Conditions: Acute Migraine
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 21
Healthy volunteers: no

Brief summary:
This is a randomised, placebo controlled, double blind, crossover proof of concept study to investigate the efficacy and safety of oral LAT8881 in acute migraine, with or without aura.

Detailed description:
Subjects enrolled in the study will be randomised to receive investigational medicinal product (LAT8881 60 mg or placebo), to be taken at the onset (within one hour from the onset of pain) of a migraine headache of moderate to severe intensity \[Numeric rating scale greater than 4\]. Rescue medication should not be taken until at least 2 hours post dose. Subjects will be given a single dose of either active or placebo, to treat one migraine headache.

After treatment of one migraine headache (or a maximum 28 days) the subject will return to the clinic for re-evaluation and crossover to the second treatment. After treatment of one migraine headache in the second treatment period or a maximum of 28 days from commencement of the second treatment period, the subject will return to the clinic for re-evaluation. An End of study visit (telephone) will occur 7 days after the end of the second treatment period.

Arms:
arm 1: Subjects will be given two 30 mg capsules of the investigational medicinal product (LAT8881), and instructed to take both capsules within the first hour of the onset of a migraine of moderate to severe intensity. arm 2: Subjects will be given two capsules of placebo, and instructed to take both capsules within the first hour of the onset of a migraine of moderate to severe intensity.

Interventions: intervention 1: LAT8881 intervention 2: Placebo
Intervention descriptions: intervention 1: Two 30 mg capsules of LAT8881 intervention 2: Two capsules of placebo

Protocol document:
Prot_000.pdf: 
 
 
 
 
Official title: A proof of concept study of the efficacy and safety of 
oral LAT8881 in acute migraine 
 
 
NCT number: NCT04153409 
 
Document date: July 25, 2019 
 
 
 
 
 


Protocol number LAT-MIG-001 
Lateral Pharma Pty Ltd 
 
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Clinical study title 
A proof of concept study of the efficacy 
and safety of oral LAT8881 in acute 
migraine 
 
Protocol number 
LAT-MIG-001 
 
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 
Dr Louise Murdoch MBBS 
 
Version  
1.0 
 
Date  
25 July 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. 
 


Protocol number LAT-MIG-001 
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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 
Study monitor 
Molecule2Market (M2M) 
Ground Floor, 35 Cotham Road 
Kew, Victoria 3101 
Phone: +61 416 020 365 
Contact: Robin Hansen (Robin@molecule2market.com.au) 
Sponsor medical representative 
Jolanta Airey MD 
5 Portobello Place 
Wheelers Hill VIC 3150 Australia 
Phone: +61 409 020 209 
Email: jolanta.airey@sjaconsultant.com 
 


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Table of contents 
Protocol signatures .............................................................................................................................................. 2 
General study information .................................................................................................................................... 3 
List of figures ........................................................................................................................................................ 7 
List of abbreviations ............................................................................................................................................. 8 
1. 
Protocol synopsis .................................................................................................................................. 10 
2. 
Study schedule of assessments and procedures ................................................................................. 20 
3. 
Introduction and background information .............................................................................................. 21 
3.1 
Acute migraine ............................................................................................................................. 21 
3.2 
LAT8881 ...................................................................................................................................... 22 
3.2.1 
Non-clinical studies ...................................................................................................................... 22 
3.2.2 
Clinical studies ............................................................................................................................. 25 
4. 
Study objectives .................................................................................................................................... 27 
4.1 
Primary objective ......................................................................................................................... 27 
4.2 
Secondary objectives .................................................................................................................. 27 
4.3 
Exploratory objectives ................................................................................................................. 27 
5. 
Study design .......................................................................................................................................... 28 
5.1 
Overall study design .................................................................................................................... 28 
5.2 
Justification of study design......................................................................................................... 28 
5.3 
Justification of dose ..................................................................................................................... 29 
5.4 
Number of planned subjects ........................................................................................................ 29 
5.5 
Duration of study ......................................................................................................................... 29 
5.6 
Duration of subject participation .................................................................................................. 29 
5.7 
Withdrawal of subjects from study ............................................................................................... 29 
5.8 
Replacement of subjects ............................................................................................................. 30 
6. 
Study population .................................................................................................................................... 31 
6.1 
Inclusion criteria ........................................................................................................................... 31 
6.2 
Exclusion criteria ......................................................................................................................... 31 
6.3 
Contraception requirements ........................................................................................................ 32 
6.4 
Dietary, lifestyle and other restrictions ........................................................................................ 33 
7. 
Study treatments ................................................................................................................................... 34 
7.1 
Description ................................................................................................................................... 34 
7.2 
Formulation .................................................................................................................................. 34 
7.2.1 
LAT8881 capsules ....................................................................................................................... 34 
7.2.2 
Placebo capsules ........................................................................................................................ 34 
7.3 
Manufacturer ............................................................................................................................... 34 
7.4 
Storage ........................................................................................................................................ 34 
7.5 
Packaging and labelling ............................................................................................................... 34 
7.6 
Randomisation and blinding ........................................................................................................ 34 


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7.7 
Dispensing of investigational product .......................................................................................... 35 
7.8 
Method for assigning subject study number ................................................................................ 35 
7.9 
Accountability of study supplies .................................................................................................. 35 
7.10 
Doses and treatment regimens ................................................................................................... 35 
7.11 
Dose reduction/dose adjustments ............................................................................................... 35 
8. 
Treatment compliance ........................................................................................................................... 36 
8.1 
Unblinding .................................................................................................................................... 36 
8.1.1 
Medical emergency ..................................................................................................................... 36 
8.1.2 
End of study ................................................................................................................................. 36 
8.2 
Concomitant medications and treatments ................................................................................... 36 
8.2.1 
Prohibited medications ................................................................................................................ 36 
8.2.2 
Prohibited treatments .................................................................................................................. 37 
8.2.3 
Permitted medications ................................................................................................................. 37 
9. 
Study procedures .................................................................................................................................. 38 
9.1 
Subject informed consent ............................................................................................................ 38 
9.2 
Screening visit (Visit 1) ................................................................................................................ 38 
9.3 
First treatment period (Visit 2) ..................................................................................................... 39 
9.4 
Visit 3 ........................................................................................................................................... 39 
9.5 
End of second treatment period (Visit 4) ..................................................................................... 40 
9.6 
End of study (Visit 5) ................................................................................................................... 40 
9.7 
Early withdrawal visit ................................................................................................................... 40 
10. 
Study endpoints ..................................................................................................................................... 41 
10.1 
Primary endpoint ......................................................................................................................... 41 
10.2 
Secondary endpoints ................................................................................................................... 41 
10.3 
Safety endpoints .......................................................................................................................... 41 
10.4 
Exploratory endpoints .................................................................................................................. 41 
11. 
Study measurements ............................................................................................................................ 42 
11.1 
Clinical assessments ................................................................................................................... 42 
11.1.1 
Medical history ............................................................................................................................. 42 
11.1.2 
Demographics ............................................................................................................................. 42 
11.1.3 
Electrocardiogram ....................................................................................................................... 42 
11.1.4 
Vital signs .................................................................................................................................... 42 
11.1.5 
Physical examination ................................................................................................................... 42 
11.1.6 
Height and weight ........................................................................................................................ 42 
11.2 
Laboratory assessments ............................................................................................................. 43 
11.2.1 
Clinical safety testing ................................................................................................................... 43 
11.2.2 
Pregnancy.................................................................................................................................... 43 
11.3 
Adverse event monitoring ............................................................................................................ 43 
11.4 
Concomitant medications ............................................................................................................ 43 
11.5 
Efficacy assessments .................................................................................................................. 43 
11.5.1 
Pain intensity ............................................................................................................................... 43 
11.5.2 
Migraine symptoms ..................................................................................................................... 44 


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11.5.3 
Subject satisfaction ...................................................................................................................... 44 
12. 
Study oversight ...................................................................................................................................... 45 
12.1 
Within-subject stopping criteria ................................................................................................... 45 
12.2 
Suspension or premature termination of the study ..................................................................... 45 
13. 
Adverse events ...................................................................................................................................... 46 
13.1 
Definitions .................................................................................................................................... 46 
13.1.1 
Adverse event .............................................................................................................................. 46 
13.1.2 
Adverse drug reaction/Suspected adverse (drug) reaction ......................................................... 46 
13.1.3 
Suspected unexpected serious adverse reactions ...................................................................... 46 
13.1.4 
Causality ...................................................................................................................................... 46 
13.1.5 
Severity (intensity) of adverse event ........................................................................................... 47 
13.1.6 
Serious adverse event ................................................................................................................. 47 
13.2 
Recording of adverse events ....................................................................................................... 47 
13.3 
Clinical lab abnormalities and other abnormal assessments ...................................................... 48 
13.4 
Reporting of serious adverse events ........................................................................................... 48 
13.5 
Followup of adverse events and serious adverse events ........................................................... 49 
14. 
Statistical analysis ................................................................................................................................. 50 
14.1 
General considerations ................................................................................................................ 50 
14.2 
Sample size ................................................................................................................................. 50 
14.3 
Analysis populations .................................................................................................................... 50 
14.3.1 
Full analysis set ........................................................................................................................... 50 
14.3.2 
Per protocol population ................................................................................................................ 50 
14.3.3 
Safety population ......................................................................................................................... 50 
14.4 
Subject disposition ....................................................................................................................... 50 
14.5 
Analysis of efficacy data .............................................................................................................. 50 
14.5.1 
Analgesic use .............................................................................................................................. 51 
14.6 
Analysis of safety data ................................................................................................................. 51 
14.6.1 
Extent of exposure ....................................................................................................................... 51 
14.6.2 
Adverse events ............................................................................................................................ 51 
14.6.3 
Clinical laboratory evaluations ..................................................................................................... 52 
14.6.4 
Other safety measures ................................................................................................................ 52 
15. 
Study management ............................................................................................................................... 53 
15.1 
Regulatory and ethical considerations ........................................................................................ 53 
15.1.1 
Regulatory compliance and ethical conduct ................................................................................ 53 
15.1.2 
Ethics committee review .............................................................................................................. 53 
15.1.3 
Informed consent process ........................................................................................................... 53 
15.1.4 
Protocol amendments .................................................................................................................. 53 
15.1.5 
Protocol deviations ...................................................................................................................... 54 
15.2 
Quality control and quality assurance ......................................................................................... 54 
15.2.1 
Training of staff ............................................................................................................................ 54 
15.2.2 
Study monitoring .......................................................................................................................... 54 
15.2.3 
Data management and quality control ......................................................................................... 55 
15.2.4 
Audits and inspections ................................................................................................................. 55 


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15.3 
Documentation, record access and archiving ............................................................................. 56 
15.3.1 
Maintenance of essential documents/supplements at study site during the study ..................... 56 
15.3.2 
Data protection ............................................................................................................................ 56 
15.3.3 
Data retention & archiving ........................................................................................................... 57 
15.4 
Study administration .................................................................................................................... 57 
15.4.1 
Study agreements ....................................................................................................................... 57 
15.4.2 
Confidentiality .............................................................................................................................. 57 
15.4.3 
Insurance ..................................................................................................................................... 58 
15.4.4 
Reporting ..................................................................................................................................... 58 
15.4.5 
Publication policy ......................................................................................................................... 58 
16. 
References ............................................................................................................................................ 59 
 
List of tables 
Table 1: Summary of LAT8881 effects in various preclinical pain models ................................................ 23 
Table 2: Summary of clinical studies with LAT8881 .................................................................................. 26 
 
List of figures 
Figure 1: LAT8881 amino acid sequence .................................................................................................. 22 
Figure 2: Continuous recording of the effect of LAT8881 on membrane potential .................................... 24 
Figure 3: Overall study design for LAT-MIG-001 ....................................................................................... 28 
 


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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 
cGMP 
Current Good Manufacturing Practice 
CGRP 
calcitonin gene-related peptide 
CI 
confidence interval 
(e)CRF 
(electronic) case report form 
CTN 
Clinical Trial Notification (scheme) 
DHE 
Dihydroergotamine 
EC 
ethics committee 
ECG 
electrocardiogram 
FAS 
Full analysis set 
FOCBP 
female of child bearing potential 
g 
gram 
GCP 
Good clinical practice 
hCG 
human chorionic gonadotropin 
hGH 
human growth hormone 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IHS 
International Headache Society 
IUD 
intrauterine device 
im 
intramuscular 
IMP  
Investigational medicinal product  
iv 
intravenous 
kg 
kilogram 
m 
metre 
m2 
square metre 
MAO-A 
monoamine oxidase A 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
millilitre 


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Abbreviation 
Definition 
mOhm 
milliohm 
mV 
millivolt 
n 
number (of subjects) 
NRS 
Numeric rating scale 
NSAID 
nonsteroidal antiinflammatory drug 
PCI 
PCI Pharma Services  
PIC/S 
Pharmaceutical Inspection Cooperation Scheme 
PIS 
Participant information sheet 
PP 
per protocol 
PT 
Preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
Subject ID 
unique number given to each subject on screening 
t 
time 
SUSAR 
suspected unexpected serious adverse reaction 
TCA 
tricyclic antidepressant 
TEAE 
Treatment emergent adverse event 
 
TGA 
Therapeutic Goods Administration 
TIA 
transient ischaemic attack 
TYR 
tyrosine 


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1. Protocol synopsis 
Title: 
A Proof of concept study of the efficacy and safety of oral LAT8881 in acute 
migraine  
Protocol 
number 
LAT-MIG-001 
Clinical 
phase 
IIa 
Principal 
investigator 
Dr Louise Murdoch MBBS 
Study site 
Emeritus Research 
Level 2/1180 Toorak Rd 
Camberwell  
VIC 3124,  
Australia 
Investigation
al medicinal 
product (IMP) 
LAT8881 (Tyr-hGH177-191), 30 mg capsules and matching placebo. 
Two capsules to be taken at the onset (within one hour from the onset of pain) of a 
migraine headache of moderate to severe intensity. Total daily dose of IMP: 0 or 
60 mg LAT8881 
Indication 
Treatment of acute migraine with or without aura  
Study 
description 
This is a randomised, placebo controlled, double blind, crossover phase IIa proof 
of concept study to investigate the efficacy and safety of oral LAT8881 in acute 
migraine with or without aura. Subjects enrolled in the study will be randomised to 
receive IMP (LAT8881 60 mg or placebo), to be taken at the onset (within one 
hour from the onset of pain) of a migraine headache of moderate to severe 
intensity [Numeric rating scale (NRS) ≥4]. Rescue medication should not be taken 
until at least 2 hours post dose. Subjects will be given a single dose of IMP, to 
treat one migraine headache. 
After treatment of one migraine headache (or a maximum 28 days) the subject will 
return to the clinic for re-evaluation and crossover to the second treatment.  
After treatment of one migraine headache in the second treatment period or a 
maximum of 28 days from commencement of the second treatment period, the 
subject will return to the clinic for re-evaluation.  
An End of study visit (telephone) will occur 7 days after the end of the second 
treatment period.  
Subjects will complete diaries to record menstrual cycle, onset, and nature of 
migraine and non-migraine headaches, pain scores at time of IMP dosing and 
various time points post dose, associated symptoms, episodes of vomiting and 
rescue medication. Adverse events will be monitored.   
Number of 
subjects 
planned 
It is planned to have 20 subjects complete the study, defined as taking one dose of 
IMP in each treatment period and attending the followup (End of study) visit.  
Assuming up to 20% of subjects do not treat one migraine headache in each 


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treatment period or dropout of the study, 26 subjects will be enrolled in the study.  
If the dropout rate or noncompletion rate is higher than anticipated, additional 
subjects may be enrolled to ensure 20 subjects complete the study. 
Study 
objectives 
Primary 
To evaluate the effect of oral LAT8881 on migraine headache compared with 
placebo, when assessed by the headache severity on an 11 point Numeric Rating 
Scale (NRS) 
Secondary 
1. To evaluate the effect of oral LAT8881 on migraine associated symptoms 
compared with placebo, when assessed by the change in symptoms based on 
a 11 point Likert scale 
2. To investigate the percentage of subjects achieving “no headache pain” 
following treatment with oral LAT8881 for a migraine headache compared with 
placebo at any timepoint to 8 hours post dose, with no use of rescue 
medication 
3. To evaluate the safety and tolerability of single doses of oral LAT8881 in 
subjects with migraine headache 
Exploratory 
1. To investigate the percentage of subjects who are “sustained pain-free,” 
defined as having no headache pain following treatment with oral LAT8881 for 
a migraine headache compared with placebo, with no use of rescue 
medication and no relapse of headache pain within 24 hours (24-hour 
sustained pain-free) after administration 
2. To investigate the time to first pain-free timepoint following treatment with oral 
LAT8881 for a migraine headache compared with placebo to 24 hours post 
dose, with no use of rescue medication  
3. To determine the need for extra analgesic (rescue) medication after treatment 
with oral LAT8881 administration for a migraine headache, compared with 
placebo 
4. To investigate subject satisfaction with treatment of a migraine headache 
5. To investigate other factors influencing the extent of change in pain score and 
symptom scores in subjects with migraine headaches 
Endpoints 
Primary endpoint 
Change in migraine headache pain score, using an 11-point NRS, (0 = none, 10 = 
worst imaginable), from the time of dosing (t = 0 min) to 0.5, 1.0, 1.5, 2, 4, 8 and 
24-hours post dose. Pain is recorded in a subject diary and should reflect the 
subject’s pain at the time of recording. 
Secondary efficacy endpoints 
1. Change in migraine-associated symptoms of nausea, photophobia and 
phonophobia. Symptoms are assessed on an 11- point Likert scale (0 = no 
symptoms, 10 = severe symptoms), at time of dosing and at 0.5, 1.0, 1.5, 2, 4, 
8 and 24 hours post dose. 
2. Change in each subject’s most troublesome symptom that may include 
nausea, photophobia and phonophobia, cognitive impairment, dizziness and 


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functional disability. Symptoms are assessed on an 11- point Likert scale (0 = 
no symptoms, 10 = severe symptoms at time of dosing and at 0.5, 1.0, 1.5, 2, 
4, 8 and 24 hours post dose.  
3. The percentage of subjects achieving “no headache pain” at 0.5, 1.0, 1.5, 2, 4 
and 8 hours post dose. 
Safety endpoints 
1. Changes in physical examinations and vital signs  
2. Changes in clinical laboratory tests  
3. Percentage of treatment emergent adverse events (TEAEs), including serious 
adverse events (SAEs), and suspected unexpected serious adverse reactions 
(SUSARs)  
4. Changes in concomitant medications  
Exploratory endpoints 
1. The percentage of subjects who are “sustained pain-free,” defined as having 
no migraine headache pain at 24 hours, with no use of rescue medication and 
no relapse of headache pain within 24 hours (24-hour sustained pain-free) 
after administration  
2. The time to first pain-free timepoint following treatment with oral LAT8881 
compared with placebo to 24 hours post dose, with no use of rescue 
medication  
3. Supplemental analgesic medication use in the 24 hour post treatment period 
4. Subject satisfaction with each treatment based on a 7-point Likert Scale, 
overall preference for Treatment 1 or Treatment 2, and historical comparison 
with usual treatment  
5. Association between change in headache pain and symptom scores and 
selected subject baseline characteristics, including for example, migraine 
with/without aura, relationship to menstrual cycle. 
Study 
population: 
Inclusion criteria 
Subjects must meet the following criteria to be entered into the study: 
1. Males or females aged 18 to 75 years at the time of consent 
2. Diagnosis of episodic migraine headache at least 12 months ago with or 
without aura as defined in ICHD-3-beta2  
3. Onset of migraine headache before age 50  
4. Medical history of 2 – 8 migraine headache attacks per month for the previous 
12 months; ≥ 75% of attacks progress to moderate or severe pain within 2 
hours (ie, rapidly-escalating) 
5. Minimum 48 hours on average between migraine headache attacks 
6. Acute headache medication on ≤ 14 days/month in the 3 months prior to 
screening 
7. Willing and able to comply with all study procedures including completion of a 
headache diary and a migraine diary on the day of a migraine headache 
8. Female subjects must be: 


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a) of non-child-bearing potential [surgically sterilised or postmenopausal (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  
9 
Male subjects with female partners of childbearing potential must use 
adequate and highly effective methods of contraception, from screening until 
28 days after their last IMP administration. 
10 Subjects must be sufficiently competent in English to understand the purposes 
and risks of the study and to provide written informed consent  
Exclusion criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Unable to distinguish migraine from other primary headache conditions 
2. Average of 15 or more headache (migraine or nonmigraine) days per month  
or history of more than 25% of headaches occurring at time of wakening (wake 
up headaches)  
3. History of aura lasting more than 60 minutes 
4. History of vomiting within 2 hours of onset of a migraine headache in more 
than 25% of migraine headaches 
5. Medication overuse headache, defined as: 
a.  use of opioids, triptans or ergot alkaloids or any combination of these 
medications for treatment of headaches 10 or more days per month 
during the 90 days prior to screening OR 
b. Non-steroidal anti-inflammatory drugs (NSAIDs) or simple analgesics 
for treatment of headaches on more than 14 days per month during 
the 90 days prior to screening 
6. Recent (3 years) history of frequent or chronic hemiplegic/ basilar migraine, 
tension headache, retinal migraine, ophthalmoplegic migraine as per ICHD 
classification, or treatment resistant atypical migraine  
7. Hospital admission for status migrainosis or medication overuse headache 
within 6 months of screening 
8. Current clinically significant systemic disease or neurological or psychiatric 
condition which in the opinion of the investigator or sponsor could jeopardise 
the safety of the subject or the validity of the study results 
9. Cerebrovascular disease, including but not limited to a history of stroke or 
recent (3 years) transient ischaemic attack (TIA) 
10. Major surgery within 6 weeks of screening or planned during the study period 
11. Clinically significant abnormality as assessed by the investigator or sponsor’s 
medical monitor on haematology, biochemistry, vital signs, physical 
examination or 12-lead electrocardiogram (ECG) 
12. Malignancy within 5 years of screening, with the exception of carcinoma in 
situ, non-melanoma skin cancers and prostate cancer not requiring treatment 
or on stable (> 6 months) treatment with hormone therapy 


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13. History of alcohol abuse, illicit or illegal drug use in the last 2 years 
14. Use of prohibited medications or treatments within the specified time period 
before Screening or planned during the study 
15. Participation in another clinical trial or administration of any investigational 
product or experimental product within 60 days or 5 half-lives (whichever is 
longer) prior to screening 
16. History of significant hypersensitivity to LAT8881 (formerly known as 
AOD9604), excipients in the drug product formulation or drugs of a similar 
chemical or pharmacological class. 
17. Surgical or medical conditions which could significantly alter drug absorption, 
distribution, metabolism or excretion 
18. 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 
Study  
medications 
Prohibited medications and treatments 
Medications for migraine prophylaxis are prohibited: 
• 
from 6 months prior to screening and throughout the study: 
o 
Calcitonin gene-related peptide pathway monoclonal antibodies 
CGRP antagonists, eg erenumab (Aimovig) 
• 
from 3 months prior to screening and throughout the study 
o 
Antiepileptic drugs including valproate, topiramate 
o 
Betablockers  
o 
Triptans (eg naratriptan for premenstrual migraine)  
o 
Tricyclic antidepressants (TCAs) 
o 
Botulinum toxin 
o 
Calcium channel blockers 
o 
MAO-A inhibitors 
o 
Nerve blocks 
o 
Serotonin-norepinephrine (noradrenaline) reuptake inhibitor: eg 
venlafaxine, duloxetine 
o 
Selective serotonin reuptake inhibitors, eg fluoxetine, sertraline 
• 
from Screening and throughout the study 
o 
NSAIDs 
Investigational drugs for prophylaxis or treatment of migraine or other medical 
conditions 
Any other medications which may impact on pain assessments are prohibited if 
taken within 24 hours prior to taking the dose of IMP. 
The following treatments are prohibited during the study, including during the 
screening period: 
• 
Neuromodulation devices, including TENS, eTENS, vagus nerve stimulation 
devices and acupuncture 


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Permitted medications 
The following medications are permitted: 
1 
Rescue analgesics, 2 or more hours after dose of IMP: prescription and 
nonprescription drugs including Standard of Care medications for treatment of 
acute migraine headache 
2 
Other medications eg vitamins, herbal/dietary supplements (including Chinese 
medicines), oral and IUD contraceptives, hormone replacement therapy, not 
on the prohibited medications list which have been stable for 3 months prior to 
screening. 
Study 
procedures 
Screening (Visit 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. During the screening procedure, subjects will 
undergo screening assessments including medical history, height, weight, 12-lead 
ECG, vital signs, and full physical examination. In addition to eligibility criteria, 
medical history will include details of history of migraine headaches: average 
duration (shortest and longest), description of nature (throbbing, aggravating 
factors, unilateral/bilateral, aura), severity and associated symptoms including 
most troublesome symptom and relationship to menstrual cycle. 
Concomitant medications will be recorded. Blood will be collected for routine 
haematology and biochemistry 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 will be given two diaries after 
completion of the above screening tests. The headache diary will be used to 
record menstrual cycles, and onset and nature of headaches (both migraine and 
non-migraine). In addition, they will be instructed to complete a migraine diary 
during a migraine headache to collect pain and symptom scores and concomitant 
medications. Scores will be recorded before taking their usual migraine medication 
and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours after taking their usual migraine 
medication. The screening diaries will be completed for a minimum of 28 days. If 
the subject does not experience a migraine headache in this period or menstrual 
bleeding (menstruating females only), the screening diary period may be extended 
up to 35 days. 
Note that diary entries completed prior to Day 1 will be used only to confirm 
compliance with diary completion requirements on the day of a migraine, to verify 
the nature of migraine headache and the subject’s most troublesome symptom.  
Visit 2 
Treatment period 1  
Subjects will return to the unit on Day 1 (Visit 2) with their diaries completed from 
Day -28 to Day -1 inclusive. If a subject has not experienced a migraine headache 
or menstrual bleeding (menstruating females only) during the 28-day period, the 
screening diary period may be extended by 7 days.  
On Day 1, assessments including 12-lead ECG, vital signs, a targeted physical 
examination, recording of concomitant medications, review of the subject’s diaries, 
blood and urine sampling for safety monitoring, and urine sampling for pregnancy 


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testing in FOCBP, will be conducted. Results from safety monitoring tests are not 
required prior to randomisation.  
Eligibility will be confirmed and subjects will be randomised to LAT8881 60 mg or 
placebo.  
Subjects will leave the unit with their two diaries, and one dose of IMP and 
instructions to take the dose within one hour of the onset of a migraine headache 
of moderate to severe intensity (NRS ≥4). The headache diary will be used to 
record menstrual cycles and onset and nature of headaches (both migraine and 
non-migraine). The migraine diary will be used during a migraine headache to 
collect pain and symptom scores and concomitant medications before taking the 
IMP and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours after taking the dose. No analgesics 
or antimigraine medication other than medications for routine prophylaxis not on 
the Prohibited medicines list may be taken within 24 hours prior to taking the dose 
of IMP. Rescue medication is permitted a minimum of 2 hours post IMP dose. The 
subject’s symptoms including nausea, photophobia and phonophobia plus the 
subject’s most troublesome symptom if other than nausea, photophobia or 
phonophobia will be recorded at the time of dosing and at 0.5, 1.0, 1.5, 2, 4, 8 and 
24 hours after taking the dose. Episodes of vomiting will also be recorded. 
The subject will be instructed to phone the clinic within one business day of taking 
the dose. 
On Day 15, if the subject has not phoned the clinic, the subject will be phoned to 
remind them to complete their diaries and to phone the clinic when the dose has 
been taken.  
Subjects will return to the clinic for Visit 3 within 5 business days after taking the 
dose or a maximum of 28 days after Visit 2 if IMP has not been taken. 
Visit 3 
Assessments including 12-lead ECG, vital signs, a targeted physical examination 
and concomitant medications will be recorded and the subject’s diaries will be 
reviewed. Blood and urine samples will be taken for safety monitoring and urine for 
pregnancy test (FOCBP only). Subject satisfaction with Treatment period 1 IMP 
will be recorded. Results from safety monitoring tests are not required prior to 
dosing. 
Treatment period 2 
Subjects will leave the clinic with their diaries and one dose of IMP (alternate 
treatment), instructions to take the dose within one hour of the onset of a migraine 
headache of moderate to severe intensity (NRS ≥4),  but not less than 48 hours 
after last dose and instructions to complete the diaries as for Treatment period 1. 
No analgesics or antimigraine medication other than medications for routine 
prophylaxis not on the Prohibited medicines list may be taken within 24 hours prior 
to taking the dose of IMP. Rescue medication is permitted a minimum of 2 hours 
post dose. 
The subject will be instructed to phone the clinic within one business day of taking 
the dose. 
If the subject has not phoned the clinic, the subject will be phoned 14 days after 
Visit 3 to remind them to complete their diaries and to phone the clinic when the 


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dose has been taken.  
Subjects will return to the clinic for Visit 4 within 5 business days, after taking the 
dose or a maximum of 28 days after Visit 3 if IMP has not been taken. 
Visit 4 
Subjects will return to the clinic with their diaries at completion of Treatment 
period 2.  
Blood and urine samples will be taken for safety analysis. 12-lead ECG, vital signs, 
concomitant medications, targeted physical examination results and adverse 
events will be recorded. Subjects will be asked to complete assessments for 
Subject satisfaction of IMP Treatment period 2 and overall preference.   
End of study, Visit 5 
Subjects will be phoned 7 days after Visit 4 to review any new or changed adverse 
events or changes in concomitant medications.  
Early withdrawal 
An early withdrawal visit should be conducted within 7 days of the subject 
withdrawal, and/or a minimum 48 hours after last dose of IMP. 
Subjects who are completing an early withdrawal visit will return with their diaries 
and IMP.  
Blood and urine samples will be taken for safety analysis. 12-lead ECG, vital signs, 
concomitant medications, targeted physical examination results and adverse 
events will be recorded. Subjects will be asked to complete assessments for 
Subject satisfaction.   
Statistical 
analysis 
No formal statistical sample size estimation has been performed due to the 
exploratory nature of this study. Rather the sample size is based on clinical and 
practical considerations. 
The safety population includes all subjects who receive at least one dose of IMP 
and will be the population used for the analysis of safety endpoints. The full 
analysis set (FAS) population will be used to present demographic and other 
baseline characteristics and summaries of efficacy endpoints. A per-protocol (PP) 
population will be used as the primary population for efficacy analyses and to 
analyse exploratory endpoints. The PP population will be based on IMP exposure, 
including the time of any episodes of vomiting and major protocol deviations.  
The descriptive summaries for the categorical variables will include counts and 
percentages. The descriptive summaries for the continuous variables will include 
number of subjects (n), means, medians, standard deviations, and minimum and 
maximum values. All data will be listed for all subjects. As this is a Phase IIa proof 
of concept study, no formal statistical hypotheses are being specified although 
some may be investigated as part of the data presentation. A p-value of <0.05 will 
be declared statistically significant. Treatment period order will be ignored in any 
treatment comparisons. Results will be presented in a descriptive format by 
treatment within each treatment period and overall. Treatment comparisons will 
take into account the paired nature of the treatment responses where feasible.  
Individual pain score-time profiles for each treatment within each subject will be 
presented graphically. The difference between the NRS pain scores at each 


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timepoint for LAT8881 60 mg compared with placebo within each subject will be 
estimated and presented graphically. The number of subjects, mean, standard 
deviation, minimum and maximum NRS pain score at each timepoint, change from 
baseline, difference between treatments at each timepoint and change from 
baseline difference between treatments will be presented for each treatment 
overall and within each treatment period. 
Nausea, photophobia and phonophobia symptom scores will be summarised and 
presented in the same way as the pain scores. The number and percent of 
headaches with each most troublesome symptom of migraine including nausea, 
cognitive impairment, dizziness, functional disability, photophobia phonophobia 
and vomiting will be summarised for each treatment. The most troublesome 
symptom scores will be summarised and presented in the same way as the pain 
scores.  
The number and percent of subjects with 'no headache pain' at each time point will 
be presented for each treatment. Two-way tables will present the 
presence/absence of pain classified for each treatment at each timepoint. Absence 
of pain will be defined as a pain NRS score of 0 or 1. 
The number and percent of subjects who are “sustained pain-free” at 24 hours 
after dose of IMP will be presented by treatment. A two-way table will present the 
“sustained pain-free” status for subjects on each treatment.  
The number and percent of subjects will be summarised by their first pain-free 
timepoint. A two-way table will present the classification of each subject’s first 
pain-free timepoint by treatment. Kaplan-Meier curves will present the time to first 
pain-free timepoint.  
Patient Satisfaction for each treatment recorded on a 7-point Likert scale and the 
within-subject difference between treatments will be summarised. The mean 
difference between treatments will be compared with a paired t-test and the 95% 
confidence interval for the mean difference will be presented. The number and 
percent of subjects from the overall satisfaction score will be presented for each 
treatment.    
Additional exploratory analyses to investigate the association between change in 
headache pain and symptom scores and selected subject baseline characteristics 
will be undertaken in a similar fashion with descriptive statistics. 
Adverse event data will be coded to system organ class and preferred term using 
the Medical Dictionary for Regulatory Activities (MedDRA). A by-subject AE data 
listing, including verbatim term, preferred term, system organ class, severity and 
relationship to investigational product will be provided. The number and 
percentage of subjects experiencing any treatment-emergent AE and the number 
of individual adverse events, overall, and by system organ class and preferred 
term will be tabulated. Treatment emergent adverse events will also be 
summarised by severity and relationship to investigational product.  
Absolute values and changes from baseline in vital signs, haematology and clinical 
chemistry parameters will be tabulated at each visit. 
Prior and concomitant medications will be listed by subject and coded using the 
most current World Health Organisation (WHO) drug dictionary and summarised 
by WHO Drug Class and preferred term for each treatment period and treatment 


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group. Medical history will be listed by subject. 
Further details of the statistical methodology to be used in the analysis and 
reporting of the study results, including methods for handling missing data, and 
early withdrawals, will be provided in a statistical analysis plan that will be finalised 
prior to database lock. 
Anticipated 
study 
Duration: 
Approximately 9 months 
Participant 
duration: 
Maximum participation duration is 14 weeks (98 days): Screening (28 - 35 days), 
Treatment period 1 (28 days), Treatment period 2 (28 days), followup (7 days) 


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2. Study schedule of assessments and procedures 
 
Screening 
Treatment period 1 
End of 
period 1  
Treatment period 2 
End of period 2, 
early withdrawal 
End of study 
Visit no 
1 
2 
 
 
3 
 
 
4 
5 (phone) 
Study day 
-28 to -1 
(+7days) 
1 
Telephone 
(if required) 
Headache 
episode 
29 ± 21  
Telephone 
(if required) 
Headache 
episode 
57 ± 2 1 
64 ± 22 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility  
 
X 
 
 
 
 
 
 
 
 
Enrolment and randomisation 
 
X 
 
 
 
 
 
 
 
 
Medical history, demographics 
X 
 
 
 
 
 
 
 
 
 
Height and weight 
 
X 
 
 
 
 
 
 
 
 
 
12 lead ECG  
X 
X 
 
 
X 
 
 
 
X 
 
Pregnancy test3 
X 
X 
 
 
 
X 
 
 
 
 
Vital signs 
X 
X 
 
 
X 
 
 
 
X 
 
Physical examination 
X4 
X5 
 
 
X5 
 
 
 
X5 
 
Clinical laboratory safety testing6 
X 
X 
 
 
X 
 
 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
IMP issued 
 
X 
 
 
 
X 
 
 
 
 
IMP administration7 
 
 
 
X 
 
 
 
X 
 
 
Adverse event assessment 
 
 
X 
 
X 
 
X 
 
X 
X 
Headache diary8 
X 
 
 
X 
 
 
 
X 
X 
 
Migraine diary9  
X 
 
 
X 
 
 
 
X 
 
 
Patient satisfaction survey 
 
 
 
 
X 
 
 
 
X 
 
 
1 Or maximum 5 business days after dose of IMP 
2 Or 7 days after Visit 4 
3 Females of child bearing potential only, blood test at screening, urine other occasions 
4 Full physical examination 
5 Targeted physical examination 
6 Haematology, biochemistry, urinalysis 
7 Migraine episode only 
8 Headache diary during both non-migraine and migraine headaches 
9 Migraine diary, during migraine headaches  


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3. Introduction and background information 
3.1 
Acute migraine 
Migraine is a disabling neurovascular disorder, characterised by moderate to severe headaches which 
are usually throbbing, affect one side of the head and are accompanied by nausea and sensitivity to light 
and/or sound. It is one of the most common chronic conditions worldwide.  
The most common migraine types are migraine without aura (common migraine) and migraine with aura 
(classic migraine).3 
Migraine without aura is identified by headache symptoms lasting 4–72 hours, commonly with a unilateral 
location, pulsating quality of moderate or severe intensity, aggravated by routine physical activity and 
associated with nausea and/or light and sound sensitivity. Diagnosis is based on at least five attacks.3  
Migraine with aura is identified by recurrent attacks, lasting minutes, of unilateral fully reversible visual, 
sensory or other central nervous system symptoms that usually develop gradually and are commonly 
followed by headache and associated migraine symptoms. Diagnosis of migraine with aura requires at 
least two such attacks.3 
Recognition of the pathophysiology of migraine has evolved from the belief that it was a primary 
consequence of intracranial vasodilation, to the more recent theory that it is initiated by a complex series 
of neural and vascular events.4 According to this theory, migraine is primarily a neurogenic process with 
secondary changes in cerebral perfusion. The headache pain itself is considered to be due to activation 
of the trigeminovascular pathway, but it has been suggested that there are multiple neuronal functional 
abnormalities which are involved in the initiation of a migraine.5 
Migraine prevalence is reported to be between 2.6% and 21.7%, with an average of approximately 12%.6 
In the 2016 Global Burden of Disease Study,7 migraine (including medication overuse headache) ranked 
in the top ten of years lived with disability in all 195 countries and territories investigated, and overall was 
the second largest cause of disability. 
In the years prior to puberty, migraine is more common among boys than girls. However, by the onset of 
puberty, migraine is more prevalent in girls. Females in their late teens are about twice as likely to suffer 
from migraine as males of the same age.8 The prevalence of migraine peaks in both sexes and is at its 
highest from ages 25 to 55 years, when there is a substantial loss of productivity because of work 
absences and reduced efficiency. In Australia, it is estimated that the total economic cost from migraine 
in 2018 was $35.7 billion, consisting of $14.3 billion of health system costs, $16.3 billion of productivity 
costs, and $5.1 billion of other costs.9 There are also additional significant wellbeing costs for these 
individuals and their families.  
Selecting the optimal treatment for a particular patient is challenging because the severity, frequency, 
and characteristics of migraine can vary between individuals or even within the same individual over time. 
Treatment plans are usually individualised and based on a number of factors, such as patient preference, 
the severity and frequency of attacks, co-morbidities and concomitant medications.  
The American Headache Society guidance for the treatment of acute migraine10 is to use non-steroidal 
anti-inflammatory drugs (NSAIDs), including aspirin, non-opioid analgesics, paracetamol, or caffeinated 
analgesic combinations (eg aspirin + paracetamol + caffeine) for mild-to-moderate attacks. For moderate 
or severe attacks and mild-to-moderate attacks that respond poorly to NSAIDs or caffeinated 
combinations, migraine-specific agents (triptans, dihydroergotamine) are suggested.  
For some patients, acute treatments are not sufficiently effective or are not well tolerated and 
preventative medication may be suggested. However, non-compliance with chronic medication or side 
effects from treatment may reduce the effectiveness of such interventions. The availability of an effective 


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acute therapy, with a novel mechanism of action and good tolerability, will improve the options for 
patients with acute migraine who do not wish to progress to chronic preventative therapies.  
Some of the clinical features of migraine, such as allodynia and hyperalgesia, resemble the symptoms of 
neuropathic pain, leading to the suggestion that migraine might be a neuropathic pain disorder.11 It is in 
this context that it has been suggested that LAT8881, with its demonstrated activity in preclinical 
neuropathic pain models and evidence of inhibition of neuronal excitability (Section 3.2.1.1), might be a 
useful therapeutic agent for migraine. 
This is the first clinical study with LAT8881 in migraine and will assess its potential for treating acute 
migraine in a proof of concept trial. 
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). 
 
Figure 1: LAT8881 amino acid sequence 
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. 
A clinical study is currently in progress to evaluate the efficacy and safety of LAT8881 in neuropathic 
pain. This study is being conducted at four Australian and two UK sites, and is planned to recruit up to 55 
subjects, so that 44 subjects complete the study.  
3.2.1 Non-clinical studies 
3.2.1.1 Non-clinical models  
As there are no established specific pharmacological models of migraine,12 non-clinical studies 
supporting a role for LAT8881 in migraine are based on its activity in relieving neuropathic pain as this 
action has been suggested to be relevant to its potential role in migraine.11 These studies are 
summarised in Table 1. Further details are provided in the Investigator’s Brochure. 
 


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Table 1: Summary of LAT8881 effects in various preclinical pain models 
Model 
Predominant 
pain type 
Outcome 
measure 
LAT881 dose 
(mg/kg) 
Results 
Study No 
Peripheral nerve 
ligation 
Neuropathic 
PWT 
1, 2, 5  
single dose 
Dose -related increase in PWT at 1, 2 and 
4 hours post-dose, compared with vehicle 
(effect at 5mg/kg comparable to positive 
control gabapentin at 100mg/kg po) 
PDS005 
Oxaliplatin 
neuropathy 
Neuropathic 
PWT 
5 
single dose 
Increased PWT at 1, 2 and 4 hours post-
dose, compared with pre-dose 
 
PDS0011 
Reserpine-induced 
fibromyalgia 
Central 
PWT 
5 
single dose 
Increased PWT at 4 and 6 hours post-
dose, compared with vehicle 
PDS0011 
Post-surgical pain 
Nociceptive 
PWT 
5 
two doses 
(Day 1 pre-
surgery and 
Day 2) 
Increased PWT at 2 and 4 hours post-
second dose on Day 2, compared with 
vehicle 
PDS0011 
Carageenan-
induced 
hyperalgesia 
Inflammatory 
PWL 
5 
single dose 
Increased PWL at 4 hours post-dose, 
compared with vehicle 
PDS0011 
MIA arthralgia 
Nociceptive 
and 
neuropathic 
WBR 
5 
single dose 
WBR similar to vehicle control at all time 
points 
 
PDS0011 
Formalin 
Nociceptive 
PLT 
5 
single dose 
given 90 
minutes before 
formalin 
Reduced PLT at 5 minutes after formalin, 
compared with vehicle control (effect lost 
by 10 mins post dose) 
PDS0011 
Diabetic 
neuropathy 
Neuropathic 
PWT 
5 
single dose 
Increased PWT at 1, 2 and 4 hours post-
dose, compared with pre-dose 
 
PDS0011 
Oxaliplatin 
neuropathy 
Neuropathic 
ACT, CTI 
3, 10 
single dose 
Both doses reduced ACT compared with 
pre-dose. Non-significant increase in CTI 
latency, compared with pre-dose (effects 
on ACT and CTI comparable to positive 
control 15mg/kg duloxetine ip) 
C1106117 
Oxaliplatin 
neuropathy 
Neuropathic 
ACT, CTI 
3, 10 daily for 
 6 days 
Significant decrease in ACT at 10 mg/kg 
on Day 6 of dosing, compared with 
vehicle. Significant increase in CTI latency 
after 5 and 6 days treatment, compared 
with vehicle 
C1106317 
ACT = acetone cooling test; CTI = cool tail immersion; ip = intraperitoneal; PLT = paw latency time; po = per oral; 
PWL = paw withdrawal latency; PWT = paw withdrawal threshold; WBR = weight bearing ratio 


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3.2.1.2 Mechanism of action 
LAT8881 induced a membrane potential hyperpolarisation and inhibition of neuronal excitability when 
incubated with spinal cord slices taken from rats with confirmed neuropathic symptoms ((Study PDS003b, 
Figure 2). This is considered to be relevant to its potential therapeutic activity in migraine. 
 
Figure 2: Continuous recording of the effect of LAT8881 on membrane potential  
Mean resting membrane potential was reduced from -49.3 ± 2.4 mV (mean ± SEM) to a new steady state 
resting potential of -63 ± 2.4 mV in the presence of 10 µM LAT8881. When normalised to control resting 
potential, the LAT8881-induced inhibition amounted to a 30.6 ± 11.1% (P=0.033) change in membrane 
potential. 
Membrane potential hyperpolarisation was consistently associated with a significant reduction in neuronal 
input resistance with LAT8881, from a mean control resting value of 579.6 ± 178.9 MOhm to 301.0 ± 
103.2 MOhm (P=0.012) in the presence of LAT8881, amounting to a 278.6 ± 77.8 MOhm reduction in 
neuronal input resistance. When normalised relative to control, LAT8881-induced inhibition was 
associated with a reduction in input resistance to 49.4 + 4.4 % of control (P=0.00003). 
3.2.1.3 Non-clinical safety studies 
Studies in rats and monkeys at doses up to 10 mg/kg LAT8881 administered 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. 
 


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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 2Table 2: Summary of clinical studies with LAT8881). These studies were designed to investigate 
the safety and tolerability of LAT8881 and subsequently its efficacy in the treatment of obesity 
(METAOD005, METAOD006).  
A seventh study (LAT-NP-001) to investigate the safety and efficacy of LAT8881 in neuropathic pain at a 
dose of 60 mg per day (30 mg twice daily) has recently commenced and is recruiting subjects. No results 
from this study are yet available. 


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Table 2: 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 
LAT-NP-001 
Oral, capsule Neuropathic pain 
associated with either 
postherpetic neuralgia or 
diabetic peripheral 
neuropathy  
0, 60 mg  
Daily for 4 weeks 
55 
(anticipated) 
No results 
available 
 
In all development studies for obesity, 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 effect of oral LAT8881 on migraine headache compared with placebo, when assessed by 
the headache severity on an 11-point Numeric Rating Scale (NRS) 
4.2 
Secondary objectives 
1. To evaluate the effect of oral LAT8881 on migraine-associated symptoms compared with placebo, 
when assessed by the change in symptoms based on a 11- point Likert scale 
2. To investigate the percentage of subjects achieving “no headache pain” following treatment with oral 
LAT8881 compared with placebo at any timepoint to 8 hours post dose, with no use of rescue 
medication 
3. To evaluate the safety and tolerability of single doses of oral LAT8881 in subjects with migraine 
headache 
4.3 
Exploratory objectives 
1. To investigate the percentage of subjects who are “sustained pain-free,” defined as having no 
headache pain following treatment with oral LAT8881 compared with placebo, with no use of rescue 
medication and no relapse of headache pain within 24 hours (24-hour sustained pain-free) after 
administration 
2. To investigate the time to first pain-free timepoint following treatment with oral LAT8881 compared 
with placebo to 24 hours post dose, with no use of rescue medication  
3. To determine the need for extra analgesic (rescue) medication after treatment with oral LAT8881 
administration, compared with placebo 
4. To investigate subject satisfaction with treatment  
5. To investigate other factors influencing the extent of change in pain score and symptom scores in 
subjects with migraine 


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5. Study design 
5.1 
Overall study design 
This is a randomised, placebo-controlled, double-blind, crossover, Phase IIa study to investigate the 
efficacy and safety of oral LAT8881 in acute migraine headache with or without aura. The overall study 
design is shown in  
 
Figure 3. Details of the procedures during each phase are described in Section 9. 
 
 
 
 
 
 
 
Figure 3: Overall study design for LAT-MIG-001 
Subjects entered into the study will be randomised to receive IMP (LAT8881 60 mg or placebo), to be 
taken at the onset (within one hour from the onset of pain) of a migraine headache of moderate to severe 
intensity. Rescue medication should not be taken until at least 2 hours post dose. Subjects will be given 
one dose of IMP (2 capsules), to treat one migraine headache. 
After treatment of one migraine headache (or a maximum 28 days) the subject will return to the clinic for 
re-evaluation and crossover to the second treatment. In the second treatment period, they will take IMP in 
the same manner as in treatment period 1. 
A followup (End of study) visit will occur within 7 days after treatment of one migraine headache in the 
second treatment period or a maximum 8 weeks from randomisation. 
Subjects will complete diaries to record menstrual cycle (in menstruating females), onset and nature  of 
migraine and non-migraine headaches, pain scores at time of IMP dosing and various time points post 
dose, associated symptoms and rescue medication. Adverse events will be monitored.   
5.2 
Justification of study design 
The design of this Phase IIa proof of concept trial as a randomised, double blind, placebo controlled, 
crossover study has, in general, followed clinical trial guidelines developed by the International Headache 
Society.13  
The crossover design was chosen to increase efficiency. As each subject acts as his/her own control the 
trial requires a smaller number of subjects than for a parallel group design. The crossover design also 
allows subject treatment preferences to be assessed.  
Period and carryover effects are potential disadvantages of a crossover trial design, but these 
considerations are considered unlikely to impact significantly on this study. As eligible subjects are 
required to have a stable pattern of migraine history, 2–8 attacks per month for the previous 12 months, 
and LAT8881 is a single dose, symptomatic treatment, no period effect is anticipated. Available 
preclinical pharmacodynamic data does not suggest that a single dose of LAT8881 would have a 
carryover effect, and a washout period of at least 48 hours between dosing is considered adequate. 
Preclinical and clinical safety data have not shown any significant adverse effects with LAT8881 that 
SCREENING 
Treatment 1 
Treatment 2 
End of Study 
28 days 
Maximum 
duration 35 days 
Treatment of one 
migraine. 
Maximum duration 
28 days 
Treatment of one 
migraine. 
Maximum duration 
28 days 
7 days after 
completion of 
Treatment 2 


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would affect a subsequent treatment period, nor are there any notable AEs that would enable subjects to 
discriminate between active and placebo treatments.  
5.3 
Justification of dose 
The dose of 60 mg is based on preclinical studies in neuropathic pain models and preclinical and clinical 
safety data with LAT8881. In a number of models of neuropathic pain, LAT8881 significantly increased 
paw withdrawal time to a painful stimulus (a measure of analgesia) at dose of 5 mg/kg. This dose 
approximates to a dose of 0.8 mg/kg in man, based on normalisation to body surface area.14 Given that 
LAT8881 has a good clinical safety profile at doses up to 54 mg/day, refer study METAOD004, and that a 
dose of 60 mg (30 mg twice per day) is currently being evaluated in a study in neuropathic pain, it was 
determined that a 60 mg dose would be an appropriate dose for initial evaluation of LAT8881 in migraine 
headache.  
Full details of these preclinical and clinical studies are available in the Investigator’s Brochure. 
Following this study, it is planned to investigate the dose response to LAT8881 in patients with migraine 
headaches and to determine a minimum effective and optimal therapeutic dose. 
5.4 
Number of planned subjects  
It is planned to have 20 subjects complete the study, defined as taking one dose of IMP in each treatment 
period and attending the followup (End of study) visit.  
Assuming up to 20% of subjects do not treat one migraine headache in each treatment period or dropout 
of the study, 26 subjects will be enrolled in the study.  
If the dropout rate or non-completion rate is higher than anticipated, additional subjects may be enrolled 
to ensure 20 subjects complete the study. 
5.5 
Duration of study 
Approximately 9 months 
5.6 
Duration of subject participation  
Maximum participation duration is 14 weeks (98 days): Screening (28-35 days), Treatment period 1 (28 
days), Treatment period 2 (28 days), followup (7 days). 
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  


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• 
Subject is lost to followup  
• 
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 one week of 
the subject withdrawal, and/or a minimum 48 hours after last dose of IMP. 
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 followup. 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 
Males or females aged 18 to 75 years at the time of consent 
2 
Diagnosis of episodic migraine headache at least 12 months ago with or without aura as defined in 
ICHD-3-beta2  
3 
Onset of migraine headache before age 50  
4 
Medical history of 2 – 8 migraine headache attacks per month for the previous 12 months; ≥ 75% of 
attacks progress to moderate or severe pain within 2 hours (ie, rapidly-escalating) 
5 
Minimum 48 hours on average between migraine headache attacks 
6 
Acute headache medication on ≤ 14 days/month in the 3 months prior to screening 
7 
Willing and able to comply with all study procedures including completion of a headache diary and a 
migraine diary on the day of a migraine headache  
8 
Female subjects must be: 
a) of non-child-bearing potential [surgically sterilised or postmenopausal (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  
9 
Male subjects with female partners of childbearing potential must use adequate and highly effective 
methods of contraception, from screening until 28 days after their last IMP administration. 
10 Subjects must be sufficiently competent in English to understand the purposes and risks of the study 
and to provide written informed consent 
6.2 
Exclusion criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Unable to distinguish migraine from other primary headache conditions 
2. Average of 15 or more headache (migraine or nonmigraine) days per month or history of more than 
25% of headaches occurring at time of wakening (wake up headaches)  
3. History of aura lasting more than 60 minutes 
4. History of vomiting within 2 hours of onset of a migraine headache in more than 25% of migraine 
headaches 
5. Medication overuse headache, defined as: 
a. use of opioids, triptans or ergot alkaloids or any combination of these medications for 
treatment of headaches 10 or more days per month during the 90 days prior to screening OR 
b. Non-steroidal anti-inflammatory drugs (NSAIDs) or simple analgesics for treatment of 
headaches on more than 14 days per month during the 90 days prior to screening 
6. Recent (3 years) history of frequent or chronic hemiplegic/ basilar migraine, tension headache, retinal 
migraine, ophthalmoplegic migraine as per ICHD classification, or treatment resistant atypical 
migraine  


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7. Hospital admission for status migrainosis or medication overuse headache within 6 months of 
screening 
8. Current clinically significant systemic disease or neurological or psychiatric condition which in the 
opinion of the investigator or sponsor could jeopardise the safety of the subject or the validity of the 
study results 
9. Cerebrovascular disease, including but not limited to a history of stroke or recent (3 years) transient 
ischaemic attack (TIA) 
10. Major surgery within 6 weeks of screening or planned during the study period 
11. Clinically significant abnormality as assessed by the investigator or sponsor’s medical monitor on 
haematology, biochemistry, vital signs, physical examination or 12-lead electrocardiogram (ECG) 
12. Malignancy within 5 years of screening, with the exception of carcinoma in situ, non-melanoma skin 
cancers and prostate cancer not requiring treatment or on stable (> 6 months) treatment with 
hormone therapy 
13. History of alcohol abuse, illicit or illegal drug use in the last 2 years 
14. Use of Prohibited medications or treatments within the specified time period before Screening or 
planned during the study 
15. Participation in another clinical trial or administration of any investigational product or experimental 
product within 60 days or 5 half-lives (whichever is longer) 
16. History of significant hypersensitivity to LAT8881 (formerly known as AOD9604), excipients in the 
drug product formulation or drugs of a similar chemical or pharmacological class. 
17. Surgical or medical conditions which could significantly alter drug absorption, distribution, metabolism 
or excretion 
18. 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 
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 and /or partner 
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 
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  


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- 
double barrier method 
- 
male condom plus spermicide 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 (eg calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception. 
6.4 
Dietary, lifestyle and other restrictions 
There are no specific dietary, lifestyle or other restrictions for this study, apart from those listed in the 
Inclusion and Exclusion criteria or the prohibited medications and treatments list.  


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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 2 
capsules. One bottle will contain sufficient capsules for the treatment of one migraine headache in 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 is formulated and the capsules are filled by PCI Pharma 
Services (PCI), Port Melbourne, Victoria, Australia under cGMP conditions. 
PCI Pharma is 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 2 IMP capsules (2 capsules of 
formulated LAT8881 or 2 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 
box, 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.15  
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.  


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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 8.1). 
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, 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 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 prescriptions for IMP, 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 at the end of each treatment period 
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 dose of IMP (two capsules) with water within one hour of the onset 
of a migraine headache of moderate to severe intensity.  
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).  


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8. Treatment compliance 
Subjects will be asked to return their IMP bottles for a capsule count at each end of treatment period visit. 
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.  
8.1 
Unblinding 
8.1.1 Medical emergency 
In a medical emergency, when management of a subject’s condition requires knowledge of the study 
drug, the code may be broken to determine the treatment allocation of the subject. Details will be 
provided in the Study manual. 
Wherever possible, such emergencies should be discussed with the study medical monitor and/or 
sponsor before breaking the code and disclosure of the treatment allocation (or as soon as possible 
thereafter). The date, reason for and name of the individual breaking the code will be documented along 
with a list of unblinded persons. 
8.1.2 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. 
8.2 
Concomitant medications and treatments 
8.2.1 Prohibited medications 
Medications for migraine prophylaxis are prohibited: 
• 
 from 6 months prior to Screening and throughout the study: 
o 
Calcitonin gene-related peptide pathway monoclonal antibodies CGRP antagonists, eg 
erenumab (Aimovig) 
• 
from 3 months prior to Screening and throughout the study 
o 
Antiepileptic drugs including valproate, topiramate 
o 
Betablockers  
o 
Triptans (eg naratriptan for premenstrual migraine)  
o 
Tricyclic antidepressants (TCAs) 
o 
Botulinum toxin 
o 
Calcium channel blockers 
o 
MAO-A inhibitors 
o 
Nerve blocks 
o 
Serotonin-norepinephrine (noradrenaline) reuptake inhibitor: eg venlafaxine, duloxetine 
o 
Selective serotonin reuptake inhibitors, eg fluoxetine, sertraline 
• 
from Screening and throughout the study 
o 
NSAIDs 
• 
Investigational drugs for prophylaxis or treatment of migraine or other medical conditions 


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Any other medications which may impact on pain assessments are prohibited if taken within 24 hours 
prior to taking the dose of IMP. 
8.2.2 Prohibited treatments 
The following treatments are prohibited during the study, including during the screening period: 
• 
Neuromodulation devices, including TENS, eTENS, vagus nerve stimulation devices and 
acupuncture 
8.2.3 Permitted medications 
The following medications are permitted: 
1 
Rescue analgesics, 2 or more hours after dose of IMP: prescription and nonprescription drugs 
including Standard of Care medications for treatment of acute migraine headache 
2 
Other medications eg vitamins, herbal/dietary supplements (including Chinese medicines), oral and 
IUD contraceptives, hormone replacement therapy, not on the prohibited medications list which have 
been stable for 3 months prior to screening. 
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 both the generic and the Trade name. 


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9. Study procedures 
The Schedule of Assessments for the study are provided in Section 2. 
9.1 
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.  
9.2 
Screening visit (Visit 1) 
After written informed consent has been obtained, a unique Screening Number (Subject ID) will be 
assigned and screening assessments may commence.  
During the screening procedure, Days -28 to Day – 1 inclusive, subjects will undergo screening 
assessments including medical history, height, weight, 12-lead ECG, vital signs, and full physical 
examination. In addition to eligibility criteria, medical history will include details of history of migraine 
headaches, average duration (shortest and longest), description of nature (throbbing, aggravating factors, 
unilateral/bilateral, aura), severity and associated symptoms including most troublesome symptom and 
relationship to menstrual cycle (menstruating females). 
Concomitant medications will be recorded. Blood will be collected for routine haematology and 
biochemistry 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 will be given two diaries after completion of the above 
screening tests, shown how to record and to list concomitant medications. The headache diary will be 
used to record menstrual cycles, and onset and nature of headaches (both migraine and non-migraine). 
In addition, they will be instructed to complete a migraine diary during a migraine headache to collect pain 
and symptom scores and concomitant medications. Scores will be recorded before taking their usual 
migraine medication and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours after taking their usual migraine medication.  
The screening diaries will be completed for a minimum of 28 days. If the subject does not experience a 
migraine headache in this period or menstrual bleeding (menstruating females only), the screening diary 
period may be extended by 7 days, ie up to 35 days total. 
Note that diary entries completed prior to Day 1 will be used only to confirm compliance with diary 
completion requirements on the day of a migraine headache, to verify the nature of migraine headache 
and the subject’s most troublesome symptom. 


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9.3 
First treatment period (Visit 2) 
Subjects will return to the unit on Day 1 (Visit 2) with their diaries completed from Day -28 to Day -1 
inclusive. If a subject has not experienced a migraine headache or menstrual bleeding (menstruating 
females only) during the 28-day period, the screening diary period may be extended to 35 days.  
On Day 1, assessments including 12-lead ECG, vital signs, a targeted physical examination, recording of 
concomitant medications, review of the subject’s diaries, blood and urine sampling for safety monitoring, 
and urine sampling for pregnancy testing in FOCBP, will be conducted. Results from safety monitoring 
tests are not required prior to randomisation.  
Eligibility will be confirmed and subjects will be randomised to LAT8881 60 mg or placebo.  
Subjects will leave the unit with their two diaries, and one dose of IMP and instructions to take the dose 
within one hour of the onset of a migraine headache of moderate to severe intensity (NRS ≥4). The 
headache diary will be used to record menstrual cycles and onset and nature of headaches (both 
migraine and non-migraine). The migraine diary will be used during a migraine headache to collect pain 
and symptom scores and concomitant medications before taking the IMP and at 0.5, 1.0, 1.5, 2, 4, 8 and 
24 hours after taking the dose. No analgesics or antimigraine medication other than medications for 
routine prophylaxis not on the Prohibited medicines list may be taken within 24 hours prior to taking the 
dose of IMP. Rescue medication is permitted a minimum of 2 hours post dose. The subject’s symptoms 
including nausea, photophobia and phonophobia plus the subject’s most troublesome symptom if other 
than nausea, photophobia or phonophobia will be recorded immediately before dosing and at 0.5, 1.0, 
1.5, 2, 4, 8 and 24 hours after taking the dose. Episodes of vomiting will also be recorded. 
The subject will be instructed to phone the clinic within 24 hours (or one business day) of taking the dose. 
On Day 15, if the subject has not phoned the clinic, the subject will be phoned to remind them to 
complete their diaries, and to phone the clinic when the dose has been taken.  
Subjects will return to the clinic for Visit 3 within 5 business days after taking the dose or a maximum of 
28 days after Visit 2. Subjects should be reminded to bring their diaries and medication container to the 
visit.  
9.4 
Visit 3 
Assessments including 12-lead ECG vital signs, a targeted physical examination and concomitant 
medications will be recorded and the subject’s diaries will be reviewed. Blood and urine samples will be 
taken for safety monitoring and pregnancy testing (FOCBP). Subject satisfaction with Treatment Period 1 
IMP will be recorded (if dose taken). Results from safety monitoring tests are not required prior to dosing. 
Treatment period 2 
Subjects will leave the clinic with their diaries and one dose of IMP (alternate treatment), to take the dose 
within one hour of the onset of a migraine of moderate to severe intensity (NRS ≥ 4), but not less than 48 
hours after last dose, and instructions to complete the diaries as for Treatment period 1. No analgesics or 
antimigraine medication other than medications for routine prophylaxis not on the Prohibited medicines 
list may be taken within 24 hours prior to taking the dose of IMP. Rescue medication is permitted a 
minimum of 2 hours post dose. 
The subject’s symptoms including, nausea, photophobia and phonophobia plus the subject’s most 
troublesome symptom if other than nausea, photophobia or phonophobia will be recorded at the time of 
dosing and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours after taking the dose. Episodes of vomiting will also be 
recorded 
The subject will be instructed to phone the clinic within 24 hours (or one business day) of taking the 
second dose. 


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If the subject has not phoned the clinic, the subject will be phoned 14 days after Visit 3 to remind them to 
complete their diaries, and to phone the clinic when the dose has been taken.  
Subjects will return to the clinic for Visit 4 within 5 business days after taking the dose or a maximum of 
28 days after Visit 3. 
9.5 
End of second treatment period (Visit 4)  
Subjects will return to the clinic with their diaries and medication containers at completion of Treatment 
Period 2.  
Blood and urine samples will be taken for safety analysis. 12-lead ECG, vital signs, concomitant 
medications, targeted physical examination results and adverse events will be recorded. Subjects will be 
asked to complete assessments for subject satisfaction for Treatment period 2, if dose taken and overall 
preference for Treatment 1 or 2 if both doses have been taken.   
9.6 
End of study (Visit 5)  
Subjects will be phoned one week after Visit 4 to review any new or changed adverse events or changes 
in concomitant medications.  
9.7 
Early withdrawal visit  
An early withdrawal visit should be conducted within one week of the subject withdrawal, and/or a 
minimum 48 hours after last dose of IMP. 
Subjects who are completing an early withdrawal visit will return with their diaries and unused IMP.  
Blood and urine samples will be taken for safety analysis. 12-lead ECG, vital signs, concomitant 
medications, targeted physical examination results and adverse events will be recorded. Subjects will be 
asked to complete assessments for subject satisfaction.   


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10. Study endpoints 
10.1 Primary endpoint 
Change in migraine headache pain score, using an 11-point NRS, (0 = none, 10 = worst imaginable), 
from the time of dosing (t = 0 min) to 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. Pain is recorded in a 
subject diary and should reflect the subject’s pain at the time of recording. 
10.2 Secondary endpoints 
1. Change in migraine-associated symptoms of nausea, photophobia and phonophobia. Symptoms are 
assessed on an 11- point Likert scale with 0 = no symptoms and 10 being severe symptoms at time 
of dosing and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. 
2. Change in each subject’s most troublesome symptom that may include nausea, photophobia and 
phonophobia cognitive impairment, dizziness and functional disability. Symptoms are assessed on an 
11- point Likert scale with 0 = no symptoms and 10 being severe symptoms at time of dosing and at 
0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. 
3. The percentage of subjects achieving “no headache pain” at 0.5, 1.0, 1.5, 2, 4 and 8 hours post dose 
10.3 Safety endpoints 
1. Changes in physical examinations and vital signs  
2. Changes in clinical laboratory tests  
3. Percentage of Treatment emergent adverse events (TEAEs), including serious adverse events 
(SAEs), and suspected unexpected serious adverse reactions (SUSARs)  
4. Changes in concomitant medications  
10.4 Exploratory endpoints 
1. The percentage of subjects who are “sustained pain-free,” defined as having no migraine headache 
pain at 24 hours, with no use of rescue medication and no relapse of headache pain within 24 hours 
(24-hour sustained pain-free) after administration  
2. The time to first pain-free timepoint following treatment with oral LAT8881 compared with placebo to 
24 hours post dose, with no use of rescue medication  
3. Supplemental analgesic medication use in the 24 hour post treatment period 
4. Subject satisfaction with each treatment based on a 7-point Likert Scale, overall preference for 
Treatment 1 or Treatment 2, and historical comparison with usual treatment  
5. Association between change in headache pain and symptom scores and selected subject baseline 
characteristics, including for example, migraine with/without aura, relationship to menstrual cycle 


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11. Study measurements 
11.1 Clinical assessments 
11.1.1 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 migraine history, to include frequency, duration and severity of headaches, will be recorded. Sufficient 
information should be collected to confirm the diagnosis, ie intensity, throbbing/nonthrobbing, aggravating 
factors, aura, unilateral or bilateral, associated symptoms, eg photophobia, phonophobia, nausea, 
vomiting, cognitive impairment, dizziness, functional disability, most troublesome symptom.  
11.1.2 Demographics 
Demographic information will include the subject’s age, gender and ethnic affiliation. 
11.1.3 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.    
Any subject with an abnormal ECG at screening that is considered clinically significant will be excluded 
from the study. 
11.1.4 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 or semi-supine position for at least 5 minutes prior to and during 
vital signs measurement. 
11.1.5 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.  
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.  
11.1.6 Height and weight 
Height (centimetres) and weight (kilogram), without shoes, will be measured and BMI calculated.  


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11.2 Laboratory assessments 
11.2.1 Clinical safety testing 
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.  
11.2.1.1 
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 
11.2.1.2 
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 
11.2.1.3 
Liver function tests 
Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline 
phosphatase, conjugated bilirubin, total bilirubin 
11.2.1.4 
Coagulation 
Activated partial thromboplastin time, international normalised ratio 
11.2.1.5 
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. 
11.2.2 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 at other time points. 
11.3 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 13.2. 
11.4 Concomitant medications 
Changes in use or new medications used during course of study will be documented and reviewed at 
each study visit.  
11.5 Efficacy assessments 
11.5.1 Pain intensity 
Migraine pain intensity will be recorded using the NRS in a subject migraine diary at the start of dosing (t 


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= 0 min) and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. The NRS is an 11-point scale which grades 
pain from 0 (no pain) to 10 (worst pain imaginable). Pain should reflect the subject’s pain at the time of 
recording. 
11.5.2 Migraine symptoms 
Each subject will specify his/her most troublesome symptom at baseline (Day 1).  
On the day of a migraine headache, baseline information about the headache should be recorded to 
verify that the headache was an acute migraine headache including headache intensity, aura, presence 
or absence of associated symptoms, unilaterality or bilaterality of the headache, aggravation by exercise, 
throbbing or nonthrobbing.  
The subject’s symptoms will be recorded on an 11-point Likert scale. This scale allows the subject to 
record the presence of the symptom from 0 = no symptoms to 10 being severe symptoms. Symptom 
assessments will be recorded in the subject’s diary prior to dosing (t = 0 min) and at 0.5, 1, 1.5, 2, 4, 8 
and 24 hours post dose. Symptoms to be recorded include nausea, photophobia and phonophobia plus 
the subject’s most troublesome symptom (eg cognitive impairment, dizziness and functional disability) if 
other than nausea, photophobia or phonophobia. Episodes of vomiting will also be recorded. 
11.5.3 Subject satisfaction 
Subject satisfaction with treatment will be recorded at the end of each treatment period on a 7-point Likert 
scale, with 1 = very satisfied and 7 being very dissatisfied. Subjects will also be asked to record their 
satisfaction compared with their usual anti-migraine therapy. Subjects will be asked to complete the 
satisfaction survey for each Treatment period only if the dose has been taken for that period and the 
Treatment Preference survey only if doses have been taken in both Treatment periods. 


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12. Study oversight 
12.1 Within-subject stopping criteria  
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. 
12.2 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. 
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 15.1.4. 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 9.6 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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13. Adverse events 
13.1 Definitions 
13.1.1 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 (ie 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 13.3). An adverse event is defined 
as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 13.1.6. 
13.1.2 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. 
13.1.3 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 (ie 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. 
13.1.4 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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13.1.5 Severity (intensity) of adverse event 
Grade refers to the intensity of an AE and should not be confused with seriousness (refer Section 13.1.6). 
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. 
13.1.6 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.   
13.2 Recording of adverse events 
In this study, events from Screening to prior to first dose of IMP will be captured as medical history. All 


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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 visit.   
AEs that are ongoing at the End of study visit will be followed up until the event has resolved or 
stabilised. All followup 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 13.4. 
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. 
13.3 Clinical lab abnormalities and other abnormal assessments  
Abnormal laboratory findings (eg, clinical chemistry, haematology, and urinalysis) or other abnormal 
assessments (eg, 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.    
13.4 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. 
Followup 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 followup 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 13.1.3). If the sponsor considers the SAE to be drug related (ie an adverse drug 


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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.  
13.5 Followup 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. Followup investigations may be necessary according to the investigator’s medical 
judgement. 


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14. Statistical analysis 
14.1 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, data derivations and presentation. 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. All data will be listed for all subjects. Treatment 
period order will be ignored in any treatment comparisons. Results will be presented in a descriptive 
format by treatment within each treatment period and overall. Treatment comparisons will take into 
account the paired nature of the treatment responses where feasible. As this is a Phase IIa proof of 
concept study, no formal statistical hypotheses are being specified although some may be investigated 
as part of the data presentation, in which case corresponding 95% confidence intervals will be presented 
and p-values of <0.05 will be declared statistically significant. 
14.2 Sample size 
No formal statistical sample size estimation has been performed due to the exploratory nature of this 
study. Rather the sample size is based on clinical and practical considerations. 
14.3 Analysis populations 
14.3.1 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. 
14.3.2 Per protocol population 
A per-protocol (PP) population will be used for efficacy analyses and to analyse exploratory endpoints. 
The PP population will be based on IMP exposure, including the time of any episodes of vomiting and 
major protocol deviations.  
14.3.3 Safety population 
The safety population consists of all randomised subjects who receive at least one dose of IMP. The 
safety population will be used for the analysis of safety and tolerability data. Subjects will be analysed as 
treated, regardless of the randomised treatment assigned, if this differs from that to which the subject was 
randomised. 
14.4 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. 
14.5 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 


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summary tables and results will be presented for the FAS population. 
Individual pain score-time profiles for each treatment within each subject will be presented graphically. 
The difference between the NRS pain scores at each timepoint for LAT8881 60 mg compared with 
placebo within each subject will be estimated and presented graphically. The number of subjects, mean, 
standard deviation, minimum and maximum NRS pain score at each timepoint, change from baseline, 
difference between treatments at each timepoint and change from baseline difference between 
treatments will be presented for each treatment overall and within each treatment period. 
Nausea, photophobia and phonophobia symptom scores will be summarised and presented in the same 
way as the pain scores. The number and percent of headaches with each most troublesome symptom of 
migraine including nausea, cognitive impairment, dizziness, functional disability, photophobia and 
phonophobia will be summarised for each treatment. The most troublesome symptom scores will be 
summarised and presented in the same way as the pain scores. 
The number and percent of subjects with 'no headache pain' at each time point will be presented for each 
treatment. Two-way tables will present the presence/absence of pain classified for each treatment at 
each timepoint. Absence of pain will be defined as a pain NRS score of 0 or 1. 
The number and percent of subjects who are “sustained pain-free” at 24 hours after dose of IMP will be 
presented by treatment. A two-way table will present the “sustained pain-free” status for subjects on each 
treatment.  
The number and percent of subjects will be summarised by their first pain-free timepoint. A two-way table 
will present the classification of each subject’s first pain-free timepoint by treatment. Kaplan-Meier curves 
will present the time to first pain-free timepoint.  
Patient satisfaction for each treatment recorded on a 7-point Likert scale and the within-subject difference 
between treatments will be summarised. The mean difference between treatments will be compared with 
a paired t-test and the 95% confidence interval for the mean difference will be presented. Additional 
exploratory analyses to investigate the association between change in headache pain and symptom 
scores and selected subject baseline characteristics will be undertaken in a similar fashion with 
descriptive statistics. 
14.5.1 Analgesic use 
Rescue medication use over the treatment period will be listed for each subject. 
14.6 Analysis of safety data 
14.6.1 Extent of exposure 
The number of subjects exposed to study treatment, and total IMP administered within each period and 
overall, will be summarised.  
14.6.2 Adverse events 
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 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 


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• 
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 13.1 for adverse event definitions. 
14.6.3 Clinical laboratory evaluations 
Safety laboratory data (haematology, biochemistry, 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. 
14.6.4 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.  
 
 
 


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15. Study management 
15.1 Regulatory and ethical considerations 
15.1.1 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 Helsinki16 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.   
15.1.2 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.  
15.1.3 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 15.1.4. 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. 
15.1.4 Protocol amendments 
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 


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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.  
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 (eg 
protocol, PIS, ICF) to the site.  
15.1.5 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. 
15.2 Quality control and quality assurance 
15.2.1 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.  
15.2.2 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. 


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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. 
15.2.3 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, ie eCRF and laboratory data) will be integrated into a validated Data Management System 
with full audit trail capability (ie 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 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. 
15.2.4 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.  


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In accordance with ICH GCP, this study may be selected for audit. Inspection of site facilities (eg 
pharmacy, medication storage areas, laboratories) and review of study-related records may occur by the 
sponsor, sponsor’s representative, ethics committee or regulatory authority to evaluate the study conduct 
and compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
The regulatory authority or ethics committee inspectors are responsible for contacting and visiting the 
investigative site for the purpose of inspecting the facilities, if required, and, upon request, inspecting the 
various records of the study (eg 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.  
15.3 Documentation, record access and archiving 
15.3.1 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.    
15.3.2 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. 
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. 


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15.3.3 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 
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 (ie, 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, 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.  
15.4 Study administration 
15.4.1 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. 
15.4.2 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 


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unpublished. The confidentiality obligation applies to all personnel involved at the study site. However, 
authorised regulatory officials and the sponsor’s personnel (or their representatives) will be allowed full 
access to inspect and copy the records. All IMPs, 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 
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. 
15.4.3 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. 
15.4.4 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)17. 
15.4.5 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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16. References 
 
1 International Conference on Harmonisation (ICH) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical 
Practice E6(R2), 9 November 2016 
2 IHS Classification ICHD-3 https://www.ichd-3.org/1-migraine/ 
3 Headache Classification Committee of the International Headache Society (IHS) The International Classification of 
Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan; 38 (1):1-211. doi: 10.1177/0333102417738202 
4 Chawla J. Migraine Headache. Medscape Jan 31, 2019 Available at 
https://emedicine.medscape.com/article/1142556-overview. Accessed 1 May, 2019 
5 Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015 Apr 
29; 35(17):6619-29. doi: 10.1523/JNEUROSCI.0373-15.2015 
6 Yeh WZ, Blizzard L, Taylor BV. What is the actual prevalence of migraine? Brain Behav. 2018 Jun;8(6):e00950. doi: 
10.1002/brb3.950. Epub 2018 May 2. 
7 GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, 
prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic 
analysis for the Global Burden of Disease Study 2016. Lancet. 2017 Sep 16; 390: 1211-1259. doi: 10.1016/S0140-
6736(17)32154-2. 
8 Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache. 2005 Apr;45 
Suppl 1:S3-S13 
9 Deloitte Access Economics. Migraine in Australia Whitepaper. Prepared for Novartis Australia 2018. Available at 
https://www2.deloitte.com/content/dam/Deloitte/au/Documents/Economics/deloitte-au-economics-migraine-australia-
whitepaper-101018.pdf. Accessed 26 April, 2019. 
10 American Headache Society 2018.The American Headache Society position statement on integrating new 
migraine treatments into clinical practice. Headache 2019; 59: 1-18 
11 Biondi DM. Is migraine a neuropathic pain syndrome? Curr Pain Headache Rep. 2006 Jun;10(3):167-78. 
12 European Medicines Agency. Guideline on Clinical Investigation of Medicinal Products for the Treatment of 
Migraine, Doc. Ref. CPMP/EWP/788/01 Rev. 1. London, 24 January 2007 
13 Diener HC, Tassorelli C, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari MD, Goadsby PJ, 
Pozo-Rosich P, Wang SJ, Mandrekar J; International Headache Society Clinical Trials Standing Committee. 
Guidelines of the International Headache Society for controlled trials of acute treatment of migraine attacks in adults: 
Fourth edition. Cephalalgia. 2019 Feb 26 
14 FDA Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers. July 2005 
15 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) 
16 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical 
research involving human subjects. JAMA. 2013;310(20):2191-2194 
17 International Conference on Harmonisation (ICH) Note for Guidance: Structure and Content of Clinical Study 
Reports. CPMP/ICH/137/95, December 1995. 

SAP_001.pdf: 
 
Zifo RnD Solutions  
Confidential  
  
Created using Template: SAO.022.REC.Statistical Analysis Plan, Ver# 2.01  
 
Official title: A proof of concept study of the efficacy and safety of 
oral LAT8881 in acute migraine 
 
 
NCT number: NCT04153409 
 
 
Document date: February 27, 2020 
 
 
 
 


 
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Created using Template: SAO.022.REC.Statistical Analysis Plan, Ver# 2.01  
Statistical Analysis Plan  
 
Sponsor Name  
Lateral Pharma Pty Ltd  
Protocol ID  
LAT-MIG-001  
Protocol Version  
1.0 (dated 25 July 2019)  
Study Name  
LAT-MIG-001  
Study Title  
A proof of concept study of the efficacy and safety of oral LAT8881 
in acute migraine  
CRF Version  
Metadata version 1.1  
Document ID  
LAT-MIG-001_Statistical Analysis Plan  
Document Version  
1.00  
 
Author:  
  
  
  
Sangeetha, S  
Biostatistician  
   
  
  
  
 Reviewer:  
  
  
Caro Badcock  
 Consultant Statistician  
  
 
  
Signature   
Date   


 
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Confidential  
  
Created using Template: SAO.022.REC.Statistical Analysis Plan, Ver# 2.01  
Approver:  
  
  
  
Nicole Wallis  
Project Manager, Lateral Pharma Pty Ltd  
  
  
  
  
Table of Contents  
1 
Definitions ....................................................................................................................................... 6 
2 
Introduction .................................................................................................................................... 7 
2.1 
Background ............................................................................................................................. 7 
2.2 
Rationale ................................................................................................................................. 7 
3 
Study Objectives ............................................................................................................................. 8 
3.1 
Primary Objective.................................................................................................................... 8 
3.2 
Secondary Objectives .............................................................................................................. 8 
3.3 
Exploratory Objectives ............................................................................................................ 8 
4 
Study Design ................................................................................................................................... 8 
4.1 
Overview ................................................................................................................................. 8 
4.2 
Sample Size Justification ......................................................................................................... 9 
4.3 
Randomisation and Blinding ................................................................................................... 9 
4.4 
Inclusion/Exclusion Criteria ................................................................................................... 10 
4.4.1 
Inclusion Criteria: .......................................................................................................... 10 
4.4.2 
Exclusion Criteria: .......................................................................................................... 11 
4.5 
Treatment allocation............................................................................................................. 12 
5 
Assessment Schedule .................................................................................................................... 13 
6 
Interim Analysis ............................................................................................................................ 15 
7 
Efficacy and Safety Endpoints ....................................................................................................... 15 
7.1 
Primary Efficacy Endpoints ................................................................................................... 15 
7.2 
Secondary Efficacy Endpoints ............................................................................................... 15 
7.3 
Safety Endpoints ................................................................................................................... 15 
7.4 
Exploratory Endpoints ........................................................................................................... 15 


 
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8 
Statistical Methods ....................................................................................................................... 16 
8.1 
Changes to Planned Analyses ............................................................................................... 16 
8.2 
Handling Missing/Incomplete Data ...................................................................................... 17 
8.3 
Handling Outliers .................................................................................................................. 17 
8.4 
Multiplicity Adjustment ........................................................................................................ 17 
9 
Analysis Populations ..................................................................................................................... 17 
9.1 
Full Analysis Set (FAS) ........................................................................................................... 17 
9.2 
Per Protocol (PP) Population................................................................................................. 17 
9.3 
Safety Population .................................................................................................................. 18 
10 
Analysis Variables ..................................................................................................................... 18 
10.1 
Population Flags .................................................................................................................... 18 
10.2 
Treatment groups ................................................................................................................. 18 
10.3 
Visits ...................................................................................................................................... 18 
10.4 
Study Periods ........................................................................................................................ 19 
10.5 
Completion Flags ................................................................................................................... 19 
10.6 
Study Duration ...................................................................................................................... 20 
10.7 
Migraine History.................................................................................................................... 20 
10.8 
Medical History and Concurrent Diseases ............................................................................ 20 
10.9 
Prior and Concomitant Medications ..................................................................................... 20 
10.10 
Adverse Event Flags .......................................................................................................... 21 
10.11 
Laboratory Assessments ................................................................................................... 22 
10.12 
Baseline ............................................................................................................................. 22 
10.12.1 
Safety Endpoints ....................................................................................................... 22 
10.12.2 
Efficacy Endpoints ..................................................................................................... 22 
10.13 
Change from Baseline ....................................................................................................... 22 
10.14 
Extent of Exposure ............................................................................................................ 22 
10.15 
Analysis Flags .................................................................................................................... 22 


 
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10.15.1 
Difference between Treatments ............................................................................... 22 
10.15.2 
Sustained Pain-Free .................................................................................................. 23 
10.15.3 
Time Deviated from Scheduled Timepoints .............................................................. 23 
10.15.4 
Responder ................................................................................................................. 23 
10.15.5 
Time to First Pain-Free Timepoint ............................................................................ 23 
10.16 
Paired Difference in Pain-Free Subjects ............................................................................ 23 
10.17 
Preferred Treatment ......................................................................................................... 24 
10.18 
Subgroups for exploratory analysis ................................................................................... 24 
11 
Statistical Analyses ................................................................................................................... 25 
11.1 
Subject Disposition ................................................................................................................ 25 
11.2 
Protocol Deviations ............................................................................................................... 26 
11.3 
Demographic and Baseline Characteristics ........................................................................... 26 
11.4 
Migraine History.................................................................................................................... 27 
11.5 
Medical/Surgical History ....................................................................................................... 27 
11.6 
Prior and Concomitant Medications ..................................................................................... 27 
11.7 
Extent of Exposure ................................................................................................................ 28 
11.8 
Efficacy Analyses ................................................................................................................... 29 
11.8.1 
Primary Efficacy analyses – NRS Pain Scores ................................................................ 29 
11.8.1.1 
Descriptive summary ............................................................................................ 29 
11.8.1.2 
Time-Trend Plots ................................................................................................... 29 
11.8.1.3 
Mixed Effect Regression Model for repeated measurements (MMRM) .............. 30 
11.8.2 
Secondary Efficacy Analyses ......................................................................................... 31 
11.8.2.1 
NRS Symptom Scores ............................................................................................ 31 
11.8.2.2 
Time-Trend Plots ................................................................................................... 31 
11.8.2.3 
Most Troublesome Symptom ............................................................................... 31 
11.8.2.4 
Time-Trend Plots ................................................................................................... 32 
11.8.2.5 
No Headache Pain ................................................................................................. 32 
11.8.2.6 
Migraine and Headache Diary ............................................................................... 33 
11.8.3 
Exploratory Analysis ...................................................................................................... 33 


 
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11.8.3.1 
Sustained Pain-free at 24 Hours ........................................................................... 33 
11.8.3.2 
Time to First Pain-free Timepoint ......................................................................... 33 
11.8.3.3 
Subject Satisfaction Survey ................................................................................... 33 
11.8.3.4 
Association between Change in NRS Pain Score and Baseline Characteristics ..... 34 
11.9 
Safety Analyses ..................................................................................................................... 35 
11.9.1 
Adverse Events .............................................................................................................. 35 
11.9.1.1 
Overall Adverse Events ......................................................................................... 35 
11.9.1.2 
Summary of Adverse Events by SOC and PT ......................................................... 36 
11.9.1.3 
Summary of Treatment emergent Adverse Events by SOC, PT, Relationship and 
Severity 
36 
11.9.2 
Laboratory Assessments ............................................................................................... 36 
11.9.2.1 
Continuous Summary ............................................................................................ 36 
11.9.2.2 
Listings ................................................................................................................... 36 
11.9.3 
Other Safety Analyses ................................................................................................... 37 
11.9.3.1 
Vital Signs .............................................................................................................. 37 
11.9.3.2 
Physical Examination ............................................................................................. 38 
11.9.3.3 
Electrocardiogram Assessments ........................................................................... 38 
11.9.3.4 
Telephone Visits .................................................................................................... 38 
12 
Index of Tables, Listings and Graphs ........................................................................................ 38 
13 
References ................................................................................................................................ 38 
14 
Appendices ............................................................................................................................... 38 
15 
Change Log ............................................................................................................................... 39 
 


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Created using Template: SAO.022.REC.Statistical Analysis Plan, Ver# 2.01  
LAT - MIG - 001  
LAT - MIG - 001 _Statistical Analysis Plan  
Ver:  1 .0 0  
1 Definitions  
Abbreviation  
Definition  
ADR  
Adverse Drug Reaction  
ATC  
Anatomical Therapeutic Chemical Classification  
BMI  
Body Mass Index  
CI  
Confidence Interval  
CS  
Clinically Significant  
DDP  
Data Display Plan  
AE  
Adverse Event  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
EOS  
End of Study  
FAS  
Full Analysis Set  
ICH  
International Conference on Harmonisation  
IMP  
Investigational Medicinal Product  
LSMeans  
Least Square Means  
Max  
Maximum  
MedDRA  
Medical Dictionary for Regulatory Activities  
Min  
Minimum  
MMRM  
Mixed Model for Repeated Measures  
NRS  
Numeric Rating Scale  
NTF  
Note-to-File  
PP  
Per Protocol  
PT  
Preferred Term  
SAE  
Serious Adverse Event  


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SAP  
Statistical Analysis Plan  
SD  
Standard Deviation  
SOC  
System Organ Class  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TEAE  
Treatment Emergent Adverse Event  
WHODD  
World Health Organization Drug Dictionary  
  
  
2 Introduction  
2.1 Background  
Migraine is a disabling neurovascular disorder, characterised by moderate to severe headaches which 
are usually throbbing, affect one side of the head and are accompanied by nausea and sensitivity to 
light and/or sound. It is one of the most common chronic conditions worldwide.  
The most common migraine types are migraine without aura (common migraine) and migraine with 
aura (classic migraine).  
Migraine without aura is identified by headache symptoms lasting 4–72 hours, commonly with a 
unilateral location, pulsating quality of moderate or severe intensity, aggravated by routine physical 
activity and associated with nausea and/or light and sound sensitivity. Diagnosis is based on at least 
five attacks.  
Migraine with aura is identified by recurrent attacks, lasting minutes, of unilateral fully reversible 
visual, sensory or other central nervous system symptoms that usually develop gradually and are 
commonly followed by headache and associated migraine symptoms. Diagnosis of migraine with aura 
requires at least two such attacks.  
This is the first clinical study with LAT8881 in migraine and will assess its potential for treating acute 
migraine in a proof of concept trial.  
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  (previously known 
as AOD9604) and subsequently its efficacy in the treatment of obesity (METAOD005, METAOD006).  
A seventh study (LAT-NP-001) to investigate the safety and efficacy of LAT8881 in neuropathic pain at 
a dose of 60 mg per day (30 mg twice daily) has recently commenced and is recruiting subjects. No 
results from this study are yet available.  
In all development studies for obesity, 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 


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general body symptoms of abdominal pain and headache in Study METAOD004 at 54 mg. This trend 
was not observed in subsequent studies.  
3 Study Objectives  
3.1 Primary Objective  
To evaluate the effect of oral LAT8881 on migraine headache compared with placebo, when assessed 
by the headache severity on an 11-point Numeric Rating Scale (NRS)  
3.2 Secondary Objectives  
1. To evaluate the effect of oral LAT8881 on migraine-associated symptoms compared with 
placebo, when assessed by the change in symptoms based on a 11- point Likert scale  
2. To investigate the percentage of subjects achieving “no headache pain” following treatment 
with oral LAT8881 compared with placebo at any timepoint to 8 hours post dose, with no use 
of rescue medication  
3. To evaluate the safety and tolerability of single doses of oral LAT8881 in subjects with migraine 
headache   
3.3 Exploratory Objectives  
1. To investigate the percentage of subjects who are “sustained pain-free,” defined as having no 
headache pain following treatment with oral LAT8881 for a migraine headache compared with 
placebo, with no use of rescue medication and no relapse of headache pain within 24 hours 
(24-hour sustained pain-free) after administration  
2. To investigate the time to first pain-free timepoint following treatment with oral LAT8881 for 
a migraine headache compared with placebo to 24 hours post dose, with no use of rescue 
medication  
3. To determine the need for extra analgesic (rescue) medication after treatment with oral 
LAT8881 administration for a migraine headache, compared with placebo  
4. To investigate subject satisfaction with treatment of a migraine headache  
5. To investigate other factors influencing the extent of change in pain score and symptom scores 
in subjects with migraine headaches  
4 Study Design   
4.1 Overview  
This is a randomised, placebo-controlled, double-blind, crossover, Phase IIa proof of concept study to 
investigate the efficacy and safety of oral LAT8881 in acute migraine headache with or without aura.   
During the screening period, potential subjects will keep a diary to record onset and duration of 
headaches, including pain and symptom scores and concomitant medications over a 4-5 week period.  


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Females of childbearing potential will also record menstrual cycles. Subject will nominate their most 
troublesome symptom.  
Subjects entered into the study will be randomised to receive IMP (LAT8881 60 mg or placebo), to be 
taken at the onset (within one hour from the onset of pain) of a migraine headache of moderate to 
severe intensity [Numeric rating scale (NRS) ≥4]. Rescue medication should not be taken until at least 
2 hours post dose. Subjects will be given one dose of IMP (2 capsules), to treat one migraine headache.  
Subjects will complete diaries to record menstrual cycle (in menstruating females), onset and nature 
of migraine and non-migraine headaches, pain scores at time of IMP dosing and various time points 
post dose, associated symptoms and rescue medication. Adverse events will be monitored.  
After treatment of one migraine headache (or a maximum 28 days) the subject will return to the clinic 
for re-evaluation and crossover to the second treatment. In the second treatment period, they will take 
IMP in the same manner as in treatment period 1.  
A followup (End of study) visit will occur within 7 days after treatment of one migraine headache in the 
second treatment period or a maximum 8 weeks from randomisation.  
Subjects will complete diaries to record menstrual cycle (in menstruating females), onset and nature 
of migraine and non-migraine headaches, pain scores at time of IMP dosing and various time points 
post dose, associated symptoms and rescue medication. Adverse events will be monitored.   
4.2 Sample Size Justification  
It is planned to have 20 subjects complete the study, defined as taking one dose of IMP in each 
treatment period and attending the follow-up (End of study) visit.  
Assuming up to 20% of subjects do not treat one migraine headache in each treatment period or 
dropout of the study, 26 subjects will be enrolled in the study.  
If the dropout rate or non-completion rate is higher than anticipated, additional subjects may be 
enrolled to ensure 20 subjects complete the study.  
4.3 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.  
Details regarding randomisation are provided in the LAT-MIG-001_Randomisation Plan (v2.00), and 
instructions for unblinding are provided in the LAT-MIG-001_Unblinding Plan (v1.00).  


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4.4 Inclusion/Exclusion Criteria  
4.4.1 Inclusion Criteria:  
Subjects must meet the following criteria to be entered into the study:  
1. Males or females aged 18 to 75 years at the time of consent  
2. Diagnosis of episodic migraine headache at least 12 months ago with or without aura as 
defined in ICHD-3-beta  
3. Onset of migraine headache before age 50  
4. Medical history of 2 - 8 migraine headache attacks per month for the previous 12 months;   
≥ 75% of attacks progress to moderate or severe pain within 2 hours (i.e., rapidly-escalating)  
5. Minimum 48 hours on average between migraine headache attacks  
6. Acute headache medication on ≤ 14 days/month in the 3 months prior to screening  
7. Willing and able to comply with all study procedures including completion of a headache diary 
and a migraine diary on the day of a migraine headache  


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8. Female subjects must be:  
a) of non-child-bearing potential [surgically sterilised or postmenopausal (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  
9. Male subjects with female partners of childbearing potential must use adequate and highly 
effective methods of contraception, from screening until 28 days after their last IMP 
administration.  
10. Subjects must be sufficiently competent in English to understand the purposes and risks of the 
study and to provide written informed consent  
4.4.2 Exclusion Criteria:  
Subjects who meet any of the following criteria will be excluded from the study:  
1. Unable to distinguish migraine from other primary headache conditions  
2. Average of 15 or more headache (migraine or non migraine) days per month or history of more 
than 25% of headaches occurring at time of wakening (wake up headaches)  
3. History of aura lasting more than 60 minutes  
4. History of vomiting within 2 hours of onset of a migraine headache in more than 25% of 
migraine headaches  
5. Medication overuse headache, defined as:  
a. use of opioids, triptans or ergot alkaloids or any combination of these medications for 
treatment of headaches 10 or more days per month during the 90 days prior to 
screening OR  
b. Non-steroidal anti-inflammatory drugs (NSAIDs) or simple analgesics for treatment of 
headaches on more than 14 days per month during the 90 days prior to screening  
6. Recent (3 years) history of frequent or chronic hemiplegic/ basilar migraine, tension headache, 
retinal migraine, ophthalmoplegic migraine as per ICHD classification, or treatment resistant 
atypical migraine  
7. Hospital admission for status migrainosis or medication overuse headache within 6 months of 
screening  
8. Current clinically significant systemic disease or neurological or psychiatric condition which in 
the opinion of the investigator or sponsor could jeopardise the safety of the subject or the 
validity of the study results  


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9. Cerebrovascular disease, including but not limited to a history of stroke or recent (3 years) 
transient ischaemic attack (TIA)  
10. Major surgery within 6 weeks of screening or planned during the study period  
11. Clinically significant abnormality as assessed by the investigator or sponsor’s medical monitor 
on haematology, biochemistry, vital signs, physical examination or 12-lead electrocardiogram 
(ECG)  
12. Malignancy within 5 years of screening, with the exception of carcinoma in situ, nonmelanoma 
skin cancers and prostate cancer not requiring treatment or on stable (> 6 months) treatment 
with hormone therapy  
13. History of alcohol abuse, illicit or illegal drug use in the last 2 years  
14. Use of Prohibited medications or treatments within the specified time period before Screening 
or planned during the study  
15. Participation in another clinical trial or administration of any investigational product or 
experimental product within 60 days or 5 half-lives (whichever is longer)  
16. History of significant hypersensitivity to LAT8881 (formerly known as AOD9604), excipients in 
the drug product formulation or drugs of a similar chemical or pharmacological class.  
17. Surgical or medical conditions which could significantly alter drug absorption, distribution, 
metabolism or excretion  
18. 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  
4.5 Treatment allocation  
Subjects entered into the study will be randomised to receive IMP (LAT8881 60 mg or placebo), to be 
taken at the onset (within one hour from the onset of pain) of a migraine headache of moderate to 
severe intensity.   
After treatment of one migraine headache (or a maximum 28 days) the subject will return to the clinic 
for re-evaluation and crossover to the second treatment.   
  
  


 
 
LAT-MIG-001  
LAT-MIG-001_Statistical Analysis Plan  
Ver: 1.00  
  
5 Assessment Schedule  
 
1 Or maximum 5 business days after dose of IMP   
2 Or 7 days after Visit 4   
3 Females of childbearing potential only, blood test at screening, urine other occasions   


 
4 Full physical examination   
5 Targeted physical examination   
6 Haematology, biochemistry, urinalysis   
7 Migraine episode only   
8 Headache diary during both non-migraine and migraine headaches   
9 Migraine diary, during migraine headaches    
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6 Interim Analysis  
No interim analysis planned for this study.   
7 Efficacy and Safety Endpoints  
7.1 Primary Efficacy Endpoints  
Change in migraine headache pain score, using an 11-point NRS, (0 = none, 10 = worst imaginable), 
from the time of dosing to 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. Pain is recorded in a subject 
diary and should reflect the subject’s pain at the time of recording.  
7.2 Secondary Efficacy Endpoints  
1. Change in migraine-associated symptoms of nausea, photophobia and phonophobia. 
Symptoms are assessed on an 11- point Likert scale with 0 = no symptoms and 10 being severe 
symptoms at time of dosing and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose.  
2. Change in each subject’s most troublesome symptom that may include nausea, photophobia 
and phonophobia cognitive impairment, dizziness and functional disability. Symptoms are 
assessed on an 11- point Likert scale with 0 = no symptoms and 10 being severe symptoms at 
time of dosing and at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose.  
3. The percentage of subjects achieving “no headache pain” at 0.5, 1.0, 1.5, 2, 4 and 8 hours post 
dose.  
7.3 Safety Endpoints  
1. Changes in physical examinations and vital signs  
2. Changes in clinical laboratory tests  
3. Percentage of Treatment emergent adverse events (TEAEs), including serious adverse events  
(SAEs), and suspected unexpected serious adverse reactions (SUSARs)  
4. Changes in concomitant medications  
7.4 Exploratory Endpoints  
1. The percentage of subjects who are “sustained pain-free,” defined as having no migraine 
headache pain at 24 hours, with no use of rescue medication and no relapse of headache pain 
within 24 hours (24-hour sustained pain-free) after administration  
2. The time to first pain-free timepoint following treatment with oral LAT8881 compared with 
placebo to 24 hours post dose, with no use of rescue medication  
3. Supplemental analgesic medication use in the 24 hour post treatment period  
4. Subject satisfaction with each treatment based on a 7-point Likert Scale, overall preference for 
Treatment 1 or Treatment 2, and historical comparison with usual treatment  


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5. Association between change in headache pain and symptom scores and selected subject 
baseline characteristics, including for example, migraine with/without aura, relationship to 
menstrual cycle  
8 Statistical Methods  
Efficacy endpoints will be summarised in a descriptive manner and analysed using statistical methods 
described in section 11.8. Changes over time for the primary and secondary efficacy outcomes will be 
explored using a statistical model as defined in Section 11.8. The level of significance for any statistical 
tests undertaken will be 0.05 and all tests will be two-sided. Any 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)  
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 the 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 Changes to Planned Analyses  
The protocol states that, as this study is a Phase IIa proof of concept study, no formal statistical 
hypotheses are planned to be tested although some may be investigated as part of the data 
presentation. It was expected that treatment effects would be assessed using descriptive statistics 
only and hypothesis tests used minimally.   
However, by allowing subjects to be included in the Per Protocol population with a minimum of one 
dose of IMP, there is a possibility that subjects will be included with efficacy results for only one 
treatment period and unable to have an estimate of the difference between treatments. Hence, fewer 
subjects will be included in the summary results and any analyses for the difference between 
treatments.   


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In order to include the results for all subjects regardless of whether they took IMP in only one or both 
treatment periods a mixed effects model with repeated measurements (MMRM) analysis can be 
undertaken. This approach will be taken for the change from baseline NRS pain score to each 
postbaseline timepoint for each treatment only.  
The remaining endpoints of a continuous nature (change from baseline NRS symptom score, change 
from baseline NRS symptom score for the most troublesome symptom, subject satisfaction with IMP, 
subject satisfaction with IMP compared with usual medication for an acute migraine attack) may be 
analysed using the MMRM approach depending on the number of subjects who complete both 
treatment periods. The decision will be made at the blind review meeting prior to database lock.  
8.2 Handling Missing/Incomplete Data  
Partial dates will not be imputed.   
Flags identifying the study period for the start/stop dates for prior/ concomitant medications and 
adverse events will be generated (see Sections 10.9 and 10.10).   
The method for missing data imputation for the primary endpoint will be discussed during the blinded 
review meeting prior to database lock.  
8.3 Handling Outliers  
Laboratory results with modifiers will be analysed with the maximum or minimum value defined 
without the modifiers. For example, a value of “<5” will be considered as “5” for summaries.  
8.4 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 will be performed 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 finalised during the blind review of the 
data conducted prior to database lock.  
9.1 Full Analysis Set (FAS)  
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.  
9.2 Per Protocol (PP) Population  
The Per Protocol (PP) population will include all subjects who received at least one dose of IMP and 
excludes subjects who have any major protocol deviation impacting the study endpoints. Deviations 


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for exclusion from the PP population due to inadequate exposure to IMP or completeness of primary 
efficacy endpoint will be determined during the blinded review meeting prior to database lock.  
A per-protocol (PP) population will be used for efficacy analyses and to analyse exploratory endpoints.   
9.3 Safety Population  
The safety population consists of all randomised subjects who receive at least one dose of IMP.   
The safety population will be used for the analysis of safety and tolerability data. Subjects will be 
analysed as treated, regardless of the randomised treatment assigned, if this differs from that to which 
the subject was randomised.  
10 Analysis Variables  
10.1 Population Flags  
Population flags will be finalised and authorised 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 groups  
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:  
Visit as per CRF  
Study Period  Analysis Visit  
Visit 1 (Days -28 to -1)  
-  
Visit 1 (Screening)  
Day 1, Visit 2  
Period 1  
Visit 2  
Day 15, Telephone Visit 1  
Period 1  
-  
Day 29, Visit 3  
Period 1  
Visit 3  
Day 44, Telephone Visit 2  
Period 2  
-  
Day 57, Visit 4  
Period 2  
Visit 4  
Day 64, Visit 5 or Early Termination  Period 2  
Visit 5 (End of Study)  


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Analysis timepoints for efficacy endpoints within each study period will be defined as follows:  
Timepoint as per CRF  
Analysis Timepoint  
Before IMP was taken (Pre-dose)  
Pre-dose  
30 minutes after IMP taken (t=0.5 hrs)  
30 minutes  
1 hour after IMP taken (t=1 hr)  
1 hour  
1.5 hours after IMP taken (t=1.5 hrs)  
1.5 hours  
2 hours after IMP taken (t=2 hrs)  
2 hours  
4 hours after IMP taken (t=4 hrs)  
4 hours  
8 hours after IMP taken (t=8 hrs)  
8 hours  
24 hours after IMP taken (t=24 hrs)  
24 hours  
10.4 Study Periods  
• 
Screening: Day -28 to Day -1  
• 
Period 1: Visit 2 to Visit 3  
• 
Period 2: Day after Visit 3 to Visit 5*  
*Subjects who had a migraine event and took period 2 dose of IMP on the same day as Visit 3 will be 
identified and study periods for such subjects will be defined in the blinded review meeting.  
Study periods for adverse events and concomitant medications will be assigned as below. • 
 
Pre-IMP: Screening to first dose of IMP (irrespective of study period)  
• 
Period 1: IMP date at period 1 to IMP date at period 2.  
• 
Period 2: On and after IMP date at period 2.  
Study periods will be considered to set analysis visits.  
10.5 Completion Flags  
• 
Subjects are considered to have completed period 1 when Visit 3 is completed.  
• 
Subjects are considered to have completed period 2 when Visit 4 is completed.  
• 
Subjects are considered to have completed study when EOS at Visit 5 is completed.  


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10.6 Study Duration  
Study duration will be calculated as,   
Study Duration (days) = (Date of EOS / Early Termination visit – Date of Informed Consent) + 1.  
10.7 Migraine History  
Time since migraine diagnosis (years) = (Informed consent date – date of migraine 
diagnosis)+1/365.25.  
10.8 Medical History and Concurrent Diseases  
Medical history with an end date prior to Visit 2 will be considered as medical history.   
Medical history with missing end date or ongoing during Visit 2 will be considered as concurrent 
diseases. Adverse events occurring after Visit 2 and before IMP (Period 1) will also be flagged in the 
analysis datasets and summarised as concurrent diseases.   
10.9 Prior and Concomitant Medications  
Medications will be summarised by the study periods below: • 
 
Prior: Pre-Day 1  
 
•  Concomitant:  
o Pre-IMP o Post-IMP: LAT8881 60 mg and 
Placebo  
Study Period  
Rule  
Prior  
Medications that started and ended before Visit 2.  
Pre-IMP  
Medications that are ongoing on or after Visit 2 but before any dose of IMP 
(LAT8881 or placebo) irrespective of study periods.  
Post-IMP: LAT8881  
60 mg and Placebo  
Period 1: Medications that are ongoing on or after dose of IMP (LAT8881 or 
placebo) in period 1 but before IMP in period 2.  
Period 2: Medications that are ongoing on or after dose of IMP (LAT8881 or 
placebo) in period 2.  
If a subject has ongoing medication in more than one study period, then the use of that medication 
will be counted in all applicable study periods. New medications added in the corresponding study 
period and medications that are ongoing from the previous study period will be flagged and 
summarised separately within each study treatment.  
If the medication is started on the same day of IMP dosing, but timing of onset of event in relation to 
IMP dosing is not clear, then, the worst case will be considered (Post-IMP). This will also be raised to 


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the site and if this is confirmed to be before dose then a note to file (NTF) will be created stating the 
same. This will be incorporated into the analysis datasets for analysis purposes.  
10.10 Adverse Event Flags  
Adverse events will be summarised by the study periods below and flags generated:  
• 
Pre-IMP   
• 
Post-IMP: LAT8881 60 mg  
• 
Post-IMP: Placebo  
Study Period  
Rule  
Pre-IMP  
AEs started before any dose of IMP (LAT8881 or placebo) irrespective of 
periods.  
Post-IMP: LAT8881  
60 mg and Placebo  
Period 1: AEs that started on or after dose of IMP (LAT8881 or placebo) in 
period 1 but before IMP in period 2.  
Period 2: AEs that started on or after dose of IMP (LAT8881 or placebo) in 
period 2.  
An additional flag will be generated for treatment emergent adverse events (TEAE) if they occurred or 
worsened on or after the first administration of IMP (LAT8881 or placebo) irrespective of the study 
period. Adverse events occurring prior to first dose of IMP (LAT8881 or placebo) will not be considered 
as TEAEs. For example, for subjects who had taken the IMP in period 1, any AE post that dose will be 
considered as a TEAE regardless of whether it is before or after the dose of IMP in period 2. For subjects 
who had taken their first dose of IMP in period 2, i.e. did not take IMP during period 1, any AEs post 
IMP in period 2 will be considered as TEAEs.   
If an adverse event occurred in a study period and continues to other study periods, it will be counted 
in all the applicable study periods. New events occurred in the corresponding study period and events 
that are ongoing from the previous study period will be flagged and summarised separately within 
each study treatment.   
AEs that are ongoing from the previous period but just change in severity will still be considered as an 
ongoing AE. This will be identified and manually flagged during the blinded review meeting. AEs that 
are resolved and restart will be considered as a new event.   
If the event occurs on the same day of IMP dosing, but timing of onset of event in relation to IMP 
dosing is not clear, then, worst case will be considered (Post-IMP). This will also be raised to the site 
and if this is confirmed to be before dose then a note to file (NTF) will be created stating the same. 
This will be incorporated into the analysis datasets for analysis purposes.  
Related Adverse Events will be flagged for Possibly, Probably and Definitely Related adverse events.   


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All related SAEs  will be considered  Suspected unexpected serious adverse events (SUSARs) and 
included in analyses datasets.  
10.11 Laboratory Assessments  
Laboratory results marked as clinically significant will be categorised as, “Abnormal, CS” and results 
marked as not clinically significant will be categorised as, “Abnormal, NCS”. Results within normal 
range will be marked as “Normal”. Not done results will be categorised as, “Not Done”.  
10.12 Baseline  
All analysis datasets containing measurements taken at more than one visit/time point will have 
baseline flags.   
10.12.1 
Safety Endpoints  
For safety endpoints, measurement taken at Visit 2 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:  
In both study periods, for NRS Pain Score and 11 point Likert scale for Symptoms (Nausea, Photophobia 
and Phonophobia) scores, ‘Pre-dose’ measurement will be considered as baseline.   
Patients who reported migraine with missing pre-dose result for NRS or symptom scores will be flagged 
and discussed during blinded review meeting to define the baseline measurement.  
10.13 Change from Baseline  
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 Period X, Timepoint Y) – (Period X, Baseline Result)  
10.14 Extent of Exposure  
The following parameters will be derived within each study period for exposure summaries:  
Total dose administered (mg) = number of capsules consumed by the subject * dose level consumed 
in mg  
Number of capsules consumed will be determined by number of capsules returned at Visit 3 or Visit 4. 
Each bottle contains 2 capsules, and number of capsules returned will be subtracted to confirm the 
number of capsules consumed.    
10.15 Analysis Flags  
10.15.1 
Difference between Treatments  
For subjects who took IMP in both visits, difference between their scores at each timepoint will be 
calculated as below.  


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Difference at timepoint X = Score (LAT8881 60 mg) at Timepoint X – Score (Placebo) at timepoint X.  
10.15.2 
Sustained Pain-Free  
Subjects having no use of rescue medication and no relapse of headache pain within 24 hours after 
administration of IMP in each period will be separately flagged as ‘Sustained Pain-free’ for analysis.  
10.15.3 
Time Deviated from Scheduled Timepoints  
Actual time difference from ‘Time IMP was taken’ to each of the timepoints will be calculated and 
discussed during blinded review meeting and any analysis flags may be created to exclude the same.  
Time deviated (hours) = (Time the corresponding timepoint recorded - Time IMP was taken) / 60.  
Time difference between pre-dose measurement and IMP dosing should not be more than 30 mins. 
This difference will also be highlighted in the blinded review meeting.  
10.15.4 
Responder  
Subjects achieving no migraine headache pain at each time point in each study period will be 
separately flagged for analysis. Presence or absence of pain will be determined as follows:   
• 
Absence: NRS Pain score 0 or 1 at the corresponding timepoint.  
• 
Presence: NRS Pain score more than 1 at the corresponding timepoint.  
10.15.5 
Time to First Pain-Free Timepoint  
For NRS scores for pain, subjects achieving no migraine headache pain timepoints will be flagged for 
each subject within each study period. The first pain-free timepoint in which the no migraine (score 0 
or 1) achieved will be considered as the time to first pain-free timepoint. Time to first pain-free 
timepoint will be calculated based on the actual time difference as below.  
Time (hours) = (Time the corresponding timepoint recorded - Time IMP was taken) / 60.  
Subjects who did not achieve no migraine at 24 hours will be censored at 24 hours.   
10.16 Paired Difference in Pain-Free Subjects  
Difference between treatments (LAT8881 – Placebo) for No Headache Pain at each timepoint, 
Sustained Pain-Free at 24 hours and First Pain-Free Timepoint will be calculated as below for the 
percentage difference; the numerator represents the difference in the number of subjects.  
LAT8881  
Placebo  
 
Total  
Pain free  
 
Pain  
Pain free  
a  
 
b  
a + b  
Pain  
c  
 
d  
c + d  


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Total  
a + c  
 
B + d  
a + b + c + d  
  
𝑎 + 𝑐 
𝑷𝒂𝒊𝒏 𝒇𝒓𝒆𝒆 𝒇𝒐𝒓 𝒑𝒍𝒂𝒄𝒆𝒃𝒐 (%) = 
  
𝑎 + 𝑏 + 𝑐 + 𝑑 
  
𝑎 + 𝑏 
𝑷𝒂𝒊𝒏 𝒇𝒓𝒆𝒆 𝒇𝒐𝒓 𝑳𝑨𝑻𝟖𝟖𝟖𝟏 (%) = 
  
𝑎 + 𝑏 + 𝑐 + 𝑑 
  
 
𝑎 + 𝑏 
𝑎 + 𝑐 
𝑏 − 𝑐 
𝑷𝒂𝒊𝒏 𝒇𝒓𝒆𝒆 (𝑳𝑨𝑻𝟖𝟖𝟖𝟏 − 𝑷𝒍𝒂𝒄𝒆𝒃𝒐 )(%) = 
−  = 
 
  
 
𝑎 + 𝑐 + 𝑏 + 𝑑 
𝑎 + 𝑏 + 𝑐 + 𝑑 
𝑎 + 𝑏 + 𝑐 + 𝑑 
  
10.17 Preferred Treatment  
For subject satisfaction score, the preferred treatment will be flagged based on the treatment period 
and assigned treatment. I.e., If a subject has chosen ‘Treatment period 1’ as their preferred treatment, 
then the corresponding treatment group at period 1 will be flagged as their preferred treatment.  
10.18 Subgroups for exploratory analysis  
Below subgroups will be defined in the analysis datasets and used for the additional exploratory 
analyses.  
• 
Age at onset: before 15 years and at 15 years or older.  
Age at onset to be calculated as: (Date of episodic migraine diagnosis - Date of birth + 1)/ 
365.25.  
• 
Sex group: Male, Female (menstruating), Female (non-menstruating) and Female 
(postmenopausal)  
For Female subjects, menstruating and non-menstruating will be determined using the start 
and end dates of the menstrual cycle and the migraine start date. If the migraine start date is 
between start and end date of menstruation, then the subject will be considered as 
‘menstruating’ and ‘non-menstruating’ otherwise.  
Post-menopausal status can be determined by the reasons collected on the diary    
Any ambiguity in determining the category will be discussed and clarified in the blinded review 
meeting.  
• 
Nature of migraine: with aura and without aura.  


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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  
Number of analysis to be done on the primary and secondary endpoints will be confirmed based on 
subjects exposed to IMP at blinded review meeting.  
11.1 Subject Disposition  
Following categories will be summarised in subject disposition table:  
• 
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  
• 
Subjects completed the study, subjects who attended each visit within each study period - 
frequency (n) and percentage (%) based on FAS; Early Termination will be summarised in 
period 2 irrespective of when the subject discontinued from the study.   
• 
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  


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Subject disposition, status of inclusion/exclusion criteria, status of unblinding, subjects excluded from 
analysis population along with reasons 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  
11.2 Protocol Deviations  
Number and percentage of subjects with any deviation and number of deviation events will be 
summarised by treatment within each study period. The same will be sub-classified by category 
(major/minor) and description as follows:  
• 
Inclusion / Exclusion  
• 
Investigational Product  
• 
Concomitant medications  
• 
Laboratory tests  
• 
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 combined). Percentages will be based on FAS 
population. Protocol deviations occurring between Visit 2 and Visit 3 will be counted in Period 1, and 
those occurring after Visit 3 will be counted in Period 2.  
In DDP: Table 14.1.2  
Protocol deviations will be listed by subject.   
In DDP: Listing 16.2.2  
11.3 Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarised 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, height (cm), weight (kg) and BMI (kg/m2). Height, 
weight and BMI are as reported in screening.  
Percentages for childbearing potential will be based only on the female population.   


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The summary will be repeated for FAS, safety and per protocol populations (as per ICH E3 Guidelines).  
In DDP: Table 14.1.3.1 to Table 14.1.3.3  
Subject demographics will be listed by subject.   
In DDP: Listing 16.2.4.1   
11.4 Migraine History  
Migraine history will be summarised by treatment sequence. Categorical and continuous variables will 
be provided in the same table. The following variables will be presented: Time (years) since migraine 
diagnosis, Average frequency of migraine headaches per month (in last 12 months), Average frequency 
of migraine headaches per month (in last 12 months) categories (<1, 2-3, 4-5 and >5), Average duration 
of a migraine headache (hours), Number of subjects experiencing non-migraine headaches, Average 
frequency of non-migraine headaches per month (in last 12 months), Average frequency of non-
migraine headaches per month (in last 12 months) categories (<1, 2-3, 4-5 and >5), Nature of migraines 
experienced, Average duration of aura (minutes) and Associated symptoms experienced. Number and 
percentage of subjects with each most troublesome symptom will be summarised by treatment 
sequence. Symptoms to be included are: nausea, photophobia, phonophobia and other.  
Summary will be based on safety population.  
In DDP: Table 14.1.4  
Migraine history will be listed by subject.   
In DDP: Listing 16.2.4.2  
11.5 Medical/Surgical History  
The number and percentage of subjects with any medical history and number of mentions will be 
summarised by treatment sequence. The summaries will be provided by system organ class (SOC) and 
preferred term (PT). System organ class will be displayed in the descending order of frequency of 
number of mentions in the “Total” column and preferred terms will be displayed in the descending 
order of frequency within the SOC. Percentages will be based on the safety population. The summary 
will be repeated for concurrent diseases.  
Medical history and concurrent diseases will be classified as mentioned in section 10.8.  
In DDP: Table 14.1.5.1, Table 14.1.5.2    
Medical history and concurrent diseases will be listed by subject, system organ class and preferred 
term.   
In DDP: Listing 16.2.4.3  
11.6 Prior and Concomitant Medications  
Medications will be summarised by the study periods below:  


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• 
Prior or Pre-Day 1 (Visit 2)  
• 
Pre-IMP: irrespective of the study periods  
• 
Post IMP: LAT8881 60 mg and Placebo  
The number and percentage of subjects who have taken any prior medication and number of mentions 
will be summarised 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. 
Medications will be coded using the World Health Organisation’s Drug-Dictionary (WHODD) version 
September 2019 or later.   
Percentages will be based on the safety population.  
The summary will also be presented for concomitant medications by treatment overall and within each 
study period separately.   
Treatment overall: Medications reported before any IMP, irrespective of the study periods will be 
summarised as ‘Pre-IMP’. Medications reported after IMP in period 1 and before IMP in period 2 will 
be summarised under the treatment assigned at period 1. Medications reported after IMP in period 2 
will be summarised under the treatment assigned at period 2. Medications that are ongoing from the 
previous period and new events will be summarised separately within each treatment period and 
treatment.  
By Study Period: Medications reported post-IMP within each period and treatment will be summarised 
under the corresponding treatment for that period. Medications that are ongoing from the previous 
period and new events will be summarised separately within each treatment period and treatment. If 
a subject has ongoing medication in more than one study period, then the use of that medication is 
counted in all applicable study periods as ‘ongoing’.   
Rescue medications and other non-rescue medications will be presented separately. Rescue 
medications will be presented first followed by other non-rescue medications within the same table.  
Percentages will be based on the safety population.  
In DDP: Table 14.1.6.1, Table 14.1.6.2 and 14.1.6.3   
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.  
Rescue medication use over the treatment periods will be listed for each subject separately.  
In DDP: Listing 16.2.4.4 and Listing 16.2.4.5  
11.7 Extent of Exposure  
Number and percentage of subjects exposed to IMP and number of subjects not exposed to IMP will 
be summarised by study period and treatment. Continuous summary statistics will be displayed for 


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total IMP administered in mg by treatment overall and within each study period. Number and 
percentage of subjects exposed and not exposed to IMP in any one of the periods or both will also be 
summarised by study period. The summary will be based on the FAS population.  
The same will be repeated for Safety and Per Protocol populations.  
In DDP: Table 14.1.7.1, Table 14.1.7.2 and Table 14.1.7.3  
IMP administration and compliance data will be listed by treatment sequence, subject and treatment 
period for FAS population to include the IMP dispensing information.  
In DDP: Listing 16.2.5  
11.8 Efficacy Analyses  
All Efficacy summaries will be based on the Per-Protocol population. The presentation of descriptive 
summaries for the FAS population will be determined at the blind review meeting prior to database 
lock based on the difference between the numbers of subjects in each population.  
11.8.1 Primary Efficacy analyses – NRS Pain Scores  
Migraine pain intensity will be recorded using the NRS in a subject migraine diary at the pre-dose and 
at 0.5, 1.0, 1.5, 2, 4, 8 and 24 hours post dose. The NRS is an 11-point scale which grades pain from 0 
(no pain) to 10 (worst pain imaginable). Pain should reflect the subject’s pain at the time of recording.  
11.8.1.1 Descriptive summary  
A descriptive summary of NRS pain scores and absolute change from baseline results will be presented 
by treatment overall and within each study period. Timepoints to be included in this table are: Before 
IMP was taken (Pre-dose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 
hours after IMP taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 
8 hours after IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs).   
Difference between treatments:  
The difference in absolute NRS pain scores and change from baseline between both treatments will 
be summarised by timepoint. Timepoints to be included in this table are: Before IMP was taken 
(Predose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 hours after IMP 
taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 8 hours after 
IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs). 95% Confidence interval for the difference 
between treatments will also be provided.   
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Table 14.2.1.1   
11.8.1.2 Time-Trend Plots  
Time-trend plots may be created for NRS over time by subject. Each subject will be presented in a 
separate plot. X-axis will be the timepoint (hours) and Y-axis will be the NRS pain score. Plots will be 


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grouped by treatment. There may be one or two trend lines per subject based on the number of 
periods the subject took IMP.  
Time trend plots will be created to visualise and compare changes over timepoints in the NRS pain 
score for subjects in the Per-Protocol population. Mean values of change from baseline within each 
treatment group along with standard error bars will be plotted on y-axis, and timepoints will be plotted 
on the x-axis. Treatment groups will be displayed side-by-side in a single page.   
Difference in NRS pain scores between both treatments for each subject will also be plotted using time 
trend plots. Difference between LAT8881 60 mg and Placebo will be plotted in y-axis and timepoints 
will be plotted in x-axis.  
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Figure 14.2.1.2, Figure 14.2.1.3 and Figure 14.2.1.4  
NRS Migraine Pain Scores will be listed by subject.  
In DDP: Listing 16.2.6.3  
11.8.1.3 Mixed Effect Regression Model for repeated measurements (MMRM)  
A mixed effects regression model using a covariance pattern will be fitted to the absolute change from 
baseline in NRS pain scores at each post-IMP timepoint within each treatment period for the PP 
population.   
The model will have fixed effects for treatment period, timepoint, treatment and the interaction 
between timepoint and treatment. Baseline pain score within each period 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 
changes from baseline for LAT8881, Placebo and the difference between LAT8881 vs. placebo at each 
timepoint. P-values for testing the null hypothesis that the difference in least squares means between 
LAT8881 and placebo at each timepoint 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 
timepoints).  
SAS program - MMRM:  
proc mixed data=<input>;   class <subject> <study period> 
<treatment> <timepoint>;    model <change> = <baseline> <study 
period> <timepoint>|<treatment>;    random <subject> 
<subject>*<period>;   lsmeans <treatment>|<timepoint> / pdiff;   
run;  
  
In DDP: Tables 14.2.1.5  


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11.8.2 Secondary Efficacy Analyses  
11.8.2.1 NRS Symptom Scores  
A descriptive summary of NRS symptom scores and absolute change from baseline results will be 
presented by treatment overall and within each study period. Timepoints to be included in this table 
are: Before IMP was taken (Pre-dose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken 
(t=1 hr), 1.5 hours after IMP taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP 
taken (t=4 hrs), 8 hours after IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs). Symptoms 
to be presented: Nausea, Photophobia and Phonophobia.  
Difference between treatments:  
The difference in absolute NRS symptom scores and change from baseline between both treatments 
will be summarised by timepoint. Timepoints to be included in this table are: Before IMP was taken 
(Pre-dose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 hours after IMP 
taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 8 hours after 
IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs). 95% Confidence interval for the difference 
between treatments will also be provided.   
Difference between treatments will be calculated as mentioned in section 10.15.1.  
The summary will be based on Per-Protocol population.   
In DDP: Table 14.2.2.1  
11.8.2.2 Time-Trend Plots  
Time-trend plots may be created for symptom scores over time by subject and symptom. Each subject 
and symptom will be presented in a separate plot. X-axis will be the timepoint (hours) and Y-axis will 
be the NRS pain score. Plots will be grouped by treatment. There may be one or two trend lines per 
subject based on the number of periods the subject took IMP.   
Time trend plots will be created to visualise and compare changes over timepoints in the symptom 
score for subjects in the Per-Protocol population. Mean values of change from baseline within each 
treatment group along with standard error bars will be plotted on y-axis, and timepoints will be plotted 
on the x-axis. Treatment groups will be displayed side-by-side in a single page.   
Difference in symptom scores between both treatments for each subject will also be plotted using 
time trend plots. Difference between LAT8881 60 mg and Placebo will be plotted in y-axis and 
timepoints will be plotted in x-axis.  
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Figure 14.2.2.2, Figure 14.2.2.3 and Figure 14.2.2.4  
11.8.2.3 Most Troublesome Symptom  
Descriptive summary of most troublesome symptom scores and absolute change from baseline results 
will also be presented by treatment overall and within each study period. Timepoints to be included 


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in this table are: Before IMP was taken (Pre-dose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after 
IMP taken (t=1 hr), 1.5 hours after IMP taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours 
after IMP taken (t=4 hrs), 8 hours after IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs). 
Both categorical and continuous summaries will be provided in a single table.  
The summary will be based on Per-Protocol population.   
Difference between treatments:  
The difference in absolute most troublesome symptom scores and change from baseline between both 
treatments will be summarised by timepoint. Timepoints to be included in this table are: Before IMP 
was taken (Pre-dose), 30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 hours 
after IMP taken (t=1.5 hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 8 hours 
after IMP taken (t=8 hrs) and 24 hours after IMP taken (t=24 hrs). 95% Confidence interval for the 
difference between treatments will also be provided.   
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Table 14.2.3.1  
11 point Likert Migraine Symptom Scores will be listed by subject.  
In DDP: Listing 16.2.6.4  
11.8.2.4 Time-Trend Plots  
Time-trend plots may be created for most troublesome symptom scores over time by subject and 
symptom. Each subject will be presented in a separate plot. X-axis will be the timepoint (hours) and Y-
axis will be the NRS pain score. Plots will be grouped by treatment. There may be one or two trend 
lines per subject based on the number of periods the subject took IMP.   
Time trend plots will be created to visualise and compare changes over timepoints in the most 
troublesome symptom score for subjects in the Per-Protocol population. Mean values of change from 
baseline within each treatment group along with standard error bars will be plotted on y-axis, and 
timepoints will be plotted on the x-axis. Treatment groups will be displayed side-by-side in a single 
page.   
Difference in most troublesome symptom scores between both treatments for each subject will also 
be plotted using time trend plots. Difference between LAT8881 60 mg and Placebo will be plotted in 
y-axis and timepoints will be plotted in x-axis.  
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Figure 14.2.3.2, Figure 14.2.3.3 and Figure 14.2.3.4  
11.8.2.5 No Headache Pain  
Number and percentage of subjects who achieve ‘no headache pain’ (NRS pain score 0 or 1) at each 
timepoint will be presented by treatment overall. Presence or absence of pain will be determined as 


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mentioned in section 10.15.4. The paired difference in number of subjects with no headache pain 
(LAT8881 – Placebo) will be calculated as mentioned in section 10.16.  
In DDP: Table 14.2.4  
11.8.2.6 Migraine and Headache Diary  
Migraine and headache diary details will be listed by subject. Menstrual cycle details will also be listed 
by subject.  
In DDP: Listing 16.2.6.1, Listing 16.2.6.2 and Listing 16.2.6.5  
11.8.3 Exploratory Analysis  
11.8.3.1 Sustained Pain-free at 24 Hours  
Number and percentage of subjects who are “sustained pain-free” at 24 hours (as defined in section 
10.15.1) will be summarised treatment overall. The paired difference in number of subjects sustained 
pain-free (LAT8881 – Placebo) will be calculated as mentioned in section 10.16.  
The summary will be based on Per-Protocol population.  
In DDP:  Table 14.2.5  
11.8.3.2 Time to First Pain-free Timepoint  
The number and percentage of subjects with their first pain free timepoint will be presented by 
timepoint. The paired difference in the number of subjects with their first pain free timepoint will be 
calculated as mentioned in section 10.16.  
Time taken to first pain-free timepoint will also be analysed using Kaplan-Meier curve. Time to first 
pain-free timepoint will be calculated based on the actual time taken from IMP as mentioned in section 
10.15.5.  
In DDP: Table 14.2.6.1, Figure 14.2.6.2  
11.8.3.3 Subject Satisfaction Survey  
The subject’s satisfaction score for each treatment and preference for LAT8881 or placebo recorded 
on a 7-point Likert scale will be summarised as a continuous endpoint with mean, SD, median, 
minimum and maximum. Within-subject difference in the satisfaction score between treatments will 
also be summarised. Within-subject difference will be compared using paired t-test and p-values will 
be presented.  
If the assumptions for normality are not met using Shapiro-Wilk test, the non-parametric equivalent 
Wilcoxon signed-rank test will be performed, and unadjusted p-values will be presented.   
Example SAS Code:  
proc ttest data = <INDATA>;   
paired <TESTVAR1>*<TESTVAR2>; 
run;  


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The subject satisfaction score  and preference for each treatment compared to their usual medication 
for an acute migraine attack will be presented in the same manner. Subjects preferred treatment will 
be derived as mentioned in section 10.16. The number and percent of subjects preferring LAT8881 60 
mg or placebo treatment will be presented.   
The difference between the proportions of subjects preferring LAT8881 60 mg compared to placebo 
will also be presented along with the 95% confidence interval for the difference.  
In DDP: Table 14.2.7  
Subject satisfaction survey will be listed by subject.  
In DDP: Listing 16.2.6.6  
11.8.3.4 Association between Change in NRS Pain Score and Baseline Characteristics  
Descriptive Summary:  
NRS pain scores, NRS symptom scores and most troublesome symptom scores will be summarised by 
visit and subgroup within treatment.  
Descriptive summary of NRS Pain scores, NRS symptom scores and most troublesome symptom scores 
along with absolute change from baseline results will also be presented by treatment overall and 
subgroup. Timepoints to be included in this table are: Before IMP was taken (Pre-dose), 30 minutes 
after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 hours after IMP taken (t=1.5 hrs), 2 
hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 8 hours after IMP taken (t=8 hrs) 
and 24 hours after IMP taken (t=24 hrs).   
The summary will be based on Per-Protocol population.   
Difference between treatments:  
The difference in absolute scores and change from baseline between both treatments will be 
summarised by timepoint. Timepoints to be included in this table are: Before IMP was taken (Predose), 
30 minutes after IMP taken (t=0.5 hrs), 1 hour after IMP taken (t=1 hr), 1.5 hours after IMP taken (t=1.5 
hrs), 2 hours after IMP taken (t=2 hrs), 4 hours after IMP taken (t=4 hrs), 8 hours after IMP taken (t=8 
hrs) and 24 hours after IMP taken (t=24 hrs). 95% Confidence interval for the difference between 
treatments will also be provided.   
Difference between treatments will be calculated as mentioned in section 10.15.1.  
In DDP: Table 14.2.8.1 to Table 14.2.10.3  
Time trend plots:  
Time-trend plots will be created for the change from baseline NRS pain and symptom scores over time 
by treatment and subgroup. Each treatment group within a subgroup will be presented in a separate 
plot. Both treatments will be displayed side-by-side for comparison. X-axis will be the Timepoint 
(hours) and Y-axis will be the NRS pain score. Each subject will be presented by a line within the plots 


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and all subjects within a single group will be presented in the same color. Mean NRS pain score at each 
timepoint will also be plotted for reference.  
Any change in the above analysis will be discussed and finalised in the blinded review meeting.  
Subgroups are as defined in section 10.18.  
In DDP: Figure 14.2.8  
11.9 Safety Analyses  
All safety summaries will be based on the Safety population and treatment groups as treated.  
11.9.1 Adverse Events  
All Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1 or higher.   
11.9.1.1 Overall Adverse Events  
The number and percentage of subjects and number of events will be summarised by AE status (new 
event or ongoing from the previous study period), 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)  
8. Treatment-emergent adverse events leading to death  
9. Treatment-emergent adverse events leading to study discontinuation  
The above categories and study periods will be classified as defined in section 10.10.   
In DDP: Table 14.3.1.1 and Table 14.3.1.2  
All adverse events will be listed by subject, system organ class and preferred term sorted by event 
start dates. Serious adverse events and deaths due to adverse events will be listed separately.  
In DDP: Listing 16.2.7.1 to 16.2.7.3  


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11.9.1.2 Summary of Adverse Events by SOC and PT  
The number and percentage of subjects and number of events will be summarised by treatment 
overall and within each study period, system organ class and preferred terms. 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 total LAT8881 60 mg group. All adverse 
events and all serious adverse events will be summarised by Pre-IMP and Post-IMP treatments. All 
treatment emergent and similar events will be summarised by study period, treatment and the event 
status (new event or ongoing from the previous study period).  
The same will be repeated for all treatment-emergent AEs, treatment-emergent related AEs, serious 
AEs, treatment-emergent serious AEs, treatment-emergent related serious AEs, treatment-emergent 
AEs leading to discontinuation and treatment-emergent AEs leading to death.   
In DDP: Table 14.3.1.2 to Table 14.3.1.4 and Table 14.3.2.1 to Table 14.3.2.5  
11.9.1.3 Summary of Treatment emergent Adverse Events by SOC, PT, Relationship 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 summarised 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 60 mg group (all study 
periods).  
In DDP: Table 14.3.1.5   
11.9.2 Laboratory Assessments  
11.9.2.1 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. 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  
11.9.2.2 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, Visits 2 and Visit 3 will be 
listed separately.  
In DDP: Listing 16.2.8.1 to 16.2.8.5 and Listing 16.2.8.8  
Subjects with clinically significant laboratory results and subjects with out of range results will be 
separately listed by treatment sequence, category, visit and parameter.  


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In DDP: Listing 16.2.8.6 and Listing 16.2.8.7  
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  
Liver Function Tests  
Aspartate aminotransferase, alanine aminotransferase, 
gamma-glutamyl 
transferase, 
alkaline 
phosphatase, 
conjugated bilirubin, total bilirubin  
Coagulation  
Activated partial thromboplastin time, international 
normalised ratio  
Urinalysis  
Continuous: Specific gravity and pH  
Categorical: 
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)  
11.9.3 Other Safety Analyses  
11.9.3.1 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 and visit for safety population. Vital signs 
parameters include: systolic blood pressure (mmHg), diastolic blood pressure (mmHg), respiratory 
rate (breaths/min), heart rate (beats/min) and body temperature (oC).  
In DDP: Table 14.3.5.1   


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Vital signs will be listed by treatment sequence, subject ID, treatment period and visit for safety 
population.   
In DDP: Listing 16.2.9.1  
11.9.3.2 Physical Examination  
Physical examination data will be listed by treatment sequence, subject, treatment period and visit 
only.   
In DDP: Listing 16.2.9.2  
11.9.3.3 Electrocardiogram Assessments  
Number and percentage of subjects with overall findings (Normal, Abnormal Not CS and Abnormal CS) 
will be summarised by treatment overall and within each study period and visit. Percentages will be 
based on safety population.  
In DDP: Table 14.3.5.2   
ECG findings will be listed by treatment sequence, subject ID, treatment period and visit.   
In DDP: Listing 16.2.9.3  
11.9.3.4 Telephone Visits  
Telephonic visits information will be listed by treatment sequence, subject ID, treatment period and 
visit.  
In DDP: Listing 16.2.9.4  
  
  
12 Index of Tables, Listings and Graphs  
Refer LAT-MIG-001_Data Display Plan (Ver: 0.03) for the list of Tables, Listings and Graphs.  
13 References  
1. ICH. ICH Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials E9. 1998.  
2. ASA. Ethical Guidelines for Statistical Practice. Prepared by the Committee on Professional 
Ethics. 1999.  
3. ICH. ICH Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports E3. 
1995.  
14 Appendices  
Not applicable  
  


 
 
 
15 Change Log  
Version  
Authored by  
Change Date  
Change Details  
Reviewed by  
Review Date  
1.00  
Sangeetha, S  
24-Feb-2020  
Initial version  
Caro Badcock,  
Judy Bingham and  
Rachel Greaney  
24-Feb-2020  
  
  
  
  
  
  
  
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