild or moderate AE that in the Investigators opinion may be an allergic 
reaction the study may be halted. No further dosing, will occur without recommendation by the 
DSMC.  
18. PROHIBITIONS AND RESTRICTIONS IN THE STUDY 
18.1. 
Prohibited medications 
Participants must abstain from alcohol for 24 hours prior to each dosing occasion. Illicit drugs are 
prohibited. Participants should also avoid caffeine for 48 hours and grapefruit juice for 24 hours prior to 
arrival to study visit. 
 
Use of prescription or over the counter medications and vaccines are prohibited within 14 days of 
investigational product administration and during the study, with the exception of current medications 
provided the dose has been stable for at least 14 days, contraceptive medications, paracetamol, oral non-
steroidal anti-inflammatory agents and vitamins; 
Participants should also not receive any other investigational products during the study.  
Participants should also not initiate any new exercise or physical therapy regimens during the study. 
Exercise and physical therapy regimens that were in place at the Screening visit may be continued in a 
stable manner during the study. 
 
18.2. 
Contraception 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the 
following conditions applies:  
o 
Not of childbearing potential, defined as surgically sterile (documented hysterectomy, bilateral 
salpingectomy or bilateral oophorectomy) or postmenopausal (no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient); 
o 
Of childbearing potential and agrees to use a highly effective method of contraception consistently 
during the treatment period and for at least 60 days following completion of study. 
o 
A male participant with a female partner of childbearing potential is eligible to participate if he 
agrees to use acceptable contraception during the treatment period and for at least 60 days after 
the last dose of study treatment and refrains from donating sperm during this period; 
 
To prevent pregnancy in a female subject of child bearing potential (FOCBP), the FOCBP must use a highly 
effective method of contraception (failure rate of <1%), during the study and for 60 days after the last dose 
of IMP. Such methods include: 
o Abstinence from heterosexual intercourse. This should be the subject’s usual and preferred 
lifestyle OR  
o Consistent and correct use of a highly-effective form of contraception, such as: 
▪ combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal or transdermal 
administration), 


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▪ progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable or implantable administration) 
▪ intrauterine device 
▪ intrauterine hormone-releasing system 
▪ bilateral tubal occlusion OR  
o Vasectomised partner, provided that the partner is the sole sexual partner and that the 
vasectomised partner has received medical assessment of the surgical success of the 
vasectomy 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
19. Study Oversight 
19.1. 
Suspension or premature termination of the study 
Conditions may arise during the study that could prompt the study to be halted or the study site to be 
terminated. The sponsor may terminate part of, or the entire study for safety, administrative, or 
commercial reasons. Conditions that may prompt such considerations include, but are not limited to, the 
following: 
• The discovery of unexpected, serious, or unacceptable risk to participants enrolled in the study; 
• A decision on the part of Sponsor to suspend, discontinue, or shorten the study; 
• Study conduct at a study site may warrant termination under conditions that include the 
following: 
o Failure of investigator(s) to enrol eligible participants into the study; 
o Failure of the investigator to comply with country-specific regulations; 
o Submission of false information from the research facility to the sponsor, the clinical 
monitor, or 
a regulatory authority; 
o Insufficient adherence to protocol requirements; 
o A conflict of interest of the investigator, his/her institution, or site personnel that could 
negatively 
impact the integrity of the clinical study; 
o Institution or Ethics Committee under investigation for cause by a regulatory authority. 
 
Any decision by the sponsor on stopping or restarting the study must be discussed with the investigator. All 
actions are to be documented and the Ethics Committee (EC) and regulatory (competent) authority 
notified in writing as required by local regulations. Should a protocol amendment be required, this will be 
managed in accordance with Section 22.4. The study must not recommence recruitment or dosing until 
approval is received in writing from the EC (if/as required by the EC). If the study is to be terminated for 
safety reasons, any further administration of IMP will be stopped.  
If the study is terminated for safety reasons, participants will be followed up for a minimum of one week 
following the last exposure to IMP, at which time an End of Study visit should be conducted. Refer to 
Schedule 1 and 2 for follow up assessments. Any AEs/SAEs ongoing at the time of the End of Study visit will 
be followed to resolution or stabilisation (whichever is the sooner). 
 
 


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19.2. 
Continuation on to Part B 
At the conclusion of Part A of the study safety data and PK data will be collated and presented to HREC 
along with the justification for dose level and dose interval for Part B. 
20. ADVERSE EVENTS 
20.1. 
Adverse event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and may not necessarily have a causal relationship with the 
administered treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether 
or not it is related to the medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction or any worsening (i.e. any clinically significant 
adverse change in frequency and/or intensity) of a pre-existing condition, which is temporally associated 
with the use of the sponsor’s product. Anticipated fluctuations of pre-existing conditions, including the 
disease under study, that do not represent a clinically significant exacerbation or worsening need not be 
considered AEs. 
 
Laboratory reference ranges are defined by upper or lower limits of parameters of the respective 
laboratory. The investigator should ensure that each parameter out of the normal range is assessed for 
clinical significance and the potential for being an AE (refer to Schedule 1 and 2). An adverse event is 
defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 12.1.6. 
 
20.2. 
 Adverse drug reaction/Suspected adverse (drug) reaction 
An adverse drug reaction (ADR) is any AE for which there is a reasonable possibility that the drug caused 
the AE. Reasonable possibility means there is evidence to suggest a causal relationship between the IMP 
and the adverse event. 
 
20.3. 
Suspected unexpected serious adverse reactions 
Suspected unexpected serious adverse reactions (SUSARs) are Aes that are believed to be related to an 
IMP and are both unexpected (i.e. the nature or intensity is not expected from the information provided in 
the Investigator’s Brochure) and serious. SUSARs are participant to expedited reporting to the applicable 
regulatory authorities. 
 
For regulatory reporting purposes, SUSARS will be unblinded. 
 
20.4. 
Causality 
The investigator must assign causality to each adverse event in relation to the IMP based on the following 
definitions: 


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Not related: AE with an incompatible time relationship to IMP administration, and that could be 
explained by underlying disease or other drugs or is incontrovertibly not 
related to the Investigational Product 
Possibly related: AE with a reasonable time relationship to IMP administration, but which also 
could be explained by concurrent disease or other medications. 
Probably related: AE with a reasonable time relationship to IMP administration that is unlikely to 
be attributed to concurrent disease or other medications. 
Definitely related: AE with plausible time relationship to IMP administration and which cannot be 
explained by concurrent disease or concomitant medications. 
 
20.5. 
Severity (Intensity) of adverse event 
Grade refers to the intensity of an AE and should not be confused with seriousness  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental Activities of Daily Living (ADL*). 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care ADLs. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
20.6. 
Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose: 
• Results in death, 
• Is life-threatening. 
Life-threatening in the definition of serious refers to an event in which the participant was at risk of 
death at the time of the event, it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
Hospitalisation is defined as inpatient admission or care regardless of duration. Out-patient 
treatment in an emergency room is not in itself an SAE, although the reasons for it may be. 
Elective surgery, or hospital admissions and/or surgical operations planned before or during this 
study are not considered Aes if the illness or disease existed before the participant was enrolled in 
the study, provided that it did not deteriorate in an unexpected way during the study. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is medically important or is a medically significant event. 
 
Medical and scientific judgement is required to decide if prompt notification is required in situations that 
the investigator regards as medically important that did not strictly meet the criteria above but may have 
jeopardised the participant or required intervention to prevent one of the outcomes listed above, or that 
would suggest any significant hazard, contraindication, side effect or precaution that may be associated 
with the use of the IMP. Such events should also be considered as serious. 
 


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20.7. 
Recording of adverse events 
For Australian sites, all events from Screening to prior to the first dose of IMP will be captured as medical 
history. All events occurring during and following the first administration of IMP will be reported as Aes or 
SAEs (if criteria met) until the completion of the End of Study Evaluation visit. 
 
AEs that are ongoing at the End of Study Evaluation visit will be followed up until the event has resolved or 
stabilised. All follow-up information will be recorded in the participant’s source records. All spontaneously 
volunteered and enquired for, as well as observed AEs, will be recorded in the participant’s source records 
as well as the CRF. 
 
It is preferable that AEs and SAEs be reported as diagnoses if available, rather than individual signs and 
symptoms. SAEs should be reported and documented in accordance with the procedures in listed below 
The following data should be documented for each AE: the description of the event, start and stop dates, 
intensity, causality and outcome must be recorded, as well as any actions taken. 
 
20.7.1. 
Clinical lab abnormalities and other abnormal assessments  
Abnormal laboratory findings (e.g., clinical chemistry, haematology, and urinalysis) or other abnormal 
assessments (e.g., ECG, vital signs) per se are not reported as AEs. However, those abnormal findings that 
are deemed clinically significant or are associated with signs and/or symptoms must be recorded as AEs 
(and recorded as an SAE if they meet the criteria of being serious) as described previously. Clinically 
significant abnormal laboratory or other abnormal findings that are present at baseline and worsen after 
first dose of IMP are to be considered AEs (and SAEs if serious).   
The investigator should exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Usually, the abnormality 
should be associated with a clinically evident sign or symptom, or be likely to result in an evident sign or 
symptom in the near term, to be considered clinically significant. A clinically significant laboratory 
abnormality in the absence of clinical symptoms may jeopardize the subject and may require intervention 
to prevent immediate consequences.    
 
20.8. 
Reporting of serious adverse events 
Any SAE must be reported by the investigator if it occurs during the clinical study or within 2 weeks of the 
participant having received the last dose of IMP, whether or not the SAE is considered to be related to the 
IMP. This shall include pregnancy in a female participant or in a female partner of a male study participant. 
Instances of death, congenital abnormality or an event that is of such clinical concern as to influence the 
overall assessment of safety, if brought to the attention of the investigator at any time after cessation of 
IMP administration and linked by the investigator to this study, should be reported to the sponsor. 
The investigator must report an SAE on an SAE Report Form and forward the SAE Report Form, the AE form 
and the concomitant medication form to the sponsor or delegate within 24 hours of becoming aware of 
the SAE and regardless of causality. All pregnancies in a female participant or in a female partner of a male 
study participant should be reported on a Pregnancy Report Form following the same reporting process 
and timelines required for SAEs. 
 
The investigator should not wait to receive additional information to document fully the event before 
notification of a SAE, though additional information may be requested. Where applicable, information 
from relevant laboratory results, hospital case records and autopsy reports should be obtained. 


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Follow-up information on SAEs must also be reported by the investigational site to the sponsor within the 
same time frame. If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided within 24 hours of the investigator becoming aware. All SAEs will be recorded in the 
participant’s source documents and the CRF. 
 
It is the responsibility of the sponsor to determine whether a reported SAE fits the classification of a SUSAR 
(refer to Section 12.1.3). If the sponsor considers the SAE to be drug related (i.e. an adverse drug reaction), 
unexpected and fulfils the criteria for a Suspected Unexpected Serious Adverse Reaction (SUSAR), the 
sponsor has the responsibility to expedite the reporting to all concerned investigators, to the EC where 
required, and to the appropriate regulatory authorities within the pre-defined timelines. 
 
The investigator must notify their EC of SAEs occurring at the site, within the time period and in accordance 
with requirements specified by the EC. The sponsor and/or delegate will promptly notify all relevant 
investigators and the regulatory authorities of findings that could adversely affect the safety of 
participant’s, impact on the conduct of the study or alter the 
ethics approval/favourable opinion of the study. 
 
20.9. 
 Follow-up of adverse events and serious adverse events 
All AEs and all SAEs must be followed by the investigator until resolution, or until in the opinion of the 
investigator, the AE has stabilised or is recognised as permanent, or until the participant is lost to follow 
up, whichever comes first. Follow-up investigations may be necessary according to the investigator’s 
medical judgement. 
21. STATISTICAL ANALYSIS 
21.1. 
General considerations 
An analysis of Part A will be conducted when all subjects in Part A have completed Part A.  
 
A final analysis of Part B will be conducted when all subjects have completed Part B. 
 
The statistical analysis principles described below will be supplemented by a comprehensive statistical 
analysis plan (SAP) which will be finalised before the database is locked. This will contain details of 
methods for handling missing data and early withdrawals. Any changes to the statistical analysis plan will 
be described and justified in the final report.  
 
Descriptive statistics will be used to analyse the data in both Part A and Part B of the study. The descriptive 
summary for the categorical variables will include counts and percentages. The descriptive summary for 
the continuous variables will include number of participants (n), means, medians, standard deviations, and 
minimum and maximum values. Pharmacokinetic measures will be analysed as for continuous variables. 
 
In Part A and Part B, data will be tabulated and analysed with respect to subject enrolment and disposition.  
 
In Part A, demographic, baseline characteristics and prior medications summaries will be presented overall. 
Concomitant medications, PD, PK and safety measure summaries will be presented by active treatment 
dose, placebo and overall. Note that results for the subjects on placebo across all doses will be combined 
for summary purposes. 
 


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In Part B, demographic, baseline characteristics (including history of lumbar radicular pain) and prior 
medications will be presented by treatment sequence and overall. Efficacy, PD, PK, concomitant 
medications and safety measure summaries will be presented by treatment within each treatment period 
and overall.  
 
As this is a Proof-of -Concept study, no formal statistical hypotheses are being specified although some 
may be investigated as part of the data presentation, in which case corresponding 95% confidence 
intervals will be presented for treatment differences and p-values of <0.05 will be declared statistically 
significant. Treatment comparisons will take into account the paired nature of the treatment responses 
where feasible and treatment period order will be ignored in any treatment comparisons. 
 
All data will be listed for all subjects to support each table and to present all data. All statistical analyses 
will be performed using SAS unless otherwise stated in the SAP. 
 
21.2. 
Analysis populations 
21.2.1. 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all participants enrolled and randomised into the study. The FAS 
population will be used for summaries of participant disposition, demographic and baseline characteristics. 
Participants will be analysed according to the treatment group they were assigned at randomisation. 
21.2.2. 
Per protocol population 
A per-protocol (PP) population will be based on duration of IMP treatment and protocol deviations. This 
population may exclude participants with inadequate exposure to IMP or who have other protocol 
deviations. Rules for this population will be included in the SAP. The PP population is the primary 
population to analyse efficacy endpoints. Demographic and baseline characteristics of the PP population 
will also be presented. 
21.2.3. 
 Safety population 
The safety population consists of all randomised participants who received at least one dose of IMP and 
had at least one post dose safety assessment. The safety population will be used for the analysis of safety 
and tolerability. Participants will be analysed as treated, regardless of the randomised treatment assigned, 
if this differs from that to which the participant was randomised. 
21.2.4. 
PK and PD population 
The PK and PD population will include all participants who received at least one dose of IMP, had at least 
one post dose sample collection for PK and PD analysis and who did not have any clinically significant 
events or protocol deviations that may have compromised the integrity of the PK and PD results.  
21.2.5. 
Participant disposition 
The total number of participants will be summarised. The duration on study, and number of participants 
terminating the study treatment early, along with the reason for early study treatment termination will 
also be summarised. 
 


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21.3. 
Analysis of safety data 
Safety observations and measurements include study drug exposure, AEs, safety laboratory tests, vital 
signs, physical examinations and ECGs. 
21.3.1. 
Extent of exposure 
The number of participants exposed to study treatment, duration of exposure and total IMP administered, 
will be summarised for Part A and for Part B. 
21.3.2. 
Adverse events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (Version 
20.0 or later) and summarised by system organ class (SOC) and preferred term (PT). 
 
A summary of the number and percentage of participants with the following adverse events will be 
prepared for Part A: by dose (with all placebo subjects combined) and overall; Part B: by treatment within 
sequence, by treatment and overall : 
• All adverse events 
• Serious adverse events 
• Adverse events leading to premature discontinuation of IMP 
• Adverse events by intensity 
• Adverse events by relationship to IMP 
21.3.3. 
 Clinical laboratory evaluations 
Individually for Part A and Part B, safety laboratory data (haematology, clinical chemistry, and urinalysis) 
will be summarised by visit and treatment. All laboratory data will be included in the data listings. In 
addition, a separate listing of laboratory data for participants with clinically significant abnormal results will 
be prepared. 
21.3.4. 
Other safety measures 
Individually for Part A and Part B: 
• Vital signs (body temperature, respiratory rate, heart rate, and blood pressure) will be summarised 
by baseline and treatment overall and for each treatment within the treatment sequence. Changes 
over time in vital signs will be summarised. 
• Physical examination data will be listed only.  
• The number and percentage of participants receiving concomitant medications will be tabulated 
overall and by medication received. 
21.4. 
Analysis of pharmacokinetic data 
The following pharmacokinetic parameters will be derived from the plasma concentrations of LAT8881 and 
metabolites, where practicable: 
• 
Cmax Maximum plasma LAT8881 concentration 
• 
Tmax Time to maximum plasma LAT8881 concentration 
• 
AUC0-t Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification. It will only be calculated if there are at least 
three quantifiable data points. 


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• 
AUC0-inf Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification, extrapolated to infinity 
• 
T1/2  Terminal elimination half life, will only be determined if there are at least three quantifiable 
elimination phase data points. 
Plasma LAT8881 values (or those of its metabolites) below the limit of quantification will be labelled as 
(BLQ) in the plasma LAT8881 data listings and set to zero if recorded pre-dose. 
21.5. 
Analysis of efficacy data (Part B only) 
The primary population for analysis of efficacy data is the PP population. All summary tables and results of 
statistical analyses will be presented for the PP population for all efficacy endpoints. In addition, all 
summary tables and results will be presented for the FAS population. 
 
Individual pain score-time profiles for each treatment within each subject will be presented graphically. 
The difference between the VAS pain scores for “Pain Now” at each timepoint for LAT8881 compared with 
placebo within each subject will be estimated and presented graphically. The number of subjects, mean, 
standard deviation, minimum and maximum VAS pain score at each timepoint, change from baseline, 
difference between treatments at each timepoint and change from baseline difference between 
treatments will be presented for each treatment overall and within each treatment period. 
21.6. 
Analysis of exploratory endpoints 
Part A and B: Exploratory analysis of pharmacodynamic assay and/or biomarkers of LAT8881 activity will be 
completed pre and post dose on each dosing occasion throughout Part A and B of the study.  
 
Part B: Exploratory analyses will be undertaken to determine the relationship between change in current 
VAS pain scored from baseline through to 6 hours post treatment.  
 
The approaches to these investigative analyses will be detailed in the statistical analysis plan. 
21.7. 
Planned Interim Analyses 
The DSMC will monitor blinded safety data on an ongoing basis and at the completion of Part A of the 
study.  The DSMC will also review PK data from Part A, provide to HREC to determine the MDT dose for 
Part B.  
 
In Part B, an interim analysis will be undertaken after ‘at least 10 subjects’ have completed both periods 
Per Protocol. Enrolment will continue while the interim analysis is undertaken. The interim analysis will 
include results for only the 10 (or less) subjects that have completed both periods. The aim of the analysis 
includes but is not limited to: 
• Providing additional insight regarding potentially stopping the study for futility. Details will be 
provided in the DSMC charter. 
• Undertaking a sample size re-estimation based on the primary endpoint of the change in VAS “Pain 
Now” score from baseline through the 6 hours post-infusion. The standard deviation for the change 
from baseline while on placebo treatment and the correlation between the changes from baseline 
while on placebo and on active treatment will be used to estimate a sample size required to detect 
a clinically significant difference in the change from baseline while on active treatment compared 
with placebo, with a power of 80% and type I error (alpha) of 5%. Full details on this interim 
analysis will be included within the SAP. 


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22. STUDY MANAGEMENT 
22.1. 
Regulatory compliance and ethical conduct 
This study must be conducted in compliance with the study protocol, the requirements and obligations of 
the International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines, 
Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2),1 the World Medical 
Association Declaration of Helsinki23 and its amendments and all applicable local guidelines, laws and 
regulations. Investigators and other site personnel will undergo appropriate study-specific training during 
the study site initiation visit. Before initiation of the study at the site(s), the written approval / favourable 
opinion of the local and/or national independent Ethics Committee(s) and relevant Health Authority(ies) 
will be sought and obtained. 
22.2. 
Ethics Committee review 
Prior to the initiation of the study, the protocol and associated documentation (including all materials used 
to recruit participants for the study) must be given a favourable opinion by an Ethics Committee (EC). A 
copy of this written approval and any correspondence with the EC will be provided to the sponsor. The 
investigator must obtain approval from the sponsor before potential participants can undergo any study 
specific screening procedures. The investigator will comply with any additional requirements imposed by 
the EC. The investigator must submit progress reports to the EC according to local regulations and 
guidelines. The investigator must also provide their EC with any reports of SAEs from the study site in 
accordance with the EC’s requirements and timelines. 
22.3. 
Informed consent process 
The investigator will ensure that the participant is given full and adequate oral and written information 
about the nature, purpose, possible risks and potential benefits of the study. Participants must also be 
notified that they are free to discontinue from the study at any time. The participant should be given the 
opportunity to ask questions and should be allowed time to consider the information provided. The 
participant’s signed and dated informed consent must be obtained before conducting any procedure 
specifically for the study. The investigator must store the original, signed ICF with the participant’s medical 
records. A copy of the signed and dated ICF must be given to the participant. Participants who are 
incompetent and unable to freely provide informed consent and participants who are unable to read or 
speak English without the assistance of an interpreter will not be invited to participate in the study. 
If new information arises during the study that may affect the safety of the participants, the protocol and 
ICF will be amended as appropriate and submitted to the EC as outlined in Schedule 1 nd 2. Following 
approval by the EC, participants will be advised by letter of any safety related updates that may impact 
during the post-study period and be invited to discuss any concerns with the investigator. When 
applicable, participants may be requested to re-consent to ongoing their participation in the study. 
22.4. 
Protocol amendments 
Modification of the signed, EC-approved protocol must not be changed without the agreement of the 
sponsor. If it is necessary for an EC-approved study protocol to be amended, the relevant EC and, if 
required, the local regulatory authority must be informed and asked for its opinion as to whether a 
reevaluation of the ethical aspects of the study is necessary. In the UK, a substantial amendment to the 
protocol will be submitted to the Medicines and Healthcare Products Regulatory Agency for approval. The 
investigator must not implement any deviation from, or change to the protocol, without agreement by the 
sponsor and prior review and documented approval/favourable opinion of the amendment from the  
 
 


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relevant EC, except where it is necessary to eliminate an immediate hazard to study participants, or where 
the change(s) involve(s) only logistical or administrative aspect(s) of the study, for example, change in 
monitor(s) or change of telephone number(s). 
If a protocol amendment requires a change to the Participant Information Sheet (PIS) or Informed Consent 
Form (ICF), approval of the revised PIS and ICF by the sponsor and EC is required before the updated 
document can be used. Following approval, the sponsor (or delegate) will distribute new versions of 
amended documents (e.g. protocol, PIS, ICF) to the site. 
22.5. 
Protocol deviations 
No deviations from or changes to the protocol will be implemented without documented approval from 
the EC of an amendment, except where necessary to eliminate an immediate hazard(s) to study 
participants or when the change(s) involves only logistical or administrative aspects of the study. Any 
deviations from or changes to the protocol which were implemented to eliminate an immediate hazard 
and the proposed amendment, if appropriate, should be submitted to the EC for review and approval as 
soon as possible. Should any protocol deviation occur, it must be reported to the study monitor as soon as 
is reasonably practical. If a major protocol deviation occurs, the investigator must notify the sponsor and 
the appropriate EC as soon as possible or as per local requirements. 
 
All instances of noncompliance with the requirements of the Study Protocol will be captured in a Protocol 
Deviation Log. The deviation and the reason for its occurrence must be documented, reported to the 
relevant EC (if required) and included in the clinical study report.


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23. QUALITY CONTROL AND QUALITY ASSURANCE 
23.1. 
Training of staff 
Each individual involved in the study must be qualified by education, training and experience to perform 
his or her respective tasks. Site staff may be trained at investigator meetings and initiation visits by the 
sponsor or their designees. 
23.2. 
Study monitoring 
The study will be independently monitored in accordance with ICH GCP1, and applicable local regulations. 
Before the start of the study, a study monitor appointed by the sponsor will evaluate the investigational 
site to ensure facilities are adequate and to discuss responsibilities with the site staff with regards to 
following the protocol and regulatory and ethical requirements. During the study, the study monitor will 
regularly visit the site to monitor and confirm protocol, regulatory and ethical adherence, confirm data 
accuracy and provide information and support as needed. The investigator is responsible for maintaining 
source documents. The investigator must agree to allow the study monitor direct access to all relevant 
documents at each monitoring visit, including electronic medical records, and to allocate their time and the 
time of their staff to the study monitor to discuss findings and any relevant issues. Site staff will be 
provided with contact details for the study monitor and back-up persons in the event they have queries or 
require assistance. 
23.3. 
Data management and quality control 
The sponsor (or delegate) will be responsible for activities associated with the data management of this 
study. This will include setting up a database and data transfer mechanisms, along with appropriate 
validation of data and resolution of queries. 
 
Data generated within this clinical study will be handled according to the relevant SOPs of the sponsor 
and/or their delegate(s). An electronic CRF (eCRF) will be created by the data management group for 
recording of the required data and integration into the study database. All data (including electronically 
available data, i.e. eCRF and laboratory data) will be integrated into a validated Data Management System 
with full audit trail capability (i.e. a computerised log of all subsequent changes to the data will be 
recorded). Automated checks will be made against the data to ensure completeness and consistency. 
 
The database and check programs will be validated before implementation. AEs will be coded using 
MedDRA (Version 20.0 or later) and medications will be coded using the current version of the WHO Drug 
Dictionary. Missing or inconsistent data will be queried via system generated queries to the investigator for 
clarification. Subsequent modifications to the database will be documented. Data collection and entry into 
the eCRF will be completed by authorised study site personnel designated by the investigator. Appropriate 
training and security measures will be completed with the investigator and all authorised study site 
personnel prior to the study being initiated and any data being entered for any study participants. The 
eCRFs should always reflect the latest observations on the participants participating in the study; 
therefore, the eCRFs are to be completed as soon as possible during or after the participant’s visit. The 
investigator must verify that all data entries in the eCRFs are accurate and correct. If some assessments are 
not done, or if certain information is not available or not applicable or unknown, this should be indicated in 
the eCRF. The investigator will be required to sign off on the final clinical data. During the study the study 
monitor will review the eCRFs and evaluate them for completeness and consistency. The eCRF will be 


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compared with the source documents to ensure that there are no discrepancies. All entries, corrections 
and alterations are to be made by the investigator or designee. The study monitor cannot enter data into 
the eCRFs. If corrections are needed, the responsible study monitor or data manager will raise a query and 
the appropriate investigational staff will be required to provide an answer. All queries and resultant data 
changes will have an electronic audit trail, meaning that the name of the investigational staff responding to 
the query, time and date stamp are captured. 
 
The eCRF is considered a data entry form and should not constitute the original, or source document, 
unless otherwise specified. Source documents are documents used by the investigator or study site that 
relate to the participant’s medical record, that verify the existence of the participant, the inclusion and 
exclusion criteria and all records covering the participant’s participation in the study. They include, but are 
not limited to, laboratory reports, hospital records, participant files, etc. eCRFs will be completed for 
participants who have signed the ICF, are eligible for this study and have been enrolled in the study. 
23.4. 
Audits and inspections 
An audit is a systematic and independent examination of study related activities and documents to 
determine whether the evaluated study activities were conducted and the data were recorded, analysed 
and accurately reported according to the protocol, the sponsor’s standard procedures or those of the 
sponsor’s designees, ICH GCP and applicable regulatory requirements. In accordance with ICH GCP, this 
study may be selected for audit. Inspection of site facilities (e.g. pharmacy, medication storage areas, 
laboratories) and review of study-related records may occur by the sponsor, sponsor’s representative, 
Ethics Committee or regulatory authority to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. The regulatory authority or Ethics Committee inspectors 
are responsible for contacting and visiting the investigative site for the purpose of inspecting the facilities, 
if required, and, upon request, inspecting the various records of the study (e.g. source documents, CRFs, 
essential documentation, and other pertinent data) ensuring that participant confidentiality is respected. 
 
The investigator should contact the sponsor or designee immediately if they are contacted by a regulatory 
agency or Ethics Committee about an inspection at their centre. If an audit or inspection occurs, the 
Investigator and institution agree to allow the auditor/inspector direct access to all relevant documents 
and allocate their time and the time of their staff to the auditor/inspector to discuss findings and any 
relevant issues. 
24. DOCUMENTATION, RECORD ACCESS AND ARCHIVING 
24.1. 
Maintenance of essential documents/supplements at study site during the study 
At the beginning of the study, an Investigator’s Study File will be established at the study site. The 
investigator/institution is responsible for maintaining the study documents during the study as specified in 
the ICH GCP1 guidelines and applicable regulatory requirement(s). The investigator/institution must take 
measures to prevent accidental or premature destruction of these documents. These files must be suitable 
and available for inspection at any time by the sponsor, study monitor, and/or applicable regulatory 
authorities. 
24.2. 
Data protection 
To protect the participant’s identity, a unique participant identification code (Participant ID) will be 
assigned by the investigator to each study participant and used in lieu of the participant’s name when the 
investigator reports SAEs and/or other study-related data. The participant’s study number, rather than the 


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participant’s name, will appear on all documents and will be cross referenced by the participant’s date of 
birth. Personal information will be treated as confidential, but may need to be reviewed by authorised 
representatives of the sponsor (and/or delegate), the EC and regulatory authority(ies). The participant’s 
consent to direct access to his/her original medical records for data verification purposes must be obtained 
prior to that participant’s involvement in the study. Participants will be informed that data will be held on 
file by the sponsor and that these data may be viewed by staff including the study monitor and by external 
auditors on behalf of the sponsor and appropriate regulatory authorities. Participants will also be informed 
that a study report will be prepared and may be submitted to regulatory authorities and that the study 
results may be published. However, participants will be identified in such reports only by study 
identification number (Participant ID), gender and age. All participant data will be held in strict confidence.  
 
The PIS will explain that electronic study data will be stored in a computer database, maintaining 
confidentiality in accordance with the applicable local privacy regulations. Participant data in the database 
will be identified by Participant ID number only. Electronic CRFs will also identify participants by Participant 
ID only and will be maintained and stored in accordance with the applicable local privacy regulations. The 
PIS will also explain that for data verification purposes, authorised representatives of the investigator, 
sponsor, regulatory authorities or ECs may require direct access to parts of the hospital or practice records 
relevant to the study including the participant’s source documents and/or medical record. 
24.3. 
Data retention & archiving 
All study records (including the Investigator’s Study File containing Essential Documents as defined in ICH 
GCP1) and source data must be available for retrospective review or audit. 
 
Source documents are original documents, data, and records from which the participant’s CRF data are 
obtained. These include, but are not limited to: hospital records, participant’s source documents/files, 
clinical and office charts, laboratory and pharmacy records, diaries, radiographs, IMP accountability logs, 
and correspondence. CRF entries may be considered source data if the CRF is the site of the original 
recording (i.e., there is no other written or electronic record of data). In this case, a note to the file should 
indicate which CRFs data points are considered source data. At completion of the study the investigator is 
responsible for the archiving of the study records for their site. 
 
All source data, clinical records and laboratory data relating to the study must be archived for no less than 
2 years after the last approval of a marketing authorisation application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region, or at least two years have elapsed 
after formal discontinuation of clinical development of the IMP. Study documents should be retained for a 
longer period as required by local regulatory requirements or by an agreement with the sponsor. In 
Australia and UK, records should be retained by the trial sponsor for at least 15 years following completion 
of the trial. It is the responsibility of the sponsor to inform the investigator/Institution as to when the 
documents no longer need to be retained. 
 
No study document should be destroyed without prior written agreement between the sponsor and the 
investigator. If the investigator leaves the Institution, the responsibility for all study documents must be 
transferred to another person at the institution. If the investigator wishes to assign the study records to 
another party or move them to another location, he/she must notify the sponsor in writing of the new 
responsible person and/or the new location. 


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25. STUDY ADMINISTRATION 
25.1. 
Study agreements 
Financing and insurance of this study will be outlined in separate agreement(s) between the sponsor and 
all relevant parties. 
 
Payments will relate to the number of participants as well as the cost of clinical visits, laboratory 
investigations and other services outside of normal routine examinations and specifically connected with 
the conduct of this study. This agreement will cover payment for eCRFs fully completed in conformity with 
the protocol. The fee for participants who withdraw prematurely from the study will be on a pro-rata basis 
reflecting the percentage of study activities completed. Neither the sponsor nor its designee is financially 
responsible for further testing/treatment of any medical condition that may be detected during the 
screening process. In addition, in the absence of specific arrangements, neither the sponsor nor its 
designee is financially responsible for further treatment of the participant’s condition beyond the time 
period specifically outlined in this protocol. The investigator(s) must comply with all the terms, conditions 
and obligations of the study agreement for this study. In the event of any inconsistency between this 
protocol and the study agreement, the study agreement shall prevail. 
25.2. 
Confidentiality 
In signing the final protocol, every participating investigator agrees to keep all information and results 
concerning the study and the investigational product confidential for as long as the data remain 
unpublished. The confidentiality obligation applies to all personnel involved at the study site. However, 
authorised regulatory officials and the sponsor’s personnel (or their representatives) will be allowed full 
access to inspect and copy the records. All IMPs, participant bodily fluids and/or other materials collected 
shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the sponsor 
and the EC. 
 
All CRFs as well as all reports and communications relating study involvement will identify each participant 
only by the participant identification code (Participant ID). The investigator will maintain a current 
confidential Participant Identification List of full names of all participants in this study. This list will allow 
the investigator to reveal the identity of the participants if they need to be contacted for safety reasons. 
This information will be held in the strictest confidence and will only be used if needed for emergency 
purposes. 
25.3. 
Insurance 
The sponsor has appropriate liability insurance cover available to enable it to indemnify and hold the 
investigator(s) and relevant staff as well as any hospital, institution, EC or the like, harmless from any 
claims for damages for unexpected injuries, including death, that may be caused by the IMP but only to the 
extent that the claim is not caused by the fault or negligence of the participants or investigator(s). This 
insurance is held in accordance with the applicable local legal requirements. Further details of this and 
financial arrangements are specified in the agreements with the study site. 
25.4. 
Reporting 
A final integrated clinical/statistical report will be prepared that is compliant with the ICH Note for 
Guidance: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95)24. 
 


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25.5. 
Publication policy 
By signing the study protocol, the investigator agrees with the use of results of the study for the purposes 
of national and international registration, publication and information for medical professionals. If 
necessary, the authorities will be notified of the investigator’s name, address, qualifications and extent of 
involvement. 
 
An investigator shall not publish any data related to this study (poster, abstract, paper, slide presentation, 
etc.) without having consulted with the sponsor in advance. The objectives, the content and the results of 
the present study should be considered confidential. All data and results are the exclusive property of the 
sponsor. 
 
Except for legal reasons, the investigator will not reveal the result of the study to a third party without a 
mutual agreement about the analysis and interpretation of the data with the sponsor. 
AEs will be assessed by the Site PI, and in the event of an SAE, the CPI and Sponsor must be notified by the 
Site PI or delegate within 24 hours of observing or being informed of the event.   


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26. REFERENCES 
 
1 International Conference on Harmonisation (ICH) Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2), 9 November 2016 
 
2 International Association for the Study of Pain. IASP taxonomy. 2017. Available from 
https://www.iasppain.org/Taxonomy#Neuropathicpain  [Accessed 22 February 2018]  
 
3 van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general 
population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-62 
 
4 Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D et al. Neuropathic 
pain. Nat Rev Dis Primers. 2017 Feb; 3:17002 
 
5 Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH et al. 
Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. 
Lancet Neurol. 2015 Feb;14(2):162-73 
 
6 Australian Pain Society. Topic 35: Managing neuropathic pain: a stepwise approach. 
Available at 
https://www.apsoc.org.au/PDF/Publications/Veterans_MATES_35_Neuropathic_Pain_Ther
Brief_JUN13.pdf. Accessed 20 March 2018 
 
7 Lai K-Y et al. LanCLs add glutathione to dehydroamino acids generated at phosphorylated 
sites in the proteome.  Cell 184: 10, P2680-2695.E26, MAY 13, 2021. 
https://doi.org/10.1016/j.cell.2021.04.001  

SAP_001.pdf: 
Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
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CONFIDENTIAL 
Page 1 of 27
 
 
STATISTICAL ANALYSIS PLAN 
A Two-part Proof-of-Concept Study Assessing the Safety and Efficacy of LAT8881 
in Lumbar Radicular Pain. 
Protocol No.: LAT-NP-002 
Product Code: LAT8881 
 
PREPARED FOR: 
Lateral Pharma Pty Ltd 
 
L45/600 Bourke Street  
 
Melbourne, Vic 3000, Australia 
 
PREPARED BY: 
 
 
 
 
 
  
 
DATE OF ISSUE: 
15/06/2023 
 
 
VERSION/STATUS: Version 2.0 (Final) 
 
 
AUTHORS: 
 
Caro-Ann Badcock (on-behalf of Lateral Pharma) 
Stuart Mudge 
 
 
 
 
 


Protocol Number: LAT-NP-002 
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SAP APPROVAL 
 
By my signature, I confirm that this SAP has been reviewed and has been approved for use on the 
LAT-NP-002 study: 


Protocol Number: LAT-NP-002 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION ............................................................................................................................... 4 
2. 
PROJECT OVERVIEW ....................................................................................................................... 4 
2.1 
Study Design ......................................................................................................................................... 4 
2.2 
Sample Size ........................................................................................................................................... 6 
2.3 
Study Objectives ................................................................................................................................... 7 
2.4 
Study Endpoints .................................................................................................................................... 7 
3. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 9 
3.1 
Data Capture ....................................................................................................................................... 11 
3.2 
Statistical Programming...................................................................................................................... 12 
4. 
ANALYSIS SETS .............................................................................................................................. 15 
4.1 
Analysis Population Descriptions ....................................................................................................... 15 
5. 
PROTOCOL DEVIATIONS ................................................................................................................ 15 
6. 
SUBJECT DISPOSITION ................................................................................................................... 16 
6.1 
General Subject Disposition ............................................................................................................... 16 
6.2 
Death .................................................................................................................................................. 16 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................... 17 
7.1 
Demographics ..................................................................................................................................... 17 
7.2 
Medical history ................................................................................................................................... 17 
7.3 
Lumbar Radicular Pain History ........................................................................................................... 17 
7.4 
Pregnancy Test ................................................................................................................................... 17 
7.5 
Eligibility ............................................................................................................................................. 17 
7.6 
Urine Drug and Alcohol Breath Test ................................................................................................... 17 
7.7 
SARS-CoV-2 Screening ........................................................................................................................ 17 
8. 
TREATMENT EXPOSURE ................................................................................................................ 18 
9. 
PHARMACOKINETICS .................................................................................................................... 18 
10. 
PHARMACODYNAMICS.............................................................................................................. 18 
11. 
EFFICACY (Part B only) ............................................................................................................... 18 
12. 
SAFETY ....................................................................................................................................... 21 
12.1 
Adverse Events (AEs) .......................................................................................................................... 21 
12.2 
Prior and Concomitant Medication .................................................................................................... 23 
12.3 
Laboratory .......................................................................................................................................... 23 
12.4 
Vital Signs............................................................................................................................................ 25 
12.5 
Body Measurements .......................................................................................................................... 25 
12.6 
Physical Examination .......................................................................................................................... 25 
12.7 
12-Lead ECG ........................................................................................................................................ 26 
13. 
HANDLING OF MISSING DATA ................................................................................................... 27 
14. 
CHANGES AND CLARIFICATIONS TO THE PLANNED ANALYSIS .................................................. 27 
15. 
INTERIM ANALYSES ................................................................................................................... 27 
16. 
SOFTWARE ................................................................................................................................ 27 
17. 
REFERENCES .............................................................................................................................. 27 
 
 
 
 


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ABBREVIATIONS 
 
AE 
AST 
Adverse event 
Aspartate aminotransferase 
BMI 
CK 
COVID-19 
CRF 
CSR 
Body mass index 
Creatinine Kinase 
Novel Coronavirus (Sars-Cov-2) 
Case Report Form  
Clinical Study Report 
 
 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
EDC 
FAS 
Electronic Case Report Form 
Electronic Data Capture 
Full Analysis Set 
FBC 
IMP 
Full Blood Count 
Investigational Medicinal Product 
LOQ 
Limit of Quantification 
MTD 
PGIC 
PI 
PICF 
PD 
PK 
PP 
PT 
QST 
Maximum Tolerated Dose 
Patients General Impression of Change 
Principal Investigator 
Patient Information and Consent Form 
Pharmacodynamic 
Pharmacokinetics 
Per Population 
Preferred term 
Quantitative Sensory Test 
SAP 
SOC 
TEAE 
Statistical Analysis Plan 
System organ class 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 
 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) provides the details of the planned statistical analyses of the data 
from the LAT-NP-002 study. 
 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. In addition, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-hoc 
analyses performed will be clearly identified as such in the CSR. 
 
2. PROJECT OVERVIEW 
2.1 Study Design 
This is a Proof-of-Concept study that consists of two parts 
2.1.1 Part A (single ascending dose study) 
Part A will be a double-blind, randomized, placebo-controlled, single ascending dose (SAD) study 
within 8 healthy volunteers of intravenous administration of LAT8881 over 5 minutes.   
 
The SAD study will enrol 8 participants and each participant will have three treatment days, 1 
infusion per dosing day on days 1, 4 and 7 as well as two short visits for safety blood sampling on 


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Day 3 and 6 (Figure 1). The 8 participants will be split into two groups of 4 participants each (3 IMP 
and 1 placebo), with the two groups dosed a few days apart.  
 
Participants will arrive on the morning of each treatment day, receive a single infusion, leave that 
afternoon (no overnight stay). Participants on a given dosing day will be dosed at staggered 
intervals as determined by PI.  
 
Treatments will be on Days 1 (0.8 mg/kg), Day 4 (1.2 mg/kg) and Day 7 (1.8 mg/kg) or placebo to 
allow sufficient washout and consideration of any safety observed following each dosing day. Day 3 
and 6 safety blood results will be reviewed prior dosing on the following dosing day.  
 
Participants will fast for 8 hours pre-dose and 4 hours post dose for each dosing occasion.  
Participants will be randomised, so on each treatment day per group, 3 participants receive 
LAT8881 and 1 receive placebo (different participants to receive placebo each treatment day). 
Participants will remain at the clinic until 6 hours post-infusion in order to collect blood samples for 
PK analysis and for review of safety and tolerability. Safety assessments will be reviewed in a clinic 
exit visit 7 days after the last infusion. 
 
Figure 1: Part A Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
2.1.2 Part B (Cross-Over Study) 
Part B will be a placebo-controlled randomized double blind cross-over safety and efficacy study of 
LAT8881. Up to 20 participants will be randomized into two groups and will receive either a single 
dose of LAT8881 [the dose selected from Part A of the study] or placebo via intravenous 
administration over 10 minutes on two consecutive days. 
 
Participants will be randomly assigned to one of two groups, active then placebo or placebo then 
active (Figure 2).  
 
After passing screening, participants will be admitted for two nights: 
1. A study staff member will contact the participant for 3 consecutive days to obtain a verbal 
pain score out of 10 to confirm that their mean resting radicular pain meets the study 
 
2. The participant will arrive the evening prior to dosing, and will complete a final review of 
inclusion/exclusion criteria.  
3. Baseline assessments will be completed on the first day of dosing prior to IMP administration 
4. The participant will then receive their first dose.  
5. Collection of blood samples for PK/ PD analysis and assessments for review of safety, 
tolerability and efficacy are listed in the Schedule of Assessments. 
 
The participants will stay overnight.  
If the PK from the Part A demonstrates elimination in <6 hours (assessed by concentration below 
LOQ of assay),  
Part A
Healthy 
Participants
Day -62 to 
-2 
Screening
Day 1 
0.8mg/kg
or Placebo
Day 4 
1.2mg/kg
or Placebo
Day 7 
1.8mg/kg
or Placebo
FollowUp/ETV 
7 days ±2
Randomised, placebo controlled ascending dose. 
Data safety review, decision on dose for Part B. 
Blood Sampling Visit also required on Day 3 and 6  


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6. The following morning the participants will cross-over and receive their second dose. 
7. Collection of blood samples for PK analysis and assessments for review of safety, tolerability 
and efficacy are listed in the Schedule of Assessments.
8. Participants will remain at the clinic until 6 hours post the second infusion and then may be 
discharged. 
At the discretion of the Investigator and in consultation with the Study Sponsor, the requirement for 
subjects to be admitted to the clinic from the evening before Day 1 through to discharge at the end 
of Day 2 can be waived. In such circumstances, items 1 through 8 above will still apply, with the 
following modification to item #2:
- 
During the morning of Day 1 the following will be undertaken prior to dosing: a) a complete 
final review of inclusion/exclusion criteria, b) a written account of the activities the participant 
undertook on Day 0.
- 
Prior to dosing on Day 2, a written account of the activities the participant undertook after 
discharge at the end of Day 1.
Safety assessments will be reviewed 7 days after the last infusion by clinic exit visit.
Participants will fast for 8 hours pre-dose and 4 hours post dose for each dosing occasion.
Figure 2: . Part B Study Design
2.2 Sample Size
No formal statistical sample size estimation has been performed due to the exploratory nature of this 
study. The sample size is based on clinical and practical considerations. 
For Part A, a total of 8 participants will be dosed on each of three occasions with an increased dose 
(6 subjects) or placebo (2 subjects). It is expected that the sample size of 8 subjects (split into two 
groups of 4 subjects each (3 IMP and 1 placebo), with the two groups dosed a few days apart) 
should be adequate for evaluation of safety, tolerability, PK and PD parameters in this SAD study.
For Part B, a proof-of-concept, up to 20 participants, based on the PI’s experience from design and 
management of lumbar radicular pain subjects, will be enrolled. It is expected that the sample size 
(10 participants receiving active drug then placebo and 10 receiving placebo then active drug)
should be adequate for evaluation of safety and efficacy. 
Part B 
Sciatic Pain 
Participants
Day -30 to -
2 Screening
Day 1
Day 2
Follow Up/ETV 
7 days ±2
LAT8881 
1.8mg/kg
or 
Placebo
2 night observation (unless waived by Investigator)
LAT8881
1.8mg/kg or 
Placebo
Randomised, crossover


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2.3 Study Objectives 
2.3.1 Primary Objectives 
Part A: 
 
Evaluate the safety and tolerability of intravenous LAT8881 using an ascending dose schedule  
 
Part B: 
 
Evaluate the analgesic efficacy of LAT8881 in patients with lumbar radicular pain 
 
2.3.2 Secondary Objectives 
Part A:  
 
Evaluate the plasma concentrations and the PK properties of LAT8881 administered as an IV 
injection in healthy participants using a dose escalating design 
 
Establish the dose regimen for Part B of the study 
 
Part B:  
 
 
Evaluate the effect of Intravenous LAT8881, compared with placebo, VAS pain scores at rest 
 
Confirm the safety of LAT8881 in participants with lumbar radicular pain 
 
2.3.3 Exploratory Objectives 
Part A: 
 
Collect blood samples to investigate (and possibly validate) a pharmacodynamic assay 
and/or biomarkers of LAT8881 activity 
Part B:  
 
Evaluate mechanical Quantitative Sensory Test (QST) assessment on affected lower limb 
using Von Frey Aesthesiometer on two occasions, once prior to dosing and once post 
dosing. 
 
Evaluate the effect of Intravenous LAT8881, compared with placebo, VAS pain scores during 
straight-leg raise nerve stretch 
 
Bang Binding Index assessment, whereby participant will be asked to record which dosing 
occasion they believe they got the active IP. 
 
Collect blood samples to investigate (and possibly validate) a pharmacodynamic assay 
and/or biomarkers of LAT8881 activity 
 
2.4 Study Endpoints 
2.4.1 Primary Endpoints 
Part A 
Safety and tolerability 
 
Incidence, severity, and causality of AEs  
 
Incidence and severity of clinical laboratory abnormalities  
 
Change from baseline in vital signs (blood pressure, temperature, respiratory rate, and heart 
rate)  
 
Change from baseline in 12-lead ECG parameters  
 
Incidence and severity of AEs 
 


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Part B 
 
The change in pain from baseline during and after each infusion on a VAS 0-10 numerical 
rating scale of “pain now” with measures taken as the infusion starts and at 15 minute 
intervals for the first hour, then every thirty minutes for an additional two hours, then hourly 
until 6 hours from infusion commencement 
 
2.4.2 Secondary Endpoints 
Part A 
 
Pharmacokinetic profile 
 
Part B 
 
Comparison of radicular “pain now” scores as peak change from baseline and area under the 
curve comparing the two arms over the full six hours 
 
Comparison of patients’ general impression of change between dosing arms 
 
Adverse event rates in each dosing arm 
2.4.3 Exploratory Endpoints 
Part A 
 
Pharmacodynamic assay and/or biomarkers of LAT8881 activity 
 
Part B 
 
Mechanical QST assessment using Von Frey Aesthesiometer 
 
Evaluate the effect of intravenous LAT8881, compared with placebo, on VAS radicular pain 
scores during straight-leg raise nerve stretch  
 
Bang Binding Index assessment, whereby participant will be asked to record which dosing 
occasion they believe they got the active IP. 
 
Pharmacodynamic assay and/or biomarkers of LAT8881 activity. 
 
2.5 Changes to analyses from protocol 
These changes relate to Part B of the study only. 
 
Interim analysis: 
The planned interim analysis after at least 10 subjects had completed the study was undertaken 
after 14 subjects completed the study. The rationale for including 14 subjects within the interim 
analysis was based on a number of factors, including: 
- 
The observation that 2 of the subjects received less than the full dose (estimated to be 60-
65%) due to technical issues with the infusion equipment. Both the sponsor and the PI 
agreed that it was wise to include at least an additional 2 subjects within the interim analysis 
- 
At the time recruitment approached 12 completed subjects, the recruitment rate was 
relatively strong, which resulted in 14 subjects completing the study before the interim 
analysis was initiated. 
 
The planned initial graphical outputs were produced. 
 
No re-estimation of the sample size was undertaken.  Based on: (i) the planned graphical outputs, 
(ii) some additional blinded post-hoc graphical presentations (not discussed in this SAP), (iii) the 
expectation that 17 subjects were expected to complete the study by 12 May 2023, (iv) dosing an 
additional 3 subjects to reach the target of 20 could take another 3-6 months, and (v) the inclusion of 
additional subjects would be unlikely to change any treatment signal in the data to such an extent 
that continuing recruitment is justified, the recommendation was made to close the study on 12 May 
2023, with the last patient last visit then expected on 19 May 2023.  
 


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Final analyses: 
The data presentation and analysis for the Bang Binding Index assessment has been included in 
this SAP as it was inadvertently missed in the previous version of the SAP. 
 
After review of the interim analysis outputs where extensive variation in pain scores over time and 
an unexpected effect of being in the clinic for 24 hours possibly reducing pre-dose pain score on 
Day 2, particularly for pain at rest, the following decisions were made as to changes to the final 
analysis outputs. 
 
 
Pain at rest:  
o The mean change from baseline from 1 to 2 hours and from 4 to 6 hours are included 
to provide an easily interpretable summary measure of the pain response profile.  
o The area under the subject profile curve has been removed because it is less 
meaningful in a clinically useful interpretation of the pain response profile 
o A scatter plot presenting the paired responses for baseline pain with Placebo on the 
x-axis, LAT8881 on the y-axis, a diagonal line representing no difference and 
symbols with different shapes and colours representing each treatment sequence to 
investigate the possible presence of a Day or treatment carry-over effect. 
o Scatter plot in the same format as for baseline pain, for the mean change from 
baseline from 1 to 2 hours and for the mean change from baseline from 4 to 6 hours 
to provide a graphical presentation showing the pattern of any treatment differences 
in the presence of a possible Day effect.  
 
 
Pain on leg raise: 
o All analyses completed for pain at rest will be repeated for pain on leg raise. Given 
the impact of Day 1 on Day 2 pain at rest scores, pain on leg raise may provide more 
insight as to the “proof of concept” for LAT8881.  
  
3. STATISTICAL CONSIDERATIONS 
 
Data analysis will be performed according to 
 Standard Operating 
Procedures (SOPs). 
 
The general analytical approach for all endpoints will be descriptive in nature 
Unless otherwise stated, the following statistical approaches will be taken: 
 
Continuous variables:   
Descriptive statistics will include the number of non-missing values, 
mean, standard deviation (SD), median, minimum, and maximum.  The 
minimum and maximum values will be presented to the same number 
of decimal places as recorded in the raw data; mean and median will 
be presented to 1 decimal place more than raw data; and SD will be 
presented to two more decimal places than the raw data.   
 
Categorical variables:   
Descriptive statistics will include frequency counts and percentages per 
category.  Percentages will be rounded to one decimal place, with the 
denominator being the number of subjects in the relevant population 
with non-missing data. 
 
Imputation:                             No imputation will be performed for missing data. 
 
Confidence intervals (CIs):  If required, CIs will be two sided and will use 95% confidence levels. 
Any analyses requiring significance testing will use a two-sided test at 
the 5% significance level. 
 


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Unscheduled visits:                Unscheduled visits will be excluded from visit-based summary 
                                               Tables, but will be included in data listings. 
 
Early withdrawal visits           Early withdrawal visits will be excluded from visit-based 
                                              summary tables but will be included in data listings. 
 
 


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3.1 Data Capture
3.1.1 Database
The primary method of data collection is via the study database, developed within the chosen 
Electronic Data Capture (EDC) platform, IBM Clinical Development. The database has been 
designed based on the final protocol, the system/core configuration, electronic Case Report Form 
(eCRF) specifications and/or mock eCRF and consistency check specifications.
Data will be entered directly into the EDC system. Site-collected data will be entered directly from 
source notes at the site and will be verified by Clinical Research Associates (CRAs) to ensure data 
integrity. 
Refer to the Data Management Plan for further details.
3.1.2 Third Party Data
Safety Laboratory
Central safety laboratory data will be received at 
 from PARC Clinical Research. 
This data transfer will occur once the central safety laboratory, SA Pathology, transfers the data to 
PARC as specified in the Data Transfer Specification. Data transfers are being processed at the end 
of each cohort throughout the study, with each transfer being reconciled against the CRF data.  
The final data transfer(s) will be incorporated into the End of Study analysis once the final transfer 
has been received, reconciled and all issues are considered resolved.
No unit conversion of laboratory data is planned.
PK Laboratory
PK samples will be analyzed by HMS Trust Laboratory. PK analyses will be documented in a 
separate PK Analysis Plan and analyses will be performed by PKPD Systems. The PK Analysis 
Report will be incorporated directly into the appendices of the CSR.  
PD Laboratory
PD samples will be analysed by collaborators selected by Lateral Pharma. Analysis of PD data will 
be considered outside the scope of this SAP.


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3.2 Statistical Programming 
3.2.1 Baseline 
Baseline will be defined as the last available assessment prior to the first IMP administration. For 
part B, baseline will be assigned separately for the two treatment periods..   
3.2.2 Change from Baseline 
Part A: 
 
 
=(
 
(
 
) 
Part B, Period 1:  
 
 
=(
 
(
 1 
 
) 
Part B, Period 2:  
 
 
=(
 
(
 2 
 
) 
 
3.2.3 Study Day 
Part A: Study Day will be derived as the number of days relative to date of first administration of 
study drug, where the day of first administration = 1. 
Part B: Study Day will be number of days relative to date of administration of study drug for each 
period, where the day of administration = 1. 
3.2.4 Listings, Tables and Figures 
Listings, tables and figures will be delivered as individual .rtf files in accordance with the mock 
listings, tables and figures, with separate sets of outputs for each study part. 
 
Data listings will present all data, with subjects grouped by treatment regimen (part A) or treatment 
sequence (part B). 
 
3.2.5 Treatment groups – Part A 
 
Tabulations will summarize data by treatment group, the pooling of all the study drug, and total (all 
groups). All placebo participants will  be grouped in a single cohort for tabulation summaries. 
 
For Part A, treatment groups within tables are planned to be presented as: 
 
LAT8881 
(0.8mg/kg) 
(N=X) 
LAT8881 
(1.2mg/kg) 
(N=X) 
LAT8881 
(1.8mg/kg) 
(N=X) 
LAT8881 
(All Doses) 
(N=X) 
Placebo 
(N=X) 
Total 
(N=X) 
 
 
 


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3.2.6 Treatment groups – Part B 
LAT8881 will be administered at a dose of 1.8 mg/kg via an infusion pump at a constant rate over 10  
minutes. 
The placebo formulation will be presented as above but without the LAT8881 active.
 
Tabulations for part 2 will summarise data as follows: 
Demographics and baseline characteristic data, will be summarised by: 
 
LAT8881 1.8 mg/kg /Placebo 
 
Placebo/LAT8881 1.8 mg/kg 
 
Total 
Visit based tabulations will be summarised by treatment received (LAT8881 1.8 mg/kg or Placebo) 
and total, and timepoint relative to within period dosing. Treatment will be assigned to individual 
records based on the treatment period. Timepoints will be: 
• Screening (summarised as total only) 
• Day 1- predose/Day 2-predose (combination of Day 1 and Day 2, summarised by 
treatment) 
• Day 1- dose/Day 2-dose (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 5min/Day 2-5min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 10min/Day 2-10min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 15min/Day 2-15min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 20min/Day 2-20min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 30min/Day 2-30min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 45min/Day 2-45min (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 1hr/Day 2-1hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 1.5hr/Day 2-1.5hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 2hr/Day 2-2hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 2.5hr/Day 2-2.5hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 3hr/Day 2-3hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 3.5hr/Day 2-3.5hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 4hr/Day 2-4hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 5hr/Day 2-5hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 1- 6hr/Day 2-6hr (combination of Day 1 and Day 2, summarised by treatment) 
• Day 9/ETV (summarised as total only) 
 
o Event based tabulations (e.g. adverse events, concomitant medications and deviations) will 
be summarised by treatment and total. Treatment will be assigned to individual records 
based on the treatment period of the start date of the event. 
• Adverse Events: 
• 
Events started prior to the Day 1 study drug administration will only be 
considered as Medical History. 
• 
If start date is after Day 1 study drug administration, then it will be assigned to 
the treatment received in Period 1. 
• 
If start date is after the Day 2 study drug administration, then it will be 
assigned to the treatment received in Period 2. 
• Protocol Deviations: 
• 
If date is before Day 1 then it will be assigned to Screening 
• 
If date of deviation is after Day 1 study drug administration,then it will be 
assigned to the treatment received in Period 1. 
• 
If start date is after the Day 2 study drug administration, then it will be 
assigned to the treatment received Period 2. 
• Concomitant Medications: 


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• 
Based on start and end dates – if subject was on medication within a given 
period then that medication will be summarised within that period. If subject 
took medication across both periods then it would be counted in both 
treatment columns. 
o Treatment Exposure will be summarised by sequence and total 
 
 


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4. ANALYSIS SETS 
 
Four (4) analysis sets will be used for the analyses: Full Analysis Set, Per Protocol population, Safety 
Population and PK/PD Population. Analyses planned for the PK/PD Population will be documented 
separately. 
4.1 Analysis Population Descriptions 
4.1.1 Full Analysis Set 
The Full Analysis Set (FAS) consists of all participants enrolled and randomised into the study. The 
FAS population will be used for summaries of participant disposition, demographic and baseline 
characteristics. Participants will be analysed according to the treatment group they were assigned at 
randomisation. 
4.1.2 Per Protocol population 
A per-protocol (PP) population will be based on duration of IMP treatment and protocol deviations. 
This population may exclude participants with inadequate exposure to IMP or who have other protocol 
deviations. The PP population is the primary population to analyse efficacy endpoints. Demographic 
and baseline characteristics of the PP population will also be presented. 
4.1.3 Safety population 
The safety population consists of all randomised participants who received at least one dose of IMP 
and had at least one post dose safety assessment. The safety population will be used for the analysis 
of safety and tolerability. Participants will be analysed as treated, regardless of the randomised 
treatment assigned, if this differs from that to which the participant was randomised. 
4.1.4 PK and PD population 
The PK and PD population will include all participants who received at least one dose of IMP, had at 
least one post dose sample collection for PK and PD analysis and who did not have any clinically 
significant events or major protocol deviations that may have compromised the integrity of the PK 
and PD results. 
5. PROTOCOL DEVIATIONS 
Analysis Set: FAS 
 
All protocol deviations will be listed, grouped by participant and treatment group. 
 
The protocol deviation summary table will include: 
 
The total number of minor protocol deviations 
 
The total number of major protocol deviations 
 
The number of participants who reported at least one minor protocol deviation 
 
The number of participants who reported at least one major protocol deviation 
 
 
 
 
 
 
 
 
 
 


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6. SUBJECT DISPOSITION 
Analysis Set: FAS 
6.1 General Subject Disposition 
A listing of subject disposition will present: 
 
Date of informed consent 
 
Date of randomization 
 
Date of first treatment 
 
Date of last treatment  
 
Date of completion / early withdrawal 
 
Primary reason for early withdrawal 
 
The number and percentage of subjects entering and discontinuing the study will be summarised 
along with the reason for discontinuation.   
The subject disposition summary table will include: 
 
Number of subjects who received at least one dose of study medication 
 
Number of subjects who completed the full study 
 
Number of subjects withdrawn early 
 
Reason for early withdrawal 
 
6.2 Death 
Death related details will be listed only if required. 
 
 


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7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Analysis Set: FAS 
7.1 Demographics 
7.1.1 Parameters 
 
Date of birth 
 
Age (years) 
 
Sex (male/female) 
 
BMI 
 
Race  
 
Ethnicity 
 
Child-bearing potential 
 
Menopausal status 
 
Smoking Habits 
7.1.2 Biostatistical methods 
Demographic data, inclusive of but not restricted to that listed in 7.1.1 above, will be listed for each 
participant and summarized using descriptive statistics, tabulated overall for Part A and by treatment 
sequence and overall for Part B. 
7.2 Medical history 
All medical history data will be listed. 
 
Medical history (other than disease under study) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®) and summarised by system organ class (SOC) and preferred term 
(PT).  
7.3 Lumbar Radicular Pain History 
All lumbar radicular pain history will be listed for each participant by treatment sequence for Part B 
only.  
7.4 Pregnancy Test 
Pregnancy test data will be listed for positive results only.    
7.5 Eligibility 
All eligibility data will be listed. 
7.6 Urine Drug and Alcohol Breath Test 
Any positive urine drug screen and alcohol screen tests will be listed. 
7.7 SARS-CoV-2 Screening 
Any positive SARS-CoV2 screening results will be listed. 
 


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8. TREATMENT EXPOSURE 
Analysis Set: Safety Population 
8.1.1 Parameters 
 
Date of drug infusion 
 
Start time of infusion 
 
End time of infusion 
 
Date/Time of last meal 
 
Study drug dose (mg) 
 
Total volume to be infused (mL) 
 
Actual volume infused (mL) 
8.1.2 Biostatistical methods 
 
All study drug administration data will be listed. 
 
Extent of exposure to LAT8881 and placebo will be summarised for Part A and B as: 
 
 
Total IMP administered (mg): Sum of all doses (mg) 
 
Total Number of participants exposed to study treatment: Sum of all participants 
treated with LAT8881 
 
Duration of exposure (hours): (Date / Time last treatment – Date / Time of first 
treatment) + 1 
 
9. PHARMACOKINETICS 
Analysis Set: PK Population 
 
Refer to PK Analysis Plan 
 
All results of pharmacokinetic assays will be reported in listings. 
10. PHARMACODYNAMICS 
Refer to PD Analysis Plan. 
 
11. EFFICACY (PART B ONLY) 
Analysis Set: Full Analysis Set and Per Protocol population 
 
Parameters: 
 
 
Pain now VAS score: 
O Change from Baseline to hours 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 and 6,  
O Percentage change from baseline to hours 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 
and 6 
O Peak change from baseline over 6 hours 
O Mean change from baseline over 1 to 2 hours 
O Mean change from baseline over 5 to 6 hours 
 
Pain on leg raise VAS score: 
O Change from Baseline to hours 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 and 6,  
O Percentage change from baseline to hours 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 
and 6 


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O Peak change from baseline over 6 hours 
O Mean change from baseline over 1 to 2 hours 
O Mean change from baseline over 5 to 6 hours 
 
Patients general impression of change at hour 6 on Day 1 and on Day 2 
 
Mechanical QST assessment using Von Frey Aesthesiometer 
 
Bang Binding Index assessment at 6 hours on Day 2 
 
11.1.1 Biostatistical methods 
Efficacy will be assessed based on the difference between treatments in the following measures: 
 
Pain NowScores (VAS) 
 
“Pain now” scores, change from baseline, percentage change from baseline and summary scores 
(i.e. maximum change from baseline, mean change from baseline over 1 to 2 hours and mean 
change from baseline over 4 to 6 hours) will be listed for all study participants at each timepoint by 
treatment sequence.  
 
Descriptive statistics including the number of participants, mean, standard deviation, median, 
minimum and maximum for the VAS “pain now” score at each timepoint along with the change from 
baseline and percentage change from baseline will be presented by treatment group within 
treatment period and overall. The mean, standard deviation, median, minimum and maximum for the 
change from baseline over 6 hours, the mean change from baseline over 1 to 2 hours and the mean 
change from baseline from 4 to 6 hours will be presented by treatment group within treatment period 
and overall. 
 
Graphical presentations will include those presented for the interim analysis: 
1. Individual subject VAS scores-time profiles by timepoint and by sequence (left panel 
LAT8881-Placebo, right panel Placebo-LAT8881) 
2. Group mean VAS scores by timepoint and day, two sequences combined (one panel only)  
3. Group mean VAS scores by timepoint and day in each panel, and by sequence (left panel 
LAT8881-Placebo, right panel Placebo-LAT8881) 
 
Additional graphical presentations will include: 
4. Individual subject change from baseline -time profiles by post-dose timepoint and by 
sequence (left panel LAT8881-Placebo, right panel Placebo-LAT8881) 
5. Group mean change from baseline by post-dose timepoint by treatment, two sequences 
combined (one panel only)  
6. Group mean change from baseline by post-dose timepoint and by sequence (left panel 
LAT8881-Placebo, right panel Placebo-LAT8881) 
7. Difference between treatments in the change from baseline at each post-dose timepoint by 
sequence (left panel LAT8881-Placebo, right panel Placebo-LAT8881) 
8. Difference between treatments in the change from baseline at each post-dose timepoint by 
treatment (one panel only) 
9. A scatter plot for baseline scores with Placebo score on the x-axis, LAT8881 score on the y-
axis, a diagonal line with slope=1 representing no difference between treatments will be 
overlaid on the plot, symbols and symbol colour will be used to identify treatment sequence. 
10. Maximum change from baseline will be presented using the same scatter plot format as for 
baseline scores 
11. Mean change from baseline over 1 to 2 hours will be presented using the same scatter plot 
format as for baseline scores 
12. Mean change from baseline over 5 to 6 hours will be presented using the same scatter plot 
format as for baseline scores  
 
 


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To  estimate the difference between LAT8881 and Placebo in the change from baseline “pain now” 
VAS over all session time points, a generalised linear mixed effects model will be fitted. Fixed-
effects will include treatment, session time point and period (i.e. Day) factors; baseline will be 
included as a covariate. Random effects for participants and participant by period will be included to 
take into account the repeated measures on each participant and the cross-over nature of the study. 
The covariance structure for the random effects is assumed to follow a compound symmetry 
structure. The estimated adjusted (least squares) mean change from baseline for each treatment at 
each session time, the difference between the treatments, the 95% confidence interval for the 
difference and the p value for the difference will be presented. A p value of <0.05 will be declared 
statistically significant. The model assumes no carry-over treatment effect and assumes that any 
period (i.e Day) effect will affect subjects in both treatment sequences in a similar manner. 
  
The same model will be fitted to the change from baseline “pain on leg raise” VAS scores. 
As reflected in the scientific literature and regulatory authority guidelines, what consitutes a 
minimally significant change in baseline pain score can vary from subject-to-subject, whether the 
pain is acute or chronic, and on the mechanism of the pain. For the purposes of this study, the 
sponsor considers a 0.9 cm reduction to represent a minimally clinically significant change in pain as 
reported on the VAS, with the desired target reduction from baseline in the range of 0.9 to 3 cm.  
 
Provocation Assessment with VAS 
 
The pain on leg raise VAS score, change from baseline, percentage change from baseline, 
maximum change from baseline, mean change from baseline from 1 to 2 hours and mean change 
from baseline from 4 to 6 hours will be listed for all study participants at each timepoint by treatment 
sequence as for the “pain now” endpoints. Descriptive summary tables and analyses will be as per 
the “pain now” endpoints. 
 
Patients general impression of change 
The assessment responses will be listed for all participants by treatment sequence and visit.  
 
The number and percentage of participants in each rating category will be summarised by treatment 
within period (i.e. Day) and overall. 
 
A graphical presentation will take the form of a heat map with the rating categories for Placebo on 
the x-axis and the rating categories for LAT8881 on the y-axis. Each cell will contain the percentage 
of subjects with the corresponding combination of PGIC and will be colour-coded to represent the 
weight of evidence for the corresponding percentage. 
 
The categories of general impression of change: 
 
Very much improved 
 
Much improved 
 
Slightly improved 
 
No change 
 
Slightly worse 
 
Much worse 
 
Very much worse 
 
Quantitative Sensory Test (QST) assessment  
The Affected and Non-affected dermatome monofilament pain assessment data will be listed for all 
study participants at each timepoint by treatment sequence.  
 
The number and percentage of participants with pain at each filament will be summarised by type of 
dermatome and treatment sequence at each timepoint with the number of subjects, mean, standard 
deviation, median, minimum and maximum by treatment group within treatment period and overall. 
 


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Bang Binding Index assessment 
 
The Bang Binding Index assessment identifying which Day the subject believed they were treated 
with the active treatment will be listed for all study participants. 
 
The number and percentage of participants who correctly identified when they were using active 
treatment will be presented by treatment sequence and overall. 
 
Sub-group Assessment of Demographic Factors 
The contribution of demographic factors (listed in 7.1.1 above) to any differences in efficacy between 
treatment groups will be investigated.  
 
 
 
12. SAFETY  
Analysis Set: Safety Population 
 
The following Safety analyses will be performed if there is enough data to warrant the 
analysis tables. If there is not enough data, we will write a paragragh describing the safety 
events. 
12.1 Adverse Events (AEs) 
AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities 
(MedDRA, version 24.1) by system organ class (SOC) and preferred term (PT), classified from 
verbatim terms. 
 
All AEs recorded during the study will be listed, grouped by participant and treatment group. 
 
A Treatment Emergent Adverse Event (TEAE) is defined as any untoward medical occurrence 
reported or observed after the start of dosing with study drug and prior to the End of Study visit.  
Conditions present before the first dose of study drug that increase in severity after the first study drug 
administration will also be considered TEAEs. Where an AE start date is partially or fully missing, and 
it is unclear as to whether the AE started after treatment administration, it will be assumed to be a 
TEAE. 
AE summaries will be restricted to TEAEs only. 
 
An overview summary table of TEAEs will be provided for:  
 
Part A  by treatment group and overall  
 
Part B by treatment within sequence, by treatment and overall 
Table will include number of participants reporting at least one of the following: 
 
TEAE 
 
Grade 3+ TEAE 
 
Related TEAE  
 
Serious TEAE 
 
Serious and related TEAE  
 Number of participants discontinued from treatment due to a TEAE 
 Number of participants withdrawn from the study due to a TEAE 
 Number of deaths 
 
For the TEAE summaries, participants who experience the same TEAE more than once will be 
counted only once for that event within each category (PT, SOC or overall).  
 


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The number and percentage of participants experiencing a TEAE, will be summarised for each SOC 
and PT by cohort and overall for the following categories of events, by severity:  
 
 
All TEAEs  
 
All TEAEs related to the study drug  
 
All Grade 3+ TEAEs  
 
All serious TEAEs  
 
All serious TEAEs related to the study drug  
 
The number and percentage of participants experiencing a TEAE will be summarised for each SOC 
and PT by maximum severity and cohort for all TEAEs and all TEAEs related to study medication. If 
a participant experiences the same AE at more than one severity grade, the most severe rating or the 
stronger causal relationship to investigational product will be given precedence.  Only severities that 
are populated will be reported. 
 
 


Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
Effective:  17/SEP/2020 
CONFIDENTIAL 
Page 23 of 27
 
12.2 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using The WHO Drug Dictionary September 2021 
release, with Preferred Name (PN) and Anatomical Therapeutic Chemical (ATC) code.  
 
A prior medication will be defined as a medication that was commenced prior to the first study drug 
administration.  A concomitant medication will be defined as a medication taken after first study drug 
administration. Medications stopped on the same day as first study drug administration will be 
considered as prior medication only.   
 
Prior and concomitant medication summaries will be presented in separate tabulations. All 
medications will be listed for each participant, with each medication flagged as to whether they are a 
prior medication, concomitant medication, or both. For part A, prior medications will be presented 
overall and concomitant medications will be presented by treatment group and overall 
For part B, prior medications will be presented by treatment sequence and overall, and concomitant 
medications and safety measure summaries will be presented by treatment within each treatment 
period and overall. 
 
Table summaries will be presented using frequency counts and percentages. For the summaries of 
prior and concomitant medications, subjects who take the same medication (in terms of the lowest 
level ATC) more than once will be counted only once for that medication.  
12.3 Laboratory 
12.3.1 Parameters 
Laboratory Tests 
Parameters
Hematology  
Haemoglobin  
Red blood cell count (RBC)  
Red cell distribution width 
(RCD)  
Haematocrit/Packed cell 
volume (PCV)  
RBC Indices:  
Mean cell volume 
(MCV)  
Mean corpuscular 
haemoglobin (MCH)  
Mean platelet volume 
(MPV)  
Platelets  
White blood cell 
(WBC) count with 
Differential:  
Neutrophils  
Lymphocytes  
Monocytes  
Eosinophils  
Basophils  
Clinical 
Chemistry  
  
Sodium 
Potassium  
Chloride  
Bicarbonate  
Anion Gap  
Urea  
Creatinine  
Albumin 
Alkaline phosphatase 
(ALP)  
Gamma-glutamyl 
transferase (GGT)  
Alanine 
Aminotransferase 
(ALT)  
Creatinine Kinase
(CK)  
eGFR  
Uric acid  
Glucose (non-fasting) 
Calcium  
Ionised Calcium  
Phosphate  
Total Protein  
Globulin  
Bilirubin  
Aspartate 
Aminotransferase 
(AST)  
Lactate 
dehydrogenase (LD)  
Routine Urinalysis 
(if positive urine 
dipstick)  
Bilirubin, Specific gravity, pH, Nitrate, Protein, 
Leucocyte esterase, Blood, Ketones, Glucose, 
Urobilinogen, Creatinine.  
Microscopic 
examination (if blood 
or protein is 
abnormal)  


Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
Effective:  17/SEP/2020 
CONFIDENTIAL 
Page 24 of 27
 
Pregnancy testing  
Highly sensitive serum  
FSH
FSH for confirmation of post memopausal status 
Other Tests  
Serology: (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)  
 
12.3.2 Biostatistical methods 
Individually for Part A and Part B, all laboratory parameters will be listed with flags for values outside 
the reference ranges and values considered to be clinically significant by the investigator. 
 
Each parameter will be summarised descriptively (including actual values and changes from 
baseline) by visit and treatment.  
 
Categorical interpretations of each record (Normal, Abnormal – Not Clinically Significant (NCS), 
Abnormal – Clinically Significant (CS)) will be summarised for each scheduled visit, as well as the 
worst case, in a separate set of tables, ordered as follows from best to worst case: Normal, 
Abnormal – NCS, Abnormal – CS.  The worst case finding will reflect all post-baseline assessments, 
including unscheduled and early discontinuation visits. 
 
Maximum shift tables will also be presented for hematology and chemistry variables, presenting a 
summary of the shifts from baseline values to the most extreme post-baseline value, where all 
scheduled and unscheduled visit results will be assessed to determine the maximum shift. The 
maximum shift will be determined based on the absolute change from baseline, considering both 
shifts in the negative and positive direction.  Both the baseline and maximum shift values will then 
be converted to “Low”, “Normal” or “High” using the associated reference ranges.  
 
 


Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
Effective:  17/SEP/2020 
CONFIDENTIAL 
Page 25 of 27
 
12.4 Vital Signs 
12.4.1 Parameters 
 
Systolic Blood Pressure (SBP) (mmHg) 
 
Diastolic Blood Pressure (DBP) (mmHg) 
 
Heart Rate (beats/minute) 
 
Respiratory Rate (breaths/minute) 
 
Temperature (°C) 
12.4.2 Biostatistical methods 
Individually for Part A and Part B: 
All vital signs data will be listed for all participants , with flags for values outside the site’s reference 
range.  
 
Vital sign parameters will be summarized by presenting summary statistics for observed values and  
change from baseline values for each scheduled visit and timepoint.  
 
The incidence rates of notable vital sign abnormalities will be summarized using the following set of 
normal ranges:  
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Heart Rate (beats/min) 
 
Pulse Oximetry (%) 
 
Respiratory Rate breaths/min) 
 
Temperature (°C) 
12.5 Body Measurements 
12.5.1 Parameters 
 
Weight (kg)  
 
Height (cm) 
 
Body mass index (BMI) (kg/m2)  
12.5.2 Biostatistical methods 
BMI, height and weight data, will be listed for all participants. 
 
Body measurement data will also be summarised. 
12.6 Physical Examination 
12.6.1 Parameters 
 
Gastroinstestinal (GI) 
 
Renal  
 
Cardiovascular 
 
Musculoskeletal 
 
Dermatological 
 
Neurological 
 
Extremities 
 
Respiratory 
 
General appearance 
 
Thyroid 
 
HEENT (Head, Eyes, Ears, Nose, Throat) 
 
Other (free text) 
12.6.2 Biostatistical methods 
Physical examination data will be listed for all paricipants by scheduled visit. 
 
 


Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
Effective:  17/SEP/2020 
CONFIDENTIAL 
Page 26 of 27
 
12.7 12-Lead ECG 
12.7.1 Parameters 
 
The following ECG parameters are collected in triplicate for each timepoint: 
o PR interval (msec) 
o QRS interval (msec) 
o QT interval (msec) 
o Heart rate (beats/minute) 
o QTcB Interval (msec) 
o QTcF Interval (msec) 
 
ECG result (Normal, Abnormal – Not clinically significant, Abnormal – Clinically significant) 
 
ECG abnormality (as appropriate) 
 
12.7.2 Biostatistical methods 
ECG parameters will be listed for all participants and time points. 
 
Observed values, and absolute change from baseline, will be summarised descriptively for all ECG 
parameters by scheduled visit and timepoint for part A and by sequence and overall for part B.    
 
The number and percentage of participants with ECG findings will also be summarized by scheduled 
visit and timepoint part A and by sequence and overall for part B.  This table will include a summary 
of the number and percentage of participants with abnormal results for each parameter at each 
timepoint, using the set of normal ranges provided. 
 
A maximum shift table will also be presented for ECG Result, presenting a summary of the shifts 
from baseline values to the most extreme post-baseline value, where all scheduled and 
unscheduled visit results will be assessed to determine the maximum shift, ordered (best to worst 
case) by Normal, Abnormal – NCS, Abnormal – CS. 
 
 
 


Protocol Number: LAT-NP-002 
15 June 2023 
Document status: SAP Version 2.0 (Final) 
 
BM S01-A, v3.0 
Statistical Analysis Plan 
Effective:  17/SEP/2020 
CONFIDENTIAL 
Page 27 of 27
 
13. HANDLING OF MISSING DATA 
Only recorded data will be analysed/presented and any subjects who have missing data will only 
have observed data reported, with no imputation for missing data. 
14. CHANGES AND CLARIFICATIONS TO THE PLANNED ANALYSIS 
Any changes to the statistical analysis plan will be described and justified in the final report. 
15. INTERIM ANALYSES 
In Part B, a blinded interim analysis was undertaken after 14 subjects have completed both periods. 
Enrolment will continue while the interim analysis is undertaken.  
 
The interim  analysis was to be done in two parts. Initially, 6 tables comprising a listing and table for 
separately for pain assessment score for pain at rest and pain following leg raise; a listing and 
summary table for patients general impression of change, will developed.  
In addition, the pain scores will be summarised graphically as follows: 
 
Figure 1: Group mean VAS scores at Rest by timepoint, two sequences combined (one 
panel only)  
 
Figure 2: Group mean VAS scores at Rest by timepoint and by sequence (left panel 
Treatment A then Treatment B, right panel Treatment B then Treatment A) 
 
Figure 3: Group mean VAS scores following leg raise by timepoint, two sequences combined 
(one panel only)  
 
Figure 4: Group mean VAS scores following leg raise by timepoint and by sequence (left 
panel Treatment A then Treatment B, right panel Treatment B then Treatment A) 
 
All analyses had subject numbers assigned randomly and treatment sequence labelled A and B  to 
maintain blind. The results were used to make an initial futility assessment. If the decision is made to 
proceed then, secondly, the full interim analysis was to be completed as per full listings and tables 
within this document. 
 
The DSMC team will provide additional insight regarding potentially stopping the study for futility. 
Details will be provided in the DSMC charter. 
 
  
16. SOFTWARE 
The following software will be used to perform the statistical analyses: Statistical Analysis System 
(SAS®) Version 9.4 or higher (SAS Institute, Cary, North Carolina, USA). 
 
17. REFERENCES 
1) LAT8881 Protocol Version 5.0 - 03 Feb 2023 
2) Lateral LAT-NP-002_4.1_Annotated.pdf