Conditions: Neuropathic Pain Diabetic Peripheral Neuropathy (DPN) Post Herpetic Neuralgia (PHN)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 53
Healthy volunteers: no

Brief summary:
This is a randomised, placebo-controlled, double-blind, crossover, phase IIa study to investigate the efficacy and safety of oral LAT8881 in neuropathic pain.

Detailed description:
This is a randomised, placebo-controlled, double-blind, crossover, phase IIa study to investigate the efficacy and safety of oral LAT8881 in neuropathic pain. After a one week baseline period, subjects entered into the study will be randomised to receive Investigational Medicinal Product (IMP) (LAT8881 or placebo) twice daily for four weeks.

The first treatment period will be followed by a washout period of two weeks and then a second baseline period of one week. Subjects will not take any IMP over these three weeks.

After the second baseline period, subjects will cross over to receive the second treatment (either LAT8881 or placebo, whichever treatment was not received in the first treatment period) twice daily for four weeks.

The pharmacokinetics (PK) of LAT8881 will be investigated in 15 subjects (PK subjects) at selected Australian sites.

Arms:
arm 1: 1 x 30 mg capsule of LAT8881 taken by mouth, twice daily (morning and evening) during the four-week treatment period. arm 2: 1 x 30 mg capsule of placebo, taken by mouth, twice daily (morning and evening) during the four-week treatment period.

Interventions: intervention 1: LAT8881 intervention 2: Placebo
Intervention descriptions: intervention 1: LAT8881 oral capsule intervention 2: Placebo oral capsule

Protocol document:
Prot_000.pdf: 
 
 
 
Official Title: A Phase IIa study of the efficacy and safety of oral LAT8881 
in neuropathic pain 
 
 
 
NCT Number: NCT03865953 
 
 
Document date: October 9, 2019 
 
 
 


Protocol Number LAT-NP-001 
 
 
Lateral Pharma Pty Ltd 
 
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Clinical Study Title 
A Phase IIa study of the efficacy and safety of 
oral LAT8881 in neuropathic pain 
 
Protocol No. 
EudraCT No. 
LAT-NP-001 
2018-004534-15 
 
Drug name 
LAT8881 
Clinical phase 
IIa 
Sponsor  
Lateral Pharma Pty Ltd 
14/114 William St  
Melbourne, Vic 3000 
Australia 
Phone: +61 (0)400 151 490 
Email: dk@lateral-pharma.com 
 
Principal Investigator 
Professor Tony Pickering B.Sc., Ph.D., MB ChB (Birm), F.R.C.A. 
Biomedical Sciences Building, 
University Walk, Bristol BS8 1TD 
United Kingdom 
Phone: +44 (0) 117 331 2311 
Email:tony.pickering@bristol.ac.uk 
 
Version:  
5.0 
Date  
9 October, 2019 
This version supercedes all previous versions listed below: 
Original Protocol: Version 1.0, 10 December 2018 
Amendment 1: Version 2.0, 29 March, 2019 
Amendment 2: Version 3.0, 17 May, 2019 
Amendment 3: Version 4.0, 15 July and 27 August, 2019 
This clinical study will be performed in compliance with Good Clinical Practice (GCP) guidelines, including 
archiving 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. 
 
 


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Protocol signatures 
Investigator’s statement 
The undersigned Investigator(s) agree: 
1. To conduct the study in accordance with the study protocol, ICH Guideline for Good Clinical Practice E6(R2),1 and 
applicable regulations and guidelines. 
2. To ensure that all persons at their investigational site assisting with the clinical study, are adequately informed and 
trained about the study protocol, the investigational product and their study-related duties and functions. 
3. That alteration of the procedures described in the study protocol, other than to protect subject safety, rights, or 
welfare, is not allowed without prior written approval from Lateral Pharma Pty Ltd (“Lateral”) and if appropriate, the 
relevant Ethics Committee.  
4. That subjects’ study-specific data will be kept in the subjects’ files and documented in the case report form in a 
complete and accurate manner. All requested study-related records will be made available for direct access to 
Lateral’s representatives for monitoring or auditing the study. 
5. To allow authorised qualified delegates of Lateral to perform regular visits to monitor the study conduct and study 
data. 
6. To ensure that the investigational product is dispensed in accordance with the protocol and only to subjects enrolled in 
the study.  
7. To dispose of used and unused investigational product and materials as instructed by Lateral. 
 
 
Investigator Name (Print) 
 
Investigational Site 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
Investigator Name (Print) 
 
Investigational Site 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
Sponsor Name (Print) 
 
 
 
 
 
Sponsor Signature 
 
Date 
 
 


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General Study Information 
Contract Research Organisations 
Australia 
 
 
 
 
United Kingdom 
 
Molecule2Market (M2M) 
Ground Floor, 35 Cotham Road  
Kew, Victoria 3101 
Contacts: Robin Hansen (robin@molecule2.com.au) 
Anne De Luca (anne@molecule2.com.au) 
Tyger Thomas 
86-90 Paul Street, 3rd Floor,  
London, EC2A 4NE 
Contact: Mark Thomas (mark.thomas@euclinical.com) 
Sponsor Medical Representative 
Jolanta Airey MD 
5 Portobello Place 
Wheelers Hill VIC 3150 Australia 
Phone: +61 409 020 209 
Email: jolanta.airey@sjaconsultant.com 
Pharmacokinetic Processing 
TetraQ Research Infrastructure Centre 
The University of Queensland 
Herston QLD 4029 
Australia  
Phone: +61 7 3365 5115 
 
 
 


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Table of Contents 
Protocol signatures ............................................................................................................................................... 2 
General Study Information .................................................................................................................................... 3 
List of Abbreviations ............................................................................................................................................. 8 
1. 
Protocol synopsis ................................................................................................................................... 11 
2. 
Study schedule of assessments and procedures .................................................................................. 23 
2.1 
Screening, First Baseline Period, First Treatment Period and Washout ..................................... 23 
2.2 
Second Baseline Period, Second Treatment Period and Follow Up ........................................... 24 
3. 
Introduction and background information .............................................................................................. 25 
3.1 
Neuropathic pain .......................................................................................................................... 25 
3.2 
LAT8881 ....................................................................................................................................... 25 
3.2.1 
Nonclinical studies ....................................................................................................................... 26 
3.2.2 
Clinical studies ............................................................................................................................. 28 
4. 
Study objectives ..................................................................................................................................... 30 
4.1 
Primary objective .......................................................................................................................... 30 
4.2 
Secondary objectives ................................................................................................................... 30 
4.3 
Exploratory objectives .................................................................................................................. 30 
5. 
Study design .......................................................................................................................................... 31 
5.1 
Overall study design ..................................................................................................................... 31 
5.2 
Justification of study design ......................................................................................................... 31 
5.3 
Justification of dose ...................................................................................................................... 32 
5.4 
Number of planned subjects ........................................................................................................ 32 
5.5 
Duration of study .......................................................................................................................... 32 
5.6 
Duration of subject participation ................................................................................................... 33 
5.7 
Withdrawal of subjects from study ............................................................................................... 33 
5.8 
Replacement of subjects .............................................................................................................. 33 
6. 
Study population .................................................................................................................................... 34 
6.1 
Inclusion criteria ........................................................................................................................... 34 
6.2 
Exclusion criteria .......................................................................................................................... 34 
6.3 
Contraception requirements ......................................................................................................... 35 
6.4 
Dietary, lifestyle and other restrictions ......................................................................................... 36 
7. 
Study Treatments ................................................................................................................................... 37 
7.1 
Description ................................................................................................................................... 37 
7.2 
Formulation .................................................................................................................................. 37 
7.2.1 
LAT8881 capsules ....................................................................................................................... 37 
7.2.2 
Placebo capsules ......................................................................................................................... 37 
7.3 
Manufacturer ................................................................................................................................ 37 
7.4 
Storage ......................................................................................................................................... 37 
7.5 
Packaging and labelling ............................................................................................................... 37 


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7.6 
Randomisation and blinding ......................................................................................................... 37 
7.7 
Dispensing of investigational product .......................................................................................... 38 
7.8 
Method for assigning subject study number ................................................................................ 38 
7.9 
Accountability of study supplies ................................................................................................... 38 
7.10 
Doses and treatment regimens .................................................................................................... 38 
7.11 
Dose reduction/dose adjustments ................................................................................................ 38 
7.12 
Treatment compliance .................................................................................................................. 38 
7.13 
Unblinding .................................................................................................................................... 39 
7.13.1 
Medical Emergency ...................................................................................................................... 39 
7.13.2 
End of study ................................................................................................................................. 39 
7.14 
Concomitant medications ............................................................................................................. 39 
7.14.1 
Permitted medications .................................................................................................................. 39 
7.14.2 
Prohibited medications ................................................................................................................. 39 
8. 
Study procedures ................................................................................................................................... 41 
8.1 
Subject informed consent............................................................................................................. 41 
8.2 
Screening visit (Day -28 to Day -1), Visit 1 .................................................................................. 41 
8.2.1 
Screening Stage 1 (initial screening) ........................................................................................... 41 
8.2.2 
Screening Stage 2 (first baseline) ................................................................................................ 42 
8.3 
First treatment period (Days 1 to 28), Visits 2 to 4 ...................................................................... 42 
8.3.1 
Day 1, Visit 2 ................................................................................................................................ 42 
8.3.2 
Day 14 (± 1), Visit 3 ...................................................................................................................... 43 
8.3.3 
Day 28 (± 1), Visit 4 ...................................................................................................................... 43 
8.4 
Washout (Days 29-42) ................................................................................................................. 44 
8.5 
Second baseline period (Days 43-49) .......................................................................................... 44 
8.6 
Second treatment period (Days 50-77), Visits 5 to 7 ................................................................... 44 
8.6.1 
Day 50 (± 1), Visit 5 ...................................................................................................................... 44 
8.6.2 
Day 63 (± 1), Visit 6 ...................................................................................................................... 45 
8.6.3 
Day 77 (± 1), Visit 7 ...................................................................................................................... 45 
8.7 
End of Study visit ......................................................................................................................... 46 
8.7.1 
Day 91 (± 2) Visit 8 ....................................................................................................................... 46 
8.8 
Early withdrawal visit .................................................................................................................... 46 
9. 
Study Endpoints ..................................................................................................................................... 47 
9.1 
Primary endpoint .......................................................................................................................... 47 
9.2 
Secondary endpoints ................................................................................................................... 47 
9.3 
Safety endpoints .......................................................................................................................... 47 
9.4 
Pharmacokinetic endpoints .......................................................................................................... 48 
9.5 
Exploratory endpoints .................................................................................................................. 48 
10. 
Study measurements ............................................................................................................................. 49 
10.1 
Clinical assessments .................................................................................................................... 49 
10.1.1 
Medical history ............................................................................................................................. 49 
10.1.2 
Demographics .............................................................................................................................. 49 
10.1.3 
painDETECT questionnaire ......................................................................................................... 49 


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10.1.4 
Electrocardiogram ........................................................................................................................ 49 
10.1.5 
Vital signs ..................................................................................................................................... 49 
10.1.6 
Physical examination ................................................................................................................... 49 
10.1.7 
Height and weight ........................................................................................................................ 50 
10.1.8 
QST phenotype ............................................................................................................................ 50 
10.2 
Laboratory assessments .............................................................................................................. 50 
10.2.1 
Clinical safety testing ................................................................................................................... 50 
10.2.2 
Pharmacokinetics ......................................................................................................................... 51 
10.3 
Adverse event monitoring ............................................................................................................ 51 
10.4 
Concomitant medications ............................................................................................................. 51 
10.5 
Efficacy assessments ................................................................................................................... 51 
10.5.1 
Pain intensity ................................................................................................................................ 51 
10.5.2 
Patient reported outcomes ........................................................................................................... 52 
11. 
Study Oversight ..................................................................................................................................... 53 
11.1 
Within-subject stopping criteria .................................................................................................... 53 
11.2 
Suspension or premature termination of the study ...................................................................... 53 
12. 
Adverse events ...................................................................................................................................... 54 
12.1 
Definitions .................................................................................................................................... 54 
12.1.1 
Adverse event .............................................................................................................................. 54 
12.1.2 
Adverse drug reaction/Suspected adverse (drug) reaction ......................................................... 54 
12.1.3 
Suspected unexpected serious adverse reactions ...................................................................... 54 
12.1.4 
Causality ...................................................................................................................................... 54 
12.1.5 
Severity (Intensity) of adverse event ............................................................................................ 55 
12.1.6 
Serious adverse event ................................................................................................................. 55 
12.2 
Recording of adverse events ....................................................................................................... 55 
12.3 
Clinical lab abnormalities and other abnormal assessments ....................................................... 56 
12.4 
Reporting of serious adverse events ........................................................................................... 56 
12.5 
Follow-up of adverse events and serious adverse events ........................................................... 57 
13. 
Statistical analysis .................................................................................................................................. 58 
13.1 
General considerations ................................................................................................................ 58 
13.2 
Sample size .................................................................................................................................. 58 
13.3 
Analysis populations .................................................................................................................... 58 
13.3.1 
Full Analysis Set ........................................................................................................................... 58 
13.3.2 
Per protocol population ................................................................................................................ 58 
13.3.3 
Safety population ......................................................................................................................... 58 
13.3.4 
PK population ............................................................................................................................... 58 
13.4 
Subject disposition ....................................................................................................................... 59 
13.5 
Analysis of efficacy data............................................................................................................... 59 
13.5.1 
NPRS ........................................................................................................................................... 59 
13.5.2 
Patient reported outcomes ........................................................................................................... 59 
13.5.3 
Analgesic use ............................................................................................................................... 60 
13.6 
Analysis of safety data ................................................................................................................. 60 
13.6.1 
Extent of exposure ....................................................................................................................... 60 


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13.6.2 
Adverse events ............................................................................................................................ 60 
13.6.3 
Clinical laboratory evaluations ..................................................................................................... 60 
13.6.4 
Other safety measures ................................................................................................................. 60 
13.7 
Analysis of pharmacokinetic data ................................................................................................ 60 
13.8 
Analysis of exploratory endpoints ................................................................................................ 61 
14. 
Study management ................................................................................................................................ 62 
14.1 
Regulatory and ethical considerations ......................................................................................... 62 
14.1.1 
Regulatory compliance and ethical conduct ................................................................................ 62 
14.1.2 
Ethics Committee review.............................................................................................................. 62 
14.1.3 
Informed consent process ............................................................................................................ 62 
14.1.4 
Protocol amendments .................................................................................................................. 62 
14.1.5 
Protocol deviations ....................................................................................................................... 63 
14.2 
Quality control and quality assurance .......................................................................................... 63 
14.2.1 
Training of staff ............................................................................................................................ 63 
14.2.2 
Study monitoring .......................................................................................................................... 63 
14.2.3 
Data management and quality control ......................................................................................... 64 
14.2.4 
Audits and inspections ................................................................................................................. 64 
14.3 
Documentation, record access and archiving .............................................................................. 65 
14.3.1 
Maintenance of essential documents/supplements at study site during the study ...................... 65 
14.3.2 
Data protection ............................................................................................................................. 65 
14.3.3 
Data retention & archiving ............................................................................................................ 65 
14.4 
Study administration ..................................................................................................................... 66 
14.4.1 
Study agreements ........................................................................................................................ 66 
14.4.2 
Confidentiality ............................................................................................................................... 66 
14.4.3 
Insurance ..................................................................................................................................... 67 
14.4.4 
Reporting ...................................................................................................................................... 67 
14.4.5 
Publication policy ......................................................................................................................... 67 
15. 
References ............................................................................................................................................. 68 
Appendix 1: Protocol Amendments .................................................................................................................... 70 
 
List of Tables 
Table 1: Summary of clinical studies with LAT8881 .......................................................................................... 29 
 
List of Figures 
Figure 1: Amino acid sequence of LAT8881 .............................................................................................. 26 
Figure 2: Effects of LAT8881 on PWT of the ipsilateral hind paws in Chung model rats. ......................... 27 
Figure 3: Effects of LAT8881 on PWT of the contralateral hind paws in Chung model rats. .................... 27 
Figure 4: Overall study design for LAT-NP-001 ......................................................................................... 31 
 
 


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List of Abbreviations 
Abbreviation 
Definition 
µg 
Microgram 
µl 
Microlitre 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AUC0-inf 
Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification, extrapolated to infinity 
AUC0-t 
Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification 
BDI-II 
Beck Depression Inventory-II 
BLQ 
Below limit of quantification 
BPI 
Brief Pain Inventory 
cGMP 
Current good manufacturing practice 
CI 
Confidence interval 
Cmax 
Maximum plasma drug concentration 
(e)CRF 
(electronic) Case report form 
CTN 
Clinical Trial Notification (scheme) 
DPN 
Diabetic peripheral neuropathy 
EC 
Ethics committee 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
FOCBP 
Female of child bearing potential 
g 
Gram 
GCP 
Good clinical practice 
HbA1c 
Glycosylated haemoglobin 
hCG 
Human chorionic gonadotropin 
hGH 
Human growth hormone 
HPT 
Heat Pain Threshold 
IASP 
International Association for the Study of Pain 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP  
Investigational medicinal product  
Investigator 
A person responsible for the conduct of the clinical trial at a trial site. If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 


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Abbreviation 
Definition 
kg 
Kilogram 
m 
Metre 
m2 
Square metre 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mL 
millilitre 
mN 
millinewton 
MPS 
Mechanical Pain Sensitivity 
n 
Number (of subjects) 
NeuPSIG 
Neuropathic Pain Special Interest Group 
NP 
Neuropathic pain 
NPRS 
Numeric pain rating scale 
NPSI 
Neuropathic Pain Symptom Inventory 
PCI 
PCI Pharma Services 
PD-Q 
painDETECT questionnaire 
PGIC 
Patient Global Impression of Change 
PHN 
Postherpetic neuralgia 
PIC/S 
Pharmaceutical Inspection Co-operation Scheme 
PIS 
Participant Information Sheet 
PK 
Pharmacokinetics 
PK subjects 
Subjects in whom pharmacokinetics are measured 
PP 
Per protocol 
PT 
Preferred term 
PWT 
Paw withdrawal threshold 
QST 
Quantitative sensory testing 
QST subjects 
Subjects in whom quantitative sensory testing is undertaken 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SF-MPQ-2 
Short-form McGill Pain Questionnaire 2 
SOC 
System organ class 
SOP 
Standard operating procedure 
Subject ID 
Unique number given to each subject on screening 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Terminal elimination half life 


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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
 
TGA 
Therapeutic Goods Administration 
Tmax 
Time to maximum plasma LAT8881 concentration 
TYR 
Tyrosine 
WDT 
Warm Detection Threshold 
 
 
 
 


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1. Protocol synopsis 
Title: 
A Phase IIa study of the efficacy and safety of oral LAT8881 in neuropathic 
pain  
Protocol Number 
LAT-NP-001 
Clinical Phase 
IIa 
Principal 
Investigator 
Professor Tony Pickering B.Sc., Ph.D., MB ChB (Birm), F.R.C.A. 
Biomedical Sciences Building, 
University Walk, Bristol BS8 1TD 
United Kingdom 
 
Study Site(s) 
Emeritus Research, Victoria, Australia 
Australian Medical Research, New South Wales, Australia 
AusTrials Pty Ltd, Queensland, Australia 
University Hospitals Bristol NHS Trust, Bristol, United Kingdom 
Queen Elizabeth University Hospital, Glasgow, United Kingdom  
Full contact details are provided in the Site Contact List. 
Investigational 
Medicinal Product 
(IMP) 
LAT8881 (Tyr-hGH177-191), 30 mg capsules and matching placebo. 
One capsule to be taken in the morning and one in the evening. Total daily 
dose of IMP: 0 or 60 mg LAT8881 
Indication 
Neuropathic pain (NP), associated with either postherpetic neuralgia (PHN) 
or diabetic peripheral neuropathy (DPN) 
Study Description 
This is a randomised, placebo-controlled, double-blind, crossover, phase IIa 
study to investigate the efficacy and safety of oral LAT8881 in neuropathic 
pain. After a one week baseline period, subjects entered into the study will be 
randomised to receive IMP (LAT8881 or placebo) twice daily for four weeks.  
The first treatment period will be followed by a washout period of two weeks 
and then a second baseline period of one week. Subjects will not take any 
IMP over these three weeks. 
After the second baseline period, subjects will cross over to receive the 
second treatment (either LAT8881 or placebo, whichever treatment was not 
received in the first treatment period) twice daily for four weeks. 
The pharmacokinetics (PK) of LAT8881 will be investigated in 15 subjects 
(PK subjects) at selected Australian sites. Quantitative sensory testing (QST) 
for Warm Detection Threshold (WDT), Mechanical Pain Sensitivity (MPS) and 
Heat Pain Threshold (HPT) will be performed in up to 20 subjects (QST 
subjects) in each treatment period, before the first dose and on the last day of 
each period. No subject will have both PK and QST analyses. 
Number of 
Subjects Planned 
It is planned to have 44 subjects complete the study. Assuming a 20% 
dropout, 55 subjects will be recruited. 
Study Objectives 
Primary 
• 
To evaluate the efficacy of oral LAT8881 in NP compared with 
placebo, when assessed by change in mean pain intensity scores 


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from baseline to the end of four weeks treatment, based on an 
11 point numeric pain rating scale (NPRS) 
Secondary 
• 
To investigate the effect of oral LAT8881 in NP compared with 
placebo at different timepoints (up to 6 hours) following a single dose 
and after 4 weeks treatment, as measured by the NPRS (PK subjects 
only) 
• 
To investigate the effect of oral LAT8881 on mean pain scores in NP 
compared with placebo after 1, 2 and 3 weeks of dosing, as measured 
by the NPRS 
• 
To determine the proportion of responders to oral LAT8881 in NP 
compared with placebo 
• 
To investigate the maximum effect of oral LAT8881 in NP, compared 
with placebo, as determined by the maximum change from mean 
NPRS baseline after 1, 2, 3 or 4 weeks treatment 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on 
functioning in subjects with NP when measured by the 7-item short 
form Brief Pain Inventory (BPI) Interference Scale 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on 
pain symptoms in subjects with NP, when measured by the short-form 
McGill Pain Questionnaire 2 (SF-MPQ-2) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on 
symptoms in subjects with NP, when measured by the Neuropathic 
Pain Symptom Inventory (NPSI) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on 
emotional functioning when measured by the Beck Depression 
Inventory-II (BDI-II) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on 
overall health and quality of life in subjects with NP, when measured 
by the Patient Global Impression of Change (PGIC) scale 
• 
To determine the change from baseline in paracetamol rescue 
medication use during oral LAT8881 administration, compared with 
placebo 
• 
To evaluate the safety and tolerability of oral LAT8881 in NP after a 
single dose and after four weeks treatment  
• 
To investigate the pharmacokinetics of twice daily oral LAT8881 in 15 
subjects with NP after a single dose and after 4 weeks treatment with 
oral LAT8881 
Exploratory 
• 
To investigate the relationship between baseline subject 
characteristics, such as clinical diagnosis (PHN or DPN) and QST 
parameters, and the change in NPRS after oral LAT8881 treatment, 
compared with placebo 
• 
To investigate the change from baseline on specified QST parameters 
(WDT, MPS, HPT) after four weeks treatment with oral LAT8881, 


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compared with placebo 
• 
To investigate the relationship between plasma LAT8881 
concentrations and the change in mean pain score in subjects with NP 
• 
To investigate the impact of variability in NPRS scores during the first 
baseline period on the difference between baseline and 4 week NPRS 
scores after LAT8881 or placebo 
Endpoints 
Primary Endpoint 
• 
Absolute change in mean pain score, using an 11 point NPRS, from 
baseline to the last week of each treatment period. Pain is recorded 
once daily in a subject diary, in the evening, and should reflect the 
subject’s average pain over the last 24 hours  
Baseline mean pain for each subject is defined as the mean of the last five 
available ratings of daily pain, recorded in each baseline period. 
End of treatment mean pain for each subject is defined as the mean of the 
last five available ratings of daily pain, recorded in the last 7 days of each 4 
week treatment period. 
Secondary Endpoints 
• 
Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after the first dose 
of IMP in each treatment period, compared with the score recorded no 
more than 60 minutes before the first dose of IMP in that treatment 
period (PK subjects only) 
• 
Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after a single dose 
of IMP, following four weeks treatment with IMP in each treatment 
period, compared with the score recorded no more than 60 minutes 
before this dose (PK subjects only) 
• 
Change in mean pain scores from baseline after 1, 2 and 3 weeks of 
dosing with IMP in each treatment period, using an 11 point NPRS. 
Mean pain scores at weeks 1, 2 and 3 are defined as the mean of the 
last five available ratings of daily pain in the subject diary, recorded in 
the previous 7 days of treatment 
• 
30% responder rate, based on the proportion of subjects achieving 
≥ 30% reduction in mean NPRS from baseline to the end of 4 weeks 
treatment in each treatment period 
• 
50% responder rate, based on the proportion of subjects achieving 
≥ 50% reduction in mean NPRS from baseline to the end of 4 weeks 
treatment in each treatment period 
• 
Maximum change in mean NPRS from baseline after 1, 2, 3 or 4 
weeks treatment in each treatment period 
• 
Change in functioning from baseline to the end of 4 weeks treatment 
in each treatment period, as assessed by the BPI interference scale 
• 
Change in pain characteristics and intensity from baseline to the end 
of 4 weeks treatment in each treatment period, as assessed by the 
SF-MPQ-2  
• 
Change in neuropathic pain symptoms from baseline to the end of 4 
weeks treatment in each treatment period, as assessed by NPSI 


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• 
Change in emotional functioning from baseline to the end of 4 weeks 
treatment in each treatment period, as assessed by the BDI-II 
• 
PGIC at the end of each four week treatment period 
• 
Paracetamol (rescue medication) use per week over each treatment 
period compared with the preceding baseline 
Safety Endpoints 
• 
Physical examinations and vital signs 
• 
ECG  
• 
Clinical chemistry and haematology analyses 
• 
Urinalysis 
• 
Number and type of Treatment Emergent Adverse Events (TEAEs), 
including serious adverse events (SAEs), and suspected unexpected 
serious adverse reactions (SUSARs) 
• 
Concomitant medications 
Pharmacokinetic Endpoints 
• 
Pharmacokinetic parameters: Cmax, Tmax, AUC0-inf in each treatment 
period, after a single dose and at the end of four weeks treatment in 
PK subjects  
Exploratory Endpoints 
• 
Association between change in mean NPRS from baseline to the end 
of four weeks treatment and selected subject baseline characteristics, 
including clinical diagnosis and pre-treatment QST parameters 
• 
Change from baseline in specified QST parameters (WDT, MPS, 
HPT), to the end of four weeks treatment, in each treatment period 
• 
Correlation between plasma LAT8881 concentration and the change 
in mean NPRS from baseline to the end of four weeks treatment in PK 
subjects 
• 
Change in mean NPRS score from baseline to the last week of each 
treatment period, after omission of subjects with the 25% most 
variable first baseline NPRS scores 
Study Population: 
Inclusion Criteria 
Subjects must meet the following criteria to be entered into the study: 
1. 
Clinical diagnosis of post herpetic neuralgia, with pain persisting for at 
least 3 months after the onset of herpes zoster rash 
OR  
2. 
Clinical diagnosis of distal painful polyneuropathy due to Type I or 
Type II diabetes mellitus with: 
a) 
symmetrical, bilateral pain in the lower extremities for at least 3 
months and 
b) 
diabetes under control for at least 3 months prior to 
randomisation, as indicated by a glycated haemoglobin level 


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(HbA1c) of ≤ 11% (97 mmol/mol) and on a stable dose of insulin 
or oral diabetic medication for 3 months prior to screening, and  
c) 
no change in diabetic medication planned for the duration of the 
study 
3. 
Positive sensory symptoms (mechanical or thermal) associated with 
neuropathic pain, confirmed by: 
a) 
painDETECT questionnaire (PD-Q) and  
b) 
Clinical assessment, showing signs of neuropathic pain in either 
a dermatomal (PHN) or distal symmetrical distribution (DPN) 
4. 
Aged 18 to 75 years  
5. 
Subjects must be sufficiently competent in English to understand the 
purposes and risks of the study and able to give voluntary written 
informed consent to participate in the study 
6. 
Willing and able to comply with all study procedures 
7. 
Completion of at least five NPRS scores during the week preceding 
randomisation 
8. 
An average daily pain score on the NPRS of at least 4 and no more than 
8 in the last five diary entries before randomisation  
9. 
No more than one score on the NPRS of 9 or more, and no more than 
one score of 2 or less, in the last five diary entries before randomisation 
10. 
Females of child bearing potential must have a negative pregnancy test 
at Visit 1 (Screening) and at Visit 2 (Day 1) prior to administration of IMP 
11. 
Female subjects must be: 
a) 
of non child-bearing potential [surgically sterilised or post–
menopausal (12 months with no menses without alternative 
medical cause)] OR 
b) 
not pregnant, breast feeding or planning to become 
pregnant AND willing to comply with the medically 
acceptable contraceptive requirements of the study from 
Screening to at least 28 days after the last IMP 
administration  
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the 
study: 
1. 
Presence of moderate to severe pain from other causes that may 
confound assessment or self-evaluation of NP.  
2. 
Subjects with both DPN and PHN  
3. 
Skin conditions in the affected area that could alter sensation or 
assessments 
4. 
History of or current clinically significant gastrointestinal, hepatic, renal, 
cardiovascular, respiratory, endocrine, oncological, immunological, 
neurological, ophthalmological, haematological or psychiatric disorder 
or any other condition, which in the opinion of the investigator or sponsor 


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would jeopardise the safety of the subject or the validity of the study 
results  
5. 
Medical history of, or currently active, human immunodeficiency virus, 
hepatitis B or hepatitis C virus   
6. 
Clinically significant abnormal 12-lead electrocardiogram (ECG) 
7. 
Immunocompromised state, or conditions known to be associated with 
an immunocompromised state 
8. 
Clinically significant or unstable medical or psychological condition that 
would compromise participation in the study 
9. 
Recent history of malignancy within 5 years preceding screening 
(except resected cervical or skin cancer [except melanoma]). Subjects 
who have had no evidence of disease in the last 5 years are eligible 
10. 
Active herpes zoster infection on screening 
11. 
Current alcohol abuse, illicit or illegal drug use 
12. 
Use of prohibited medication (see study medications) 
13. 
Previous treatment with LAT8881 (formerly identified as AOD9604) 
within the last 5 years 
14. 
Participation in an investigational trial within 60 days or 5 half-lives 
(whichever is longer) prior to screening 
15. 
History of significant hypersensitivity to LAT8881 or drugs of a similar 
pharmacological class (e.g. somatropin) 
16. 
Surgical or medical conditions which could significantly alter drug 
absorption, distribution, metabolism or excretion 
17. 
An employee of the sponsor or research site personnel directly affiliated 
with this study, whether biological or legally adopted, or their immediate 
family members, defined as a spouse, parent, sibling, or child 
18. 
Previous neurolytic or neurosurgical therapy for PHN or DPN 
19. 
PK subjects: 
a) 
Blood or plasma donation of more than 500 mL during the 
3 months prior to randomisation 
b) 
History of fainting during phlebotomy 
Study  
Medications 
Permitted medications 
The following medications are permitted: 
• 
Subjects may take their usual oral medications for PHN or DPN, 
providing the dose has been stable for at least 30 days before 
randomisation and is maintained for the duration of the study until the 
end of study visit  
• 
Diabetics must be on stable diabetic medication for at least 3 months 
before randomisation, and the medication must be maintained at the 
same dose until the end of study visit  
• 
Subjects may also take the following medications, provided the 
regimen is stable for 30 days before randomisation and remains 


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steady from randomisation to the end of study visit: 
- 
benzodiazepine 
- 
anxiolytic, such as buspirone 
- 
serotonin and noradrenaline (norepinephrine) reuptake inhibitor  
- 
oral aspirin (≤ 150 mg/day)  
- 
tricyclic antidepressant  
• 
In addition, up to 4 g per day of paracetamol (rescue medication) may 
be taken except within 4 hours of the first and last clinic visit in each 
treatment period 
 
Prohibited medications 
The following medications are prohibited. 
• 
Patch containing 8% capsaicin (Qutenza), if applied within the last six 
months before randomisation  
• 
Current or recent (within 7 days of randomisation) use of any other 
topically applied pain medication  
• 
Cryotherapy, intrathecal/epidural opioids, systemic corticosteroids or 
botulinum toxin if administered in the last 6 months. Topical or inhaled 
corticosteroids are permitted. .A short course (< 7days) of oral 
prednisolone or equivalent for other conditions, up to 4 weeks preceding 
Day 1, is allowed 
• 
Steroid or local anaesthetic nerve blocks within the last 12 months 
Study Procedures 
Screening (Days -28 to -1) 
Potential subjects will be required to provide written informed consent prior to 
any study-specific screening procedures being performed. A unique 
Screening Number (Subject ID) will be assigned. 
There will be two stages within the screening procedure. In the first stage 
(Screening Stage 1, Days -28 to Day -8), subjects will undergo screening 
assessments including medical history, height, weight, PD-Q, 12-lead ECG, 
vital signs, and physical examination. Concomitant medications will be 
recorded. Blood will be collected for routine haematology and clinical 
chemistry screening and, in female subjects of child-bearing potential, to test 
for pregnancy. A urine sample will be collected for urinalysis.  
Subjects deemed likely to be eligible for the trial after completion of the above 
screening tests will be given access to a diary and training on how to record 
daily pain scores. 
In the second screening stage (Screening Stage 2, First Baseline Period, 
Days -7 to -1) subjects will complete their diary from Days -7 to -1 inclusive. 
This will be their first baseline period if confirmed to be eligible and enrolled in 
the study.  
Up to 20 potentially eligible subjects will also have QST scheduled within 
seven days of the first treatment.  
First Treatment Period (Days 1-28) 
Subjects will return to the unit on Day 1 (Visit 2) with their diary completed 


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from Days -7 to -1 inclusive. Diary records will be reviewed to assess pain 
scores. Other assessments, including weight, PD-Q, ECG, vital signs and a 
targeted physical examination will also be conducted on Day 1. Concomitant 
medications will be recorded. Blood and urine samples will be taken for safety 
monitoring. Urine samples in female subjects of child-bearing potential will be 
tested for evidence of pregnancy. Results from safety monitoring tests are not 
required prior to dosing. Eligible subjects will be enrolled and randomised to 
LAT8881 or placebo. 
Subjects will complete baseline assessments for Patient Reported Outcomes 
(interference scale of the short form BPI, SF-MPQ-2, NPSI, BDI-II). In PK 
subjects, a pre-dose NPRS will be completed and a pre-dose blood sample 
taken for PK analysis. QST subjects will have a pre-dose QST assessment, if 
not completed within the previous 7 days. 
Subjects (except PK subjects) will take their first dose of IMP and remain in 
the clinic for up to one hour to check for any adverse events. 
PK subjects will take their first dose of IMP and remain in the clinic for at least 
6 hours. At scheduled times over this period, blood samples will be taken for 
PK analyses and NPRS assessments.  
All subjects will leave the unit with sufficient IMP for the first treatment period.  
On Day 14 (Visit 3), subjects will take their morning IMP dose and return to 
the clinic. Weight, vital signs, a targeted physical examination, concomitant 
medications and adverse events will be recorded. Subject compliance with 
medication and diary entries will be checked. Subjects will be reminded to 
continue their medication and to record daily entries into their diary. 
On the morning of Day 28 (Visit 4, Last Day of First Treatment Period), 
subjects will not take their morning dose of IMP. They will make their morning 
diary entry and return to the clinic. At the clinic, weight, ECG, vital signs, a 
targeted physical examination, concomitant medications and adverse events 
will be recorded. Blood and urine samples will be taken for safety analysis. 
Subjects will complete assessments for Patient Reported Outcomes 
(interference scale of the short form BPI, SF-MPQ-2, NPSI, BDI-II, PGIC). In 
PK subjects, a pre-dose NPRS will be completed and a pre-dose blood 
sample will be taken for PK analysis. 
Subjects (except PK and QST subjects) will then take their morning dose of 
IMP and leave the clinic. PK subjects will take their morning dose of IMP and 
stay for at least 6 hours. At scheduled times over this period, blood samples 
will be taken for PK analyses and NPRS assessments will be undertaken. 
QST subjects will take their morning dose of IMP and will have specified QST 
parameters (WDT, MPS and HPT) assessed 2 hours after this dose. An 
appointment for a QST assessment will be scheduled within seven days of 
the first dose of the second treatment period. 
All subjects will take their second Day 28 IMP dose in the evening. 
Washout (Days 29 to 42) 
Subjects will be asked to discontinue their IMP after their evening dose on 
Day 28. Daily diary NPRS entries should be continued. 


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Second Baseline Period (Days 43 to 49) 
Subjects will continue daily diary entries and will not take any IMP over Days 
43 to 49 inclusive (second baseline).  
Second Treatment Period (Days 50-77) 
Subjects will return to the unit on Day 50 (Visit 5) with their diary completed 
from Days 29 to 49 inclusive. QST subjects will have a pre-dose QST 
assessment, if not completed within the previous 7 days. 
On Day 50, assessments including weight, ECG, vital signs, a targeted 
physical examination and concomitant medications will be recorded and the 
subject’s pain diary (Days 43-49 inclusive) will be reviewed. Blood and urine 
samples will be taken for safety monitoring. Results from safety monitoring 
tests are not required prior to dosing. 
Subjects will complete their second baseline assessments for Patient 
Reported Outcomes (interference scale of short form BPI, SF-MPQ-2, NPSI, 
BDI-II). In PK subjects, a pre-dose NPRS will be completed and a pre-dose 
blood sample taken for PK analysis. 
Subjects (except PK subjects) will take their allocated IMP and remain in the 
clinic for up to one hour to check for any adverse events.  
PK subjects will take their allocated IMP and remain in the clinic for at least 6 
hours. At scheduled times over this period, blood samples will be taken for 
PK analyses and NPRS assessments will be undertaken.  
All subjects will leave the unit with sufficient IMP for the second treatment 
period. 
On Day 63 (Visit 6), subjects will take their morning IMP dose and return to 
the clinic. Weight, vital signs, a targeted physical examination, concomitant 
medications and adverse events will be recorded. Subject compliance with 
medication and diary entries will be checked. Subjects will be reminded to 
continue their medication and to record daily entries into their diary. 
On the morning of Day 77 (Visit 7, Last Day of Second Treatment Period), 
subjects will not take their morning dose of IMP. They will make their morning 
diary entry and return to the clinic. At the clinic, weight, ECG, vital signs, a 
targeted physical examination, concomitant medications and adverse events 
will be recorded. Blood and urine samples will be taken for safety analysis. 
Subjects will complete assessments for Patient Reported Outcomes 
(interference scale of the short form BPI, SF-MPQ-2, NPSI, BDI-II, PGIC). In 
PK subjects, a pre-dose NPRS will be completed and a pre-dose blood 
sample will be taken for PK analysis. 
Subjects (except PK and QST subjects) will then take their morning dose of 
IMP and leave the clinic. PK subjects will take their morning dose of IMP and 
stay for at least 6 hours. At scheduled times over this period, blood samples 
will be taken for PK analyses and NPRS will also be monitored. QST subjects 
will take their morning dose of IMP and will have QST parameters (WDT, 
MPS, HDT) assessed two hours after this dose. 
All subjects will take their second Day 77 IMP dose in the evening. They will 
be asked to discontinue their IMP after taking the Day 77 evening dose. 
End of Study (Day 91) 


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At the end of study visit, weight, vital signs, a targeted physical examination, 
concomitant medications and adverse events will be recorded. Blood and 
urine samples will be taken for safety analysis.  
Early withdrawal 
Subjects who withdraw early will be asked to attend an end of study visit. This 
visit should be scheduled approximately two weeks after the last dose was 
taken. 
Statistical 
Analysis 
With a total sample size of 44 evaluable subjects there is 90% power to 
demonstrate a statistically significant difference in the mean change from 
baseline NPRS for the active treatment compared with placebo of at least 1 
unit. This assumes that the standard deviation of the change from baseline 
NPRS is 2, the correlation between active and placebo responses within a 
subject is 0.5 and there is a 2-sided test at the 5% level of significance. 
Assuming a 20% dropout rate, it is aimed to enrol at least 55 subjects to 
obtain 44 evaluable subjects. 
The number of subjects within each treatment group is also sufficient to show 
a statistically significant change from baseline of 2 or more points on the 
NPRS. 
The primary efficacy endpoint is the change from baseline mean NPRS score 
to the end of treatment mean NPRS score after LAT8881, compared with the 
change from baseline after placebo treatment. This will be analysed in the per 
protocol (PP) population, which will be defined in a statistical analysis plan 
(SAP) before database lock. The PP will be based on the duration of IMP 
treatment and protocol deviations. 
Mixed effects regression models will be used to compare the absolute and 
percentage changes from baseline to the end of each treatment for the mean 
NPRS scores. The models will have fixed effects for period and treatment. 
Baseline mean pain score within each period by treatment combination will 
be included as a covariate. A random effect for subject will be included to 
capture the repeated measures nature of the design. 
The models for the primary endpoint will be expanded to compare the 
absolute and percentage changes from baseline for the mean NPRS scores 
after 1, 2 and 3 weeks of dosing with IMP in each treatment period. The 
model will also include a fixed effect for week (1, 2, 3 and 4), the interaction 
between treatment and week to assess whether the change from baseline for 
each treatment is different. 
 


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Daily NPRS scores for all enrolled subjects will be listed. Mean and standard 
deviation of scores during the baseline period and weeks 1, 2, 3 and 4, and 
the absolute and percentage change from baseline in each period, will be 
listed and summarised for LAT8881 and placebo treatments overall and 
within treatment sequence for all randomised subjects and for the PP 
population. The maximum change in mean NPRS from baseline, determined 
for each subject after LAT8881and placebo, will be listed and summarised. In 
PK subjects, NPRS scores at specified times up to 6 hours on Days 1, 28, 50 
and 77 will be listed and summarised. Change from pre-dose values will also 
be listed and summarised. Changes over time will be analysed using the 
same modelling approach as for the primary endpoint. 
The proportion of subjects achieving at least 30% and 50% reduction in pain 
after four weeks treatment, as assessed by the mean NPRS score, will be 
summarised with the 95% confidence interval for the percentage reduction, 
estimated by Clopper Pearson Exact methodology. A mixed effects logistic 
regression model, including the same fixed and random effect terms as for 
the primary endpoint, will be used to assess the odds of achieving a reduction 
in pain after four weeks treatment with LAT8881 compared to placebo.  
Baseline and end of treatment values for the BPI interference scale, SF-
MPQ-2, NPSI and BDI-II will be listed for LAT8881 and placebo. Values at 
each timepoint and the change from baseline will be summarised. Similarly, 
baseline and end of treatment values for QST parameters (WDT, HPT, MPS) 
will be listed for LAT8881 and placebo, and values at each timepoint and 
change from baseline will be summarised. Differences between the LAT8881 
and placebo treatments in the change from baseline reported outcomes will 
be analysed using the same model as for the primary endpoint. 
PGIC will be tabulated at the end of each treatment period and summarised. 
Paracetamol (rescue medication) use at baseline and weekly over the 
treatment period will be listed for each subject. The average weekly and 
cumulative dose of rescue paracetamol medication in each treatment period 
will be summarised by visit and treatment 
All randomised subjects who receive at least one dose of IMP and have at 
least one post dose safety assessment will be included in the safety analysis. 
Adverse events will be listed individually and will be summarised by body 
system and preferred term. Summaries will include the number and 
percentage of subjects with any adverse event, with serious adverse events, 
adverse events leading to premature discontinuation of IMP, adverse events 
by intensity and adverse events by relationship to IMP. Safety laboratory data 
will be summarised by visit and treatment, subjects with clinically significant 
abnormal results will be listed. 
Plasma drug concentrations and any derived pharmacokinetic parameters will 
be listed and summarised descriptively for all subjects who received at least 
one dose of IMP, had at least one post-dose sample collection for PK 
analysis and who did not have any clinically significant events or protocol 
deviations that may have compromised the integrity of the PK results. 
Anticipated Study 
Duration: 
Recruitment approximately 9 months, study duration approximately 13 
months 


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Subject Duration: 
Maximum participation duration is 17 weeks: screening and first baseline (up 
to 4 weeks), first treatment (4 weeks), washout (2 weeks) second baseline 
(1 week), second treatment (4 weeks), follow up (2 weeks).  
 
 


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2. Study schedule of assessments and procedures 
2.1 
Screening, First Baseline Period, First Treatment Period and Washout 
 
Screening 
Stage 1 
Screening 
Stage 2 (First 
Baseline) 
First Treatment Period 
Washout 
Visit No 
1 
2 
3 
4 
 
Study Day 
-28 to -8 
-7 to -1 
1 
14 ± 1 
28 ± 1 
29 (+/-1) to 
42 (+/-1) 
Written informed consent 
X 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
Pain diary training 
X 
 
 
 
 
 
Confirmation of eligibility  
 
 
X 
 
 
 
Enrolment 
 
 
X 
 
 
 
Randomisation 
 
 
X 
 
 
 
Medical history, demographics 
X 
 
 
 
 
 
Height,1 weight 
X 
 
X 
X 
X 
 
PD-Q 
X 
 
X 
 
 
 
12 lead ECG  
X 
 
X2 
 
X2 
 
Vital signs 
X 
 
X3 
X 
X 
 
Physical examination4 
X 
 
X5 
X5 
X5 
 
Concomitant medications 
X 
 
X 
X 
X 
 
Clinical laboratory safety testing6 
X 
 
X2,7 
 
X2 
 
Pregnancy test8 
X9 
 
X10 
 
 
 
QST sensory phenotype assessment11 
 
 
X12 
 
X 
 
IMP administration 
 
 
X13 
X 
X13 
 
Adverse event assessment 
X14 
X14 
X 
X 
X 
 
Blood sampling for PK analysis15 
 
 
X16 
 
X16 
 
Daily NPRS ratings17 
 
X 
X18 
X 
X18 
X 
Short form BPI assessment 
 
 
X 
 
X 
 
Short form McGill questionnaire 2 
 
 
X 
 
X 
 
Neuropathic Pain Symptom Inventory 
 
 
X 
 
X 
 
Beck Depression Index-II 
 
 
X 
 
X 
 
PGIC 
 
 
 
 
X 
 
 
1 Height measured only at screening 
2 Pre-dose 
3 Pre-dose and 0.5 hours post-dose 
4 Includes assessment of area of pain 
5 Targeted physical examination 
6 Haematology, clinical chemistry, urinalysis 
7 Results of clinical laboratory tests not required prior to dosing 
8 Females of child bearing potential only 
9 Blood pregnancy test 
10 Urine pregnancy test 
11 QST subjects only 
12 QST to be assessed pre-dose, within 7 days of the first dose 
13 Supervised administration 
14 SAEs only (UK subjects only) 
15 PK subjects only 
16 Pre-dose and up to 6 hours post-dose  
17 Each evening, throughout baseline, treatment and washout periods 
18 Additional ratings pre-dose and up to 6 hours post-dose in PK subjects 


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2.2 
Second Baseline Period, Second Treatment Period and Follow Up 
 
Second 
Baseline 
Period 
Second Treatment Period 
End of Study 
Visit No 
 
5 
6 
7 
8 
Study Day 
43 to 49 
50 ± 1 
63 ± 1 
77 ± 1 
91 ± 2 
Weight 
 
X 
X 
X 
X 
12 lead ECG 
 
X19 
 
X19 
 
Vital signs 
 
X20 
X 
X 
X 
Physical examination21 
 
X22 
X22 
X22 
X22 
Concomitant medications 
 
X 
X 
X 
X 
Clinical laboratory safety testing23 
 
X19,24 
 
X19 
X 
QST sensory phenotype assessment25 
 
X26 
 
X 
 
IMP administration 
 
X27 
X 
X27 
 
Adverse event assessment 
 
X 
X 
X 
X 
Blood sampling for PK analysis28 
 
X29 
 
X29 
 
Daily NPRS ratings30 
X 
X31 
X 
X31 
 
Short form BPI assessment 
 
X 
 
X 
 
Short form McGill questionnaire 2 
 
X 
 
X 
 
Neuropathic Pain Symptom Inventory 
 
X 
 
X 
 
Beck Depression Index-II 
 
X 
 
X 
 
PGIC 
 
 
 
X 
 
 
 
 
 
19 Pre-dose 
20 Pre-dose and 0.5 hours post-dose 
21 Includes assessment of area of pain 
22 Targeted physical examination 
23 Haematology, clinical chemistry, urinalysis 
24 Results of clinical laboratory tests not required prior to dosing 
25 QST subjects only 
26 QST to be assessed pre-dose, within 7 days of the first dose of this treatment period 
27 Supervised administration 
28 PK subjects only 
29 Pre-dose and up to 6 hours post-dose 
30 Each evening throughout baseline and treatment periods 
31 Additional ratings pre-dose and up to 6 hours post-dose in PK subjects 


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3. Introduction and background information 
3.1 
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 preclinical and clinical safety record. This is the first clinical study to 
investigate this compound in neuropathic pain. 
3.2 
LAT8881 
LAT8881 is a 16 amino acid peptide fragment based on human-growth hormone (hGH). It consists of the 
15 amino acids from the C-terminus of human growth hormone, to which a terminal tyrosine is added at 
the N-terminal end (Tyr-hGH177-191). Its molecular formula is NH2-Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-
Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, with a disulphide bridge between amino acids 7 and 14 (Figure 1). 


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Figure 1: Amino acid sequence of LAT8881 
LAT8881 was initially developed for the treatment of obesity (known during these studies as AOD9604). 
Six clinical trials involving 936 subjects were completed, with over 700 subjects treated with oral LAT8881 
(Section 3.2.2). There were no significant safety issues but the most recent efficacy study (METAOD006) 
did not meet the primary endpoint and development was discontinued for this indication in 2007. 
3.2.1 Nonclinical studies 
3.2.1.1 
Preclinical pain studies 
Oral LAT8881 was tested in a standard rat model of neuropathic pain (Chung model, a single ligation of 
the L5 spinal nerve). In this model, the animal shows some typical signs of neuropathic pain symptoms 
such as mechanical allodynia, mechanical and thermal hyperalgesia and spontaneous flinches/paw lifts.  
Tactile allodynia was assessed by measuring the paw withdrawal threshold (PWT) to mechanical 
stimulation with von Frey filaments. PWT was measured on 3 consecutive days before surgery and on 
days 6-8 after surgery. On days 12-14 after surgery, groups of 8 rats were then given a single oral dose 
of: 
• 
Vehicle: 2 ml/kg, or 
• 
LAT8881: 1, 2 or 5 mg/kg, or 
• 
Gabapentin: 100 mg/kg (as a positive control) 
PWT was measured before, 1, 2 and 4 hours after drug or vehicle administration. LAT8881 at 2 and 5 
mg/kg, significantly increased PWT in response to mechanical stimulation in the ipsilateral hind paws of 
Chung model rats in a dose-dependent manner (Figure 2). The effect of LAT8881 reached a peak around 
2 hours after dosing. The difference from vehicle was statistically significant (p<0.01) at all post-dose 
timepoints. There was no significant effect on the contralateral PWT (Figure 3). 
 
 
 


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Pre: pre-surgery; BL1: day 6-8 post-surgery; BL2: day 12-14 post-surgery, pre-dosing control;  
Vehicle: 5% DMSO in PBS. * P < 0.05, ** <0.01 and *** <0.001, compared to the same time points in the vehicle control group (one-
way ANOVA), n = 8 for each group. Gabapentin was used as a positive control. 
Figure 2: Effects of LAT8881 on PWT of the ipsilateral hind paws in Chung model rats.  
 
Pre: pre-surgery; BL1: day 6-8 post-surgery; BL2: day 12-14 post-surgery, pre-dosing control;  
Vehicle: 5% DMSO in PBS. No significant difference in each LAT8881 group when compared to the same time points in the vehicle 
control group (P .0.05, one-way ANOVA), n = 8 for each group. Gabapentin was used as a positive control. 
Figure 3: Effects of LAT8881 on PWT of the contralateral hind paws in Chung model rats.  
Subsequent screening studies were conducted with LAT8881 (5 mg/kg given orally) in seven other 
models of pain: post-surgical pain, chemotherapy-induced neuropathy, carrageenan-induced thermal 
hyperalgesia, reserpine-induced myalgia, formalin test, diabetic neuropathy and a monosodium 
iodoacetate–induced osteoarthritis model. LAT8881 showed clear efficacy in all models except for 
 


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osteoarthritis, where only a weak effect was seen. 
Current research is focused on identifying the mechanism by which LAT8881 acts in these pain models. 
Preliminary data available to date suggests an effect on nerve signaling.  
3.2.1.2 
Nonclinical safety studies 
Studies in rats and monkeys at doses up to 10 mg/kg LAT8881 intravenously for up to periods of 28 days 
had no clinically significant toxic effect in either species. Fourteen-day treatment with oral doses of 
LAT8881 up to 100 mg/kg/day was well tolerated in both rats and monkeys and without any overt 
systemic toxicity. 
Chronic toxicity testing was conducted in both rodent and non-rodent species. Doses of 0 (control), 0.5, 
20 and 100 mg/kg/day LAT8881 (0, 3.5, 140, 700 mg/m2/day) were administered orally to rats once per 
day for six months (26 weeks). There were no unscheduled deaths and no treatment-related clinical 
signs. No marked effects on body weight were observed and there were no treatment-related effects on 
food consumption, food conversion efficiency ratios, ophthalmic examination, organ weights, 
macropathology, histopathology or clinical laboratory parameters. There was no effect of LAT8881 on 
bone densitometry.   
LAT8881 0.5, 10 and 50 mg/kg/day (6, 120 and 600 mg/m2/day) or vehicle control was administered to 
cynomolgus monkeys once per day for nine months.  In this study there were no unscheduled deaths and 
no clinical signs attributable to treatment with LAT8881.  There were no treatment-related changes in 
body weight, ophthalmology, haematology, biochemistry, urinalysis, organ weights, necropsy or histology.  
There was no effect of LAT8881 on bone densitometry. 
No antibodies to LAT8881 were detected in the serum of rats and monkeys at the end of the toxicological 
studies, indicating that LAT8881 was not neutralised by an antibody reaction, and thus LAT8881 is 
considered unlikely to be immunogenic.   
Extensive genotoxicity testing has been conducted.  It is considered unlikely that LAT8881 is a potential 
genotoxic hazard to humans. 
Reproductive studies have been undertaken in rats and rabbits at doses up to 50 mg/kg/day (rabbit) and 
100 mg/kg/day (rat). The rabbit studies found no evidence of an effect on foetal development when 
administered from Days 6-18 of gestation. The rat studies involved dosing from 2 weeks pre-mating 
(males and females) up to Day 6 of lactation (females) or 2 weeks after pup delivery (males). No effect on 
reproduction was observed in these studies.  
More detailed results from the preclinical studies with LAT8881 are provided in the Investigator’s 
Brochure. 
3.2.2 Clinical studies 
Six clinical studies with LAT8881 have been completed, with over 700 subjects treated with LAT8881 
(Table 1). These studies were designed to investigate the safety and tolerability of LAT8881 and 
subsequently its efficacy in the treatment of obesity (METAOD005, METAOD006).  
 
 


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Table 1: Summary of clinical studies with LAT8881 
Study ID 
Route, 
presentation 
Study 
subjects 
Doses 
No treated 
with LAT8881 Safety conclusion 
METAOD001 
Intravenous, 
lyophilised 
Healthy males 
0, 25-400 µg/kg 
Single dose  
15 
Study drug was well 
tolerated 
METAOD002 
Intravenous, 
lyophilised 
Healthy 
clinically obese 
males 
0, 25, 50, 100 µg/kg 
Single dose  
23 
Study drug was well 
tolerated 
METAOD003 
Oral, capsule 
Healthy 
clinically obese 
males 
0, 9, 27, 54 mg 
Single dose  
17 
Study drug was well 
tolerated 
METAOD004 
Oral, capsule 
Healthy 
clinically obese 
males 
0, 9, 27, 54 mg 
Daily for 7 days 
27 
Study drug was well 
tolerated following oral 
once daily doses of 9, 27 
and 54 mg for 7 days 
METAOD005 
Oral, capsule 
Healthy 
clinically obese 
males and 
females 
0, 1, 5, 10, 20, 30 mg 
Daily for 12 weeks 
243 
Good safety profile that 
was indistinguishable 
from placebo 
METAOD006 
Oral, tablet 
Healthy 
clinically obese 
males and 
females 
0, 0.25, 0.5, 1 mg 
Daily for 24 weeks 
377 
Good safety and 
tolerability profile that 
was indistinguishable 
from placebo 
 
In all studies it was noted that the study drug was well tolerated. The only dose-related adverse event 
(AE) trend was an increased incidence of gastrointestinal effects and general body symptoms of 
abdominal pain and headache in Study METAOD004 at 54 mg. This trend was not observed in 
subsequent studies. 
More detailed results from these clinical studies with LAT8881 are available in the Investigator’s 
Brochure. 
. 
 
 


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4. Study objectives 
4.1 
Primary objective 
• 
To evaluate the efficacy of oral LAT8881 in NP compared with placebo, when assessed by change 
in mean pain intensity scores from baseline to the end of four weeks treatment, based on an 
11 point numeric pain rating scale (NPRS) 
4.2 
Secondary objectives 
• 
To investigate the effect of oral LAT8881 in NP compared with placebo at different timepoints (up to 
6 hours) following a single dose and after 4 weeks treatment, as measured by the NPRS (PK 
subjects only) 
• 
To investigate the effect of oral LAT8881 on mean pain scores in NP compared with placebo after 
1, 2 and 3 weeks of dosing, as measured by the NPRS 
• 
To determine the proportion of responders to oral LAT8881 in NP compared with placebo 
• 
To investigate the maximum effect of oral LAT8881 in NP compared with placebo, as determined by 
the maximum change from mean NPRS baseline after 1, 2, 3 or 4 weeks treatment 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on functioning in subjects with NP 
when measured by the 7-item short form Brief Pain Inventory (BPI) Interference Scale 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on pain symptoms in subjects with 
NP when measured by the short-form McGill Pain Questionnaire 2 (SF-MPQ-2) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on symptoms in subjects with NP, 
when measured by the Neuropathic Pain Symptom Inventory (NPSI) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on emotional functioning when 
measured by the Beck Depression Inventory-II (BDI-II) 
• 
To evaluate the effect of oral LAT8881, compared with placebo, on overall health and quality of life 
in subjects with NP, when measured by the Patient Global Impression of Change (PGIC) scale 
• 
To determine the change from baseline in rescue medication use during oral LAT8881 
administration, compared with placebo 
• 
To evaluate the safety and tolerability of oral LAT8881 in NP after a single dose and after four 
weeks treatment  
• 
To investigate the pharmacokinetics of twice daily oral LAT8881 in 15 subjects with NP after a 
single dose and after 4 weeks treatment with oral LAT8881 
4.3 
Exploratory objectives 
• 
To investigate the relationship between baseline subject characteristics, such as clinical diagnosis 
(PHN or DPN) and QST parameters, and the change in NPRS after oral LAT8881 treatment, 
compared with placebo 
• 
To investigate the change from baseline on specified QST parameters (WDT, MPS, HPT) after four 
weeks treatment with oral LAT8881, compared with placebo 
• 
To investigate the relationship between plasma LAT8881 concentrations and the change in mean 
pain score in subjects with NP 
• 
To investigate the impact of variability in NPRS scores during the first baseline period on the 
difference between baseline and 4 week NPRS scores after LAT8881 or placebo 
 
 


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5. Study design 
5.1 
Overall study design 
This is a randomised, placebo-controlled, double-blind, crossover, multi-site, Phase IIa study to 
investigate the efficacy and safety of oral LAT8881 in neuropathic pain. The overall study design is 
shown in Figure 4. Details of the procedures during each phase are described in Section 8. 
The pharmacokinetics (PK) of LAT8881 will be investigated on Days 1, 28, 50 and 77 in 15 subjects (PK 
subjects) at Australian sites. Quantitative sensory testing (QST) will be performed in up to 20 subjects 
(QST subjects) before the first dose on Days 1 and 50 and after the morning dose on Days 28 and 77. 
PK subjects will not participate in QST measurements and QST subjects will not participate in PK 
analyses.  
 
Screening 
Stage 1 
Screening 
Stage 2 
(First 
Baseline) 
Enrolment 
and 
Randomisation 
LAT8881 
Washout 
Second 
baseline 
Placebo 
Follow 
up 
Placebo 
Washout 
Second 
baseline 
LAT8881 
 
Up to 3 
weeks 
Days  
-7 to -1 
Day 1 
Days 
1 to 28 
Days 
29 to 42 
Days 
43 to 49 
Days 
50 to 77 
Day 91 
Figure 4: Overall study design for LAT-NP-001 
 
Potential subjects will be required to provide written informed consent prior to any study-specific 
screening procedures being performed. Screening assessments will be performed from Day -28 to  
Day -1. Subjects deemed likely to be eligible for the trial will be given access to a diary during Screening 
Stage 1 and training on how to complete it from Days -7 to -1 inclusive (Screening Stage 2, first baseline 
period). These diary results will be reviewed on Day 1 to confirm that the subject is eligible for the study. 
On Day 1, after the first baseline period, eligible subjects will be enrolled and randomised to LAT8881 or 
placebo. They will receive the investigational medicinal product (IMP) twice daily for four weeks 
(Days 1 to 28). On the morning of Day 28 they will return to the clinic for their end of first treatment visit 
and will take an IMP capsule in the morning during their clinic visit. They will take their final IMP dose for 
this treatment period in the evening. 
The first treatment period will be followed by a washout period of two weeks (Days 29 to 42 inclusive) and 
then a second baseline period of one week (Days 43 to 49 inclusive). Over these days (i.e. Days 29-49 
inclusive) subjects will not take any IMP. 
On Day 50, subjects will return to the clinic and cross over to receive the second treatment (either 
LAT8881 or placebo, whichever treatment was not received in the first treatment period) twice daily for 
four weeks (Days 50 to 77). On the morning of Day 77, they will return to the clinic for their end of second 
treatment visit and will take an IMP capsule in the morning during their clinic visit. They will take their final 
IMP dose for this treatment period in the evening. 
Subjects will return to the clinic on Day 91, two weeks after their last treatment visit, for an end of study 
visit. 
5.2 
Justification of study design 
This is the first study with LAT8881 in subjects with neuropathic pain. As such, it has been designed to 
evaluate, in a well-defined patient group, the concept that LAT8881 is safe and effective in this indication. 
Subsequent studies will evaluate other development issues, such as the optimal dosing strategy, and the 


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applicability of these results to related pain conditions. 
Subjects enrolled into this study have been diagnosed with PHN or DPN, both conditions being well 
accepted examples of neuropathic pain. Because the pain is chronic, without a period effect, and 
treatment is symptomatic rather than curative, a crossover study is considered appropriate. Indeed, 
studies with other agents have successfully demonstrated analgesic effects in PHN and DPN with a 
crossover study design.7 
A major advantage of a crossover design is the smaller number of subjects required to demonstrate 
efficacy, compared with a parallel design. In this study, 44 evaluable subjects are required to show the 
same statistical outcomes, compared with over 100 subjects had a parallel group design been utilised. 
The main disadvantage is the longer duration of the study for each subject and a higher risk of dropouts. 
It is anticipated that approximately 20% of subjects will not complete the study, based on analysis of 
Phase III studies with duloxetine, pregabalin and gabapentin in DPN and PHN8 and taking into account 
the good tolerability of LAT8881 in previous clinical studies. In an attempt to minimise dropouts in this 
study, subjects are allowed to continue on their current stable medications and will have access to rescue 
paracetamol. Should these measures not be adequate and the dropout rate is higher than anticipated, 
enrolment will continue until the required number of completing subjects is reached. 
A four week treatment period is considered to be an appropriate balance between reducing the potential 
for dropouts and ensuring that there is adequate time to observe a treatment effect. This duration has 
been accepted as usually suitable for proof of concept studies in chronic pain conditions.7 The washout 
period of two weeks was based on preclinical pharmacodynamic data, as the pharmacokinetics of 
LAT8881 does not show a temporal association with its effect in pain models.  
The power of the study was set at 90% to lessen the potential for a false negative outcome. To obtain this 
statistical power with a pragmatic sample size, the study was designed with two arms only (LAT8881 
60 mg/day or placebo). Standard randomisation and double-blinding procedures are applied to ensure 
the validity of the study. 
QST phenotype assessment will be based on three parameters: Warm Detection Threshold (WDT), Heat 
Pain Threshold (HPT) and Mechanical Pain Sensitivity (MPS) as these parameters explain a large part of 
the variability in sensory profiles.9  
The efficacy outcome measures in this trial are based on those recommended by international 
consensus16 and are described in Section 10.5. 
5.3 
Justification of dose 
The dose of 60 mg/day is based on both preclinical efficacy studies and clinical data from previous 
studies with LAT8881. Preclinical studies in the Chung model of neuropathic pain and in other models of 
pain have shown an effective dose of 5 mg/kg (Section 3.2.1.1). This dose approximates to a dose of 
0.8 mg/kg in man, based on normalisation to body surface area.10 Given that LAT8881 has a good clinical 
safety profile at doses up to 54 mg/day, it was determined that a 60 mg/day dose, given in two divided 
doses, would be appropriate.  
Subsequent studies will investigate a dose response to LAT8881 in patients with neuropathic pain at 
doses below 60 mg/day to determine a minimum effective and optimal therapeutic dose. 
5.4 
Number of planned subjects  
It is planned to have 44 subjects complete the study. Assuming a 20% dropout, 55 subjects will be 
recruited. If the dropout rate is higher than 20%, additional subjects (up to 60 in total) may be recruited at 
the sponsor’s discretion to ensure 44 subjects complete the study.  
5.5 
Duration of study 
The duration of recruitment for this study is anticipated to be approximately 9 months. The duration of the 


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study will be approximately 13 months. 
5.6 
Duration of subject participation  
Maximum participation duration is 17 weeks: screening and first baseline (up to 4 weeks), first treatment 
(4 weeks), washout (2 weeks) second baseline (1 week), second treatment (4 weeks), follow up 
(2 weeks). 
5.7 
Withdrawal of subjects from study 
Subjects can terminate their participation in the study at any time, without giving a reason and without 
prejudice to further treatment. Subjects may also be withdrawn at any time at the discretion of the 
investigator(s) or sponsor for safety, behavioral or administrative reasons.   
Subjects who discontinue from the study should always be asked about the reason(s) for their 
discontinuation and about the presence of any Adverse Events.  The reason(s) for withdrawal will be 
documented in the case report form (CRF). 
Possible reasons for discontinuation of a subject may include: 
• 
Withdrawal of consent by the subject 
• 
Serious or significant AE or laboratory abnormality 
• 
Non-compliance with the protocol  
• 
The need to take medication which may interfere with study measurements or is contraindicated 
• 
New inter-current diseases, which may affect the safety of the IMP  
• 
Subject is lost to follow-up  
• 
Withdrawal for other reasons 
• 
Lateral terminating the study for administrative, financial, or other reasons    
Subjects withdrawing from the study will be requested to attend an End of Study Visit. If the subject 
withdraws during the treatment period, the subject should attend the End of Study visit within 14 days of 
the last dose of LAT8881 where possible.  
Any new AEs occurring during that period must also be reported in the CRF and must be followed up until 
resolved, unless, in the investigator’s opinion, the condition is unlikely to resolve. This visit is primarily for 
the purposes of monitoring subject safety. 
Any AEs that are continuing at the time of withdrawal from the study, should, wherever possible, be 
followed to resolution or stabilisation, whichever is earlier. 
Reasonable efforts will be made to contact subjects who are lost to follow-up.  These must be 
documented in the subject’s source documents.  
5.8 
Replacement of subjects 
Subjects who withdraw after randomisation will not be replaced. 
  
 


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6. Study population 
6.1 
Inclusion criteria 
Subjects must meet the following criteria to be entered into the study: 
1. Clinical diagnosis of post herpetic neuralgia, with pain persisting for at least 3 months after the 
onset of herpes zoster rash 
OR  
2. Clinical diagnosis of distal painful polyneuropathy due to Type I or Type II diabetes mellitus with: 
a) 
symmetrical, bilateral pain in the lower extremities for at least 3 months and 
b) 
diabetes under control for at least 3 months prior to randomisation, as indicated by a 
glycated haemoglobin level (HbA1c) of ≤ 11% (97 mmol/mol) and on a stable dose of 
insulin or oral diabetic medication for 3 months prior to screening, and  
c) 
no change in diabetic medication planned for the duration of the study 
3. 
Positive sensory symptoms (mechanical or thermal) associated with neuropathic pain, 
confirmed by: 
a) painDETECT Questionnaire (PD-Q) and  
b) Clinical assessment, showing signs of neuropathic pain in either a dermatomal (PHN) or 
distal symmetrical distribution (DPN) 
4. Aged 18 to 75 years 
5. Subjects must be sufficiently competent in English to understand the purposes and risks of the 
study and able to give voluntary written informed consent to participate in the study 
6. Willing and able to comply with all study procedures 
7. Completion of at least five NPRS scores during the week preceding randomisation 
8. An average daily pain score on the NPRS of at least 4 and no more than 8 in the last five diary 
entries before randomisation  
9. No more than one score on the NPRS of 9 or more, and no more than one score of 2 or less, in 
the last five diary entries before randomisation 
10. Females of child bearing potential must have a negative pregnancy test at Visit 1 (Screening) 
and at Visit 2 (Day 1) prior to administration of IMP 
11. Female subjects must be: 
a) of non child-bearing potential [surgically sterilised or post–menopausal (12 months with 
no menses without alternative medical cause)] OR 
b) not pregnant, breast feeding or planning to become pregnant AND willing to comply with 
the medically acceptable contraceptive requirements of the study from Screening to at 
least 28 days after the last IMP administration  
6.2 
Exclusion criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Presence of moderate to severe pain from other causes that may confound assessment or self-
evaluation of NP 
2. Subjects with both DPN and PHN  
3. Skin conditions in the affected area that could alter sensation or assessments 


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4. History of or current clinically significant gastrointestinal, hepatic, renal, cardiovascular, 
respiratory, endocrine, oncological, immunological, neurological, ophthalmological, 
haematological or psychiatric disorder or any other condition, which in the opinion of the 
investigator or sponsor would jeopardise the safety of the subject or the validity of the study 
results  
5. Medical history of, or currently active, human immunodeficiency virus, hepatitis B or hepatitis C 
virus   
6. Clinically significant abnormal 12-lead ECG 
7. Immunocompromised state, or conditions known to be associated with an immunocompromised 
state 
8. Clinically significant or unstable medical or psychological condition that would compromise 
participation in the study 
9. Recent history of malignancy within 5 years preceding screening (except resected cervical or 
skin cancer [except melanoma]). Subjects who have had no evidence of disease in the last 5 
years are eligible  
10. Active herpes zoster infection on screening 
11. Current alcohol abuse, illicit or illegal drug use 
12. Use of prohibited medication (see study medications) 
13. Previous treatment with LAT8881 (formerly identified as AOD9604) within the last 5 years 
14. Participation in an investigational trial within 60 days or 5 half-lives (whichever is longer) prior to 
screening 
15. History of significant hypersensitivity to LAT8881 or drugs of a similar pharmacological class 
(e.g. somatropin) 
16. Surgical or medical conditions which could significantly alter drug absorption, distribution, 
metabolism or excretion 
17. An employee of the sponsor or research site personnel directly affiliated with this study, whether 
biological or legally adopted, or their immediate family members, defined as a spouse, parent, 
sibling, or child 
18. Previous neurolytic or neurosurgical therapy for PHN or DPN 
19. PK subjects: 
a. Blood or plasma donation of more than 500 mL during the 3 months prior to randomisation 
b) History of fainting during phlebotomy 
6.3 
Contraception requirements 
Subjects must be willing to comply with the contraceptive requirements of the study.  
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 28 days after the last dose 
of IMP. Such methods include: 
• 
Abstinence from heterosexual intercourse. This should be the subject’s usual and preferred 
lifestyle OR  
• 
Consistent and correct use of a highly-effective form of contraception, such as: 
- 
combined (estrogen and progestogen containing) hormonal contraception associated with 


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inhibition of ovulation (oral, intravaginal or transdermal administration), 
- 
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable administration) 
- 
intrauterine device 
- 
intrauterine hormone-releasing system 
- 
bilateral tubal occlusion OR  
• 
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. 
6.4 
Dietary, lifestyle and other restrictions 
Subjects should refrain from use of alcohol within 8 hours prior to all visits and during visits.    
Regular smokers who are unable to refrain from smoking cigarettes or tobacco during study visits will be 
excluded from the study. Replacement nicotine is permitted.  
 
 


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7. Study Treatments 
7.1 
Description 
The IMP is supplied as opaque, size 0 capsules, in a high-density polyethylene bottle containing 60 
capsules. One bottle will contain sufficient capsules for one treatment period. 
7.2 
Formulation 
7.2.1 LAT8881 capsules 
Each capsule contains 30 mg LAT8881 plus L-arginine, polyethylene glycol and mannitol as excipients. 
7.2.2 Placebo capsules 
Placebo capsules contain the excipients L-arginine, polyethylene glycol and mannitol only (without 
LAT8881).  
7.3 
Manufacturer 
LAT8881 is is manufactured by Polypeptide Group Torrance, California, USA in accordance with current 
Good Manufacturing Practice (cGMP).  
The active and placebo blends for encapsulation will be formulated and the capsules will be filled by PCI 
Pharma Services (PCI), Port Melbourne, Victoria, Australia under cGMP conditions. 
PCI will be responsible for quality control and stability testing. 
7.4 
Storage 
At the study site, the IMP must be stored refrigerated (2-80C) in a secure area, with access limited to 
authorised personnel.  
Subjects will also be asked to store their treatment at home under refrigeration. 
7.5 
Packaging and labelling 
IMP capsules will be packaged in bottles by PCI. Each bottle will contain 60 IMP capsules (60 capsules 
of formulated LAT8881 or 60 placebo capsules). The two bottles for treatment of each subject 
(active/placebo) will be packaged together in a clear plastic bag, according to the randomisation schedule 
prepared by the unblinded study statistician. Each bottle will appear identical to the other bottle in the 
bag, except for the treatment period number (1/2 or 2/2) on the label. 
Bottles containing the IMP capsules and the bag in which they are packed will be labelled according to 
Annex 13 of the PIC/S Guide to Good Manufacturing Practice.11  
Each bottle will have both a permanently attached label and a tear-off drug accountability label. The tear-
off accountability label must be removed and attached to the Drug Accountability log when the product is 
dispensed. On dispensing, a dispensing label will be attached permanently to the bottle.  
Details of labelling and dispensing will be provided in the Study Procedures Manual. 
7.6 
Randomisation and blinding 
A computer-generated randomisation schedule and treatment allocation will be prepared by an unblinded 
statistician prior to the start of the study.  
The treatment sequence each subject will receive will not be disclosed to the investigator, study site 
personnel, subjects, or sponsor personnel. The randomisation codes will be available to the Investigator if 
required for emergency unblinding purposes (see Section 7.13). 


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7.7 
Dispensing of investigational product  
The investigator is responsible for ensuring that IMP is dispensed in accordance with the protocol and 
only to subjects enrolled in the study.  
On the morning of Day 1, after receipt of a prescription/authorisation from the investigator (or delegate), 
the study nurse (or Investigator) will obtain the allocated treatment. The subject’s study number, initials, 
date and treatment number will be recorded in the Drug Accountability Log. The log will be countersigned 
by the investigator and must be available for inspection at any time. 
7.8 
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 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.  
The Subject ID number will be used to identify the subject throughout the study period and on all study-
related documentation. 
7.9 
Accountability of study supplies 
All supplies of IMP are provided for use only in this clinical study and must not be used for any other 
purpose. 
The investigator or designee is responsible for accountability of IMP, reconciliation and record 
maintenance. The investigator or designated site staff must maintain accountability records throughout 
the course of the study including records of the amount of IMP dispensed, the identification of the subject 
to whom the IMP was dispensed, the date and the amount dispensed. 
Subjects must bring their medication bottles with them to clinic visits during the treatment periods and the 
number of remaining capsules will be entered onto the CRF. The product, including used bottles and 
records, must be available for inspection by a study monitor during the study.  
Following completion of the study, remaining unused supplies will be returned to Lateral or destroyed as 
directed by the sponsor. 
7.10 Doses and treatment regimens 
Subjects will be instructed to take one capsule with water at approximately 12 hour intervals (morning 
and evening) at least 30 minutes before food. Once the dosing times are established, the subject should 
attempt to take the capsule at the same times throughout the treatment periods. If more than 16 hours 
has elapsed since the last dose, the dose should be missed and the next dose taken at the regular 
scheduled time.  
Subjects will be instructed to return to the clinic on Days 28 and 77 without taking their morning dose. 
7.11 Dose reduction/dose adjustments 
No within-subject dose reductions or adjustments are permitted. If a subject experiences an adverse 
event requiring (in the investigator’s opinion) temporary or permanent suspension of the IMP, the subject 
should be withdrawn from the study (refer to Section 5.7). The maximum allowed temporary suspension 
of IMP before withdrawal is 3 doses in the last 10 days or 8 doses in the 28 day treatment period. 
7.12 Treatment compliance 
Subjects will be asked to return their IMP bottles for a capsule count at each treatment visit. 


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Study drug accountability forms will be kept by pharmacy during the study and will be reviewed by the 
study monitor. Treatment compliance will be recorded in the subject’s source documents and the CRF.  
7.13 Unblinding 
7.13.1 Medical Emergency 
In a medical emergency, when management of a subject’s condition requires knowledge of the study 
drug, the code may be broken by the investigator to determine the treatment allocation of the subject. 
Details will be provided in the Study Manual. 
Such emergencies and code break should be notified to the study Medical Monitor and/or sponsor as 
soon as possible. The date, reason for and name of the individual breaking the code will be documented 
along with a list of unblinded persons. 
7.13.2 End of study 
The randomisation schedule, allowing identification of the treatment sequence received by each subject, 
will be disclosed after approval and locking of the database. 
7.14 Concomitant medications 
7.14.1 Permitted medications 
The following medications are permitted: 
• 
Subjects may take their usual oral medications for PHN or DPN, providing the dose has been 
stable for at least 30 days before randomisation and is maintained for the duration of the study 
until the end of study visit  
• 
Diabetics must be on stable diabetic medication for at least 3 months before randomisation, and 
the medication must be maintained at the same dose until the end of study visit  
• 
Subjects may also take the following medications, provided the regimen is stable for 30 days 
before randomisation and remains steady from randomisation to the end of study visit 
- 
benzodiazepine 
- 
anxiolytic, such as buspirone 
- 
serotonin and noradrenaline (norepinephrine) reuptake inhibitor  
- 
oral aspirin (≤ 150 mg/day)  
- 
tricyclic antidepressant 
• 
In addition, up to 4 g per day of paracetamol (rescue medication) may be taken except within 4 
hours of the first and last clinic visit in each treatment period 
7.14.2 Prohibited medications 
The following medications are prohibited. 
• 
Patch containing 8% capsaicin (Qutenza), if applied within the last six months before 
randomisation  
• 
Current or recent (within 7 days of randomisation) use of any other topically applied pain 
medication  
• 
Cryotherapy, intrathecal/epidural opioids, systemic corticosteroids or botulinum toxin if 
administered in the last 6 months. Topical or inhaled corticosteroids are permitted. A short course 


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(<7days) of oral prednisolone or equivalent for other conditions, up to 4 weeks preceding Day 1, 
is allowed 
• 
Steroid or local anaesthetic nerve blocks within the last 12 months 
Subjects who change concomitant medication during the study period should notify the investigator 
promptly and details of the medications used should be documented in the source documents and CRF. 
Concomitant medications will be recorded by their trade and/or generic name. 
 
 


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8. Study procedures 
The Schedule of Assessments for the study are provided in Section 2. 
8.1 
Subject informed consent 
Following identification of potential subjects, staff in the clinic will contact the subject, explain the nature 
of the study and confirm potential interest and eligibility. The Participant (Subject) Information Sheet (PIS) 
and Consent Forms (ICFs) may be provided. The subject will then be invited to attend the clinic for further 
information, signing of the ICF and conduct of screening procedures. 
The investigator must provide adequate information regarding the study, including its purpose, possible 
risks and potential benefits. Subjects must also be advised that they are free to discontinue from the 
study at any time. Subjects must be given time to review the study information and ask any questions. 
Written informed consent must be provided by the subject before any tests or investigations outlined in 
the study protocol are carried out. 
The ICF must be personally signed and dated by both the investigator and the subject. The investigator 
must store the original, signed ICF with the subject’s medical notes/source documents. A copy of the 
signed and dated ICF will be given to the subject.  
Screening procedures may commence immediately following signing of the ICF.  
8.2 
Screening visit (Day -28 to Day -1), Visit 1 
After written informed consent has been obtained, a unique Screening Number (Subject ID) will be 
assigned and screening assessments may commence. Screening assessments may be performed on 
different days if required.  
Screening assessments will be conducted in two stages: Stage 1 (initial screening) and Stage 2 (first 
baseline period). 
8.2.1 Screening Stage 1 (initial screening) 
During Stage 1 of the screening period (Days -28 to Day -8), subjects will undergo the following 
screening assessments: 
• 
Medical history 
• 
Demographics 
• 
Height, weight and BMI 
• 
PD-Q assessment 
• 
12-lead ECG 
• 
Vital signs 
• 
Physical examination, including clinical assessment of pain  
• 
Concomitant medications 
• 
Blood sample for routine haematology and clinical chemistry screening and, in female subjects of 
child-bearing potential, to test for pregnancy 
• 
Urine sample for urinalysis 
Subjects deemed likely to be eligible for the trial after initial screening will be given access to a diary and 
training on how to record daily pain assessments each evening. They will be instructed to complete the 
diary from Days -7 to -1 inclusive and to return on Day 1, for confirmation of study eligibility. They will also 
be reminded not to take paracetamol within 4 hours of the next clinic visit. 


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Up to 20 subjects deemed likely to be eligible for inclusion in the study after initial screening will also 
have a QST scheduled within seven days of the first dose.  
8.2.2 Screening Stage 2 (first baseline) 
Subjects deemed likely to be eligible for the trial will record their pain assessments each evening in their 
diary. 
8.3 
First treatment period (Days 1 to 28), Visits 2 to 4 
8.3.1 Day 1, Visit 2 
Subjects will return to the unit on Day 1 (Visit 2) with their diary completed from Days -7 to -1 inclusive.  
The following assessments will be undertaken on Day 1: 
• 
Review of the subject’s pain diary 
• 
Weight 
• 
PD-Q 
• 
ECG 
• 
Vital signs 
• 
Targeted physical examination, including assessment of painful regions 
• 
Concomitant medications 
• 
Blood sample for routine haematology and clinical chemistry assessments 
• 
Urine sample for urinalysis (dipstick) and, in female subjects of child-bearing potential, a urine 
sample for pregnancy testing  
Results from safety monitoring tests are not required prior to dosing. Eligible subjects will be enrolled, 
assigned a unique Randomisation Number and randomised to LAT8881 or placebo. 
Subjects will complete baseline assessments for Patient Reported Outcomes: 
• 
Interference scale of the short form BPI 
• 
SF-MPQ-2 
• 
NPSI 
• 
BDI-II 
In PK subjects, a pre-dose NPRS will be completed (maximum one hour before dosing) and a pre-dose 
blood sample taken for PK analysis. QST subjects will have a pre-dose QST assessment, if not 
completed within the previous 7 days. 
Subjects (except for PK subjects) will take their first dose of IMP and remain in the clinic for up to one 
hour to check for any adverse events. Vital signs will be measured 30 (+/-10) minutes after IMP dosing. 
PK subjects will take their first dose of IMP and remain in the clinic for at least 6 hours. At scheduled 
times (2, 5, 15, 30, 60 minutes, 2, 4 and 6 hours after IMP dosing), blood samples will be taken for PK 
analysis. NPRS will be monitored at 0.5, 1, 2, 4 and 6 hours. Vital signs will be measured 30 (+/-10) 
minutes after IMP dosing. 
Before leaving the clinic, each subject will be reminded to take a dose of IMP twice daily and to continue 
recording pain scores in their diary each evening. 
All subjects will leave the unit with sufficient IMP for the first treatment period.  


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8.3.2 Day 14 (± 1), Visit 3 
On Day 14 (Visit 3), subjects will take their morning IMP dose and return to the clinic with their medication 
bottle. The following assessments will be undertaken: 
• 
Weight 
• 
Vital signs 
• 
Targeted physical examination 
• 
Concomitant medications  
• 
Adverse events 
• 
Compliance with medication 
• 
Compliance with diary entries  
Subjects will be reminded to continue their medication and to continue to record daily NPRS entries into 
their diary. They will be asked to return on Day 28 with their medication bottle, but without taking their 
morning dose of IMP. They will also be reminded not to take paracetamol within 4 hours of the next clinic 
visit. 
8.3.3 Day 28 (± 1), Visit 4 
On the morning of Day 28 (Visit 4, Last Day of First Treatment Period), subjects will not take their 
morning dose of IMP. They will return to the clinic with their medication bottle.  
The following assessments will be undertaken: 
• 
Weight 
• 
ECG 
• 
Vital signs 
• 
Targeted physical examination 
• 
Concomitant medications 
• 
Blood and urine samples for safety analysis (haematology, clinical chemistry, urinalysis) 
• 
Adverse events 
• 
Compliance with medication 
• 
Compliance with diary entries  
Subjects will also complete assessments for Patient Reported Outcomes: 
• 
Interference scale of the short form BPI 
• 
SF-MPQ-2 
• 
NPSI 
• 
BDI-II 
• 
PGIC 
Subjects (except PK and QST subjects) will take their morning dose of IMP and leave the clinic. They will 
take their Day 28 evening dose and then discontinue treatment until their next visit on Day 50. They will 
be asked to continue daily NPRS diary entries, and to return to the unit on Day 50 with their medication 
bottle. They will also be reminded not to take paracetamol within 4 hours of the next clinic visit. 
In PK subjects, a pre-dose NPRS will be completed (maximum one hour before dosing) and a pre-dose 
blood sample will be taken for PK analysis. PK subjects will take their morning dose of IMP and remain in 


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the clinic for at least 6 hours. At scheduled times (2, 5, 15, 30, 60 minutes, 2, 4 and 6 hours after IMP 
dosing), blood samples will be taken for PK analysis. NPRS will be monitored at 0.5, 1, 2, 4 and 6 hours. 
Subjects will then leave the clinic. They will take their Day 28 evening dose and then discontinue 
treatment until their next visit on Day 50. They will be asked to continue daily diary entries, and to return 
to the unit on Day 50 with their medication bottle. They will also be reminded not to take paracetamol 
within 4 hours of the next clinic visit. 
QST subjects will take their morning dose of IMP and will have QST parameters (WDT, MPS, HPT) 
assessed 2 hours after this dose. An appointment for a QST assessment will be scheduled within seven 
days of the start of the next treatment period. They will then leave the clinic. They will take their Day 28 
evening dose and then discontinue treatment until their visit on Day 50. They will be asked to continue 
daily diary entries, and to return to the unit on Day 50 with their medication bottle. They will also be 
reminded not to take paracetamol within 4 hours of the next clinic visit. 
8.4 
Washout (Days 29-42) 
The first treatment period will be followed by a washout period of two weeks (Days 29 to 42 inclusive). 
Subjects will continue their NPRS diary entries each evening, but will not take any IMP. 
8.5 
Second baseline period (Days 43-49) 
During the second baseline period (Days 43 to 49 inclusive), subjects will continue their diary entries and 
will not take any IMP. They will record their NPRS rating each evening. 
8.6 
Second treatment period (Days 50-77), Visits 5 to 7 
Subjects will return to the unit on Day 50 (± 1) with their diary completed from Days 29 to 49 inclusive and 
with their medication bottle. 
8.6.1 Day 50 (± 1), Visit 5 
Subjects will return on Day 50, and the following assessments will be undertaken: 
• 
Review of the subject’s pain diary (Days 43-49 inclusive) 
• 
Weight 
• 
ECG 
• 
Vital signs 
• 
Targeted physical examination, including assessment of area of pain  
• 
Concomitant medications 
• 
Blood and urine samples for safety analysis (haematology, clinical chemistry, urinalysis) 
Results from safety monitoring tests are not required prior to dosing. Subjects will also complete their 
second baseline assessments for Patient Reported Outcomes: 
• 
Interference scale of short form BPI 
• 
SF-MPQ-2 
• 
NPSI 
• 
BDI-II 
In PK subjects, a pre-dose NPRS will be completed (maximum one hour before dosing) and a pre-dose 
blood sample taken for PK analysis. QST subjects will have a pre-dose QST assessment, if not 
completed within the previous 7 days. 
Subjects (except for PK subjects) will take their allocated IMP and will remain in the clinic for up to one 


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hour to check for adverse events. Vital signs will be measured 30 (+/-10) minutes after IMP dosing. 
PK subjects will take their allocated IMP and will remain in the clinic for at least 6 hours. At scheduled 
times (2, 5, 15, 30, 60 minutes, 2, 4 and 6 hours after IMP dosing), blood samples will be taken for PK 
analysis. NPRS will be monitored at 0.5, 1, 2, 4 and 6 hours. Vital signs will be measured 30 (+/-10) 
minutes after IMP dosing. 
All subjects will leave the unit with sufficient IMP for the second treatment period. They will be reminded 
to complete their NPRS diary each evening. 
8.6.2 Day 63 (± 1), Visit 6 
On Day 63 (Visit 6), subjects will take their morning IMP dose and return to the clinic with their medication 
bottle. The following assessments will be undertaken: 
• 
Weight 
• 
Vital signs 
• 
Targeted physical examination 
• 
Concomitant medications 
• 
Adverse events  
• 
Compliance with medication 
• 
Compliance with diary entries 
Subjects will be reminded to continue their medication and to record daily entries into their diary. They will 
be asked to return on Day 77 with their medication bottle, but without taking their morning dose of IMP. 
They will also be reminded not to take paracetamol within 4 hours of the next clinic visit. 
8.6.3 Day 77 (± 1), Visit 7 
On the morning of Day 77 (Visit 7, Last Day of Second Treatment Period), subjects will not take their 
morning dose of IMP. They will return to the clinic with their medication bottle and the following 
assessments will be undertaken: 
• 
Weight 
• 
ECG 
• 
Vital signs 
• 
Targeted physical examination 
• 
Concomitant medications 
• 
Blood and urine samples for safety analysis (haematology, clinical chemistry, urinalysis) 
• 
Adverse events 
• 
Compliance with medication 
• 
Compliance with diary entries  
Subjects will also complete assessments for Patient Reported Outcomes: 
• 
Interference scale of the short form BPI 
• 
SF-MPQ-2 
• 
NPSI 
• 
BDI-II 


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• 
PGIC 
Subjects (except PK and QST subjects) will take their morning dose of IMP and leave the clinic. They will 
take their second Day 77 IMP dose in the evening and then discontinue treatment. 
In PK subjects, a pre-dose NPRS will be completed (maximum one hour before dosing) and a pre-dose 
blood sample will be taken for PK analysis. 
PK subjects will take their first dose of IMP and remain in the clinic for at least 6 hours. At scheduled 
times (2, 5, 15, 30, 60 minutes, 2, 4 and 6 hours after IMP dosing), blood samples will be taken for PK 
analysis. NPRS will be monitored at 0.5, 1, 2, 4 and 6 hours. They will leave the clinic and take their 
second Day 77 IMP dose in the evening. They will then discontinue treatment. 
QST subjects will take their morning dose of IMP and will have QST parameters (WDT, MPS, HPT) 
assessed 2 hours after this dose. They will leave the clinic and will take their second Day 77 dose in the 
evening. They will then discontinue treatment. 
All subjects will be asked to bring their medication bottle to the End of Study visit. 
8.7 
End of Study visit 
8.7.1 Day 91 (± 2) Visit 8 
At the end of study visit, subjects will return with their medication bottle. The following assessments will 
be undertaken: 
• 
Weight 
• 
Vital signs 
• 
Targeted physical examination 
• 
Concomitant medications 
• 
Blood and urine samples for safety analysis (haematology, clinical chemistry, urinalysis)  
• 
Adverse events 
8.8 
Early withdrawal visit  
Subjects who do not complete the study will be asked to return for an End of Study visit (Section 8.7.1). 
This visit should be scheduled approximately two weeks after the last dose was taken. 
 
 


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9. Study Endpoints 
9.1 
Primary endpoint 
• 
Absolute change in mean pain score, using an 11 point NPRS, from baseline to the last week of 
each treatment period. Pain is recorded once daily in a subject diary in the evening, and should 
reflect the subject’s average pain over the last 24 hours  
Baseline mean pain for each subject is defined as the mean of the last five available ratings of daily pain, 
recorded in each baseline period. 
End of treatment mean pain for each subject is defined as the mean of the last five available ratings of 
daily pain, recorded in the last 7 days of each 4 week treatment period. 
9.2 
Secondary endpoints 
• 
Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after the first dose of IMP in each treatment 
period, compared with the score recorded no more than 60 minutes before the first dose of IMP 
in that treatment period (PK subjects only) 
• 
Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after a single dose of IMP, following four 
weeks treatment with IMP in each treatment period, compared with the score recorded no more 
than 60 minutes before this dose (PK subjects only) 
• 
Change in mean pain scores from baseline after 1, 2 and 3 weeks of dosing with IMP in each 
treatment period, using an 11 point NPRS. Pain scores at weeks 1, 2 and 3 are defined as the 
mean of the last five available ratings of daily pain in the subject diary, recorded in the previous 7 
days of treatment 
• 
30% responder rate, based on the proportion of subjects achieving ≥ 30% reduction in mean 
NPRS from baseline to the end of 4 weeks treatment in each treatment period 
• 
50% responder rate, based on the proportion of subjects achieving ≥ 50% reduction in mean 
NPRS from baseline to the end of 4 weeks treatment in each treatment period 
• 
Maximum change in mean NPRS from baseline after 1, 2, 3 or 4 weeks treatment in each 
treatment period 
• 
Change in functioning from baseline to the end of 4 weeks treatment in each treatment period, as 
measured by the BPI interference scale 
• 
Change in pain characteristics and intensity from baseline to the end of 4 weeks treatment in 
each treatment period, as assessed by the SF-MPQ-2  
• 
Change in neuropathic pain symptoms from baseline to the end of 4 weeks treatment in each 
treatment period, as assessed by NPSI 
• 
Change in emotional functioning from baseline to the end of 4 weeks treatment in each treatment 
period, as assessed by the BDI-II 
• 
PGIC at the end of each four week treatment period 
• 
Paracetamol (rescue medication) use per week over each treatment period compared with the 
preceding baseline 
9.3 
Safety endpoints 
• 
Physical examinations and vital signs 
• 
ECG 
• 
Clinical chemistry and haematology analyses 


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• 
Urinalysis 
• 
Number and type of Treatment Emergent Adverse Events (TEAEs), including serious adverse 
events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) 
• 
Concomitant medications 
9.4 
Pharmacokinetic endpoints 
• 
Pharmacokinetic parameters: Cmax, Tmax, AUC0-inf in each treatment period, after a single dose 
and at the end of four weeks treatment in PK subjects  
9.5 
Exploratory endpoints 
• 
Association between change in mean NPRS from baseline to the end of four weeks treatment 
and selected subject baseline characteristics, including clinical diagnosis and pre-treatment QST 
parameters 
• 
Change from baseline in specified QST parameters (WDT, MPS, HPT) to the end of 4 weeks 
treatment, in each treatment period 
• 
Correlation between plasma LAT8881 concentration and the change in mean NPRS from 
baseline to the end of four weeks treatment in PK subjects 
• 
Change in mean NPRS score from baseline to the last week of each treatment period, after 
omission of subjects with the 25% most variable first baseline NPRS scores 
 
 


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10. Study measurements 
10.1 Clinical assessments 
10.1.1 Medical history 
The medical history will include any conditions reported by the subject or noted by the investigator in 
each body system, including allergies or drug sensitivities, past surgeries and any history of substance 
abuse (drug or alcohol) and will be recorded at screening. A review of the subject’s medication use will 
also occur. 
A diagnosis of shingles or diabetes and the date (month/year) at which PHN or DPN was first reported 
should be confirmed by an independent source (e.g. general practitioner, hospital records). 
10.1.2 Demographics 
Demographic information will include the subject’s age, gender and ethnic affiliation. 
10.1.3 painDETECT questionnaire 
The PD-Q consists of seven pain sensory symptom items (burning, tingling/prickling, light touching, 
sudden pain attacks/electric shock-type pain, cold/heat, numbness, slight pressure), one pain course 
pattern item, and one pain radiation item. From this questionnaire, a PD-Q total score, ranging from -1 to 
38 is calculated. A total score ≥19 indicates a neuropathic component is likely, ≤12 indicates a 
neuropathic component is unlikely and scores 13-18 are considered uncertain i.e. a neuropathic pain 
component can be present.12 The English version of the PD-Q is widely used and is reported to be 
reliable as a screening tool for neuropathic pain, although it has yet to be fully validated.13,14 
The PD-Q will be used in conjunction with clinical assessment to facilitate diagnosis of neuropathic pain. 
10.1.4 Electrocardiogram 
12-lead ECGs will be performed with subjects lying in a supine or semi-supine position for at least 5 
minutes prior to measurement. All ECG tracings will be reviewed by the Investigator or an appropriately 
medically qualified reviewer designated this responsibility by the Investigator.    
10.1.5 Vital signs 
Resting supine or semi-supine blood pressure (systolic and diastolic), heart rate, and respiratory rate will 
be evaluated. The same arm should be used throughout the study.  Body temperature (tympanic), will 
also be evaluated as part of vital signs. 
Subjects should be resting in a supine position for at least 5 minutes prior to and during vital signs 
measurement. 
10.1.6 Physical examination 
Physical examinations are to be performed by a medically qualified physician according to their standard 
medical practice. Any new or worsening abnormality, clinical sign or finding must be documented. 
A full physical examination is to be performed at the first screening visit. At other scheduled time points, a 
targeted (symptom directed) physical examination, as clinically indicated, is to be performed. All physical 
examinations will include assessment of the area of pain. 
A full physical examination will include assessments of the head (eyes, ears, nose, mouth, throat), skin, 
neurological system, respiratory system, cardiovascular system, musculoskeletal system, abdomen (liver 
and spleen), lymph nodes and extremities, general appearance, and any additional assessments needed 
to establish baseline status or change from baseline or evaluate symptoms or adverse events.  


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Neuropathies other than PHN and DPN will be excluded by clinical assessment at screening. Nerve 
conduction studies are not required for this assessment. 
10.1.7 Height and weight 
Height (centimetres) and weight (kilogram), without shoes, will be measured at the screening visit and 
BMI calculated. Weight (without shoes) will be measured at all other visits.  
10.1.8 QST phenotype 
QST measurements will be undertaken by a researcher specifically trained in this procedure at sites 
which have experience in the technique. Three parameters will be tested: Warm Detection Threshold 
(WDT), Mechanical Pain Sensitivity (MPS) and Heat Pain Threshold (HPT). Tests will be undertaken at a 
painful dermatome in PHN subjects or at a painful peripheral site in DPN subjects.   
10.1.8.1 
WDT  
A thermal sensory testing device is used, with a baseline temperature of 320C.The subject should feel 
this as neutral, i.e. neither hot nor cold. The temperature is then ramped continuously by 10C per sec and 
the subject is asked to press the stop button when they first perceive a warming of the skin. This is 
repeated a second and third time, each time starting with the thermode at the baseline temperature. The 
average threshold temperature of the three measurements is recorded. 
10.1.8.2 
MPS  
The MPS uses a set of 7 pinprick stimulators with standardised stimulus intensities (8, 16, 32, 64, 128, 
256, and 512 mN) and contact areas (tip diameter 0.25 mm). The stimuli are applied in a balanced order 
and the painfulness of each stimulus recorded with a numeric rating scale from 0 to 100, with 0 
representing no pain and 100 corresponding to the individual’s maximum pain imaginable. Each painful 
sensation will always have a value greater than 0. MPS is the geometric mean of all numerical ratings for 
pinprick stimuli. 
10.1.8.3 
HPT 
The Heat Pain Threshold (HPT) uses the same device as for the WDT. In this test, the temperature is 
increased as before but this time the subject is asked to press the stop button as soon as the “warm” or 
“hot” sensation changes its quality to an additional sensation of “burning”, “stinging”, “drilling” or “aching”. 
The procedure is repeated two more times and the mean threshold temperature is recorded. 
Full details of the QST procedures will be provided in the QST manual. 
10.2 Laboratory assessments 
10.2.1 Clinical safety testing 
Blood and urine samples will be taken at screening, on Days 1, 28, 50, 77 and at the end of study visit. 
Blood samples will be tested at one nominated laboratory per study site. Urinalysis (dipstick) will be 
performed at the investigational site. 
Details of the volume of blood and type of tubes required for the following tests will be provided in the 
Study Manual. At the investigator’s discretion, sample collection may be repeated if an abnormal result 
occurs due to technical or other reasons. 
The following tests will be performed.  
10.2.1.1 
Haematology 
Haemoglobin, haematocrit, red blood cell count, white blood cell count with differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils), platelet count, mean corpuscular haemoglobin, mean 
corpuscular volume, mean corpuscular haemoglobin concentration 


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10.2.1.2 
Clinical chemistry 
Glucose, sodium, potassium, chloride, bicarbonate, calcium (corrected), creatinine, urea, uric acid, 
amylase, lipase, triglyceride, HDL-cholesterol, LDL-cholesterol, total cholesterol, total protein, lactate 
dehydrogenase, creatine kinase, C-reactive protein, albumin, phosphate. HbA1c will be measured in 
DPN subjects only and only at screening. 
Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline 
phosphatase, conjugated bilirubin, total bilirubin 
Activated partial thromboplastin time, international normalised ratio 
10.2.1.3 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, urobilinogen, bilirubin, nitrite, leukocytes. 
If urinalysis on dipstick is positive for leukocytes and/or blood/haemoglobin, a microscopic examination 
including erythrocytes, leucocytes, bacteria, casts, epithelial cells and crystals will be performed.  
10.2.1.4 
Pregnancy  
Human chorionic gonadotropin levels (hCG) will be measured in blood samples from females of child-
bearing potential at screening. Urine hCG will be measured on Day 1. 
10.2.2 Pharmacokinetics 
Blood samples (4 mL) will be taken pre-dose (within 30 minutes of dosing) and 2, 5, 15, 30, 60 minutes, 
2, 4 and 6 hours after IMP ingestion. Blood samples will be obtained by direct venepuncture or via an 
indwelling cannula. Samples taken 2, 5 and 15 minutes after dosing should be within +/- 1 minute of the 
stated time, samples at later time points within +/- 5 minutes of the stated time. 
Blood samples will be collected into K2-EDTA tubes which contain 20 µl of 10X Protease Inhibitor 
Cocktail (Sigma Aldrich Product No. P2714) and have been previously cooled to 2-80C. Blood samples 
will be kept on ice immediately after collection to minimise degradation and centrifuged within 60 minutes 
post-collection in a pre-cooled (refrigerated) centrifuge. The resulting PK plasma samples will be 
transferred to clean, pre-labelled polypropylene tubes and stored frozen prior to analysis. Pre-dose 
samples will be centrifuged separately prior to dosing.  
Further details will be provided in the Laboratory Manual. 
Samples will be analysed under GLP conditions by TetraQ Research Infrastructure Centre at The 
University of Queensland, Herston QLD 4029 Australia, using a method developed by TetraQ. An initial 
batch of 25% of the total number of samples will be tested. If all samples tested are below the limit of 
quantification of the assay, further analyses will not be undertaken until the sensitivity of the assay is 
significantly increased. 
10.3 Adverse event monitoring 
Subjects will be asked by direct questioning at each visit whether they have experienced any AEs. Aes 
will be assessed as described in Section 12.2. 
10.4 Concomitant medications 
Changes in use or new medications used during course of study will be documented and reviewed at 
each study visit.  
10.5 Efficacy assessments 
10.5.1 Pain intensity 
10.5.1.1 
NPRS 


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The NPRS is an 11 point scale which grades pain from 0 (no pain) to 10 (worst pain imaginable). It is a 
recommended core outcome for the assessment of pain intensity in clinical trials of chronic pain 
treatments.16 
Subjects will be asked to rate the intensity of their average pain over the previous 24 hours in a diary. 
Entries should be made at the same time each evening. 
10.5.2 Patient reported outcomes 
10.5.2.1 
Short form BPI 
The interference scale of the short form BPI15 has been recommended by international consensus16 as a 
core outcome measure of physical functioning in chronic pain clinical trials. It measures the interference 
of pain on seven items (general activity, mood, walking ability, work, relations with other people, sleep, 
enjoyment of life). Each scale is graded from 0 (does not interfere) to 10 (completely interferes). The 
result is the mean of the scores from the seven items.  
10.5.2.2 
SF-MPQ-2 
The SF-MPQ-217 is a measure of both neuropathic and non-neuropathic pain, modified from the 
commonly used McGill Pain Questionnaire18 and Short-form McGill Pain Questionnaire.19 The SF-MPQ-2 
adds seven symptoms characteristic of neuropathic pain to the SF-MPQ and has response scales from 0 
to 10.  
10.5.2.3 
NPSI 
The NPSI was designed specifically for the assessment of the different symptoms of neuropathic pain.20 
It contains ten items related to different pain descriptors (e.g. burning, squeezing, electric-shock, 
stabbing, tingling), allowing the assessment of the different dimensions of neuropathic pain, and two 
items on frequency and duration of pain. Each pain descriptor is rated on an 11-point numeric rating 
scale from 0 (no pain) to 10 (worst imaginable pain). Total pain intensity score is calculated by the sum of 
the 10 descriptors.  
10.5.2.4 
BDI-II 
The BDI-II21 consists of 21 items; each item is a list of four statements arranged in increasing severity 
about a particular symptom of depression. Each statement is scored from 0 to 3. Each of the 21 items is 
summed to give a single score for the BDI-II. 
10.5.2.5 
PGIC 
The PGIC is a single-item rating by subjects of their improvement with treatment during a clinical trial.22 It 
asks the subject to rate their improvement with therapy on a 7-point scale ranging from very much worse 
to very much improved, with no change as the mid-point.  
 


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11. Study Oversight 
11.1 Within-subject stopping criteria  
Administration of IMP will continue within an individual subject if, in the investigator’s opinion, it is safe to 
do so.   
The following criterion constitutes a contraindication to further administration of IMP to an individual 
subject: 
• 
Any experience, which is considered, by the investigator and/or the sponsor to be serious, 
and severe and clinically significant, which would suggest significant hazard that may be 
associated with the use of the IMP 
If the above criterion becomes applicable during the study, the subject must not receive further doses of 
IMP. Such subjects will be withdrawn and follow the withdrawal procedures as described in Section 5.7. 
11.2 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 subjects 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 subjects 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 14.1.4. 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, subjects will be followed up for a minimum of two weeks 
following the last exposure to IMP, at which time an End of Study visit should be conducted. Refer to 
Section 8.7.1 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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12. Adverse events 
12.1 Definitions 
12.1.1 Adverse event  
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
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 Section 12.3). An adverse event is defined 
as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 12.1.6. 
12.1.2 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. 
12.1.3 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 subject to expedited reporting to the applicable 
regulatory authorities.  
For regulatory reporting purposes, SUSARS will be unblinded. 
12.1.4 Causality 
The investigator must assign causality to each adverse event in relation to the IMP based on the 
following definitions: 
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. 


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12.1.5 Severity (Intensity) of adverse event 
Grade refers to the intensity of an AE and should not be confused with seriousness (refer Section 12.1.6). 
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 ADL**. 
Grade 4  
Life-threatening consequences; urgent intervention indicated. 
Grade 5  
Death related to AE. 
Activities of Daily Living (ADL) 
*Instrumental ADL – refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-Care ADL – refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
12.1.6 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 subject 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 subject 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 subject 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.   
12.2 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.  


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In the UK, all SAEs will be recorded from the time of the subject signing an informed consent. All non 
serious Aes 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 subject’s source records. All spontaneously 
volunteered and enquired for, as well as observed AEs, will be recorded in the subject’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 Section 12.4. 
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. 
12.3 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.    
12.4 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 
subject 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 subject or in a female partner of a male study subject. 
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 subject or in a female 
partner of a male study subject 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. 
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 subject’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 


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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 subjects, impact on the conduct of the study or alter the 
ethics approval/favourable opinion of the study.  
12.5 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 subject is lost to follow up, 
whichever comes first. Follow-up investigations may be necessary according to the investigator’s medical 
judgement. 
 
 


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13. Statistical analysis 
13.1 General considerations 
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, early withdrawals, and potential covariates. Any changes to the 
statistical analysis plan will be described and justified in the final report.  
The descriptive summary for the categorical variables will include counts and percentages. The 
descriptive summary for the continuous variables will include number of subjects (n), means, medians, 
standard deviations, and minimum and maximum values. Pharmacokinetic measures will be analysed as 
for continuous variables. All data will be listed for all subjects. All confidence intervals (CIs) will be 95%, 
unless stated otherwise. All statistical analyses will be performed using SAS unless otherwise stated.   
13.2 Sample size 
The sample size estimation is based on the following assumptions: 
• 
Power of 90% 
• 
The mean change from baseline NPRS for the active treatment compared with placebo is at least 
1 unit 
• 
Standard deviation of the change from baseline in NPRS pain score is 2 
• 
Correlation between active and placebo response is 0.5 
• 
The test is two sided 
• 
The dropout rate is 20% 
The number of subjects within each treatment group is also sufficient to show a statistically significant 
change from baseline of 2 or more points on the NPRS. 
13.3 Analysis populations 
13.3.1 Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects enrolled and randomised into the study. The FAS 
population will be used for summaries of subject disposition, demographic and baseline characteristics. 
Subjects will be analysed according to the treatment group they were assigned at randomisation. 
13.3.2 Per protocol population 
A per-protocol (PP) population will be based on duration of IMP treatment and protocol deviations. This 
population may exclude subjects 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. 
13.3.3 Safety population 
The safety population consists of all randomised subjects 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. Subjects will be analysed as treated, regardless of the randomised treatment assigned, if this 
differs from that to which the subject was randomised. 
13.3.4 PK population 
The PK population will include all subjects who received at least one dose of IMP, had at least one post-


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dose sample collection for PK analysis and who did not have any clinically significant events or protocol 
deviations that may have compromised the integrity of the PK results. 
13.4 Subject disposition 
The total number of subjects will be summarised. The duration on study, and number of subjects 
terminating the study treatment early, along with the reason for early study treatment termination will also 
be summarised. 
13.5 Analysis of efficacy data 
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. 
13.5.1 NPRS 
The primary efficacy endpoint is the absolute change from baseline mean NPRS score to the end of 
treatment NPRS score after LAT8881, compared with the change from baseline after placebo treatment.  
Daily NPRS scores for all enrolled subjects will be listed only. Mean and standard deviation of scores 
during the baseline period and weeks 1, 2, 3 and 4, and the absolute and percentage change from 
baseline in each period, will be listed for each subject and summarised for LAT8881 and placebo 
treatments overall and within treatment sequence for all randomised subjects and for the PP population. 
The maximum change in mean NPRS from baseline to weeks 1, 2, 3 and 4, determined for each subject 
after LAT8881and placebo, will be listed and summarised. 
Mixed effects regression models will be used to compare the absolute and percentage changes from 
baseline to the end of each treatment for the mean NPRS scores. The models will have fixed effects for 
period and treatment. Baseline mean pain score within each period by treatment combination will be 
included as a covariate. A random effect for subject will be included to capture the repeated measures 
nature of the design. 
The models for the primary endpoint will be expanded to compare the absolute and percentage changes 
from baseline for the mean NPRS scores after 1, 2 and 3 weeks of dosing with IMP in each treatment 
period. The model will also include a fixed effect for week (1, 2, 3 and 4), the interaction between 
treatment and week to assess whether the change from baseline for each treatment is different. 
The mean score at each visit, change from baseline, difference between treatments in the change from 
baseline and corresponding 95% confidence intervals will be presented. Comparisons will be declared 
statistically significant if p<0.05. 
In PK subjects, NPRS scores at specified times up to 6 hours on Days 1, 28, 50 and 77 will be listed and 
summarised. Change from pre-dose values will also be listed and summarised. Changes over time will be 
analysed using the same modelling approach as for the primary endpoint. 
The proportion of subjects achieving at least 30% and 50% reduction in pain after four weeks treatment, 
as assessed by the mean NPRS score, will be summarised with the 95% confidence interval for the 
percentage reduction, estimated by Clopper Pearson Exact methodology. A mixed effects logistic 
regression model, including the same fixed and random effect terms as for the primary endpoint, will be 
used to assess the odds of achieving a reduction in pain at Day 28 and Day 77 with LAT8881 compared 
to placebo.  
13.5.2 Patient reported outcomes 
Baseline and end of treatment values for the BPI interference scale, SF-MPQ-2, NPSI and BDI will be 
listed for LAT8881 and placebo. Values at each timepoint and the change from baseline will be 
summarised. PGIC will be tabulated at the end of each treatment period and summarised. Differences 


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between the LAT8881 and placebo treatments in the change from baseline reported outcome will be 
analysed using the same model as for the primary endpoint. 
13.5.3 Analgesic use 
Paracetamol (rescue medication) use at baseline and weekly over the treatment period will be listed for 
each subject. The average weekly and cumulative dose of rescue paracetamol medication in each 
treatment period will be summarised by visit and treatment. 
13.6 Analysis of safety data 
13.6.1 Extent of exposure 
The number of subjects exposed to study treatment, duration of exposure and total IMP administered, will 
be summarised.  
13.6.2 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 subjects with the following adverse events will be prepared: 
• 
All adverse events 
• 
Serious adverse events 
• 
Adverse events leading to premature discontinuation of IMP 
• 
Adverse events by intensity 
• 
Adverse events by relationship to IMP 
All summaries of adverse events will include only treatment emergent adverse events (TEAEs). Refer 
Section 12.1 for adverse event definitions. 
13.6.3 Clinical laboratory evaluations 
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 subjects with clinically significant abnormal results will be prepared. 
13.6.4 Other safety measures 
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 subjects receiving concomitant medications will be tabulated overall and 
by medication received.  
13.7 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 


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value above the limit of quantification 
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 
AUC0-t will only be calculated if there are at least three quantifiable data points. 
T1/2 will only be determined if there are at least three quantifiable elimination phase data points. 
Plasma LAT8881 values below the limit of quantification will be labelled as (BLQ) in the plasma LAT8881 
data listings and set to zero if recorded pre-dose. 
The change in PK parameters on the last day of treatment compared with those determined after the 
initial dose will be investigated using a paired t-test. The mean change after repeated dosing will be 
presented with the corresponding 95% confidence interval and p value.  
13.8 Analysis of exploratory endpoints  
Exploratory analyses will be undertaken to determine the relationship between change in mean NPRS 
from baseline to the end of four weeks treatment and baseline parameters, such as the clinical diagnosis 
(PHN or DPN) and baseline QST parameters. The effect of treatment on changes in QST parameters 
(WDT, HPT, MPS) from baseline to the end of four weeks treatment will also be analysed. 
The effect of the variability in NPRS scores within the first baseline period on the ability to detect a 
treatment difference will be examined. 
The relationship between plasma LAT8881 and NPRS in PK subjects will also be investigated. 
The approaches to these investigative analyses will be detailed in the statistical analysis plan. 
 
 


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14. Study management 
14.1 Regulatory and ethical considerations 
14.1.1 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.   
14.1.2 Ethics Committee review 
Prior to the initiation of the study, the protocol and associated documentation (including all materials used 
to recruit subjects 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 subjects 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.  
14.1.3 Informed consent process 
The investigator will ensure that the subject is given full and adequate oral and written information about 
the nature, purpose, possible risks and potential benefits of the study. Subjects must also be notified that 
they are free to discontinue from the study at any time. The subject should be given the opportunity to 
ask questions and should be allowed time to consider the information provided. 
The subject’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 subject’s medical 
records. A copy of the signed and dated ICF must be given to the subject.  
Subjects who are incompetent and unable to freely provide informed consent and subjects 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 subjects, the protocol and ICF 
will be amended as appropriate and submitted to the EC as outlined in Section 14.1.4. Following approval 
by the EC, subjects 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, subjects 
may be requested to re-consent to ongoing their participation in the study. 
14.1.4 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 re-
evaluation of the ethical aspects of the study is necessary. In the UK, a substantial amendment to the 


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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 
relevant EC, except where it is necessary to eliminate an immediate hazard to study subjects, 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.  
14.1.5 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 subjects 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. 
14.2 Quality control and quality assurance 
14.2.1 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.  
14.2.2 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. 


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14.2.3 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 subjects. 
The eCRFs should always reflect the latest observations on the subjects participating in the study; 
therefore, the eCRFs are to be completed as soon as possible during or after the subject’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 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 subject’s medical record, that verify the existence of the subject, the inclusion and exclusion 
criteria and all records covering the subject’s participation in the study. They include, but are not limited 
to, laboratory reports, hospital records, subject files, etc. 
eCRFs will be completed for subjects who have signed the ICF, are eligible for this study and have been 
enrolled in the study. 
14.2.4 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 


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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 subject 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.  
14.3 Documentation, record access and archiving 
14.3.1 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 sites. 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.    
14.3.2 Data protection 
To protect the subject’s identity, a unique subject identification code (Subject ID) will be assigned by the 
investigator to each study subject and used in lieu of the subject’s name when the investigator reports 
SAEs and/or other study-related data. The subject’s study number, rather than the subject’s name, will 
appear on all documents and will be cross referenced by the subject’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 subject’s 
consent to direct access to his/her original medical records for data verification purposes must be 
obtained prior to that subject’s involvement in the study. 
Subjects 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. Subjects 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, subjects will be 
identified in such reports only by study identification number (Subject ID), gender and age. All subject 
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. Subject data in the database 
will be identified by Subject ID number only. Electronic CRFs will also identify subjects by Subject 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 subject’s source documents and/or medical record. 
14.3.3 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 subject’s CRF data are 


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obtained. These include, but are not limited to: hospital records, subject’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.  
14.4 Study administration 
14.4.1 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 subjects 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 subjects 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 
subject’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. 
14.4.2 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 IHPT, subject 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 subject 


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only by the subject identification code (Subject ID). The investigator will maintain a current confidential 
Subject Identification List of full names of all subjects in this study. This list will allow the investigator to 
reveal the identity of the subjects 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. 
14.4.3 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 subjects 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. 
14.4.4 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. 
14.4.5 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. 
 
 
 


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15. 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.iasp-
pain.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_TherBrief_JUN13.pdf. 
Accessed 20 March 2018 
7 Gewandter JS, Dworkin RH, Turk DC, McDermott MP, Baron R, Gastonguay MR et al. Research designs for proof-
of-concept chronic pain clinical trials: IMMPACT recommendations. Pain. 2014 Sep;155(9):1683-95. 
8 See Drugs@FDA for duloxetine, pregabalin and gabapentin at www.fda.gov/drugsatfda 
9 Vollert J, Maier C, Attal N, Bennett DLH, Bouhassira D, Enax-Krumova EK et al. Stratifying patients with peripheral 
neuropathic pain based on sensory profiles: algorithm and sample size recommendations. Pain. 2017 
Aug;158(8):1446-1455 
10 FDA Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers. July 2005 
11 Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme. Guide to Good 
Manufacturing Practice for Medicinal Products Annexes[Internet]. Geneva: PIC/S Secretariat; 1 January 2017. 
Available from https://www.picscheme.org/en/publications?tri=gmp (accessed 17 March 2018) 
12 Freynhagen R, Baron R, Gockel U, Tölle TR. painDETECT: a new screening questionnaire to identify neuropathic 
components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20. 
13 Tampin B, Briffa NK, Goucke R, Slater H. Identification of neuropathic pain in patients with neck/upper limb pain: 
application of a grading system and screening tools. Pain. 2013 Dec;154(12):2813-22. doi: 
10.1016/j.pain.2013.08.018. Epub 2013 Aug 22. 
14 Tampin B, Bohne T, Callan M, Kvia M, Melsom Myhre A, Neoh EC, Bharat C, Slater H. Reliability of the English 
version of the painDETECT questionnaire. Curr Med Res Opin. 2017 Apr;33(4):741-748. doi: 
10.1080/03007995.2017.1278682. Epub 2017 Feb 5. 
15 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994 
Mar;23(2):129-38. 
16 Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP et al. IMMPACT. Core outcome 
measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005 Jan;113(1-2):9-19. 
17 Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, Bhagwat D, Everton D, Burke LB, 
Cowan P, Farrar JT, Hertz S, Max MB, Rappaport BA, Melzack R. Development and initial validation of an expanded 
and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain. 2009 Jul;144(1-2):35-42. doi: 
 


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10.1016/j.pain.2009.02.007. Epub 2009 Apr 7. 
18 Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975;1:277–99 
19 Melzack R. The short-form McGill Pain Questionnaire. Pain 1987;30:191–7 
20 Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E, Rostaing S, Lanteri-Minet M, Collin E, 
Grisart J, Boureau F. Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 2004 
Apr;108(3):248-57. 
21 Beck AT, Steer RA, Brown GK. BDI-II: Beck Depression Inventory Manual. 2nd ed. San Antonio, TX: Psychological 
Corporation; 1996 
22 W. Guy, ECDEU Assessment Manual For Psychopharmacology, DHEW Publication No. ADM 76–338, US 
Government Printing Office, Washington, DC, USA, 1976 
23 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical 
research involving human subjects. JAMA. 2013;310(20):2191-2194 
24 International Conference on Harmonisation (ICH) Note for Guidance: Structure and Content of Clinical Study 
Reports. CPMP/ICH/137/95, December 1995. 
 
 


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Appendix 1: Protocol Amendments 
Note that changes to the cover page, page footer and table of contents, which are self-explanatory, are 
not listed as amendments. 
Section 
Changed From 
Changed To 
Justification 
V2, 29 March, 2019 
Doses and 
treatment 
regimens:  
Section 7.10 
 
Added . If more than 16 hours has 
elapsed since the last dose, the dose 
should be missed and the next dose 
taken at the regular scheduled time. 
Provides information 
about missing a dose 
Prohibited 
Medications: 
Synopsis and 
Section 7.14.2 
 
Added: A short course (<7days) of oral 
prednisolone or equivalent for other 
conditions, up to 4 weeks preceding 
Day 1, is allowed 
Clarification of prohibited 
medications 
Early withdrawal 
visit: Section 8.8 
 
Added: This visit should be scheduled 
approximately two weeks after the last 
dose was taken. 
Clarification of timing of 
the End of Study visit 
after Early Withdrawal 
Medical History: 
Section 10.1.1. 
will be recorded from 
screening until dosing 
with IMP on day 1 
will be recorded at screening 
Correction to timing of 
medical history 
Exclusion 
criteria 6: 
Synopsis and 
Section 6.2 
Clinically significant 
abnormal 12-lead 
electrocardiogram 
(ECG) 
Clinically significant abnormal 12-lead 
electrocardiogram (ECG) at screening 
It is only at screening that 
an abnormal clinically 
significant ECG 
mandates exclusion from 
the study. 
Electrocardiogram: 
Section 10.1.4 
Any subject with an 
abnormal ECG that is 
considered clinically 
significant will be 
excluded from the 
study 
Any subject with an abnormal ECG at 
screening that is considered clinically 
significant will be excluded from the 
study 
It is only at screening that 
an abnormal clinically 
significant ECG 
mandates exclusion from 
the study.  
Clinical chemistry: 
Section 10.2.1.2 
calcium (corrected) 
creatinine, 
calcium (corrected), creatinine, 
Comma added to 
separate tests 
Clinical chemistry: 
Section 10.2.1.2 
 
Added HbA1c will be measured in 
DPN subjects only and only at 
screening. 
HbA1c is a screening test 
for DPN subjects 
V3, 17 May, 2019 
Synopsis and 
Sections 5.1, 
8.2.1, 8.2.2, 
10.5.1.1 
Electronic diary 
diary 
Diary is not electronic 
Synopsis and 
Section 9.1 
or since the last diary 
entry (whichever is 
shorter) 
Deleted this text 
Simplified diary 
instructions 
Exclusion 6: 
Clinically significant 
Clinically significant abnormal 12-lead 
Subjects may be 


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Section 
Changed From 
Changed To 
Justification 
Synopsis and 
Section 6.2 
abnormal 12-lead 
electrocardiogram 
(ECG) at screening 
electrocardiogram (ECG) 
excluded if they have an 
abnormal ECG at 
screening or pre-dose on 
Day 1 
Electrocardiogram: 
Section 10.1.4 
Any subject with an 
abnormal ECG at 
screening that is 
considered clinically 
significant will be 
excluded from the 
study 
Any subject with an abnormal ECG at 
screening or pre-dose on Day 1 that is 
considered clinically significant will be 
excluded from the study. 
 
Subjects may be 
excluded with an 
abnormal ECG pre-dose 
on Day 1 
V4, 15 July, 2019 
General Study 
Information 
 
 
Australian contact details 
updated, UK contact 
added 
Synopsis 
Genesis Research 
Services deleted 
 
Updated current list of 
trial sites and addresses 
Table 1 
36 
289 
27 
243 
Subject numbers 
corrected 
Section 7.2.1 
Active Pharmaceutical 
Ingredient 
LAT8881 capsules 
 
Corrected terminology 
Sections 7.3, 7.5 
Pharmaceutical 
Packaging 
Professionals Pty Ltd 
(PPP) 
PCI Services (PCI) 
PPP has been acquired 
by PCI 
Section 10.1.4 
Deleted: Any subject 
with an abnormal ECG 
at screening or pre-
dose on Day 1 that is 
considered clinically 
significant will be 
excluded from the 
study. 
 
Section 6.2 already 
covers this 
V4, 27 August, 2019 
Section 7.13.1 
Investigator asked to 
advise Sponsor/ 
Medical Monitor before 
breaking code 
Investigator may break code without 
prior notification to Sponsor/Medical 
Monitor 
Requested by MHRA 
Section 12.2 
SAEs which occur after 
signing of the informed 
consent to first IMP 
administration are 
recorded as medical 
history 
In the UK, SAEs which occur after 
signing of informed consent will be 
recorded as an SAE on the database 
Requested by MHRA 


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Section 
Changed From 
Changed To 
Justification 
V5, 9 October 2019 
Synopsis, 
Sections 5.1, 8.2.1 
At least 20 QST 
subjects 
Up to 20 QST subjects 
Delay in QST recruitment 
 

SAP_001.pdf: 
 
 
 
 
 
Official Title: A Phase IIa study of the efficacy and safety of oral 
LAT8881 in neuropathic pain 
NCT Number: NCT03865953 
 
Document date: May 27, 2020 
 


 
 
 
28 May  2020 
 
 
 
 
 


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Table of Contents 
1 
Definitions ....................................................................................................................................... 6 
2 
Introduction .................................................................................................................................... 7 
2.1 Background .................................................................................................................................... 7 
2.2 Rationale ........................................................................................................................................ 8 
3 
Study Objectives .............................................................................................................................. 9 
3.1 Primary Objective .......................................................................................................................... 9 
3.2 Secondary Objectives .................................................................................................................... 9 
3.3 Exploratory Objectives................................................................................................................. 10 
4 
Study Design .................................................................................................................................. 10 
4.1 Overview ...................................................................................................................................... 10 
4.2 Sample Size Justification .............................................................................................................. 11 
4.3 Randomization and Blinding ........................................................................................................ 11 
4.4 Inclusion/Exclusion Criteria ......................................................................................................... 11 
4.4.1 
Inclusion Criteria: ........................................................................................................... 11 
4.4.2 
Exclusion Criteria: .......................................................................................................... 12 
4.5 Treatment allocation ................................................................................................................... 13 
5 
Assessment Schedule .................................................................................................................... 15 
5.1 Screening, First Baseline Period, First Treatment Period and Washout ..................................... 15 
5.2 Second Baseline Period, Second Treatment Period and Follow Up ............................................ 16 
6 
Interim Analysis ............................................................................................................................. 17 
6.1 Unblinding and Dissemination of Results .................................................................................... 17 
7 
Efficacy and Safety Endpoints ....................................................................................................... 17 
7.1 Primary Efficacy Endpoints .......................................................................................................... 17 
7.2 Secondary Efficacy Endpoints ...................................................................................................... 17 
7.3 Safety Endpoints .......................................................................................................................... 18 
7.4 
Pharmacokinetic endpoints ................................................................................................... 18 
7.5 
Exploratory endpoints ........................................................................................................... 18 
8 
Statistical Methods........................................................................................................................ 18 


 
 
8.1 Handling Missing/Incomplete Data ............................................................................................. 19 
8.2 Handling Outliers ......................................................................................................................... 19 
8.3 Multiplicity Adjustment ............................................................................................................... 19 
9 
Analysis Populations...................................................................................................................... 19 
9.1 Full Analysis Set ........................................................................................................................... 19 
9.2 Per protocol population .............................................................................................................. 20 
9.3 Safety population ........................................................................................................................ 20 
9.4 QST population ............................................................................................................................ 20 
10 Analysis Variables ............................................................................................................................. 20 
10.1 
Population Flags .................................................................................................................... 20 
10.2 
Treatment .............................................................................................................................. 20 
10.3 
Visits....................................................................................................................................... 20 
10.4 
Study Periods ......................................................................................................................... 21 
10.5 
Completion Flags ................................................................................................................... 21 
10.6 
Prior and Concomitant Medications ...................................................................................... 21 
10.7 
Rescue Medications ............................................................................................................... 22 
10.8 
Medical History and Concurrent Diseases ............................................................................. 22 
10.9 
Adverse Event Flags ............................................................................................................... 22 
10.10 Laboratory Assessments .......................................................................................................... 23 
10.11 painDETECT Questionnaire ...................................................................................................... 23 
10.12 Baseline.................................................................................................................................... 23 
10.12.1 
Safety Endpoints ........................................................................................................ 23 
10.12.2 
Efficacy Endpoints ...................................................................................................... 23 
10.13 Change from Baseline .............................................................................................................. 24 
10.14 Treatment Compliance ............................................................................................................ 24 
10.15.1 
NPRS Mean Scores ......................................................................................................... 25 
10.16 Analysis Flags ........................................................................................................................... 25 
10.16.1 
Responder .................................................................................................................. 25 


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10.16.2 
Maximum Reduction ................................................................................................. 26 
10.16.3 
Baseline NPRS Variability ........................................................................................... 26 
11 Statistical Analyses ........................................................................................................................... 26 
11.1 
Subject Disposition ................................................................................................................ 26 
11.2 
Protocol Deviations ............................................................................................................... 27 
11.3 
Demographic and Baseline Characteristics ........................................................................... 28 
11.4 
Medical History and Concurrent Diseases ............................................................................. 28 
11.5 
Prior and Concomitant Medications ...................................................................................... 28 
11.5.1 Rescue Medications ........................................................................................................... 29 
11.6 
Efficacy Analyses .................................................................................................................... 29 
11.6.1 Primary Efficacy analyses – Mean daily NPRS scores ......................................................... 29 
11.6.1.1 Descriptive summary ................................................................................................... 29 
11.6.1.2 Mixed Effect Regression Model .................................................................................. 29 
11.6.2 Secondary Efficacy analyses ............................................................................................... 31 
11.6.2.1 Percentage change from baseline in mean NPRS scores ............................................ 31 
11.6.2.2 Responder analysis ...................................................................................................... 31 
11.6.2.3 Maximum change from baseline ................................................................................. 32 
11.6.2.4 Patient reported outcomes ......................................................................................... 32 
11.6.2.5 NPRS and baseline covariates ..................................................................................... 33 
11.6.3 Exploratory Analyses .......................................................................................................... 33 
11.6.3.1 QST Parameters ........................................................................................................... 33 
11.6.3.2 NPRS and baseline variability ...................................................................................... 34 
11.7 
Safety Analyses ...................................................................................................................... 34 
11.7.1 Adverse Events ................................................................................................................... 34 
11.7.1.1 Overall Adverse Events ................................................................................................ 34 
11.7.1.2 Summary of Adverse Events by SOC and PT ............................................................... 35 
11.7.1.3 Summary of Adverse Events by SOC, PT and Severity ................................................ 35 
11.7.2 Laboratory Assessments ..................................................................................................... 35 
11.7.2.1 Continuous Summary .................................................................................................. 35 
11.7.2.2 Shift Summary ............................................................................................................. 35 
11.7.2.3 Listings ......................................................................................................................... 36 
11.7.3 Other Safety Analyses ........................................................................................................ 36 


 
 
11.7.3.1 Extent of Exposure ...................................................................................................... 36 
11.7.3.2 Vital Signs .................................................................................................................... 37 
11.7.3.3 Physical Examination ................................................................................................... 37 
11.7.3.4 Electrocardiogram Assessments ................................................................................. 37 
12 Changes to Planned Analyses ........................................................................................................... 37 
13 Index of Tables, Listings and Graphs ................................................................................................ 39 
14 References ........................................................................................................................................ 39 
15 Appendices ....................................................................................................................................... 40 
15.1 
painDETECT questionnaire .................................................................................................... 40 
15.2 
QST phenotype ...................................................................................................................... 40 
15.2.1 WDT .................................................................................................................................... 40 
15.2.2 MPS..................................................................................................................................... 40 
15.2.3 HPT ..................................................................................................................................... 40 
15.3 
Pain intensity ......................................................................................................................... 40 
15.3.1 NPRS ................................................................................................................................... 40 
15.4 
Patient reported outcomes ................................................................................................... 41 
15.4.1 Short form BPI .................................................................................................................... 41 
15.4.2 SF-MPQ-2 ............................................................................................................................ 41 
15.4.3 NPSI .................................................................................................................................... 41 
15.4.4 BDI-II ................................................................................................................................... 41 
15.4.5 PGIC .................................................................................................................................... 41 
16 Change Log ....................................................................................................................................... 42 
 


 
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1 Definitions 
Abbreviation 
Definition 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC0-inf 
Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification, extrapolated to infinity 
AUC0-t  
Area under LAT8881 concentration time curve from dosing to the last observed 
concentration value above the limit of quantification 
BDI-II 
Beck Depression Inventory-II 
BMI 
Body mass index 
BPI 
Brief Pain Inventory 
CI 
Confidence interval 
Cmax 
Maximum plasma drug concentration 
CV 
Co-efficient of variation 
CS 
Clinically Significant 
eCRF 
Electronic Case report form 
DPN 
Diabetic peripheral neuropathy 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
HbA1c 
Glycosylated haemoglobin 
hCG 
Human chorionic gonadotropin 
HPT 
Heat Pain Threshold 
IASP 
International Association for the Study of Pain 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
LLOQ 
Lower limit of quantification 
LS 
Least square 
m 
Number of events / mentions 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS 
Mechanical Pain Sensitivity 
Min 
Minimum 
Max 
Maximum 
n 
Number of subjects 
NCS 
Not clinically significant 
NeuPSIG 
Neuropathic Pain Special Interest Group 


 
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NPRS 
Numeric pain rating scale 
NPSI 
Neuropathic Pain Symptom Inventory 
PC 
Plasma concentration 
PD-Q  
painDETECT questionnaire 
PGIC 
Patient Global Impression of Change 
PHN 
Postherpetic neuralgia 
PK  
Pharmacokinetics 
PP 
Per protocol 
PT 
Preferred term 
PWT 
Paw withdrawal threshold 
QST 
Quantitative sensory testing 
SAS 
Statistical Analysis System 
SAE 
Serious adverse event 
SD 
Standard deviation 
SF-MPQ-2  
Short-form McGill Pain Questionnaire 2 
SOC 
System organ class 
Subject ID 
Subject identifier 
SUSAR 
Suspected unexpected serious adverse reaction 
T1/2 
Terminal elimination half life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma LAT8881 concentration 
WDT 
Warm Detection Threshold 
WHODD 
World Health Organization’s Drug-Dictionary 
2 Introduction 
2.1 Background 
Neuropathic pain (NP) is defined as pain caused by a lesion or disease of the somatosensory nervous 
system.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 


 
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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%. 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.i 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. 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. 
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 preclinical and clinical safety record. This is the first 
clinical study to investigate this compound in neuropathic pain. 
. 
2.2 Rationale 
Six clinical studies with LAT8881 have been completed, with over 700 subjects treated with LAT8881. 
These studies were designed to investigate the safety and tolerability of LAT8881 and subsequently 
its efficacy in the treatment of obesity (METAOD002, METAOD003, METAOD004, METAOD005, 
METAOD006).  
In all studies it was noted that the study drug was well tolerated. The only dose-related adverse event 
(AE) trend was an increased incidence of gastrointestinal effects and general body symptoms of 
abdominal pain and headache in Study METAOD004 at a dose of 54 mg orally daily. This trend was 
not observed in subsequent studies METAOD005 and METAOD006 which evaluated lower daily 
doses. 


 
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3 Study Objectives 
3.1 Primary Objective 
1. To evaluate the efficacy of oral LAT8881 in NP compared with placebo, when assessed by 
change in mean pain intensity scores from baseline to the end of four weeks treatment, 
based on an 11 point numeric pain rating scale (NPRS) 
3.2 Secondary Objectives 
1. To investigate the effect of oral LAT8881 in NP compared with placebo at different timepoints 
(up to 6 hours) following a single dose and after 4 weeks treatment, as measured by the NPRS 
(PK subjects only) 
2. To investigate the effect of oral LAT8881 on mean pain scores in NP compared with placebo 
after 1, 2 and 3 weeks of dosing, as measured by the NPRS 
3. To determine the proportion of responders to oral LAT8881 in NP compared with placebo 
4. To investigate the maximum effect of oral LAT8881 in NP compared with placebo, as 
determined by the maximum change from mean NPRS baseline after 1, 2, 3 or 4 weeks 
treatment 
5. To evaluate the effect of oral LAT8881, compared with placebo, on functioning in subjects with 
NP when measured by the 7-item short form Brief Pain Inventory (BPI) Interference Scale 
6. To evaluate the effect of oral LAT8881, compared with placebo, on pain symptoms in subjects 
with NP when measured by the short-form McGill Pain Questionnaire 2 (SF-MPQ-2) 
7. To evaluate the effect of oral LAT8881, compared with placebo, on symptoms in subjects with 
NP, when measured by the Neuropathic Pain Symptom Inventory (NPSI) 
8. To evaluate the effect of oral LAT8881, compared with placebo, on emotional functioning when 
measured by the Beck Depression Inventory-II (BDI-II) 


 
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9. To evaluate the effect of oral LAT8881, compared with placebo, on overall health and quality 
of life in subjects with NP, when measured by the Patient Global Impression of Change (PGIC) 
scale 
10. To determine the change from baseline in rescue medication use during oral LAT8881 
administration, compared with placebo 
11. To evaluate the safety and tolerability of oral LAT8881 in NP after a single dose and after four 
weeks treatment  
12. To investigate the pharmacokinetics of twice daily oral LAT8881 in 15 subjects with NP after a 
single dose and after 4 weeks treatment with oral LAT8881 
3.3 Exploratory Objectives 
1. To investigate the relationship between baseline subject characteristics, such as clinical 
diagnosis (PHN or DPN) and QST parameters, and the change in NPRS after oral LAT8881 
treatment, compared with placebo 
2. To investigate the change from baseline on specified QST parameters (WDT, MPS, HPT) after 
four weeks treatment with oral LAT8881, compared with placebo 
3. To investigate the relationship between plasma LAT8881 concentrations and the change in 
mean pain score in subjects with NP 
4. To investigate the impact of variability in NPRS scores during the first baseline period on the 
difference between baseline and 4 week NPRS scores after LAT8881 or placebo 
4 Study Design 
4.1 Overview 
This is a randomised, placebo-controlled, double-blind, crossover, multi-site, Phase IIa study to 
investigate the efficacy and safety of oral LAT8881 in neuropathic pain. The overall study design is 
shown below. 
The pharmacokinetics (PK) of LAT8881 will be investigated on Days 1, 28, 50 and 77 in 15 subjects (PK 
subjects) at Australian sites. Quantitative sensory testing (QST) will be performed in at least 20 
subjects (QST subjects) before the first dose on Days 1 and 50 and after the morning dose on Days 28 
and 77. PK subjects will not participate in QST measurements and QST subjects will not participate in 
PK analyses.  
 
Up to 3 
weeks 
Days  
-7 to -1  
Day 1 
Days 
1 to 28 
Days 
29 to 42 
Days 
43 to 49 
Days 
50 to 77 
Day 
91 
Screening  
Stage 1 
Screening  
Stage 2 
First  
( 
Baseline) 
Enrolment 
and 
Randomisation 
LAT8881 
Washout 
Second  
baseline 
Placebo 
Follow  
up 
Placebo 
Washout 
Second  
baseline 
LAT8881 


 
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Figure 1: Overall study design for LAT-NP-001 
4.2 Sample Size Justification 
It is planned to have 44 subjects complete the study. Assuming a 20% dropout, 55 subjects will be 
recruited. If the dropout rate is higher than 20%, additional subjects (up to 60 in total) may be recruited 
at the sponsor’s discretion to ensure 44 subjects complete the study. 
The sample size estimation is based on the following assumptions: 
• 
Power of 90% 
• 
The mean change from baseline NPRS for the active treatment compared with placebo is at 
least 1 unit 
• 
Standard deviation of the change from baseline in NPRS pain score is 2 
• 
Correlation between active and placebo response is 0.5 
• 
The test is two sided 
• 
The dropout rate is 20% 
The number of subjects within each treatment group is also sufficient to show a statistically significant 
change from baseline of 2 or more points on the NPRS. 
4.3 Randomization and Blinding 
A computer-generated randomisation schedule and treatment allocation will be prepared by an 
unblinded statistician prior to the start of the study. 
The treatment sequence each subject will receive will not be disclosed to the investigator, study site 
personnel, subjects, or sponsor personnel. The randomisation codes will be available to the Investigator 
if required for emergency unblinding purposes. 
Details regarding Randomization is provided in LAT-NP-001_Randomization Plan (v1.00), and 
unblinding plan is provided in LAT-NP-001_Unblinding Plan (v1.00). 
4.4 Inclusion/Exclusion Criteria 
4.4.1 
Inclusion Criteria: 
Subjects must meet the following criteria to be entered into the study: 
1. Clinical diagnosis of post herpetic neuralgia, with pain persisting for at least 3 months after the 
onset of herpes zoster rash OR  
2. Clinical diagnosis of distal painful polyneuropathy due to Type I or Type II diabetes mellitus 
with: 
a) symmetrical, bilateral pain in the lower extremities for at least 3 months and 
b) diabetes under control for at least 3 months prior to randomisation, as indicated by a 
glycated haemoglobin level (HbA1c) of ≤ 11% (97 mmol/mol) and on a stable dose of 
insulin or oral diabetic medication for 3 months prior to screening, and  
c) no change in diabetic medication planned for the duration of the study 


 
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3. Positive sensory symptoms (mechanical or thermal) associated with neuropathic pain, 
confirmed by: 
a) painDETECT Questionnaire (PD-Q) and  
b) Clinical assessment, showing signs of neuropathic pain in either a dermatomal (PHN) 
or distal symmetrical distribution (DPN) 
4. Aged 18 to 75 years 
5. Subjects must be sufficiently competent in English to understand the purposes and risks of the 
study and able to give voluntary written informed consent to participate in the study 
6. Willing and able to comply with all study procedures 
7. Completion of at least five NPRS scores during the week preceding randomisation 
8. An average daily pain score on the NPRS of at least 4 and no more than 8 in the last five diary 
entries before randomisation  
9. No more than one score on the NPRS of 9 or more, and no more than one score of 2 or less, in 
the last five diary entries before randomisation 
10. Females of child bearing potential must have a negative pregnancy test at Visit 1 (Screening) 
and at Visit 2 (Day 1) prior to administration of IMP 
11. Female subjects must be: 
a) of non child-bearing potential [surgically sterilised or post–menopausal (12 months 
with no menses without alternative medical cause)] OR 
b) not pregnant, breast feeding or planning to become pregnant AND willing to comply 
with the medically acceptable contraceptive requirements of the study from Screening 
to at least 28 days after the last IMP administration  
4.4.2 
Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Presence of moderate to severe pain from other causes that may confound assessment or 
selfevaluation of NP 
2. Subjects with both DPN and PHN  
3. Skin conditions in the affected area that could alter sensation or assessments 
4. History of or current clinically significant gastrointestinal, hepatic, renal, cardiovascular, 
respiratory,  
endocrine,  
oncological,  
immunological,  neurological, 
 ophthalmological, haematological or psychiatric disorder or any other condition, which in the 
opinion of the investigator or sponsor would jeopardise the safety of the subject or the validity 
of the study results  
5. Medical history of, or currently active, human immunodeficiency virus, hepatitis B or hepatitis 
C virus   
6. Clinically significant abnormal 12-lead ECG 
7. Immunocompromised  state,  or  
conditions  
known  to  
be  
associated 
 with  
an immunocompromised state 
8. Clinically significant or unstable medical or psychological condition that would compromise 
participation in the study 


 
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9. Recent history of malignancy within 5 years preceding screening (except resected cervical or 
skin cancer [except melanoma]). Subjects who have had no evidence of disease in the last 5 
years are eligible  
10. Active herpes zoster infection on screening 
11. Current alcohol abuse, illicit or illegal drug use 
12. Use of prohibited medication (see study medications) 
13. Previous treatment with LAT8881 (formerly identified as AOD9604) within the last 5 years 
14. Participation in an investigational trial within 60 days or 5 half-lives (whichever is longer) prior 
to screening 
15. History of significant hypersensitivity to LAT8881 or drugs of a similar pharmacological class 
(e.g. somatropin) 
16. Surgical or medical conditions which could significantly alter drug absorption, distribution, 
metabolism or excretion 
17. An employee of the sponsor or research site personnel directly affiliated with this study, 
whether biological or legally adopted, or their immediate family members, defined as a spouse, 
parent, sibling, or child 
18. Previous neurolytic or neurosurgical therapy for PHN or DPN 
19. PK subjects: 
a) Blood or plasma donation of more than 500 mL during the 3 months prior to 
randomisation 
b) History of fainting during phlebotomy 
4.5 Treatment allocation 
The IMP is supplied as opaque, size 0 capsules, in a high-density polyethylene bottle containing 60 
capsules. One bottle will contain sufficient capsules for one treatment period. Each capsule contains 
30 mg LAT8881 plus L-arginine, polyethylene glycol and mannitol as excipients. Placebo capsules 
contain the excipients L-arginine, polyethylene glycol and mannitol only (without LAT8881). 
On Day 1, after the first baseline period, eligible subjects will be enrolled and randomised to LAT8881 
or placebo. They will receive the investigational medicinal product (IMP) twice daily for four weeks 
(Days 1 to 28). On the morning of Day 28 they will return to the clinic for their end of first treatment 
visit and will take an IMP capsule in the morning during their clinic visit. They will take their final IMP 
dose for this treatment period in the evening. 
The first treatment period will be followed by a washout period of two weeks (Days 29 to 42 inclusive) 
and then a second baseline period of one week (Days 43 to 49 inclusive). Over these days (i.e. Days 
2949 inclusive) subjects will not take any IMP. 
On Day 50, subjects will return to the clinic and cross over to receive the second treatment (either 
LAT8881 or placebo, whichever treatment was not received in the first treatment period) twice daily 
for four weeks (Days 50 to 77). On the morning of Day 77, they will return to the clinic for their end of 


 
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second treatment visit and will take an IMP capsule in the morning during their clinic visit. They will 
take their final IMP dose for this treatment period in the evening. 
 


 
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5 Assessment Schedule 
5.1 Screening, First Baseline Period, First Treatment Period and Washout 
 


 
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5.2 Second Baseline Period, Second Treatment Period and Follow Up 
 


 
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6 
Interim Analysis 
There is no interim analysis planned for this study. 
6.1 Unblinding and Dissemination of Results 
There is no interim analysis planned for this study, so this section is not applicable. 
7 Efficacy and Safety Endpoints 
7.1 Primary Efficacy Endpoints 
1. Absolute change in mean pain score, using an 11 point NPRS, from baseline to the last week of 
each treatment period. Pain is recorded once daily in a subject diary in the evening, and should 
reflect the subject’s average pain over the last 24 hours  
Baseline mean pain for each subject is defined as the mean of the last five available ratings of daily 
pain, recorded in each baseline period. 
End of treatment mean pain for each subject is defined as the mean of the last five available ratings of 
daily pain, recorded in the last 7 days of each 4 week treatment period. 
7.2 Secondary Efficacy Endpoints 
1. Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after the first dose of IMP in each treatment 
period, compared with the score recorded no more than 60 minutes before the first dose of 
IMP in that treatment period (PK subjects only) 
2. Change in NPRS score at 0.5, 1, 2, 4 and 6 hours after a single dose of IMP, following four weeks 
treatment with IMP in each treatment period, compared with the score recorded no more than 
60 minutes before this dose (PK subjects only) 
3. Change in mean pain scores from baseline after 1, 2 and 3 weeks of dosing with IMP in each 
treatment period, using an 11 point NPRS. Pain scores at weeks 1, 2 and 3 are defined as the 
mean of the last five available ratings of daily pain in the subject diary, recorded in the previous 
7 days of treatment 
4. 30% responder rate, based on the proportion of subjects achieving ≥ 30% reduction in mean 
NPRS from baseline to the end of 4 weeks treatment in each treatment period 
5. 50% responder rate, based on the proportion of subjects achieving ≥ 50% reduction in mean 
NPRS from baseline to the end of 4 weeks treatment in each treatment period 
6. Maximum change in mean NPRS from baseline after 1, 2, 3 or 4 weeks treatment in each 
treatment period 
7. Change in functioning from baseline to the end of 4 weeks treatment in each treatment period, 
as measured by the BPI interference scale 
8. Change in pain characteristics and intensity from baseline to the end of 4 weeks treatment in 
each treatment period, as assessed by the SF-MPQ-2  
9. Change in neuropathic pain symptoms from baseline to the end of 4 weeks treatment in each 
treatment period, as assessed by NPSI 


 
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10. Change in emotional functioning from baseline to the end of 4 weeks treatment in each 
treatment period, as assessed by the BDI-II 
11. PGIC at the end of each four week treatment period 
12. Paracetamol (rescue medication) use per week over each treatment period compared with the 
preceding baseline 
7.3 Safety Endpoints 
1. Physical examinations and vital signs 
2. ECG 
3. Clinical chemistry and haematology analyses 
4. Urinalysis 
5. Number and type of Treatment Emergent Adverse Events (TEAEs), including serious adverse 
events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) 
6. Concomitant medications 
7.4 
Pharmacokinetic endpoints 
1. Pharmacokinetic parameters: Cmax, Tmax, AUC0-inf in each treatment period, after a single dose 
and at the end of four weeks treatment in PK subjects  
7.5 
Exploratory endpoints 
1. Association between change in mean NPRS from baseline to the end of four weeks treatment 
and selected subject baseline characteristics, including clinical diagnosis and pre-treatment 
QST parameters 
2. Change from baseline in specified QST parameters (WDT, MPS, HPT) to the end of 4 weeks 
treatment, in each treatment period 
3. Correlation between plasma LAT8881 concentration and the change in mean NPRS from 
baseline to the end of four weeks treatment in PK subjects 
4. Change in mean NPRS score from baseline to the last week of each treatment period, after 
omission of subjects with the 25% most variable first baseline NPRS scores 
8 Statistical Methods 
Efficacy endpoints will be summarized in a descriptive manner and analyzed using statistical methods 
described in section 11.7. The level of significance for statistical tests will be 0.05 and all tests will be 
two-sided. All p-values will be displayed to four decimal places, with p-values less than 0.0001 
presented as '<0.0001' and p-values greater than 0.9999 presented as ‘>0.9999’. All analyses will be 
done using SAS (version 9.4, SAS Institute Inc., Cary, NC, USA). 
Safety endpoints will be summarised in a descriptive manner.  
Continuous data will be reported using the following descriptive statistics:  
1. Number of observations (n) 


 
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2. Mean and standard deviation (SD) 
3. Minimum (min) and maximum (max)  
4. Median 
Minimum and maximum values will be reported to the precision of the endpoint reported with 
maximum of three decimal places; the mean will be presented with one decimal place more and the 
standard deviation two decimal places more than the precision of the endpoint reported. Categorical 
data will be presented using frequency (n = number of subjects; m = number of events) and percentage 
(%).  
Listings will be provided for all data recorded in eCRF to study subject profiles. All listings will be sorted 
by treatment sequence, subject ID, study period and date (if applicable). Unscheduled visit data will 
only be listed and not included in summaries.  
8.1 Handling Missing/Incomplete Data 
For medications / adverse events, if start date is partial then the first day/first month will be imputed. 
If end date is partial then the last day/last month will be imputed. Medications/Adverse Events with 
missing year will be considered as concomitant/TEAE respectively (assuming worst case). If an AE 
started during the same month/year as first dose of IMP in period 1, then the date will be imputed as 
first IMP date and considered as TEAE (assuming worst case). 
Flags identifying the study period for the start/stop dates for prior/ concomitant medications and 
adverse events will be generated (see Sections 10.6, 10.9). Imputed dates will be used for analyses 
and collected dates recorded in database will be listed. 
The method for missing data imputation for the primary endpoint will be discussed during the blinded 
review meeting prior to database lock. 
8.2 Handling Outliers 
Laboratory results with modifiers will be analyzed with the maximum or minimum value defined 
without the modifiers. For example, a value of “<5” will be considered as “5” for summaries.  
8.3 Multiplicity Adjustment 
Since there is only one primary endpoint defined in the study as per the protocol, multiplicity 
adjustment is not required. Although, hypothesis tests for secondary and efficacy endpoints will be 
performed and caution must be taken when interpreting these results. Adjusted p-values using 
Bonferroni method may be derived for post-hoc analyses if deemed necessary. 
9 Analysis Populations 
Membership of the analysis populations will be reviewed and finalized during the blind review of 
the data conducted prior to database lock. 
9.1 Full Analysis Set 
The Full Analysis Set (FAS) consists of all subjects enrolled and randomised into the study. The FAS 
population will be used for summaries of subject disposition, demographic and baseline characteristics.  


 
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Subjects will be analysed according to the treatment group they were assigned at randomisation. 
9.2 Per protocol population 
The Per Protocol (PP) population will include all subjects who received at least one dose of IMP and 
excludes subjects with <80% treatment compliance or who have other major protocol deviations 
impacting the study endpoints. Deviations for exclusion from the PP population due to inadequate 
exposure to IMP or completeness of primary efficacy endpoint will be determined during blinded 
review meeting. Per-protocol population will be defined for each study period separately. 
The PP population is the primary population to analyse efficacy endpoints. Demographic and baseline 
characteristics of the PP population will also be presented. 
9.3 Safety population 
The safety population consists of all randomised subjects 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. Subjects will be analysed as treated, regardless of the randomised treatment 
assigned, if this differs from that to which the subject was randomised. 
9.4 QST population 
The QST population will include all subjects who received at least one dose of IMP, had Quantitative 
sensory testing at pre-dose and post-dose in at least one of the study periods for one of the 
parameters: Warm Detection Threshold (WDT), Mechanical Pain Sensitivity (MPS) and Heat Pain 
Threshold (HPT).  
10 Analysis Variables 
10.1 
Population Flags 
Population flags will be finalized and authorized by the Study Statistician and Sponsor during the blind 
review meeting prior to database lock as per definitions provided in Section 9. These flags will be 
included in the analysis datasets. 
10.2 
Treatment  
The following treatment variables along with corresponding numeric equivalents will be included as 
core variables in all analysis datasets: 
• Planned / Actual Treatment Sequence : LAT8881 60 mg-Placebo, Placebo-LAT8881 60 mg • 
Planned / Actual Treatment: LAT8881 60 mg, Placebo  
10.3 
Visits 
Analysis visits will be defined as follows within each study period: 
Visit as per Protocol 
Study Period 
Analysis Visit 
Visit 1 (Days -28 to -1) 
Pre-Treatment 
Screening 


 
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Day 1, Visit 2 
Period 1 
Visit 2/Visit 5 
Day 14, Visit 3 
Period 1 
Visit 3/Visit 6 
Day 28, Visit 4 
Period 1 
Visit 4/Visit 7 
Day 50, Visit 5 
Period 2 
Visit 2/Visit 5 
Day 63, Visit 6 
Period 2 
Visit 3/Visit 6 
Day 77, Visit 7 
Period 2 
Visit 4/Visit 7 
Day 91, Visit 8 or Early Termination 
- 
EOS / Early Termination 
For NPRS scores, post-baseline summaries will be based on weeks within study: 
• 
Week 1 (Days 1-7 and 50-56) 
• 
Week 2 (Days 8-14 and 57-62) 
• 
Week 3 (Days 15-21 and 63-69)  
• 
Week 4 (Days 22-28 and 70-76)  
Timepoints will be included for NPRS data as ‘Pre-dose’ and ‘X hours post-dose’ for subjects with 
measurements taken at timepoints. NPRS will be derived using diary scores as detailed in Section 
10.15. 
10.4 
Study Periods 
Duration between initial screening and end of first treatment (Days -28 to 28) is considered as study 
period 1; washout (Days 29 to 42) is considered as washout period; duration between second 
baseline period up to end of study visit (Days 43 to 91) is considered as study period 2. Study periods 
will be considered to set analysis visits. 
10.5 
Completion Flags 
• 
Subjects are considered to have completed period 1 when Day 28 visit is completed. • 
Subjects are considered to have completed period 2 when Day 77 visit is completed. 
• 
Subjects are considered to have completed study when EOS at Day 91 visit is completed. 
10.6 
Prior and Concomitant Medications 
Medications that ended before first dose of IMP (LAT8881 or placebo) in the first treatment period are 
considered as prior medications. If medications are ongoing or they start on or after first dose of IMP 
(LAT8881 or placebo) they are considered concomitant. 
Medications that started on or after first dose of IMP in treatment period 1 or during wash-out will be 
counted in the first treatment period and allocated to the treatment received in treatment period 1.  


 
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Medications that started on or after first dose of IMP in treatment period 2 will be counted in the 
second treatment period and assigned to the treatment received in treatment period 2. If medication 
occurred in first study period and continued to second, it will be counted in both study periods (as 
‘New’ in period 1 and ‘Ongoing’ in period 2).  
Programming note for concomitant medications: 
• 
Period 1, Ongoing - if CM start date is prior to first dose of IMP in period 1 and end date is on 
or after first dose of IMP in period 1. 
• 
Period 1, New - if CM start date is on or after first dose of IMP and before first IMP date in 
period 2. 
• 
Period 2, Ongoing - medications that were new or ongoing in period 1, with end date on or 
after first IMP date in period 2. 
• 
Period 2, New - if CM start date is on or after first dose of IMP in period 2. 
Concomitant medications will either be flagged as "Ongoing" or "New" within a study period, but not 
in both. 
10.7 
Rescue Medications 
Rescue medications will be flagged for analysis. Additionally, cumulative dose in milligrams (mg) will 
be calculated within each study period. If a subject has ongoing rescue medication in both study 
periods, then the cumulative dose within each study period will be calculated. 
10.8 
Medical History and Concurrent Diseases 
Medical history with an end date prior to first dose of IMP in the first treatment period is considered 
as medical history, and those that are ongoing on and after first dose of IMP are considered as 
concurrent diseases.  
10.9 
Adverse Event Flags 
Treatment emergent adverse event (TEAE) flags will be marked for adverse events if they occurred or 
worsened on or after the first administration of IMP in the first study period. Adverse events occurring 
during screening and first baseline period will not be considered as TEAEs.  
If the events cannot be determined as TEAE due to partial dates, then the worst case will be considered 
and they will be flagged as TEAE in the respective study period based on AE start date. 
Related Adverse Events will be flagged for Possibly, Probably and Definitely Related adverse events. 
Adverse events that started on or after first dose of IMP in treatment period 1 or during wash-out will 
be counted in the first treatment period and allocated to the treatment received in treatment period 
1.  AEs that commenced on or after first dose of IMP in treatment period 2 will be counted in the 
second treatment period and assigned to the treatment received in treatment period 2. If an adverse 
event occurred in first period and continued to second period, it will be counted in both study periods 
(as ‘New’ in period 1 and ‘Ongoing’ in period 2). If AEs have same month/year as IMP date, then the 


 
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decision regarding whether to consider them as ‘Ongoing’ or ‘New’ within the period will be decided 
in the blinded review meeting. 
Suspected unexpected serious adverse events (SUSARs) will be flagged by the Sponsor and included in 
analyses datasets. 
Programming note for adverse events: 
• 
Period 1, Ongoing - if AE start date is prior to first dose of IMP in period 1 and end date is on 
or after first dose of IMP in period 1. 
• 
Period 1, New - if AE start date is on or after first dose of IMP and before first IMP date in 
period 2. 
• 
Period 2, Ongoing - AEs that were new or ongoing in period 1, with end date on or after first 
IMP date in period 2. 
• 
Period 2, New - if AE start date is on or after first dose of IMP in period 2. 
Adverse events will either be flagged in "Ongoing" or "New" within a study period, but not in both. 
10.10 Laboratory Assessments 
Laboratory results marked as clinically significant will be categorized as, “Abnormal, CS” and results 
marked as not clinically significant will be categorized as, “Abnormal, NCS”. Results within normal 
range will be marked as “Normal”. Not done results will be categorized as, “Not Done”.  
If repeat assessments are taken within the same scheduled visit/date, then the latest assessment will 
be considered for analysis. All laboratory parameters will be reported in SI units. 
10.11 painDETECT Questionnaire 
The PD-Q total scores (range -1 to 38) indicating a neuropathic pain component will be categorized as 
follows: <12 = Unlikely, 13-18 = Uncertain, >19 = Likely 
10.12 Baseline 
10.12.1 
Safety Endpoints 
For safety endpoints, latest measurement taken prior to Day 1 dosing in the first study period will be 
considered as baseline for both study periods. 
10.12.2 
Efficacy Endpoints 
Baseline will be derived for efficacy endpoints within each study period: 
• 
Period 1 baseline:  
• 
NPRS score: Mean of the last five available ratings of daily pain recorded in baseline 
period 1. 


 
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• 
NPRS score with timepoints: For subjects with NPRS collected at timepoints in baseline 
and week 4 visits, baseline will be defined as the pre-dose assessment at the 
respective visit. 
• 
Secondary Efficacy endpoints: Latest measurement taken prior to Day 1 dosing.  
• 
Period 2 baseline:  
• 
NPRS score: Mean of the last five available ratings of daily pain recorded in baseline 
period 2. If there are less than 5 ratings in baseline period 2, then baseline from period 
1 will be considered. 
• 
NPRS score with timepoints: For subjects with NPRS collected at timepoints in baseline 
and week 4 visits, baseline will be defined as the pre-dose assessment at the 
respective visit. If pre-dose assessment is missing, then pre-dose assessment from the 
respective visit in period 1 will be considered. 
• 
Secondary Efficacy endpoints: Latest measurement taken on/after Day 43 and prior 
to Day 50 dosing. If baseline measurement is missing in period 2, then baseline from 
period 1 will be considered. 
10.13 Change from Baseline 
Change and % Change between Baseline and post-baseline result will be calculated for all efficacy and 
safety endpoints within each study period as below: 
• 
Change = Result at Day x – Baseline Result 
• 
% Change = 
x100 
When baseline NPRS score = 0, % change from baseline will be calculated using an imputed value of 
0.1 at baseline. The range of the NPRS score is 0-10; an imputed value of 0.1 is deemed small enough 
to be close to zero for percentage change calculations. This imputation will not be included in absolute 
or change from baseline results. 
For subjects with NPRS collected at timepoints in baseline and week 4 visits, change and % change 
from baseline will be calculated using pre-dose values for timepoints 0.5, 1, 2, 4, 6 hours at each visit.  
10.14 Treatment Compliance 
The following parameters will be derived within each study period for treatment compliance 
summaries: 
• 
Total dose administered = number of dose administered days * 60 mg 
• 
Total dose assigned = 28 days * 60 mg 
Total dose administered & assigned will only be calculated for LAT8881 group, and will be 
identified as ‘-‘ for Placebo group. 


 
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• 
Treatment compliance (%) = 
 *100 
Total number of capsules = number of dose administered days * 2 (2 capsules per day, 30 mg each) 
• 
Treatment Duration (days) = (Date of Last Dose – Date of First Dose) + 1 
10.15 Efficacy Endpoints 
10.15.1 
NPRS Mean Scores 
NPRS mean daily score ranging from 0 (no pain) to 10 (worst imaginable pain) will be derived at 
baseline and weeks 1 to 4 for each treatment period. Baseline mean score is defined in Section 10.12.2. 
The mean daily pain score each week during treatment is the arithmetic mean of the last 5 available 
ratings of daily pain recorded in each 7 day period within each treatment period. Standard deviations 
(SD) of the mean scores will be included in analyses datasets. If a subject has <5 non-missing ratings, 
the mean score will be set to missing for the respective week. 
10.15.2 
Short form BPI 
Short form BPI total mean score ranging from 0 (does not interfere) to 10 (completely interferes) is 
the arithmetic mean of seven items. No correction will be done for missing data if the subject has 
omitted a few items. Mean scores will be calculated on the available items. 
10.15.3 
SF-MPQ-2  
SF-MPQ-2 total mean score is the arithmetic mean of available scores ranging from 0 (no pain) to 10 
(worst imaginable pain). No correction will be done for missing data if the subject has omitted a few 
items. Mean scores will be calculated on the available items.  
10.15.4 
NPSI 
NPSI total score is the sum of the scores of the 10 descriptors ranging from 0 (no pain) to 100 (worst 
imaginable pain). The total score will not be calculated if data is missing in at least one of the 
subscales. 
10.15.5 
BDI-II 
BDI-II total score is the sum of the scores of the 21 items ranging from 0-63. The total score will not 
be calculated if data is missing in at least one of the subscales. Total score of 0–13 is considered 
minimal range, 14–19 is mild, 20–28 is moderate, and 29–63 is severe. 
10.16 Analysis Flags 
10.16.1 
Responder 
Subjects achieving > 30% and > 50% reduction in mean NPRS score from baseline to the end of 4 weeks 
treatment in each study period will be separately flagged for analysis. Subjects who achieved the 
reduction will be flagged as ‘1’ and who did not will be flagged as ‘2’. 


 
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10.16.2 
Maximum Reduction 
For NPRS scores, maximum reduction from baseline (that is, maximum negative change from baseline) 
for a subject within each study period will be flagged. Time to maximum change in days and week at 
which maximum reduction was attained will be included. 
10.16.3 
Baseline NPRS Variability 
Baseline NPRS mean score will be recorded along with the respective standard deviations for each 
subject. Subjects will be sorted by SD (highest to lowest) for the first baseline results. Subjects having 
variability in quartiles 1 to 3 (i.e., 75%), will be flagged for analysis (i.e. subjects with the 25% most 
variable baseline results for treatment period 1 will be excluded). 
11 Statistical Analyses 
Summaries will be based on treatment sequence for the following: 
• 
Subject Disposition 
• 
Demographic and Baseline Characteristics 
• 
Prior Medications 
• 
Medical / Surgical History 
“Total” columns will be included in these summaries. For all other analyses, summaries will be based 
on treatment overall and within study periods. 
Following conventions will be used for the choice of treatment sequence / group in summaries: 
• 
FAS Population – Planned treatment sequence / group 
• 
Safety Population – Actual treatment sequence / group 
• 
Per-protocol Population – Actual treatment sequence / group 
• 
QST Population – Actual treatment sequence / group 
Analysis of Plasma concentration and Pharmacokinetic data will be done separately, and not included 
in this Statistical Analysis Plan. 
11.1 
Subject Disposition 
Following categories will be summarized in subject disposition table: 
• 
Subjects enrolled (who met all the inclusion criteria and none of the exclusion criteria) – 
frequency (n) 
• 
Subjects in FAS population – frequency (n)  
• 
Subjects in Safety Population – frequency (n) and percentage (%) based on FAS 
• 
Subjects in Per-Protocol Population – frequency (n) and percentage (%) based on FAS 


 
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• 
Subjects in QST Population – frequency (n) and percentage (%) based on FAS 
• 
Subjects completed the study, subjects who attended each visit within each study period 
frequency (n) and percentage (%) based on FAS  
• 
Subjects who terminated the study along with reasons - frequency (n) and percentage (%) 
based on FAS 
• 
Study duration in days – n, mean and standard deviation, median, minimum, maximum 
Note that FAS population will be displayed by planned treatment sequence and all other categories 
will be displayed by actual treatment sequence. Reasons for discontinuation will be sorted by 
descending order of frequency within the “Total” column. 
In DDP: Table 14.1.1.1 
Subject disposition, analysis populations, status of inclusion/exclusion criteria, subjects excluded from 
analysis population along with reasons and unblinding details will be listed by subject. In DDP: Listing 
16.2.1.1, Listing 16.2.1.2, Listing 16.2.1.3 and Listing 16.2.3.1 
11.2 
Protocol Deviations 
Number and percentage of subjects with any deviation and number of deviation events will be 
summarized by treatment within each study period. The same will be sub-classified by category 
(major/minor) and description as follows: 
• 
Inclusion / Exclusion 
• 
Investigational Product 
• 
CCMeds 
• 
Lab 
• 
Visit Schedule 
• 
Procedures / Tests 
• 
Randomisation 
• 
Safety Reporting 
• 
Protocol Specific Discontinuation Criteria 
• 
Other 
Deviation categories will be displayed in the descending order of frequency of total number of 
deviations in LAT8881 group (both study periods). Percentages will be based on Safety population. 
Protocol deviations occurring between screening and washout periods will be counted in Period 1, and 
those occurring between second baseline period until follow-up will be counted in Period 2. 
In DDP: Table 14.1.2.1 


 
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Protocol deviations will be listed by subject.  
In DDP: Listing 16.2.2.1 
11.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment sequence. Categorical and 
continuous variables will be provided in the same table. The following variables will be presented: age 
(years), sex, ethnicity, race, childbearing potential, neuropathic pain history (PHN or DPN), PD-Q 
(scores and categories). The latest non-missing PD-Q results will be included in this summary. 
Percentages for childbearing potential will be based only on the female population. The summary will 
be repeated for FAS, safety, per protocol and QST populations (as per ICH E3 Guidelines). In DDP: Table 
14.1.3.1 to Table 14.1.3.4  
Subject demographics, neuropathic pain history and PD-Q scores and categories will be listed by 
subject.  
In DDP: Listing 16.2.4.1, 16.2.4.3, 16.2.4.4 
11.4 
Medical History and Concurrent Diseases 
The number and percentage of subjects with any medical history and number of mentions will be 
summarized by treatment sequence. The summaries will be provided by body system class. Body 
system class will be displayed in the descending order of frequency of number of mentions in “Total” 
column. Percentages will be based on the safety population. The summary will be repeated for 
concurrent diseases. 
In DDP: Table 14.1.4.1, Table 14.1.4.2  
Medical history and concurrent diseases will be listed by subject and body system. In 
DDP: Listing 16.2.4.2 
11.5 
Prior and Concomitant Medications 
The number and percentage of subjects who have taken any prior medication and number of mentions 
will be summarized by treatment sequence. Medications will be classified by Therapeutic Main group 
(ATC Level 2) and Chemical Subgroup (ATC Level 4). The therapeutic main group and chemical 
substance group will be displayed in the descending order of frequency of total number of mentions 
in LAT8881 group (both study periods). Medications will be coded using the World Health 
Organization’s Drug-Dictionary (WHODD) version March 2019 or later. The summary will also be 
presented for concomitant medications by treatment overall and within each study period separately. 
The summary by treatment overall will only include both ‘Ongoing’ and ‘New’ medications within each 
treatment and counted once in ‘Total’ column. Percentages will be based on the safety population. 
In DDP: Table 14.1.5.1, Table 14.1.5.2.1, Table 14.1.5.2.2 
Prior and Concomitant medications will be listed by subject and therapeutic subgroup. Use of 
prohibited medications will be recorded as protocol deviations and will be listed in 16.2.2.1. 


 
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In DDP: Listing 16.2.4.5 
11.5.1 Rescue Medications 
Number and percentage of subjects who have taken any rescue medication will be summarized 
along with cumulative dose (mg) taken by treatment overall and within each study period. Extent of 
further analyses of rescue medications will be decided during the blinded review meeting. 
Rescue medication will be listed by subject. In 
DDP: Table 14.1.5.3, Listing 16.2.4.6 
11.6 
Efficacy Analyses 
All Efficacy summaries will be based on the Per-Protocol population and repeated for the FAS 
population. 
11.6.1 Primary Efficacy analyses – Mean daily NPRS scores 
11.6.1.1 Descriptive summary 
Descriptive summaries of NPRS mean scores, absolute change and % change from baseline results will 
be presented by treatment overall and within each study period. Visits to be included in this table are: 
Visit 2/5 (Baseline), Weeks within Study period: Week 1, Week 2, Week 3, Week 4. The summary will 
be repeated for Per-Protocol and FAS populations. 
Daily NPRS scores, mean scores and standard deviation, absolute change and percentage change for 
each week will be listed for all enrolled subjects.  
In DDP: Table 14.2.1.1 to 14.2.1.2, Listing 16.2.6.1.1, Listing 16.2.6.1.2 
11.6.1.1.1 
NPRS at timepoints 
For per-protocol subjects with NPRS collected at timepoints in baseline and week 4 visits, descriptive 
summaries of NPRS mean scores, absolute change and % change from baseline results will be 
presented by study period and total including timepoints 0.5, 1, 2, 4 and 6 hours after the dose of IMP 
at Visit 2/Visit 5 and Visit 4/Visit 7.  
In DDP: Table 14.2.1.3 
11.6.1.2 Mixed Effect Regression Model 
A mixed effects regression model using a covariance pattern will be fitted to the absolute change from 
baseline mean NPRS scores at weeks 1, 2, 3 and 4 within each treatment period for the PP population. 
This analysis will provide the results for the primary efficacy endpoint (change from baseline to week 
4) and for the secondary endpoint (change from baseline to weeks 1, 2 and 3). 
The model will have fixed effects for period, week, treatment and the interaction between week and 
treatment. Baseline mean pain score within each period by treatment combination will be included as 
a covariate. A random effect for subject will be included to capture the repeated measures nature of 
the design. 


 
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Least squares means and corresponding 95% confidence intervals (CI) will be presented for the mean 
change from baseline for LAT8881, Placebo and difference between LAT8881 vs. placebo at each visit.  
P-values for testing the null hypothesis that the difference in least squares means between LAT8881 
and placebo at each visit is 0 will be declared statistically significant if the p-value < 0.05. 
The covariance pattern will take into account the covariance between observations in different 
treatment periods and the covariance between observations within the same period (i.e between 
weeks). 
SAS program - MMRM: 
proc mixed data=<input>; 
class <subject> <study period> <treatment> <week>; model 
<change> = <baseline> <study period> <week> <treatment>; 
random <subject> <subject>*<period>; lsmeans <treatment> 
<week> / pdiff;   
run; 
The model will also be fitted to the absolute change from baseline in mean NPRS ratings for the FAS 
population. Extent of senstivity analyses of missing data patterns to be undertaken will be decided 
during the blinded review meeting. In DDP: Tables 14.2.2.1 to 14.2.2.2 
11.6.1.2.1 
NPRS at timepoints 
A mixed effects regression model using a covariance pattern will be fitted to the absolute change from 
pre-dose NPRS scores at timepoints 0.5, 1, 2, 4 and 6 hours post-dose at baseline and week 4 visits 
within each study period for the per-protocol subjects with NPRS collected at timepoints in baseline 
and week 4 visits.  
The model will have fixed effects for period, week, timepoint and the interaction between week and 
timepoint. Pre-dose pain score within each week will be included as a covariate. A random effect for 
subject will be included to capture the repeated measures nature of the design. 
Least squares means and corresponding 95% confidence intervals (CI) will be presented for the mean 
change from pre-dose for each timepoint at each visit. P-values for testing the null hypothesis that the 
difference in least squares means across timepoints at each visit will be declared statistically 
significantd if the p-value < 0.05.  
The covariance pattern will take into account the covariance between observations in different 
treatment periods and the covariance between observations within the same period (i.e between 
weeks). 
SAS program - MMRM: 
proc mixed data=<input>; 
class <subject> <timepoint> <week>; model 
<change> = <baseline> <week> <timepoint>; random 
<subject> <subject>*<week>; lsmeans <timepoint> 
<week> / pdiff;  run; 
In DDP: Tables 14.2.2.3 


 
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11.6.2 Secondary Efficacy analyses 
11.6.2.1 Percentage change from baseline in mean NPRS scores  
The mixed effects regression model fitted to the absolute change from baseline in mean NPRS scores 
will be fitted to the percentage change from baseline in mean NPRS scores for both the PP and FAS 
populations. No sensitivity analyses of missing data patterns will be undertaken. 
In DDP: Tables 14.2.2.1 to 14.2.2.2 
11.6.2.2 Responder analysis  
Number and percentage of subjects achieving >30% and >50% reduction in NPRS mean scores at the 
end of each treatment period (week 4) will be summarized. Proportions of responders will be 
compared between LAT8881 vs. Placebo across study periods using McNemar’s test. P-values for 
testing the null hypothesis that there is no difference between LAT8881 and placebo will be 
reported. 
SAS program – McNemar’s Test: 
proc freq data = <input>; 
table 
<responder>*<treatment>; 
exact mcnem; weight 
<subject>; 
run; 
All analyses mentioned above will be repeated for Per-Protocol and FAS Populations. 
In DDP: Table 14.2.3.1 to 14.2.3.2 
11.6.2.2.1 
Mixed Effects Logistic Regression 
A mixed effects logistic regression model, including fixed effect terms study period and treatment and 
random effect term  subject ID will be used to assess the odds of achieving a >30% and >50% reduction 
in NPRS mean scores at the end of each treatment period (week 4) with LAT8881 compared to placebo. 
This will be repeated for Per-Protocol and FAS Populations. 
SAS program - Logistic: 
proc glimmix data=<input>; 
class <subject> <study period> <treatment> ; model 
<response> (event=’1’) = <study period> <treatment> 
/ dist=binary link=logit oddsratio; 
random / subject=<subject> ; 
run; 
In DDP: Table 14.2.3.3, 14.2.3.4 


 
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11.6.2.3 Maximum change from baseline  
Maximum reduction from baseline in NPRS mean scores will be summarized. Number and percentage 
of subjects will be summarized for the week at which maximum reduction from baseline in NPRS mean 
scores was reached by treatment overall and within each study period. This will be repeated for Per 
Protocol and FAS populations. 
In DDP: Table 14.2.4.1 to 14.2.4.2 
11.6.2.3.1 
Mixed Effects Regression Model 
Mixed effects regression models will be used to compare the maximum reduction from baseline in 
NPRS mean scores. The model will have fixed effects for period and treatment. Baseline score within 
each period by treatment combination and time taken to reach maximum reduction will be included 
as covariates. A random effect for subject will be included to capture the repeated measures nature 
of the design. Least squares mean changes from baseline and corresponding 95% CI will be presented 
for LAT8881, Placebo and the difference between LAT8881 vs. placebo overall. The null hypothesis 
that the difference in least square mean changes from baseline between LAT8881 and placebo across 
study periods is 0 will be tested. Statistical significance will be declared if the p-value for the difference 
between treatments < 0.05. In DDP: Table 14.2.4.3, 14.2.4.4 
SAS Program – MMRM: 
proc mixed data=<input>; 
class <subject> <study period> <treatment>;  
model <maximum reduction> = <baseline> <study period> <treatment> <time  
to maximum reduction>; 
random <subject> <subject>*<period>; 
lsmeans <treatment>/ pdiff;   
run; 
11.6.2.4 Patient reported outcomes 
Patient Reported outomes: BPI, SF-MPQ-2, NPSI, BDI-II, PGIC will be considered for secondary efficacy 
analyses. All analyses will be repeated for Per-protocol and FAS populations. 
11.6.2.4.1 
Descriptive Summaries  
Descriptive summaries of patient reported outcomes (BPI, SF-MPQ-2, NPSI, BDI-II) and absolute 
change from baseline results will be presented by treatment overall and within each study period. 
Visits to be included in this table are: Baseline, Week 4.  
Descriptive summaries as well as number and percentage of subjects reporting each of the 
categories in PGIC scale (1 - Substantially worse, 2 - Moderately worse, 3 - Slightly worse, 4 - No 
change, 5 - Slightly improved, 6 - Moderately improved, 7 - Substantially improved) will be 
summarized by treatment overall and within each study treatment period. 
The summaries will be repeated for Per-Protocol and FAS populations. 
In DDP: Tables 14.2.5.1, 14.2.5.2, 14.2.6.1, 14.2.6.2, 14.2.7.1, 14.2.7.2, 14.2.8.1, 14.2.8.2, 14.2.9.1, 
14.2.9.2 


 
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All patient reported outcomes will be listed.  
In DDP: Listing 16.2.6.2 to 16.2.6.6 
11.6.2.4.2 
Mixed Effects Regression Model 
Mixed effects regression models will be used to compare the absolute change from baseline to week 
4 for the patient reported outcomes (BPI, SF-MPQ-2, NPSI, BDI-II, PGIC). The models will have fixed 
effects for period and treatment. Baseline score within each period by treatment combination will be 
included as a covariate for all endpoints except PGIC. A random effect for subject will be included to 
capture the repeated measures nature of the design. Least squares mean changes from baseline and 
corresponding 95% CI will be presented for LAT8881, Placebo and the difference between LAT8881 vs. 
placebo overall. The null hypothesis that the difference in least square mean changes from baseline 
between LAT8881 and placebo across study periods is 0 will be tested. Statistical significance will be 
declared if the p-value for the difference between treatments < 0.05. 
In DDP: Tables 14.2.5.3, 14.2.5.4, 14.2.6.3, 14.2.6.4, 14.2.7.3, 14.2.7.4, 14.2.8.3, 14.2.8.4, 14.2.9.3,  
14.2.9.4 
SAS program - MMRM: 
proc mixed data=<input>; 
class <subject> <study period> <treatment>; model 
<change> = <baseline> <study period> <treatment>; 
random <subject> <subject>*<period>; lsmeans 
<treatment>/ pdiff;   
run; 
Note that, PGIC will not have <baseline> in the model statement. 
11.6.2.5 NPRS and baseline covariates 
The mixed effects linear regression model will be repeated for the change from baseline in NPRS 
scores by including additional covariate: clinical diagnosis (PHN, DPN). Further analyses will be 
decided and performed in a post-hoc manner post database lock. 
In DDP: Table 14.2.10.1 
11.6.3 Exploratory Analyses 
11.6.3.1 QST Parameters 
Descriptive summaries of average QST results for parameters WDT, MPS and HPT will be presented 
by study period at Baseline and week 4 visits for test and control areas. This summary will be based 
on QST Population. 
QST assessments will be listed by subject. 
In DDP: Table 14.2.11.1, Listing 16.2.6.7 
11.6.3.1.1 
Mixed Effects Regression Model 


 
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Mixed effects regression models will be used to compare the absolute change from baseline to week 
4 for the QST parameters (WDT, MPS and HPT). Only test areas (active sites) will be considered for this 
analyses. The models will have fixed effects for period and treatment. Baseline score within each 
period by treatment combination will be included as a covariate. A random effect for subject will be 
included to capture the repeated measures nature of the design. Least squares mean changes from 
baseline and corresponding 95% CI will be presented for LAT8881, Placebo and the difference between 
LAT8881 vs. placebo overall. The null hypothesis that the difference in least square mean changes 
from baseline between LAT8881 and placebo across study periods is 0 will be tested. Statistical 
significance will be declared if the p-value for the difference between treatments < 0.05. This model 
will be based on QST population. See Section 11.6.2.4.2 for SAS program. 
In DDP: Table 14.2.11.2 
11.6.3.2 NPRS and baseline variability 
The model fitted to the change from baseline mean NPRS scores will be repeated by excluding 
subjects with highly variable baseline NPRS mean scores in first study period for Per-Protocol and 
FAS populations.  
In DDP: Table 14.2.12.1 to 14.2.12.2 
11.7 
Safety Analyses 
All safety summaries will be based on the Safety population Screening visits will not be included in 
summaries, and will only be listed. Baseline measurements will be summarized under ‘PreTreatment’ 
for all safety summaries. EOS / Early Termination visits will be summarized in ‘Total’ within last 
treatment taken. 
11.7.1 Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.0 or later. 
11.7.1.1 Overall Adverse Events 
The number and percentage of subjects and number of events will be summarized by treatment 
overall and within each study period for the following categories: 
1. All adverse events reported 
2. Treatment emergent adverse events (TEAEs) 
3. Serious adverse events 
4. Serious treatment-emergent adverse events 
5. Related treatment-emergent adverse events 
6. Related treatment-emergent serious adverse events 
7. Suspected unexpected serious adverse events (SUSARs) 


 
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8. Treatment-emergent adverse events led to death 
9. Treatment-emergent adverse events led to study discontinuation 
In DDP: Table 14.3.1.1.1, Table 14.3.1.1.2 
The summary by treatment overall will only include ‘New’ events within each treatment. All adverse 
events will be listed by subject, system organ class and preferred term sorted by event start dates.  
In DDP: Listing 16.2.7.1 to 16.2.7.5 
11.7.1.2 Summary of Adverse Events by SOC and PT 
The number and percentage of subjects and number of events will be summarized by treatment 
overall and within each study period, system organ class and preferred terms. The summary by 
treatment overall will only include both ‘Ongoing’ and ‘New’ AEs within each treatment and counted 
once in ‘Total’ column. Percentages will be based on the safety population. System organ class and 
preferred term will be displayed in the descending order of frequency of total number of events in 
LAT8881 group (both study periods). 
The same will be for treatment-emergent AEs, treatment-emergent related AEs, treatment-emergent 
serious AEs and treatment-emergent related serious AEs. In DDP: Table 14.3.1.2.1 to Table 14.3.1.5.2 
11.7.1.3 Summary of Adverse Events by SOC, PT and Severity 
The number and percentage of subjects and number of events in each system organ class, preferred 
term and severity (Grades 1-5) will be summarized by treatment overall and within each study period 
for treatment-emergent adverse events. Adverse events that are possibly, probably, definitely related 
and unrelated will be displayed in columns. System organ class and preferred term will be displayed 
in the descending order of frequency of total number of events in LAT8881 group (both study periods). 
In DDP: Table 14.3.2.1.1, Table 14.3.2.1.2 
11.7.2 Laboratory Assessments 
11.7.2.1 Continuous Summary 
Descriptive summaries of the absolute result and change from baseline in laboratory data will be 
presented by treatment overall and within each study period, parameter and visit for the safety 
population. Each laboratory category (haematology, clinical chemistry, liver function tests, 
coagulation, urinalysis) will be represented in separate tables. Both categorical and continuous results 
will be presented in the same table for urinalysis. 
In DDP: Table 14.3.4.1 to Table 14.3.4.5 
11.7.2.2 Shift Summary 
Shift in laboratory result interpretations (Normal, Abnormal Not CS and Abnormal CS) will be 
summarized by treatment within each study period and overall, parameter and visit. Each category 
(haematology, clinical chemistry, liver function tests, coagulation) will be represented in separate 
tables. Percentages will be based on safety population. 


 
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In DDP: Table 14.3.4.6 to 14.3.4.9 
11.7.2.3 Listings 
All laboratory results will be listed for all subjects by treatment sequence, visit and parameter. Out of 
range results will be highlighted. Pregnancy results collected on Screening and Day 1 will be listed 
separately. 
In DDP: Listing 16.2.8.1 to 16.2.8.5, Listing 16.2.8.7 
Subjects with clinically significant laboratory results and subjects with out of range results will be 
separately listed by treatment sequence, category, visit and parameter. In DDP: Listing 16.2.8.6 
Parameters collected in each laboratory category are listed below. 
Category 
Parameters 
Haematology 
Haemoglobin, haematocrit, red blood cell count, white blood cell count 
with differential (neutrophils, lymphocytes, monocytes, basophils, 
eosinophils), platelet count, mean corpuscular haemoglobin, mean 
corpuscular volume, mean corpuscular haemoglobin concentration 
Clinical Chemistry 
Glucose, sodium, potassium, chloride, bicarbonate, calcium (corrected), 
creatinine, urea, uric acid, amylase, lipase, triglyceride, HDL-cholesterol, 
LDL-cholesterol, total cholesterol, total protein, lactate dehydrogenase, 
creatine kinase, C-reactive protein, albumin, phosphate. HbA1c will be 
measured in DPN subjects only and only at screening.  
Liver Function Tests 
Aspartate aminotransferase, alanine aminotransferase, gammaglutamyl 
transferase, alkaline 
phosphatase, conjugated bilirubin, total bilirubin 
Coagulation 
Activated partial thromboplastin time, international normalised ratio 
Urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, urobilinogen, 
bilirubin, nitrite, leukocytes. 
If 
urinalysis 
on 
dipstick 
is 
positive 
for 
leukocytes 
and/or 
blood/haemoglobin, a microscopic examination including erythrocytes, 
leucocytes, bacteria, casts, epithelial cells and crystals will be performed. 
Pregnancy 
Human chorionic gonadotropin levels (hCG) will be measured in blood 
samples from females of child-bearing potential at screening. Urine hCG 
will be measured on Day 1. 
11.7.3 Other Safety Analyses 
11.7.3.1 Extent of Exposure 
Continuous summary statistics will be displayed for duration of exposure in days, total IMP 
administered in mg and % compliance by treatment overall and within each study period. The 
summary will be based on the Safety population. In DDP: Table 14.1.5.4 


 
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IMP administration and compliance data will be listed by treatment sequence, subject and treatment 
period for safety population. In DDP: Listing 16.2.5.1 
11.7.3.2 Vital Signs 
Descriptive summaries of absolute results and change from baseline in vital signs will be presented by 
treatment overall and within each study period, parameter, visit and timepoint (if applicable) for 
safety population. Vital signs parameters include: weight (kg), BMI (kg/m2), systolic blood pressure 
(mmHg), diastolic blood pressure (mmHg), respiratory rate (breaths/min), heart rate (beats/min) and 
body temperature (oC). 
In DDP: Table 14.3.5.2  
Vital signs will be listed by treatment sequence, subject ID, treatment period and visit for safety 
population.  
In DDP: Listing 16.2.9.1 
11.7.3.3 Physical Examination 
Physical examination data will be listed by treatment sequence, subject, treatment period and visit 
only.  
In DDP: Listing 16.2.9.2 
11.7.3.4 Electrocardiogram Assessments 
Number and percentage of subjects with overall findings (Normal, Abnormal Not CS and Abnormal CS) 
will be summarized by treatment overall and within each study period and visit. Percentages will be 
based on safety population. 
In DDP: Table 14.3.6.1  
ECG findings will be listed by treatment sequence, subject ID, treatment period and visit.  
In DDP: Listing 16.2.9.3 
12 Changes to Planned Analyses  
• 
Mixed Effect Regression analyses for change from baseline in NPRS mean scores is combined 
for weeks 1-4 within the same model, instead of week 4 and weeks 1-3 separately as defined 
in study protocol.  
• 
McNemar’s test is included to compare proportion of subjects achieving >30% and >50% 
reduction in mean NPRS scores across study periods. 
• 
Analysis of covariance is included to see the effect of treatment and placebo in maximum 
reduction from baseline adjusting for baseline NPRS mean scores and time taken to reach 
maximum reduction. 
• 
Mixed Effect Regression analyses for change from baseline in NPRS mean scores including 
clinical diagnosis (PHN, DPN) and baseline QST parameters as additional covariates is 


 
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considered as secondary analyses instead of exploratory analyses since subgroups PHN and 
DPN were considered clinically relevant. 
• 
PK Analyses is not included in this Statistical Analysis Plan, and will be done separately. PK 
Population is replaced with Per-Protocol population for subjects with NPRS assessments 
taken at timepoints in baseline and Week 4 visits. 
 


 
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13 Index of Tables, Listings and Graphs 
Refer LAT-NP-001_Data Display Plan (Ver: 2.00) for the list of Tables, Listings and Graphs. 
14 References 
1. ICH. ICH Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials E9. 1998. 
2. ICH. ICH Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports E3. 
1995. 
 


 
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15 Appendices 
15.1 
painDETECT questionnaire 
The PD-Q consists of seven pain sensory symptom items (burning, tingling/prickling, light touching, 
sudden pain attacks/electric shock-type pain, cold/heat, numbness, slight pressure), one pain course 
pattern item, and one pain radiation item. From this questionnaire, a PD-Q total score, ranging from 
1 to 38 is calculated. A total score 19 indicates a neuropathic component is likely, 12 indicates a 
neuropathic component is unlikely and scores 13-18 are considered uncertain i.e. a neuropathic pain 
component can be present. The English version of the PD-Q is widely used and is reported to be 
reliable as a screening tool for neuropathic pain, although it has yet to be fully validated. 
15.2 
QST phenotype 
QST measurements will be undertaken by a researcher specifically trained in this procedure at sites 
which have experience in the technique. Three parameters will be tested: Warm Detection Threshold 
(WDT), Mechanical Pain Sensitivity (MPS) and Heat Pain Threshold (HPT). Tests will be undertaken at 
a painful dermatome in PHN subjects or at a painful peripheral site in DPN subjects. 
15.2.1 WDT 
A thermal sensory testing device is used, with a baseline temperature of 320C.The subject should feel 
this as neutral, i.e. neither hot nor cold. The temperature is then ramped continuously by 10C per sec 
and the subject is asked to press the stop button when they first perceive a warming of the skin. This is 
repeated a second and third time, each time starting with the thermode at the baseline temperature. 
The average threshold temperature of the three measurements is recorded. 
15.2.2 MPS 
The MPS uses a set of 7 pinprick stimulators with standardised stimulus intensities (8, 16, 32, 64, 128, 
256, and 512 mN) and contact areas (tip diameter 0.25 mm). The stimuli are applied in a balanced 
order and the painfulness of each stimulus recorded with a numeric rating scale from 0 to 100, with 0 
representing no pain and 100 corresponding to the individual s maximum pain imaginable. Each painful 
sensation will always have a value greater than 0. MPS is the geometric mean of all numerical ratings 
for pinprick stimuli. 
15.2.3 HPT 
The Heat Pain Threshold (HPT) uses the same device as for the WDT. In this test, the temperature is 
increased as before but this time the subject is asked to press the stop button as soon as the “warm” 
or 
hot” sensation changes its quality to an additional sensation of  burning”, 
stinging”, 
”drilling” or 
aching”. The procedure is repeated two more times and the mean threshold 
temperature is recorded. 
15.3 
Pain intensity 
15.3.1 NPRS 
The NPRS is an 11 point scale which grades pain from 0 (no pain) to 10 (worst pain imaginable). It is a 
recommended core outcome for the assessment of pain intensity in clinical trials of chronic pain 


 
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treatments. Subjects will be asked to rate the intensity of their average pain over the previous 24 
hours in a diary. Entries should be made at the same time each evening. 
15.4 
Patient reported outcomes 
15.4.1 Short form BPI 
The interference scale of the short form BPI has been recommended by international consensus as a 
core outcome measure of physical functioning in chronic pain clinical trials. It measures the 
interference of pain on seven items (general activity, mood, walking ability, work, relations with other 
people, sleep, enjoyment of life). Each scale is graded from 0 (does not interfere) to 10 (completely 
interferes). The result is the mean of the scores from the seven items. 
15.4.2 SF-MPQ-2  
The SF-MPQ-2 is a measure of both neuropathic and non-neuropathic pain, modified from the 
commonly used McGill Pain Questionnaire and Short-form McGill Pain Questionnaire. The SF-MPQ-2 
adds seven symptoms characteristic of neuropathic pain to the SF-MPQ and has response scales from 
0 to 10. 
15.4.3 NPSI 
The NPSI was designed specifically for the assessment of the different symptoms of neuropathic pain. 
It contains ten items related to different pain descriptors (e.g. burning, squeezing, electric-shock, 
stabbing, tingling), allowing the assessment of the different dimensions of neuropathic pain, and two 
items on frequency and duration of pain. Each pain descriptor is rated on an 11-point numeric rating 
scale from 0 (no pain) to 10 (worst imaginable pain). Total pain intensity score is calculated by the 
sum of the 10 descriptors. 
15.4.4 BDI-II 
The BDI-II consists of 21 items; each item is a list of four statements arranged in increasing severity 
about a particular symptom of depression. Each statement is scored from 0 to 3. Each of the 21 items 
is summed to give a single score for the BDI-II. 
15.4.5 PGIC 
The PGIC is a single-item rating by subjects of their improvement with treatment during a clinical 
trial. It asks the subject to rate their improvement with therapy on a 7-point scale ranging from very 
much worse to very much improved, with no change as the mid-point. 


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16 Change Log 
Version 
Authored by 
Change Date 
Change Details 
Reviewed by 
Review Date 
1.00 
Shweta, P 
09-Mar-2019 
Final draft for sponsor review 
Caro Badcock 
Judy Bingham 
14-Nov-2019 
2.00 
Shweta, P 
24-May-2020 
Amended to remove PK population and re-define analysis visits Caro Badcock 
Judy Bingham 
27-May-2020 
 
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