A Phase 2, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of LX9211 in the Treatment of Postherpetic Neuralgia (RELIEF-PHN1)
Phase: PHASE2
Conditions: Postherpetic Neuralgia
Sponsor: Lexicon Pharmaceuticals

Official Title: A Phase 2, Double-blind, Randomized, Placebo controlled, Parallel-
group Study to Evaluate the Efficacy and Safety of LX9211 in the 
Treatment of Postherpetic Neuralgia (RELIEF-PHN1) 
NCT Number: NCT04662281 
Document Date: Protocol Version 3: 18-October-2021 

  
Protocol No. LX9211.202 
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1. 
Synopsis 
Name of Study Drug 
LX9211 phosphate 
Protocol Number 
LX9211.1-202-PHN 
LX9211.202 (Abbreviated number) 
Protocol Title  
 
A Phase 2, Double-blind, Randomized, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
LX9211 in the Treatment of Postherpetic Neuralgia (RELIEF-
PHN1) 
Primary Objective 
To evaluate the efficacy of LX9211 in reducing pain related to 
postherpetic neuralgia (PHN) 
Primary Efficacy 
Endpoint 
The change from Baseline (Week 2 of the Run-in Period) to Week 
6 in Average Daily Pain Score (ADPS), based on Question 5 of 
the Zoster Brief Pain Inventory (ZBPI), the 11-point numerical 
rating scale (0 [No Pain] to 10 [Pain as bad as you can imagine])  
Secondary Objectives 
To assess other effects and patient reported outcomes of LX9211 
versus placebo during and following the Week 6 double-blind 
Treatment Period  
Secondary Efficacy 
Endpoints 
• Change from Baseline to Week 6 in pain interfering with 
sleep based on Question 9F of the ZBPI “Indicate the one 
number that describes how, in the past 24-hours shingles pain 
has interfered with your: Sleep (0 [Does not interfere] to 10 
[Completely interferes])” 
• Proportion of patients with ≥30% reduction in pain intensity 
in ADPS based on Question 5 of the ZBPI from Baseline to 
Week 6 
• Proportion of patients with ≥50% reduction in pain intensity 
in ADPS based on Question 5 of ZBPI from Baseline to 
Week 6 
• Change from Baseline to Week 6 in interference in General 
Activity, Mood, Walking Ability, Normal Work (includes 
both outside the home and housework), Relations with other 
people, Sleep, and Enjoyment of Life interference based on 
the Questions 9A-G of the ZBPI 
• Proportion of patients discontinuing treatment due to lack of 
efficacy defined as increase in ADPS from Baseline of ≥30% 
based on Question 5 of the ZBPI  
• Patient Global Impression of Change (PGIC) at Week 6 
• Time to loss of efficacy from Week 6 to Week 11 among 
patients achieving ≥30% reduction in pain intensity in ADPS 
based on Question 5 of the ZBPI. 
 

  
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not permitted during the course of the study. Use of any opioid 
medications for the management of PHN within the 2 months prior 
to Screening is not permitted. Note:  Brief use (<1 week) of opioid 
medication for management of non-PHN acute pain (eg, tooth 
extraction/acute injury) ≥2 months prior to Screening Visit is 
permitted. 
Screening Period: After signing the Informed Consent Form 
(ICF), all patients will enter a Screening Period of up to 2 weeks. 
Patients using non-opioid medications that are prohibited by the 
protocol must discontinue or washout of these medications for ≥2 
weeks prior to entering the Screening period. Following 
confirmation of eligibility criteria, patients will enter the following 
study periods: 
Run-in Period: After meeting Screening eligibility criteria, 
patients will enter a 2-week single-blind Run-in Period in order to 
qualify that the criteria for moderate to severe pain are met and to 
demonstrate ≥80% compliance with taking the expected amount of 
placebo tablets. On Day 1 of the Run-in Period patients will be 
dispensed 4 tablets of single-blind placebo to be administered at 
the site. For the remainder of the Run-in Period, patients will take 
a single tablet of study drug every morning. Each evening patients 
will rate and record intensity of their PHN pain based on Question 
5 of the ZBPI by answering the question “Please rate your pain by 
indicating the one number that best describes your pain on the 
average in the last 24 hours”, on the 11-point numerical rating 
scale (0 [No Pain] to 10 [Pain as bad as you can imagine]). The 
ADPS will be calculated using all available daily pain diary data. 
The mean value of the ADPS derived over Week 2 will serve as 
the Baseline measure used for analyses. In order to qualify for 
randomization, patients must have completed ≥70% of the daily 
pain diary entries during the second week of the Run-in Phase, meet 
criteria for moderate to severe pain and demonstrate ≥80% 
compliance with taking the expected amount of placebo tablets 
during the Run-in Period. During the Run-in Period patients will 
not be allowed use of any rescue medication. On the morning of 
the Run-in Visit, patients may eat a light meal prior to the visit. 
Note:  Patients who fail Screening due to laboratory values may 
have those assessments repeated and be rescreened once after 
discussion with the Sponsor’s Medical Monitor.  
Randomization/Double-blind Treatment Period: Patients who 
successfully complete the 2-week single-blind placebo Run-in 
Period and meet all other eligibility criteria will enter a 6-week 
double-blind Treatment Period.  
 

  
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Patients will be randomly assigned in a 1:1 ratio between the 
following 2 treatment groups: 
• 
Group 1: LX9211 200 mg* / 20 mg**, once daily (qd)  
• 
Group 2: Placebo, qd matching loading and maintenance 
doses 
* Loading dose (Day 1) 
** Maintenance dose (Day 2 – Week 6 Visit)  
Implementation of the treatment randomization schedule will be 
centralized. A 1:1 ratio for assigning patients between the 
treatment groups will be accomplished by use of randomly 
permuted blocks of fixed size. 
On Day 1, patients will receive LX9211 or placebo, to be given as 
a loading dose at the clinic. The loading dose will be followed by a 
daily maintenance dose taken at home on Day 2 through end of 
Week 6. Note:  On days of clinic visits, patients will refrain from 
taking their daily dose until after the visit. 
Each evening during the double-blind Treatment Period, patients 
will be required to rate and record the average severity of their 
PHN pain over the previous 24 hours using Question 5 of the 
ZBPI, record the use of rescue medication (acetaminophen), and 
rate the interference with sleep using the ZBPI Question 9F. The 
ADPS will be calculated using all available data; however, a 
minimum of 4 days (consecutive or nonconsecutive) from the last 
week prior to each clinic visit is required for the calculation.  
If a patient is unable to tolerate their PHN, they are encouraged to 
discuss treatment options with the Investigator. At the 
Investigator’s discretion, the patient may be permitted to take 
acetaminophen (up to a maximum of 3 grams per day) as a rescue 
medication. Only the acetaminophen provided by the Sponsor as a 
rescue medicine may be used during the course of the study. The 
use of personally acquired acetaminophen is prohibited. If rescue 
medication does not provide adequate pain relief, the patient may 
discontinue from further participation in the study after 
consultation with the Investigator. Patients who discontinue prior 
to completion of the Week 6 Visit will not be replaced.  
Safety Follow-up Period: Following the double-blind Treatment 
Period, all patients will enter a 5-week single-blind Safety Follow-
up Period. During this period, patients will dose with 1 tablet of 
single-blind study drug (placebo) every morning, taken at home. 
Patients will remain blinded to the study drug being taken. Each 
evening patients will continue to rate and record the average 
severity of their PHN over the previous 24 hours using the 
 

  
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Number of Patients 
The proposed sample size is 74 patients, 37 randomized to each 
treatment group. The sample size will be reassessed at a planned 
interim analysis. The interim analysis will occur when the first 38 
patients have been accrued and followed to endpoint at Week 6. 
Based on this assessment, the sample size will be reestimated and 
can remain as originally proposed or increased. The maximum 
increase is limited to 148 patients.  
The interim analysis will allow for statistical testing of futility and 
should the prespecified futility boundary be crossed, and other 
data support a negative trial finding, consideration will be made to 
stop patient accrual. 
Approximately 30 patients will be recruited to participate in a 
qualitative patient interview substudy for English speaking 
patients in the United States (US) only.  
Study Population 
Male and female patients 18 years or older will be enrolled. 
Patients will have a diagnosis of postherpetic neuralgia defined as 
pain in the dermatomal distribution of an acute herpes zoster skin 
rash, persisting for ≥3 months from the healing of herpes zoster 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 

  
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skin rash. Patients will have to meet pain criteria at the end of the 
Run-in Period. 
Number of Study 
Sites 
Approximately 30 with the majority of sites located in the US and 
approximately 10 sites will be located in Europe  
Treatments 
Each patient will be randomized to 1 of the following groups:  
Treatment Group 
Loading Dose 
(Day 1) * 
Maintenance Dose (Day 2 to 
Week 6 / EOT/EW) ** 
Group 1: 
LX9211 200 mg*/20 mg** 
2 x 50-mg LX9211 
tablets  
+ 
2 x 50-mg LX9211 
tablets 
1 x 20-mg LX9211 
tablet, qd 
 
Group 2: 
Placebo 
2 x Placebo tablets 
+ 
2 x Placebo tablets 
1 x Placebo 
tablet, qd 
* Loading Dose (Day 1) 
** Maintenance Dose (Day 2 – Week 6 Visit) 
Route of 
Administration 
Oral 
Duration of 
Treatment 
Patients will be treated with double-blind study drug for 6 weeks. 
Patient participation will be approximately 105 days, including a 
2-week Screening Period, a 2-week single-blind Placebo Run-in 
Period, a 6-week double-blind Treatment Period, and a 5-week 
single-blind Safety Follow-up Period. 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered 
eligible to participate in the study. For patients not meeting 
eligibility requirements, the reason for exclusion must be recorded. 
Note:  Patients who are not eligible because of laboratory result(s) 
may have the laboratory test(s) repeated once during the Screening 
Period, at the discretion of the Investigator, to determine 
eligibility: 
1. Patient has given written informed consent to participate in 
the study in accordance with local regulations  
 

  
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2. Adult male or female patients ≥18 years of age at the 
Screening Visit: 
a. Females of childbearing potential must have a 
negative serum or urine pregnancy test prior to the 
start of study drug. In the case of positive urine 
pregnancy testing, a negative serum sample for 
pregnancy testing, to confirm that the patient is not 
pregnant, must be obtained prior to start of study. 
They must also agree to use adequate methods of 
contraception which include the following: condom 
with spermicidal gel, diaphragm with spermicidal 
gel, coil (intrauterine device), surgical sterilization, 
vasectomy, oral contraceptive pill, 
depo-progesterone injections, progesterone implant 
(ie, Implanon®), NuvaRing®, Ortho Evra®  
b. Nonsterile male patients with sexual partners of 
childbearing potential must agree to use adequate 
methods of contraception from Baseline through 
the Week 11 Visit 
3. Presence of PHN pain that is present for ≥3 months after 
healing of herpes zoster skin rash affecting a single 
dermatome. Patients with more than 1 involved dermatome 
may also be included, provided the affected dermatomes 
are contiguous.  
4. Moderate to severe pain as confirmed by average pain 
score using scores recorded in the pain diary in the 14 days 
prior to randomization (Run-in Period) 
5. At least 80% compliance with dosing during the 2-week 
Run-in Period, and 70% compliance with completion of 
the daily diary during the second week of the Run-in 
Period  
6. Willing to adhere to the prohibitions and restrictions 
specified in the protocol 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study:  
1. Presence of other painful conditions that may confound 
assessment or self-evaluation of PHN: 
a. Patient should not have any other neurological 
disorder or conditions that can cause symptoms that 
may mimic peripheral neuropathy or that might 
confound assessment of PHN pain. 
 

  
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b. Other causes of diffuse painful peripheral 
neuropathy such as: paraproteinemia, untreated 
hypothyroidism (previously treated hypothyroidism 
not excluded if treated and euthyroid for ≥6 
months), vitamin B12 deficiency, neurologically-
evident vasculitis, malignancy, amyloidosis, renal 
insufficiency, connective tissue disease (eg, 
Sjogren's, systemic lupus erythematosus), 
porphyria, complex regional pain syndrome, 
chronic inflammatory demyelinating 
polyradiculoneuropathy, alcoholism, HIV, 
hepatitis, uremia, syphilis, myeloma, or other 
systemic disease associated with a secondary 
painful neuropathy should be excluded. 
c. Patient should not have had any exposure to 
drugs/toxic environmental agents known to cause 
neuropathy 
2. Over the past year, met Diagnostic and Statistical Manual 
of Mental Disorders, 5th edition (DSM-5) criteria for a 
major depressive episode, any active, significant 
psychiatric disorders (eg, neurocognitive disorder, anxiety 
disorder, psychosis, bipolar disorder), or a history of 
clinically significant drug or alcohol use disorder that 
would, in the Investigator's opinion, interfere with the 
assessment and evaluation of pain during the study  
3. Mood and anxiety disorder scores defined by Hospital 
Anxiety and Depression Scale (HADS) ≥13 
4. Suspected or likely diagnosis of trigeminal neuralgia  
5. Use of opioid medications for management of PHN within 
the 2 months prior to the Screening Visit. Note:  Brief use 
(<1 week) of opioid medication for management of non-
PHN acute pain (eg, tooth extraction/acute injury) ≥2 
months prior to the Screening Visit is permitted. 
6. Use of NSAIDs for the specific treatment of PHN pain.  
7. Use of more than 1 permitted concomitant medications for 
the treatment of PHN. Note: Patients may washout 
additional PHN medications ≥1 month prior to the 
Screening Visit to reach the 1 permitted medication 
8. For non-opioid medications patient uses and is 
unwilling/unable to discontinue use of prohibited 
medications and therapies, (eg, benzodiazepines, 
dextromethorphan, herbal medications, mexiletine HCl, 
adenosine, topical analgesics including lidocaine and 
 

  
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capsaicin), applied to the same area of the body affected by 
PHN pain, nerve blocks, acupuncture, or other medications 
indicated for neuropathic pain. A patient using any of these 
interventions for neuropathic pain must discontinue the 
medication ≥1 month prior to starting the Screening Period 
and for the duration of the study. Note:  This exclusion 
criterion does not include analgesics that are not 
specifically prescribed for treatment of neuropathic pain 
(eg, nonsteroidal anti-inflammatory drugs [NSAIDs], 
aspirin, acetaminophen). In addition, patients who are 
prescribed antidepressants for a mental health disorder are 
eligible to participate as long as they do not meet 
Exclusion Criteria 2-3. 
9. A positive urine drug test for drugs of abuse including 
cannabinoids. Note: Cannabidiol (CBD), if used for mood 
or sleep, is acceptable. If used for PHN it would be 
allowed if it is the only concomitant medication being 
taken for PHN. If not the only medication being taken for 
PHN, it should be withdrawn ≥1 month prior to Screening 
10. Patient has hepatic impairment at Screening, defined as 
any of the following:  aspartate aminotransferase (AST) 
>2X upper limit of the normal reference range (ULN), 
alanine aminotransferase (ALT) >2X ULN, serum total 
bilirubin (TB) >2X ULN. Note:  If it is the opinion of the 
Investigator and the Medical Monitor that an increase in 
bilirubin is due to Gilbert’s syndrome, then the patient may 
participate. 
11. Patient has abnormal kidney function test (estimated 
glomerular filtration rate [eGFR] <60 mL/min as 
calculated using the Cockcroft-Gault equation) at 
Screening or renal dysfunction requiring hemodialysis 
12. Patient has any of the following medical conditions or 
disorders: epilepsy or seizure disorder requiring treatment 
with antiepileptic drugs 
13. Presence of clinically significant physical examination 
(PE) findings other than PHN, or laboratory or ECG 
findings that in the opinion of the Investigator, Medical 
Monitor, and/or the Sponsor, may interfere with any aspect 
of study conduct or interpretation of results including: 
a. any clinically significant abnormal heart rate or 
rhythm  
b. other ECG abnormalities that are clinically relevant 
 

  
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c. BP >160/100 mm Hg or <90/50 mm Hg 
d. presence of risk factors for torsade de points (eg, 
family history of long QT syndrome; personal 
history of NYHA class III/IV heart failure or 
structural heart disease) 
14. Receipt of any investigational agent within 30 days or 5 
half-lives, whichever is longer, prior to 
Baseline/Randomization on Day 1 
15. Receipt of any therapeutic protein, antibody/biologic- or 
antibody-based agents (eg, growth hormones or 
monoclonal antibodies) within 3 months prior to dosing on 
planned Day 1. Note:  Preventative vaccines (eg, 
influenza, pneumococcal, Tdap), will be allowed if 
administered >7 days prior to dosing. Patients who have 
previously received the shingles vaccine, but subsequently 
develop PHN and meet all inclusion and exclusion criteria, 
are eligible to participate. 
16. Prior exposure to LX9211 
17. History of any serious adverse reaction or hypersensitivity 
to any inactive component of study drug, unless the 
reaction is deemed irrelevant to the study by the 
Investigator, Medical Monitor, and/or the Sponsor 
18. Presence of any skin condition, such as ulcers, which could 
interfere with assessment of PHN 
19. Existence of any postsurgical or medical condition that, in 
the judgment of the Investigator, Medical Monitor, and/or 
the Sponsor, might interfere with the absorption, 
distribution, metabolism, or excretion of LX9211, 
including bariatric surgery, cholecystectomy, or any other 
GI surgery, except appendectomy and hernia repair, which 
are acceptable 
20. History of any major surgery within 3 months prior to 
Baseline or surgery that is anticipated to be performed 
during the study period 
21. History of any active infection within 30 days prior to 
Baseline, if deemed clinically significant by the 
Investigator, Medical Monitor, and/or the Sponsor 
22. Malignancy or active treatment for malignancy (ie, 
radiation or chemotherapy, including monoclonal 
antibodies) within 5 years prior to the Screening Visit. 
Note:  Patients with squamous or basal cell carcinomas of 
the skin, carcinomas in situ of the cervix or uterus, ductal 
 

  
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breast cancer in situ, resected low-grade prostate cancer, or 
other malignancies that, in the opinion of the Investigator 
and the Medical Monitor are considered cured, may 
participate. 
23. Donation or loss of >500 mL of blood or blood product 
within 3 months prior to Baseline 
24. Inability or difficulty swallowing whole tablets 
25. Any other condition that compromises the ability of the 
patient to provide informed consent or to comply with the 
objectives and procedures of this protocol, as judged by the 
Investigator, Medical Monitor, and/or the Sponsor 
26. Unable or unwilling to adhere to the requirements of the 
protocol, or communicate or cooperate with the 
Investigator and/or their staff for any reason 
27. Patient refuses to participate in processes if established by 
the Sponsor, to minimize duplicate patients (Verified 
Clinical Trials)  
28. Employees, or relatives of the Sponsor, Investigator or 
study center staff, with direct involvement in the proposed 
study or other studies under the discretion of the 
Investigator or study center 
29. Patient is immunocompromised (eg, secondary to 
transplant or require active immunosuppressive drugs) 
Statistical Methods 
A proposed sample size of 74 randomized patients will yield 
82.27% power to detect a true mean difference of -0.68 units 
between the LX9211 treatment group and placebo in the primary 
efficacy endpoint, assuming a common standard deviation of 1 
unit and a 2-sided significance level of α=0.05. This derivation is 
adjusted for a uniform dropout rate of 15%, that patients will be 
randomly assigned to treatment in a 1:1 ratio, and for an interim 
analysis conducted after about half of the originally proposed 
sample size has been accrued and followed to endpoint. The 
sample size can be increased to a maximum of 148 patients based 
on a reestimation procedure performed at the planned interim 
analysis. 
Continuous variables will be summarized by the mean, standard 
deviation, median, minimum, and maximum values for all patients 
with non-missing data. Categorical variables will be summarized 
by their counts and associated percentages. All data will be 
provided in individual patient listings. 
 

  
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Analysis of the primary and secondary efficacy endpoints will be 
based on the Modified Intent-to-Treat (mITT) Population, defined 
as all randomized patients who had taken ≥1 dose of study drug. 
Safety endpoints analyses will be based on the Safety Population, 
defined as those patients who received any exposure to study drug. 
A restricted maximum likelihood-based, mixed-effects model 
repeated measures (MMRM) approach will be used to assess the 
difference between LX9211 and placebo for the primary endpoint. 
The MMRM model will include fixed effects of treatment, week, 
treatment-by-week interaction, the randomization factor of 
Baseline pain severity, and Baseline score as covariate. An 
unstructured covariance structure will be used to model the within-
patient error. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. Other covariance 
structures will be explored should convergence not be met. In the 
event that a rescue medication is used, a supplementary MMRM 
model will be applied on a dataset that excludes data collected 
after the initiation of the rescue medication. To assess the 
robustness of the MMRM analyses performed under the missing at 
random (MAR) assumption, and given the long half-life of 
LX9211, pattern mixture models (PMM) with copy reference-
based multiple imputation methods will be applied to both datasets 
(with and without data collected after the initiation of the rescue 
medication). The imputed datasets will be combined by use of 
Rubin's rule and analyzed using an analysis of covariance 
(ANCOVA) model fitted for the fixed effects of treatment, the 
randomization factor of Baseline pain severity and the continuous 
fixed covariate of Baseline score. 
The number and percentage of patients who need rescue 
medication and/or prematurely dropout of the study will be 
summarized descriptively. 
For the continuous, secondary and other efficacy endpoints: ZBPI 
score, PGIC score, and NPSI score, measured at multiple time 
points, a similar modeling strategy used for the primary endpoint 
will be applied. The proportion of responders based on Question 5 
of the ZBPI, the 11-point scale (0 [no pain] to 10 [pain as bad as 
you can imagine]) will be compared between treatments using a 
Cochran-Mantel-Haenszel test stratified by the randomization 
factor of Baseline pain severity. A non-responder imputation (NRI) 
rule will be applied for all analyses based on categorical variables 
to assign outcomes to missing observations. 
The qualitative patient interview substudy will be managed by a 
vendor (RTI-Health Solutions, Research Triangle Park, NC); data 
 

  
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Table of Contents 
 
1. 
Synopsis .......................................................................................................................... 3 
2. 
List of Abbreviations and Definitions of Terms ........................................................... 22 
3. 
Introduction ................................................................................................................... 25 
3.1 
Background on LX9211 and Neuropathic Pain .................................................. 25 
3.2 
LX9211 Nonclinical Pharmacology, Pharmacodynamics and Toxicology ........ 26 
3.2.1 
In Vitro Pharmacodynamic Studies ..................................................... 26 
3.2.2 
In Vivo Pharmacodynamic Studies...................................................... 26 
3.2.3 
Safety Pharmacology ........................................................................... 27 
3.2.4 
Summary of Pharmacology ................................................................. 27 
3.3 
LX9211 Toxicology ............................................................................................ 28 
3.3.1 
Preclinical GLP-Compliant Toxicology Studies in Rats ..................... 28 
3.3.2 
Preclinical GLP-Compliant Toxicology Studies in Dogs .................... 29 
3.3.3 
Embryo-Fetal Development Study in the Rat ...................................... 30 
3.3.4 
Embryo-Fetal Development Study in the Rabbit ................................. 30 
3.4 
Clinical Trials of LX9211 in Humans ................................................................ 31 
3.5 
Rationale for Current Study ................................................................................ 32 
3.5.1 
Rationale for Selection of Dose ........................................................... 32 
3.6 
Rationale for Study Design and Control Groups ................................................ 33 
4. 
Study Objectives ........................................................................................................... 33 
4.1 
Primary Objective ............................................................................................... 33 
4.2 
Secondary Objective ........................................................................................... 33 
4.3 
Other Objectives ................................................................................................. 33 
5. 
Investigational Plan....................................................................................................... 34 
5.1 
Overall Study Design .......................................................................................... 34 
5.1.1 
Screening Period .................................................................................. 36 
5.1.2 
Run-in Period ....................................................................................... 36 
 

  
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5.1.3 
Randomization/Treatment Period ........................................................ 36 
5.1.4 
Safety Follow-up Period ...................................................................... 38 
5.1.5 
Optional Substudy................................................................................ 38 
6. 
Study Population ........................................................................................................... 38 
6.1 
Inclusion Criteria ................................................................................................ 39 
6.2 
Exclusion Criteria ............................................................................................... 40 
6.3 
Criteria for Stopping Treatment/Study Withdrawal ........................................... 43 
6.3.1 
Lost to Follow-up................................................................................. 44 
6.4 
Criteria for Termination of the Study or of a Site's Participation ....................... 44 
6.4.1 
Termination of the Study Based on Planned Interim Analysis ............ 44 
6.5 
Clinical Stopping Rules ...................................................................................... 45 
6.6 
Method of Assigning Patients to Treatment ....................................................... 45 
6.7 
Blinding and Unblinding of Study Drug............................................................. 45 
6.8 
Replacement of Patients...................................................................................... 46 
7. 
Treatment ...................................................................................................................... 46 
7.1 
LX9211 ............................................................................................................... 46 
7.1.1 
Identity ................................................................................................. 46 
7.1.2 
Tablets .................................................................................................. 47 
7.1.3 
Packaging, Labeling, and Storage ........................................................ 47 
7.1.4 
Placebo ................................................................................................. 47 
7.2 
Prior and Concomitant Medications ................................................................... 47 
7.2.1 
Prior Medication .................................................................................. 47 
7.2.2 
Concomitant Medication...................................................................... 48 
7.3 
Prohibited Medication......................................................................................... 48 
7.4 
Administration of Study Drug ............................................................................ 48 
7.4.1 
Treatment Compliance ......................................................................... 49 
7.5 
Dose Adjustment................................................................................................. 50 
8. 
Study Procedures .......................................................................................................... 50 
 

  
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8.1 
Description of Study Assessments ...................................................................... 50 
8.1.1 
Patient-reported Outcomes .................................................................. 50 
8.1.2 
Qualitative Patient Interview ............................................................... 50 
8.1.3 
Clinical Laboratory Assessments......................................................... 51 
8.1.4 
Pharmacokinetic Assessments ............................................................. 51 
8.1.5 
Safety Assessments .............................................................................. 52 
9. 
Safety Reporting ........................................................................................................... 53 
9.1 
Definitions and Special Considerations .............................................................. 53 
9.1.1 
Adverse Events .................................................................................... 53 
9.1.2 
Serious Adverse Events ....................................................................... 54 
9.1.3 
Unexpected Adverse Events ................................................................ 55 
9.2 
Assessment of Adverse Events ........................................................................... 56 
9.2.1 
Severity ................................................................................................ 56 
9.2.2 
Causality .............................................................................................. 56 
9.3 
Special Situations ................................................................................................ 57 
9.3.1 
Pregnancy............................................................................................. 57 
9.3.2 
Adverse Events of Special Interest ...................................................... 58 
9.4 
Reporting of Serious Adverse Events and Pregnancies ...................................... 58 
9.5 
Follow-up of Adverse Events ............................................................................. 59 
9.6 
Safety Oversight ................................................................................................. 59 
10. 
Statistical Methodology ................................................................................................ 60 
10.1 Determination of Sample Size ............................................................................ 60 
10.2 Analysis Populations........................................................................................... 61 
10.2.1 
Intent-to-Treat (ITT) Population .......................................................... 61 
10.2.2 
Modified Intent-to-Treat (mITT) Population ....................................... 61 
10.2.3 
Per Protocol (PP) ................................................................................. 61 
10.2.4 
Pharmacokinetics Population (PK) ...................................................... 61 
10.2.5 
Safety Population ................................................................................. 61 
 

  
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10.3 Study Endpoints .................................................................................................. 62 
10.3.1 
Primary Efficacy Endpoint .................................................................. 62 
10.3.3 
Other Efficacy Endpoints..................................................................... 62 
10.3.4 
Pharmacokinetic (PK) / Pharmacodynamic (PD) Endpoint ................ 63 
10.3.5 
Safety Endpoints .................................................................................. 63 
10.4 Statistical Methods .............................................................................................. 63 
10.4.1 
Extent of Study Drug Exposure and Compliance ................................ 63 
10.4.2 
Analyses of Efficacy Endpoints ........................................................... 64 
10.4.3 
Pharmacokinetic (PK)/ Pharmacodynamic (PD) Analyses ................. 65 
10.4.4 
Subgroup Analyses .............................................................................. 65 
10.4.5 
Safety Analyses.................................................................................... 66 
10.4.6 
Baseline Characteristics and Other Summaries ................................... 68 
11. 
Study Management ....................................................................................................... 68 
11.1 Monitoring .......................................................................................................... 69 
11.2 Protocol Deviations............................................................................................. 69 
11.3 Audits and Inspections ........................................................................................ 70 
11.4 Amendments ....................................................................................................... 70 
11.5 Record Keeping .................................................................................................. 70 
11.5.1 
Drug Accountability ............................................................................ 70 
11.5.2 
Health Insurance Portability Accountability Act of 1996 and 
Subsequent Updates ............................................................................. 70 
11.5.3 
Financial Disclosure ............................................................................ 71 
11.5.4 
Access to Original Records.................................................................. 71 
11.5.5 
Retention of Study Documents ............................................................ 71 
12. 
Administrative Structure of the Study .......................................................................... 72 
13. 
Appendix A – Schedule of Events ................................................................................ 73 
14. 
Appendix B – Amount of Blood to be Collected from Each Patient ............................ 76 
15. 
Appendix C – Ethical Standards ................................................................................... 77 
 

  
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16. 
Appendix D – Investigator Obligations ........................................................................ 79 
17. 
Appendix E – Calculations ........................................................................................... 84 
18. 
Appendix F – Hospital Anxiety and Depression Scale (HADS) .................................. 85 
19. 
Appendix G – Zoster Brief Pain Inventory (ZBPI) ...................................................... 87 
20. 
Appendix H – Patient’s Global Impression of Change (PGIC) Scale .......................... 90 
21. 
Appendix I – Neuropathic Pain Symptom Inventory (NPSI) ....................................... 91 
22. 
References ..................................................................................................................... 94 
 
Tables and Figures 
Figure 5.1–1 
Treatment Schema ............................................................................... 35 
Table 7.4-1 
Study Drug Administration .................................................................. 49 
 

  
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2. 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
AAK1 
AP2 associated kinase 1 
ADPS 
average daily pain score 
ALT 
alanine aminotransaminase 
ANOVA 
analysis of variance 
AP 
alkaline phosphatase 
AST 
aspartate aminotransaminase 
AUC 
area under the curve 
BLQ 
below limit of quantification 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cp2hr 
2-hr plasma concentrations 
Ctrough 
trough plasma concentrations 
CBD 
Cannabidiol  
CCI 
chronic constriction injury 
CFR 
Code of Federal Regulations 
CI 
confidence intervals 
CMP 
comprehensive metabolic panel 
CNS 
central nervous system 
CRO 
Contract Research Organization  
DMC 
data monitoring committee 
eCRF 
electronic Case Report Form 
ECG 
electrocardiogram 
EMG 
electromyogram 
EOT 
end of treatment 
ERC 
Ethics Review Committee 
 

  
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Abbreviation 
Definition 
eTMF 
electronic trial master file 
EW 
early withdrawal 
FDA 
U.S. Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GMR 
geometric mean ratio 
HADS 
Hospital Anxiety and Depression Scale 
HbsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus core antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LLOQ 
lower limit of quantification 
MAR 
missing at random 
MMRM 
mixed-effects model repeated measures 
MedDRA 
Medical Dictionary for Regulatory Activities 
NFR 
nociceptive flexion reflex 
NOAEL 
no observable adverse effect level 
NPSI 
Neuropathic Pain Symptom Inventory 
NRI 
non-responder imputation 
OTC 
over-the-counter 
PBMC 
peripheral blood monocytes 
 

  
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Abbreviation 
Definition 
PD 
pharmacodynamic 
PE 
physical examination 
PGIC 
Patient’s Global Impression of Change  
PK 
pharmacokinetic(s) 
PHN 
postherpetic neuralgia 
PRO 
patient-reported outcome 
RBC 
red blood cells 
SD 
standard deviation 
SAE 
serious adverse even 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SSR 
sample size reestimation 
STZ 
streptozotocin 
TCA 
tricyclic antidepressant  
Tdap 
tetanus, diphtheria and acellular pertussis vaccine, adult/adolescent 
formulation 
UA 
urinalysis 
ULN 
upper limit of the normal reference range 
US 
United States 
VAS 
visual analog scale 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
ZBPI 
Zoster Brief Pain Inventory 
 
 
 
 
 

  
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3. 
Introduction 
3.1 
Background on LX9211 and Neuropathic Pain 
Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system such as 
herpes infection and diabetes, which can lead to chronic pain syndromes such as postherpetic 
neuralgia (PHN) and diabetic peripheral neuropathic pain (DPNP) (Costigan, 2009). As a 
consequence of these conditions, patients can experience hyperalgesia (increased pain from a 
normally painful stimulus), allodynia (pain elicited by a stimulus that does not normally evoke 
pain), and spontaneous pain (pain arising without an obvious triggering event). Despite the 
availability of approved drugs for the management of neuropathic pain, a significant unmet need 
remains. Specifically, these agents do not eliminate neuropathic pain for most patients with 
fewer than half achieving a 50% reduction in pain severity (Finnerup, 2010; Snedecor, 2014). In 
addition, undesirable side effects, such as dizziness, somnolence, weight gain, cognitive and 
motor impairment, are seen in patients treated with currently available analgesic therapies. 
AP2 associated kinase 1 (AAK1) was first identified as a novel therapeutic target for neuropathic 
pain following testing of 3,097 homozygous mouse knockout lines in a broad, unbiased 
phenotypic screen (Kostich, 2016). AAK1 knockout mice showed markedly reduced persistent 
pain responses (Phase 2 flinching) in the formalin test but were otherwise normal in assays of 
acute pain (hotplate and formalin Phase 1 response) and motor function (Kostich, 2016). AAK1 
knockout mice also failed to develop mechanical allodynia following ligation of the L4 and L5 
spinal nerves (Chung model) confirming that AAK1 plays an important role in the development 
of persistent and neuropathic pain states (Kostich, 2016).  
Given this desirable profile Lexicon initiated a discovery program to identify novel, small 
molecule, AAK1 inhibitors with suitable properties to progress into clinical development for the 
treatment of neuropathic pain.  
LX9211 potently inhibits AAK1 with in vitro IC50 values ranging from 1.08 - 3 nM. In vivo 
studies show that acute oral administration of LX9211 reduced established thermal hyperalgesia 
in chronic constriction injury (CCI) rats and reduced established mechanical allodynia in 
streptozotocin (STZ)-treated rats. Separate studies confirmed that LX9211 engaged AAK1 in the 
rat spinal cord after oral administration. LX9211 showed low potential for motor impairment in 
rats with no effect observed on performance of the accelerating rotarod test. In the rat 
nociceptive flexion reflex (NFR) model, LX9211 increased the current threshold required to 
elicit an A-delta-related increase in the biceps femoris muscle electromyography (EMG) 
response after intravenous (IV) administration. Intravenous administration of LX9211 also 
reduced A-delta-related wind-up of the EMG response and plasma exposures achieved at doses 
 

  
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effective on NFR measures were within the same range as those required for efficacy in 
neuropathic pain models.  
These results support the development of LX9211 for the treatment of neuropathic pain and link 
AAK1 inhibition to a major inhibitory pain pathway, which is a powerful modulator of spinal 
dorsal horn circuits required for neuropathic pain (Fairbanks, 2009).  
3.2 
LX9211 Nonclinical Pharmacology, Pharmacodynamics and Toxicology 
Additional details can be found in the Investigator Brochure (IB). 
3.2.1 
In Vitro Pharmacodynamic Studies 
LX9211 was evaluated in a series of in vitro studies to determine potency and selectivity for 
inhibition of human AAK1. LX9211 is a potent inhibitor of AAK1 with in vitro IC50 values 
ranging from 1.08 – 3 nM. LX9211 showed good selectivity for AAK1 in a kinase panel 
consisting of 268 different assays to measure inhibition of a broad range of kinase targets. 
LX9211 was also tested for additional pharmacological activity in a panel of 41 assays (39 
targets) to assess modulation of enzymatic, ligand binding or functional activity at selected G-
protein coupled receptors, monoamine transporters, ion channels, nuclear hormone receptors and 
enzymes. LX9211 showed modest potency for inhibition of radioligand binding to the 
norepinephrine transporter (IC50 = 0.275 µM, equivalent to 106 ng/mL of LX9211). The 
projected human maximum free plasma concentration (Cmax values 16.6 ng/mL corrected for 
92.3% protein binding) of LX9211 at the projected efficacious clinical dose is 1.28 ng/mL (ie, 
16.6x [1-92.3%] = 1.28 ng/mL), indicating a margin of efficacy of approximately 83 at the IC50 
concentration of norepinephrine inhibition. 
3.2.2 
In Vivo Pharmacodynamic Studies 
In vivo studies conducted to support the development of LX9211 for the treatment of 
neuropathic pain include i) efficacy determinations in 3 neuropathic pain models in rats (CCI, 
STZ, and postherpetic neuralgia models), ii) demonstration of AAK1 target engagement in rat 
spinal cord, iii) investigation of the potential for motor impairment in the rat accelerating rotarod 
test, and iv) demonstration of efficacy in the rat NFR model, which is a translational model 
sensitive to a variety of established pain medications in humans (Sandrini, 2005). Results show 
that acute oral administration of LX9211 reduced established thermal hyperalgesia in CCI rats 
and reduced established mechanical allodynia in STZ-treated rats. The lowest dose achieving 
>50% inhibition was 0.3 mg/kg and 1 mg/kg, respectively and was associated with average 
plasma exposures of 18.7 nM and 92.3 nM, respectively, on completion of behavioral testing.  
 

  
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LX9211 showed potent in vivo efficacy in a rat model for post-herpetic neuralgia. Both single 
and multiple oral doses of 30 mg/kg LX9211 demonstrated almost complete inhibition of pain 
due to varicella-zoster virus (VZV) infection in this model. Separate studies confirmed that 
LX9211 engaged AAK1 in rat spinal cord after oral administration; the AAK1 binding site 
occupancy was 83.1% and 96% measured 3 hours (ie, at time to peak efficacy) after treatment 
with 0.3 and 1 mg/kg LX9211, respectively. LX9211 showed low potential for motor impairment 
in rats with no effect observed on performance of the accelerating rotarod test at oral doses up to 
30 mg/kg (average plasma exposure 1.65 µM). In the rat NFR model LX9211 increased the 
current threshold required to elicit an A-delta related increase in the biceps femoris muscle 
electromyogram (EMG) response after intravenous (0.3 mg/kg) or intraperitoneal (0.1 or 1 
mg/kg) administration. Intravenous administration of LX9211 (0.1 or 0.3 mg/kg) also reduced A-
delta related wind-up of the EMG response and plasma exposures achieved at doses effective on 
nociceptive flexion reflex (NFR) measures were within the same range as those required for 
efficacy in neuropathic pain models. 
3.2.3 
Safety Pharmacology 
A core battery of Good Laboratory Practice (GLP) compliant safety pharmacology studies were 
conducted to assess the effect of LX9211 phosphate on the central nervous system (CNS), 
respiratory system, and cardiovascular system using standard methodologies and procedures. In 
the CNS study in rats, transient mydriasis was observed at 8 hours postdose in rats administered 
15 mg/kg and at 4- through 24-hours postdose in rats administered 60 mg/kg. No LX9211 
phosphate related changes were present at 168 hours postdose. LX9211 phosphate produced no 
definitive, biologically relevant changes in assayed respiratory parameters (tidal volume, 
respiratory rate, minute volume) up to 168 hours postdose at doses up to 60 mg/kg in the rat. 
LX9211 phosphate inhibited human ether-a-go-go related gene (hERG) current with an IC50 of 
1.1 µM. No effects on the cardiovascular system in dogs were clearly attributed to the 
administration of LX9211 phosphate at doses up to 30 mg/kg. However, in the 30 mg/kg dose 
group, 3 out of 4 dogs had emesis within 10 minutes of dosing. In 1 dog that did not vomit 
following administration of 30 mg/kg (therefore, likely had higher exposure), the corrected QT 
(QTc) interval was slightly prolonged by up to 20 msec (+9%) at 3 hours postdose.  
3.2.4 
Summary of Pharmacology 
LX9211 showed potent in vivo efficacy in nonclinical neuropathic pain models in the rat; the 
lowest oral dose that demonstrated >50% inhibition was 0.3 mg/kg and 1 mg/kg in the CCI and 
STZ models, respectively.  
 

  
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In safety pharmacology studies, LX9211 was found to have no definitive, biologically relevant 
effects on the respiratory systems in rats at 60 mg/kg (the highest dose tested in the study). In the 
CNS study in rats, LX9211 produced a transient mydriasis, which was most likely due to the 
known pharmacology of the compound and was not considered adverse. No effects on the 
cardiovascular system in dogs were clearly attributed to the administration of LX9211 phosphate 
at doses up to 30 mg/kg. 
3.3 
LX9211 Toxicology 
GLP-compliant toxicology studies with LX9211 phosphate of 4- and 13-weeks duration have 
been conducted in the rat and the dog. The no observed adverse effect level (NOAEL) for 
LX9211 phosphate was determined to be 10 mg/kg/day after 13 weeks of dosing in the rat and 5 
mg/kg/day after 13 weeks of dosing in the dog. LX9211 phosphate tested negative in the 
standard battery of in vitro and in vivo genetic toxicology studies.  
The effects of LX9211 on embryo-fetal development have been assessed in the rat and the rabbit. 
In the rat, the NOAEL was determined to be 10 mg/kg/day. In the rabbit, the NOAEL was 4 
mg/kg/day 
Additional details can be found in the IB. 
3.3.1 
Preclinical GLP-Compliant Toxicology Studies in Rats 
In the 4-week study, LX9211 phosphate was administered by oral gavage to male and female rats 
at dose levels of 0, 3, 15, or 60 mg/kg/day. LX9211-related findings were non-adverse, generally 
reversible, and included infrequent clinical observations of decreased body weight and food 
consumption; minor clinical pathology effects; and vacuolation of macrophages in the lungs and 
epithelial cells in bile ducts, the main pancreatic duct, uterine glands, and epididymis that were 
consistent with phospholipidosis. Decreased body weight was associated with a decrease in the 
weight of prostate and atrophy (minimal) and decreased weight and secretions of seminal 
vesicles in male rats at 60 mg/kg/day. Assay results confirm that LX9211 is non-genotoxic. 
Based on the results of this study, the NOAEL for LX9211, administered as LX9211 phosphate 
by oral gavage for 4 weeks to rats, is 60 mg/kg/day. This corresponds to a Week 4 Cmax of 3010 
and 4420 ng/mL for males and females, respectively (mean of 3,630 ng/mL), and corresponding 
AUC0-24 of 65,000 and 94,900 ng*hr/mL, respectively (mean 79,200 ng*hr/mL). 
In the 13-week rat study, LX9211 phosphate was administered by oral gavage to male and 
female rats at dose levels of 0, 3, 10, or 60 mg/kg/day. At the high dose (60 mg/kg/day), there 
were 3 unexplained deaths (2 on Day 11 and 1 on Day 69). In addition, 5 high-dose animals 
experienced a total of 6 short (<1 minute) clonic convulsions; most occurred during the last 3 
 

  
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weeks of dosing. No convulsions or deaths occurred at any of the lower doses. LX9211 
phosphate-related, non-adverse effects included minor clinical observation and clinical pathology 
findings in animals administered 60 mg/kg/day. Adverse decreased body weight changes were 
noted for animals administered 60 mg/kg/day. Non-adverse cytoplasmic vacuolation, consistent 
with phospholipidosis, was observed in the kidney, lung, thyroid, pancreas, liver, epididymis, 
and uterus of animals administered 60 mg/kg/day and in the lung, uterus, liver, pancreas, and 
epididymis of animals administered 10 mg/kg/day. Adverse microscopic findings were noted in 
the kidneys of animals administered 60 mg/kg/day, characterized by slight to moderate chronic 
progressive nephropathy associated with increased kidney weights. Slight atrophy of the prostate 
was noted at 60 mg/kg/day. Based on the results of this study, the NOAEL for LX9211, 
administered as LX9211 phosphate by oral gavage for 13 weeks to rats, is 10 mg/kg/day. This 
corresponds to a Week 13 Cmax of 922 and 1,370 ng/mL for males and females, respectively 
(mean of 1,090 ng/mL), and corresponding AUC0-24 of 15,200 and 23,100 ng*hr/mL, 
respectively (mean 19,100 ng*hr/mL). This exposure at the NOAEL is approximately 10-fold 
higher than that projected at the dose in the current PHN study. 
3.3.2 
Preclinical GLP-Compliant Toxicology Studies in Dogs 
In the 4-week study, LX9211 phosphate was administered by oral gavage to male and female 
beagle dogs at dose levels of 0, 1, 2.5, or 5 mg/kg/day. LX9211-related pathology findings 
included minimal to mild increases in white blood cell (WBC) and absolute neutrophil counts 
and decreases in absolute lymphocyte and eosinophil counts in some animals at ≥1 mg/kg/day 
that were considered stress related. Minimal acute inflammation in the urinary bladder was noted 
in 3/6 (2 males and 1 female) animals, with slight urothelial hyperplasia in 2 of these animals, 
and minimal focal ulcer in the urinary bladder in 1 of these animals administered 5 mg/kg/day. 
Minimal aortic mineralization was observed in 1 female animal in the low-dose group and 1 
female animal in the mid-dose group. Minimal to slight aortic mineralization was observed in 2 
female animals in the high-dose group. Based on the results of this study, the NOAEL for 
LX9211 phosphate, administered by oral gavage for 4 weeks to dogs, is 2.5 mg/kg/day. This 
corresponds to a Week 4 Cmax of 133 and 125 ng/mL for males and females, respectively (mean 
129 ng/mL), and corresponding AUC0-24 of 1,860 and 1,090 ng*hr/mL, respectively (mean 1,470 
ng*hr/mL). 
LX9211 phosphate was also administered by oral gavage for 13 weeks to male and female 
beagle dogs at a dose of 1, 2.5, or 5 mg/kg/day. No LX9211 phosphate-related clinical 
observations, ophthalmic findings, physical examination findings, or differences in body weight, 
body weight change, food consumption, heart rate, body temperature, or pulse oximetry 
occurred. No ECG changes were attributed to LX9211 phosphate, and no LX9211 phosphate-
 

  
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related changes in hematology or urinalysis (UA) test results were noted. Two minor LX9211 
phosphate-related clinical pathology findings observed on Day 92 of the dosing phase in male 
beagles that received 5 mg/kg/day were minimally increased fibrinogen and globulin 
concentrations; these findings suggested an inflammatory response and lacked microscopic 
correlates, exhibited evidence of reversibility, and were considered not adverse based on their 
small magnitude. At the terminal sacrifice, 1 male receiving 2.5 mg/kg/day LX9211 had minimal 
muscle degeneration in the urinary bladder. At recovery sacrifice, 1 male receiving 5 mg/kg/day 
also had the same finding. The severity in both cases was minimal. This finding occurs as a 
background finding in beagle dogs (Cain, 2000).The urinary bladder changes occurred at a low 
incidence and severity, similar to published data indicating no associated clinical signs or 
evidence of bladder dysfunction. The UA data from these animals was unremarkable. The 
relationship of the urinary bladder changes to treatment, if any, is not clear. Based on the results 
of this study, the NOAEL for LX9211 phosphate, administered by oral gavage for 13 weeks to 
dogs, is 5 mg/kg/day. This dose level corresponded to mean Cmax of 506 and 515 ng/mL for 
males and females, respectively (mean 511 ng/mL), and corresponding AUC0-24 of 6,440 and 
6,810 ng*hr/mL for males and females, respectively (6,620 ng*hr/mL). 
3.3.3 
Embryo-Fetal Development Study in the Rat 
The effects of LX9211 phosphate on embryo-fetal development has been assessed in the rat. 
Doses evaluated were 0, 1, 3, and 10 mg/kg/day. Test article-related non-adverse effects included 
decreased mean body weight and body weight gain (1, 3, and 10 mg/kg/day), decreased food 
consumption (3 and 10 mg/kg/day), reduced adjusted fetal weight parameters (10 mg/kg/day), 
and unossified phalanx hindlimb skeletal variations (10 mg/kg/day). No test article-related 
effects on maternal clinical or macroscopic observations, reproductive performance, or fetal 
external, visceral or skeletal malformations were noted. Based on the results of this study, the 
NOAEL for LX9211, administered as LX9211 phosphate by oral gavage to pregnant rats during 
the period of organogenesis, is 10 mg/kg/day. On Gestation Day 12 for this dose level, the Cmax 
and AUC0-24 were 882 ng/mL and 12,000 ng*hr/mL, respectively, for LX9211. 
3.3.4 
Embryo-Fetal Development Study in the Rabbit 
In the rabbit, doses of LX9211 phosphate evaluated were 0, 0.6, 2, and 4 mg/kg/day. No test 
article related effects were noted on maternal body weight, food consumption, clinical or 
macroscopic observations, reproductive performance, cesarean section parameters, embryofetal 
toxicity, or fetal development. Based on the results of this study, the NOAEL for LX9211, 
administered as LX9211 phosphate by oral gavage to pregnant rabbits during the period of 
 

  
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organogenesis, is 4 mg/kg/day. On Gestation Day 13 for this dose level, the Cmax and AUC0-24 
were 261 ng/mL and 4200 ng*hr/mL, respectively, for LX9211. 
3.4 
Clinical Trials of LX9211 in Humans 
Three clinical studies have recently completed: LX9211.1-101-NRM, A Phase 1, Randomized, 
Double-blind, Placebo-controlled Ascending, Single-dose Study to Determine the Safety and 
Tolerability of Orally Administered LX9211 in Healthy Human Participants (SAD); LX9211.1-
102-NRM, A Phase 1, Randomized, Double-blind, Placebo-controlled Ascending Multiple-dose 
Study to Determine the Safety and Tolerability and Pharmacokinetics of Orally Administered 
LX9211 in Healthy Volunteers (MAD); and LX9211.1-103-NRM, A Phase 1, Open-label, 
Nonrandomized, 2-part Study to Evaluate the Absorption, Metabolism, Excretion, Mass Balance, 
and Absolute Bioavailability of 14C-LX9211, Following Oral and  Intravenous Administration in 
Healthy Male Subjects.  
The SAD and MAD studies included females of nonchildbearing potential and males between 
the ages of 18 to 65 years. A total of 146 subjects were enrolled in the 2 studies, 112 of whom 
were randomly assigned to receive LX9211.  
The results from the SAD study showed that LX9211 was generally well tolerated in healthy 
normal subjects at single doses up to 300 mg. Results from cohorts exposed to single-dose 
LX9211 up to 300 mg are summarized as follows: 
Adverse events were mild to moderate in intensity; there were no severe AEs, deaths, SAEs, or 
withdrawals due to AEs. The most common AEs were dizziness and headache. One subject in 
the 300 mg single-dose cohort experienced orthostatic tachycardia with an onset at 1-hour 
postdose and which lasted for 8 days. This event was reported by the Investigator as mild in 
intensity and related to study drug.  
Systemic exposure to LX9211 (Cmax, AUC0-24, AUC0-96, and AUC0-inf) increased from 5 to 300 
mg in an apparent dose-proportional manner when examined as the log functions of dose and 
exposure. Median Tmax of LX9211 was approximately 8-12 hours postdose and the mean t1/2 
ranged from 143 to 197 hours (6 to 8 days).  
Based on the pharmacokinetic (PK) profile of LX9211 in the SAD study, subjects in the MAD 
study were given a loading dose on Day 1, followed by a daily maintenance dose on Days 2-14. 
This dosage regimen permitted steady state to be achieved quickly and then maintained for the 
duration of the study. Results from this study showed that LX9211 was well tolerated in healthy 
normal subjects receiving multiple doses (14 days) up to 200 mg loading dose. All AEs were 
mild in intensity; there were no severe AEs, deaths, or SAEs. One patient discontinued due to 
reported AEs: allergic rash, urticaria, and angioedema. All AEs were assessed as mild and 
 

  
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resolved within a few days after being treated with a single oral dose of diphenhydramine. 
Overall, the AEs observed in the MAD study were similar to those reported in the SAD study. In 
both studies, the most common AEs were headache and dizziness in patients treated with 
LX9211, with the events occurring at higher frequency at doses at or above 100 mg. With few 
exceptions, these events occurred 1-3 days after dosing, lasted for 1-2 days, were considered 
mild in intensity, and resolved spontaneously. No clinically significant comprehensive metabolic 
panel (CMP), UA findings, or bladder dysfunction-related AEs were reported in any subject 
treated with LX9211 in the SAD or MAD studies with LX9211. 
In study LX9211-103, a cohort of 6 male subjects was exposed to a single oral dose of 14C-
LX9211 (nominal 50 mg free drug, approximately 52uCi). Drug-related material in urine and 
feces was collected for up to 34 days. The mean total recovery of administered radioactivity was 
77.9%, with 48.7% recovered in urine and 29.2% recovered in feces. There were no serious 
adverse events (SAEs) and the adverse events (AEs) experienced, were similar to those seen in 
the SAD and MAD studies; all were mild in severity. In the same study, a separate cohort of 6 
subjects underwent an evaluation to establish the absolute oral bioavailability of LX9211. A 
single oral dose of 50 mg of LX9211 was administered, followed by an intravenous microdose 
infusion of 14C-9211 (50 μg/200nCi). The mean oral bioavailability of LX9211 was 89.4%. 
Again, there were no SAEs and the AEs experienced were similar to those seen in the SAD and 
MAD studies; all were mild in severity. 
3.5 
Rationale for Current Study 
3.5.1 
Rationale for Selection of Dose 
The loading and maintenance dose level of LX9211 selected for evaluation in the current study 
was chosen based upon the safety, tolerability, and PK data observed from the prior single-dose 
and multiple-dose Phase 1 studies. 
The doses studied in the SAD and MAD studies, in healthy volunteers, ranged from 5 to 300 mg. 
Single-dose administration demonstrated linear PK up to the highest tested dose (300 mg). There 
were no deaths, SAEs, discontinuations due to an AE, AEs of severe intensity, or any clinically 
significant laboratory, vital sign, physical exam (PE), or electrocardiogram (ECG) findings. 
Multiple-dose administration demonstrated linear PK up to the highest tested dose (200 mg). 
There were no deaths, SAEs, discontinuations due to an AE, AEs of severe intensity, or any 
clinically significant laboratory, vital sign, PE, or ECG findings. 
Based on the observed safety and tolerability data from single doses up to 300 mg and multiple 
doses up to 200 mg for 14 days, the dose level selected in this study, 200 mg loading dose 
 

  
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followed by 20 mg maintenance doses, respectively, are expected to be well tolerated and 
represent an adequate range for dose exploration. 
3.6 
Rationale for Study Design and Control Groups 
The randomized, placebo-controlled, double-blind clinical design allows for unbiased 
comparison of efficacy and safety between LX9211 and placebo. The treatment duration (6 
weeks) selected for this study was chosen based on the expectation of seeing an efficacy signal 
for the LX9211 200 mg treatment, which was based on human safety and tolerability. 
Use of a concurrent placebo control, randomization, and double-blind administration of study 
drug are intended to minimize bias. Implementation of an unblinded interim analysis will allow 
for a reestimated increase in the sample size if indicated by the interim results. The study is 
designed as a group sequential trial to accommodate the interim analysis, and to improve upon 
such a design, the interim analysis effect size result is used not only to possibly increase the 
sample size, but to aid in decisions of early stopping for futility. The option of sample size 
reestimation (SSR) allows the study to power for a more optimistic effect, thereby minimizing 
up-front costs, while assuring a good probability of detecting a smaller important effect size by 
increasing the sample size if required. 
4. 
Study Objectives 
4.1 
Primary Objective 
To evaluate the efficacy of LX9211 in reducing pain related to postherpetic neuralgia (PHN) 
4.2 
Secondary Objective 
To assess other effects and patient reported outcomes of LX9211 versus placebo during and 
following the Week 6 double-blind Treatment Period  
4.3 
Other Objectives 
• Change from Baseline to Week 6 in the Neuropathic Pain Symptom Inventory (NPSI) 
• Change from Baseline to each week in ADPS, based on Question 5 of the ZBPI 
• Proportion of patients with ≥30% reduction from Baseline in ADPS, based on Question 5 
of the ZBPI by week 
• Proportion of patients with ≥50% reduction from Baseline in ADPS, based on Question 5 
of the ZBPI by week 
 

  
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• Cumulative distribution function of percent change in ADPS based on Question 5 of the 
ZBPI from Baseline to Week 6 comparing the LX9211 treatment group to placebo 
• Cumulative distribution function of percent change in ADPS based on Question 5 of the 
ZBPI from Week 6 to Week 11 comparing the LX9211 treatment group to placebo 
5. 
Investigational Plan 
5.1 
Overall Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in patients with PHN. 
Scheduled study visits in the clinic will occur during Screening; at the initiation of the 2-week 
single-blind placebo Run-in Period; on Day 1 (Baseline), and during Weeks 2, 4, and 6 of the 
double-blind Treatment Period, and Week 11 of the single-blind Safety Follow-up Period. 
Male and female patients, ≥18 years of age, inclusive, with prior herpes zoster skin rash and 
PHN pain persisting for ≥3 months after healing of the herpes zoster skin rash, and who meet all 
inclusion and no exclusion criteria are eligible for enrollment. 
Eligible patients may continue use 1 medication prescribed for PHN including pregabalin, 
gabapentin, and tricyclic antidepressant (TCA) medications, as long as they have been at stable 
doses for ≥1 month prior to Screening and are willing to maintain their doses for the duration of 
the study. Patients taking more than 1 permitted concomitant medication for the treatment of 
PHN and unable to washout all but 1 of these treatments for the duration of the study are not 
eligible. Use of any new medications, prescribed or over-the-counter (OTC), for treatment of 
PHN pain is not permitted during the course of the study. Use of any opioid medications for the 
management of PHN within the 2 months prior to Screening is not permitted. 
The treatment schema is summarized in Figure 5.1-1. 
 

  
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Figure 5.1–1 
Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
    
 
 
 
  
 
 
 
 
 
 
  
   
 
  
 
 
   
 
  
 
 
 
 
 
 
 

  
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5.1.1 
Screening Period 
After signing the Informed Consent Form (ICF), all patients will enter a Screening Period of up 
to 2 weeks. Patients using non-opioid medications that are prohibited by the protocol must 
discontinue or washout of these medications as directed by the protocol prior to entering the 
Screening period. Following confirmation of eligibility criteria, patients will enter the following 
study periods: 
5.1.2 
Run-in Period 
After meeting Screening eligibility criteria, patients will enter a 2-week single-blind Run-in 
Period. On Day 1 of the Run-in period, patients will be administered 4 tablets of single blind 
study drug at the site. For the remaining duration of the Run-in Period, patients will take a single 
tablet of study drug every morning. Each evening patients will rate and record intensity of their 
PHN pain based on Question 5 of the ZBPI by answering the question “Please rate your pain by 
indicating the one number that best describes your pain on the average in the last 24 hours”, on 
the 11-point numerical rating scale (0 [No Pain] to 10 [Pain as bad as you can imagine]).The 
ADPS will be calculated using all available daily pain diary data. The mean value of the ADPS 
derived over Week 2 will serve as the Baseline measure used for analyses. In order to qualify for 
randomization, patients must have completed ≥70% of the daily pain diary entries during the 
second week of the Run-in Phase, meet criteria for moderate to severe pain and demonstrate ≥80% 
compliance with taking the expected amount of placebo tablets during the Run-in Period. During 
the Run-in Period patients will not be allowed to use any rescue medication. On the morning of 
the Run-in Visit, patients may consume a light meal prior to the visit.  
Note:  Patients who fail Screening due to laboratory values may have those assessments repeated 
and be rescreened once after discussion with the Sponsor’s Medical Monitor.  
5.1.3 
Randomization/Treatment Period  
Patients who successfully complete the 2-week single-blind placebo Run-in Period and meet all 
other eligibility criteria will enter the 6-week double-blind Treatment Period. Patients will be 
randomly assigned in a 1:1 ratio between the following 2 treatment groups: 
• 
Group 1: LX9211 200 mg* / 20 mg**, once daily (qd) 
• 
Group 2: Placebo, once daily matching loading and maintenance doses 
* Loading dose (Day 1) 
** Maintenance dose (Day 2 – Week 6 Visit) 
 

  
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Implementation of the treatment randomization schedule will be centralized. A 1:1 ratio for 
assigning patients between the treatment groups will be accomplished by use of randomly 
permuted blocks of fixed size. 
On Day 1, patients will be assigned to LX9211 or placebo, to be given as a loading dose at the 
clinic. Patients will remain at the clinic for observation for 2 hours following dosing. At 2 hours, 
orthostatic vital signs will be obtained (heart rate and blood pressure) after which time patients 
may be released and a 2 hr postdose blood draw will occur. 
The loading dose will be followed by a daily maintenance dose taken at home in the morning on 
Day 2 through the Week 6 Visit. Note:  On days of clinic visits, patients will refrain from taking 
their daily dose until after the visit. 
Each evening during the double-blind Treatment Period, patients will be required to rate and 
record their average daily severity of their PHN over the previous 24 hours using Question 5 of 
ZBPI, record the use of rescue medication (acetaminophen), and rate the interference with sleep 
using Question 9F of the ZBPI. The ADPS will be calculated using all available data, however, a 
minimum of 4 days (consecutive or nonconsecutive) from the last week prior to each clinic visit 
is required for the calculation.  
On the day of randomization and at each clinic visit thereafter, patients will be provided 
individual bottles of study drug. Sufficient quantity of study drug will be provided to allow 
prescribed daily dosing until the next scheduled clinic visit. Each bottle will be labeled with a 1-
panel, double-blind label printed in black. Prior to dispensation, the Investigator/qualified 
designee will complete spaces on the study drug label to specify the Patient Number, Date 
Dispensed, and Investigator Name. In addition, the protocol number, batch number, quantity of 
tablets, route of administration, directions for use, bottle number, and storage conditions will be 
indicated.  
Except on days of clinic visits, patients should be instructed to dose with double-blind study drug 
at approximately the same time each day and before the first meal of the day. One tablet of 
double-blind study drug should be taken with 8 ounces of water and should be taken whole. If a 
patient misses a dose by more than 12 hours, that dose should be skipped, and the next dose 
should be taken as scheduled. No double doses should be taken, and dose reductions are not 
permitted. 
On days of clinic visits, double-blind study drug will not be taken in the morning prior to the 
scheduled clinic visit. Patients will take their assigned dose of double-blind study drug for that 
day per instructions from clinic staff, based on scheduled procedures. The date and time of 
administration of the last dose of study drug prior to the clinic visit will be recorded in the eCRF. 
 

  
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Blood samples for the determination of plasma LX9211 trough levels (Ctrough) will be drawn 
predose on Day 1 and at Weeks 2, 4, 6, and 11. Blood samples will be drawn 2 hours after dosing 
on Day 1 for the determination of plasma 2-hour levels (Cp2hr). 
 
 
  
On the day of randomization, patients will also receive a bottle of acetaminophen. If a patient is 
unable to tolerate their PHN, they are encouraged to discuss treatment options with the 
Investigator. At the Investigator's direction, the patient may be permitted to take acetaminophen 
(up to a maximum of 3 grams per day) as a rescue medication. If rescue medication does not 
provide adequate pain relief, the patient may discontinue from further participation in the study 
after consultation with the Investigator.  
Patients discontinuing the study prior to completion of the Week 6 Visit should be encouraged to 
return for the Week 6 Visit assessments and complete the Safety Follow-up Visit 5 weeks later. 
5.1.4 
Safety Follow-up Period 
Following completion of the 6-week double-blind Treatment Period, all patients will enter the 5-
week single-blind Safety Follow-up Period.  
During this period, patients will dose with 1 tablet of single blind study drug every morning 
taken at home. Each evening patients will continue to rate and record the average severity of 
their PHN over the previous 24 hours using Question 5 of ZBPI, record the use of rescue 
medication (acetaminophen), and rate the interference with sleep using the ZBPI. 
5.1.5 
Optional Substudy 
During the Screening Visit, patients may choose to participate in an optional substudy.  
The optional substudy, a qualitative patient interview, will include approximately 30 patients. 
The telephone interview will be designed to gain insight and understanding of patients’ 
experiences with symptoms of PHN and to assess relevance and clinical meaningfulness of 
symptom improvements (eg, reduction in pain) with LX9211 treatment. 
6. 
Study Population 
Male or female patients 18 years or older will be enrolled. Patients will have a diagnosis of 
postherpetic neuralgia defined as pain in the dermatomal distribution of an acute herpes zoster 
 

  
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skin rash, persisting for ≥3 months from the healing of herpes zoster skin rash. Patients will have 
to meet pain criteria at the end of the Run-in Period. 
The proposed sample size is 74 patients, 37 patients per treatment group. This estimate takes into 
account an expected uniform dropout rate of 15%. The sample size may be increased to a 
maximum of 148 patients based on a planned interim analysis that allows for conduct of a 
sample size reestimation procedure. 
The substudy will enroll approximately 30 patients to participate in a qualitative patient 
interview. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible to participate in the 
study. For patients not meeting eligibility requirements, the reason for exclusion must be 
recorded. Note:  Patients who are not eligible because of laboratory result(s) may have the 
laboratory test(s) repeated once during the Screening Period, at the discretion of the Investigator, 
to determine eligibility: 
1. Patient has given written informed consent to participate in the study in accordance with 
local regulations  
2. Adult male or female patients ≥18 years of age at the Screening Visit: 
a. Females of childbearing potential must have a negative serum or urine pregnancy 
test prior to the start of study drug. In the case of positive urine pregnancy testing, 
a negative serum sample for pregnancy testing, to confirm that the patient is not 
pregnant, must be obtained prior to start of study. They must also agree to use 
adequate methods of contraception which include the following: condom with 
spermicidal gel, diaphragm with spermicidal gel, coil (intrauterine device), 
surgical sterilization, vasectomy, oral contraceptive pill, depo-progesterone 
injections, progesterone implant (ie, Implanon®), NuvaRing®, Ortho Evra®  
b. Nonsterile male patients with sexual partners of childbearing potential must agree 
to use adequate methods of contraception from Baseline through the Week 11 
Visit 
3. Presence of PHN pain that is present for ≥3 months after healing of herpes zoster skin 
rash affecting a single dermatome (Patients with more than 1 involved dermatome may 
also be included, provided the affected dermatomes are contiguous) 
4. Moderate to severe pain as confirmed by average pain score using scores recorded in the 
pain diary in the 14 days prior to randomization (Run-in Period)  
 

  
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5. At least 80% compliance with dosing during the 2-week Run-in Period, and 70% 
compliance with completion of the daily diary during the second week of the Run-in 
Period  
6. Willing to adhere to the prohibitions and restrictions specified in the protocol 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the study: 
1. Presence of other painful conditions that may confound assessment or self-evaluation of 
PHN: 
a. Patient should not have any other neurological disorder or conditions that can 
cause symptoms that may mimic peripheral neuropathy or that might confound 
assessment of PHN pain. 
b. Other causes of diffuse painful peripheral neuropathy such as: paraproteinemia, 
untreated hypothyroidism (previously treated hypothyroidism not excluded if 
treated and euthyroid for ≥6 months), vitamin B12 deficiency, neurologically-
evident vasculitis, malignancy, amyloidosis, renal insufficiency, connective tissue 
disease (eg, Sjogren's, systemic lupus erythematosus), porphyria, complex 
regional pain syndrome, chronic inflammatory demyelinating 
polyradiculoneuropathy, alcoholism, HIV, hepatitis, uremia, syphilis, myeloma, 
or other systemic disease associated with a secondary painful neuropathy should 
be excluded. 
c. Patient should not have had any exposure to drugs/toxic environmental agents 
known to cause neuropathy. 
2. Over the past year, met Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition (DSM-5) criteria (American Psychiatric Association, 2016) for a major depressive 
episode, any active, significant psychiatric disorders (eg, neurocognitive disorder, anxiety 
disorder, psychosis, bipolar disorder), or a history of clinically significant drug or alcohol 
use disorder that would, in the Investigator's opinion, interfere with the assessment and 
evaluation of pain during the study  
3. Mood and anxiety disorder scores defined by Hospital Anxiety and Depression Scale 
(HADS) ≥13 
4. Suspected or likely diagnosis of trigeminal neuralgia  
5. Use of opioid medications for management of PHN within the 2 months prior to the 
Screening Visit. Note:  Brief use (<1 week) of opioid medication for management of 
 

  
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non-PHN acute pain (eg, tooth extraction/acute injury) ≥2 months prior to Screening 
Visit is permitted. 
6. Use of NSAIDs for the specific treatment of PHN pain 
7. Use of more than 1 permitted concomitant medications for the treatment of PHN. Note: 
Patients may washout additional PHN medications ≥1 month prior to the Screening Visit 
to reach the 1 permitted medication. 
8. For non-opioid medications patient uses and is unwilling/unable to discontinue use of 
prohibited medications and therapies, (eg, benzodiazepines, dextromethorphan, herbal 
medications, mexiletine HCl, adenosine, topical analgesics including lidocaine and 
capsaicin), applied to the same area of the body affected by PHN pain, nerve blocks, 
acupuncture, or other medications indicated for neuropathic pain. A patient using any of 
these interventions for neuropathic pain must discontinue the medication ≥1 month prior 
to starting the Screening Period and for the duration of the study. Note:  This exclusion 
criterion does not include analgesics that are not specifically prescribed for treatment of 
neuropathic pain (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, 
acetaminophen). In addition, patients who are prescribed antidepressants for a mental 
health disorder are eligible to participate as long as they do not meet Exclusion Criteria 2-
3. 
9. A positive urine drug test for drugs of abuse including cannabinoids. Note: Cannabidiol 
(CBD), if used for mood or sleep, is acceptable. If used for PHN it would be allowed if it 
is the only concomitant medication being taken for PHN. If not, the only medication 
being taken for PHN, it should be withdrawn ≥1 month prior to Screening. 
10. Patient has hepatic impairment at Screening, defined as any of the following:  aspartate 
aminotransferase (AST) >2X upper limit of the normal reference range (ULN), alanine 
aminotransferase (ALT) >2X ULN, serum total bilirubin (TB) >2X ULN. Note:  If it is 
the opinion of the Investigator and the Medical Monitor that an increase in bilirubin is 
due to Gilbert’s syndrome, then the patient may participate. 
11. Patient has abnormal kidney function test (estimated glomerular filtration rate [eGFR] 
<60 mL/min as calculated using the Cockcroft-Gault equation) at Screening or renal 
dysfunction requiring hemodialysis 
12. Patient has any of the following medical conditions or disorders: epilepsy or seizure 
disorder requiring treatment with antiepileptic drugs 
13. Presence of clinically significant physical examination (PE) findings other than PHN, or 
laboratory or ECG findings that in the opinion of the Investigator, Medical Monitor, 
 

  
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and/or the Sponsor, may interfere with any aspect of study conduct or interpretation of 
results including: 
a. any clinically significant abnormal heart rate or rhythm  
b. other ECG abnormalities that are clinically relevant 
c. BP >160/100 mm Hg or <90/50 mm Hg 
d. presence of risk factors for torsade de points (eg, family history of long QT 
syndrome; personal history of NYHA class III/IV heart failure or structural heart 
disease) 
14. Receipt of any investigational agent within 30 days or 5 half-lives, whichever is longer, 
prior to Baseline/Randomization on Day 1 
15. Receipt of any therapeutic protein, antibody/biologic- or antibody-based agents (eg, 
growth hormones or monoclonal antibodies) within 3 months prior to dosing on planned 
Day 1. Note:  Preventative vaccines (eg, influenza, pneumococcal, Tdap), will be 
allowed if administered >7 days prior to dosing. Patients who have previously received 
the shingles vaccine, but subsequently develop PHN and meet all inclusion and exclusion 
criteria, are eligible to participate. 
16. Prior exposure to LX9211 
17. History of any serious adverse reaction or hypersensitivity to any inactive component of 
study drug, unless the reaction is deemed irrelevant to the study by the Investigator, 
Medical Monitor, and/or the Sponsor 
18. Presence of any skin condition, such as ulcers, which could interfere with assessment of 
PHN 
19. Existence of any postsurgical or medical condition that, in the judgment of the 
Investigator, Medical Monitor, and/or the Sponsor, might interfere with the absorption, 
distribution, metabolism, or excretion of LX9211, including bariatric surgery, 
cholecystectomy, or any other GI surgery, except appendectomy and hernia repair, which 
are acceptable 
20. History of any major surgery within 3 months prior to Baseline or surgery that is 
anticipated to be performed during the study period 
21. History of any active infection within 30 days prior to Baseline, if deemed clinically 
significant by the Investigator, Medical Monitor, and/or the Sponsor 
22. Malignancy or active treatment for malignancy (ie, radiation or chemotherapy, including 
monoclonal antibodies) within 5 years prior to the Screening Visit. Note:  Patients with 
squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, 
ductal breast cancer in situ, resected low-grade prostate cancer, or other malignancies 
 

  
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that, in the opinion of the Investigator and the Medical Monitor are considered cured, 
may participate. 
23. Donation or loss of >500 mL of blood or blood product within 3 months prior to Baseline 
24. Inability or difficulty swallowing whole tablets 
25. Any other condition that compromises the ability of the patient to provide informed 
consent or to comply with the objectives and procedures of this protocol, as judged by the 
Investigator, Medical Monitor, and/or the Sponsor 
26. Unable or unwilling to adhere to the requirements of the protocol, or communicate or 
cooperate with the Investigator and/or their staff for any reason  
27. Patient refuses to participate in processes if established by the Sponsor, to minimize 
duplicate patients (Verified Clinical Trials) 
28. Employees, or relatives of the Sponsor, Investigator or study center staff, with direct 
involvement in the proposed study or other studies under the discretion of the 
Investigator or study center 
29. Patients is immunocompromised (eg, secondary to transplant or require active 
immunosuppressive drugs) 
6.3 
Criteria for Stopping Treatment/Study Withdrawal 
A patient may also be discontinued from the study for the following medical or administrative 
reasons: 
• 
Withdrawal of consent by the patient or legal guardian 
• 
Noncompliance, including refusal of the study drug and/or failure to adhere to the study 
requirements as in the study protocol 
• 
Investigator decides that, in the interest of the patient, it is not medically acceptable to 
continue participation in the study 
• 
The Sponsor terminates the study 
Note:  If a patient is discontinued from study drug before completing the entire duration of 
the Treatment Period up through Week 6/EOT/EW, they should be encouraged to complete 
all end-of-study assessments and to agree to report any AEs, including SAEs (see Section 
9.4) for 35 days following their last dose of study treatment. The date the patient is 
discontinued and the primary reason for study drug discontinuation and termination of 
participation must be recorded on the eCRF. 
 

  
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6.3.1 
Lost to Follow-up 
If a patient does not return to the clinic, attempts should be made to contact the patient (or a 
previously approved designee such as a caregiver, partner, or family member) to determine the 
reason for discontinuation. At minimum, 3 documented attempts, including 1 via certified mail, 
should be made to contact the patient before considering the patient lost to follow-up.  
6.4 
Criteria for Termination of the Study or of a Site's Participation 
If the Sponsor, Investigator, study monitor, or regulatory officials discover conditions arising 
during the study that indicate that the study should be halted or that the study center’s 
participation in the study should be terminated, this action may be taken after appropriate 
consultation between the Sponsor and Investigator. Conditions that may warrant termination of 
the study include, but are not limited to, the following: 
• 
The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in the 
study 
• 
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
• 
Failure of the Investigator to enroll patients into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent Food and Drug Administration (FDA) 
regulations 
• 
Submission of knowingly false information from the research facility to the Sponsor, study 
monitor, or the FDA 
• 
Insufficient adherence to protocol requirements  
• 
Results from a planned interim analysis; see Section 6.4.1 for details 
Study termination and follow-up would be performed in compliance with the conditions set forth 
in the following sections of the Code of Federal Regulations: 21 CFR 312.50 and 21 CFR 
312.56. 
6.4.1 
Termination of the Study Based on Planned Interim Analysis 
The study may be terminated based on the conduct of a formal interim analysis of futility.  
The interim analysis will be performed when the first 38 patients have been accrued and 
followed to endpoint at Week 6 or dropped out from the trial earlier, whichever event 
occurs first. Enrollment will not be temporarily halted while data for the interim analysis is 
being reviewed. The sample size may be increased based on the interim analysis Details of 
 

  
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the futility analysis are given in Section 10.4.5.7 of this protocol, and in the Statistical 
Analysis Plan (SAP) and Data Monitoring Committee (DMC) Charter documents.  
In addition to the planned interim analysis for futility, meetings for an independent DMC data 
reviews will be scheduled to ensure proper safety assessment during enrollment and study 
conduct. Initially, proposed timelines for meeting frequency to review unblinded safety data will 
be as follows: the DMC will develop a charter and establish criteria for when meetings are to 
occur, plus identify a time for the planned interim analysis should this latter event fall outside the 
times of the reoccurring meetings. The DMC review meetings will occur until database lock or at 
earlier time deemed suitable by the DMC. This meeting schedule may be modified based on the 
observed patient accrual rates or signals seen in the safety data. DMC members will also receive 
unblinded summaries of serious adverse events on a monthly basis to review potential emerging 
safety trends. 
6.5 
Clinical Stopping Rules 
Not applicable; however, criteria for individual patient withdrawal or study termination are 
summarized in Section 6.3 and Section 6.4, respectively. 
6.6 
Method of Assigning Patients to Treatment  
Patients will be randomly assigned between 2 parallel treatment groups in a 1:1 manner. A 
randomization Schedule will be centralized and stratified by moderate or severe pain as derived 
from the ADPS collected during the Run-in period. The desired balances will be accomplished 
by use of randomly permuted blocks of fixed size. An Interactive Voice/Web Response System 
(IXRS) will be used as a central mechanism to assign patients to study treatment.  
6.7 
Blinding and Unblinding of Study Drug 
In this double-blind study, the designated group and treatment assigned to each patient will not 
be revealed to the Investigator, the patient, or the Sponsor or their designee, until the decision is 
made to unblind the study. Data from individual patients may be unblinded if deemed medically 
necessary by the Investigator in consultation with the Sponsor, or as required by regulation for 
reporting purpose in the case of an unexpected and related SAE. The IXRS will be used to 
perform emergency unblinding by authorized individuals. 
The randomization schedule will be maintained by the designee performing IXRS for this study. 
Investigators, study site personnel associated with this trial, patients, and the Sponsor and its 
designees involved in the conduct of the study will remain blinded to individual patients’ 
treatment assignments until database lock. 
 

  
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7.1.2 
Tablets 
The study drug dose form consists of white to off-white round coated tablets containing 20 mg, 
or 50 mg of LX9211. All the tablets are visually similar in color, size, and shape. 
Tablet inactive ingredients include silicified microcrystalline cellulose, dibasic calcium 
phosphate anhydrous, croscarmellose sodium, talc, colloidal silicon dioxide, and hydrogenated 
vegetable oil.  
7.1.3 
Packaging, Labeling, and Storage 
LX9211 50-mg tablets are packaged in 30 cc high density polyethylene (HDPE) bottles 
containing pharmaceutical coil and a child resistant polyethylene screw cap with induction seal. 
Each bottle contains 2 tablets.  
LX9211 20-mg tablets are packaged in 30 cc HDPE bottles containing pharmaceutical coil and a 
child resistant polyethylene screw cap with induction seal. Each bottle contains 20 tablets. 
LX9211 tablets in HDPE bottles should be stored at 25°C (77°F); excursions are permitted 15°C 
to 30°C (59°F to 86°F). Stability testing of all the tablet strengths of LX9211 (50-mg and 20-mg) 
is ongoing. 
7.1.4 
Placebo 
The placebo dose form is visually similar in color, size, and shape to LX9211 tablets. 
Tablet ingredients include silicified microcrystalline cellulose, dibasic calcium phosphate 
anhydrous, croscarmellose sodium, talc, colloidal silicon dioxide, and hydrogenated vegetable 
oil.  
Placebo tablets are packaged in 30 cc HDPE bottles containing pharmaceutical coil and a child 
resistant polyethylene screw cap with induction seal. The 50-mg bottle contains 2 placebo tablets 
while the 20-mg bottle contains 20 placebo tablets. 
Placebo tablets in HDPE bottles should be stored at 25°C (77°F); excursions are permitted 15°C 
to 30°C (59°F to 86°F). Stability testing of placebo tablets is ongoing.  
7.2 
Prior and Concomitant Medications 
7.2.1 
Prior Medication 
All medications (prescription and OTC) taken within 30 days prior to Screening will be recorded 
on the eCRF as a prior medication. 
 

  
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7.2.2 
Concomitant Medication 
All medications and other treatments ongoing or taken from the start of the Screening Period, 
through the end of the Safety Follow-up Period of the study will be recorded on the eCRF as 
concomitant medication. This includes any ongoing medications for the treatment patients' PHN 
(ie, gabapentin, pregabalin, and tricyclic antidepressant medications). 
7.3 
Prohibited Medication 
Use of any new medications prescribed or OTC for treatment of PHN pain is not permitted 
during the course of the study. Only the acetaminophen provided by the Sponsor as a rescue 
medicine may be used during the course of the study. The use of personally acquired 
acetaminophen is prohibited. Use of any opioid medication for the management of PHN within 
the 2 months prior to Screening is not permitted. Note:  Brief use (<1 week) of opioid 
medication for management of non-PHN acute pain (eg, tooth extraction/acute injury) ≥2 months 
prior to Screening Visit is permitted. 
All medications, including the study drug, taken by patients during the study will be captured in 
the source documents and recorded on the eCRF. 
7.4 
Administration of Study Drug 
LX9211 (50-mg and 20-mg) will be supplied in tablet form to be taken orally. A placebo, that is 
visually similar in appearance to the LX9211 tablets, will be taken by patients assigned to the 
placebo group.  
On Day 1 of the Run-in Period, at the clinic, patients will be given 4 tablets from their bottle of 
Run-in study drug and will swallow it with 8 ounces (240 mL) of room temperature water. Each 
patient’s hands and mouth will be checked to ensure they have swallowed the tablets. On Days 2 
through 14, patients will be instructed to take their daily dose of study drug before the first meal 
of the day with 8 ounces of room temperature water. If a patient misses a dose by more than 12 
hours, that dose should be skipped, and the next dose should be taken as scheduled. No double 
doses should be taken, and dose reductions are not permitted.  
On Day 1 of the double-blinded Treatment Period, at the clinic, patients will be given their 
loading dose of study drug with 8 ounces (240 mL) of room temperature water to facilitate 
swallowing. Each patient’s mouth will be checked to ensure they have swallowed the tablets. 
Patients are permitted a light meal prior to arrival at the clinic on Day 1. 
On Day 2 to the Week 6 Visit, except for clinic visit days, patients will be instructed to take their 
daily maintenance dose of study drug before the first meal of the day. Study drug should be taken 
 

  
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with 8 ounces (240 mL) of water and should be taken whole. If a patient misses a dose by more 
than 12 hours, that dose should be skipped, and the next dose should be taken as scheduled. No 
double doses should be taken, and dose reductions are not permitted. On the morning of clinic 
visits, patients are allowed a light meal prior to the visit. For Weeks: 7 through Week 11, the 
same instructions will be provided to the patient.  
The study schema is presented in Figure 5.1-1. Details of study drug administration are provided 
in Table 7.4-1.  
Table 7.4-1 
Study Drug Administration 
Treatment Group 
Loading Dose 
(Day 1) * 
Daily Maintenance Dose  
(Day 2 Visit to Week 6/EOT/EW) ** 
Group 1: 
LX9211 200 mg*/20 mg** 
2 x 50-mg LX9211 
tablets 
+ 
2 x 50-mg LX9211 
tablets 
1 x 20-mg LX9211 
tablet, qd 
Group 2: 
Placebo 
2 x Placebo tablets  
+ 
2 x Placebo tablets 
1 x Placebo 
tablet, qd 
* Loading dose (Day 1) 
** Maintenance dose (Day 2 through – Week 6 Visit) 
For Weeks 7 through 11 a single tablet will be taken each day.  
7.4.1 
Treatment Compliance  
Patients will be instructed to bring their study drug bottles, including empty bottles and any 
unused study drug, to each clinic visit. Pill counts will be performed at each clinic visit by a 
member of the site staff to determine compliance. Pill count will be recorded on the study drug 
eCRF.  
Treatment compliance (%) will be calculated as: 
(Number of tablets dispensed – Number of tablets returned) X 100 
Number of tablets expected to be taken 
The number of tablets expected to be taken is equal to the number of days since the last visit. The 
Investigator/qualified designee will remind patients at each visit regarding the importance of 
 

  
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taking 1 tablet each morning per protocol. Patients will be deemed “compliant” if their calculated 
compliance is between 80% and 100%, inclusive. If a patient's compliance is noted to be <80% 
or >100%, the Investigator will ask the patient for the reason(s) of noncompliance with the 
dosing instructions, and clearly record the reason(s) in the source documents and on the eCRF 
and the patient will be reeducated on the need for compliance 
If a patient’s compliance is noted to be <80% or >100% on 2 consecutive visits, the patient 
should be counseled by study personnel, and the Sponsor/designee should be contacted to 
determine study continuation. 
7.5 
Dose Adjustment 
Dose adjustments of any study drug are not permitted or applicable during the study. For safety 
reasons, should an unacceptable risk related to study drug arise, patients may be discontinued 
from the study. 
8. 
Study Procedures 
A schedule of study assessments with detailed time points is provided in Appendix A. 
8.1 
Description of Study Assessments 
8.1.1 
Patient-reported Outcomes 
Three patient-reported outcomes (PROs), ZBPI, PGIC and NPSI, measures will be assessed on a 
validated electronic device completed at the time of the clinic visit as specified in Appendix A. 
The ZBPI, a 9-item questionnaire assesses the severity of pain and its impact on functioning in 
patients with PHN. The PGIC, a 7-point rating scale will assess patient's belief about the overall 
improvement experienced by the patient at the end of treatment. The NPSI, a 12-item 
questionnaire, assesses the different components of neuropathic pain syndromes (ie, spontaneous 
ongoing and paroxysmal pain, evoked pain, paresthesia/dysesthesia). Ten items related to 
different pain descriptors (eg, burning, squeezing, electric-shock, stabbing, tingling) allows 
assessment of the different dimensions of neuropathic pain and 2 items on frequency and 
duration of pain. 
8.1.2 
Qualitative Patient Interview 
A telephone qualitative interview substudy will be conducted for approximately 30 patients 
within 2 weeks following the Week 6 Visit or early withdrawal visit for patients within the US.  
 

  
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The purpose of the phone interview will be to gain insight and understanding of patients’ 
experiences with symptoms of PHN and to assess relevance and clinical meaningfulness of 
symptom improvements. (eg, reduction in pain). 
The qualitative patient interview will be performed as specified in Appendix A. 
8.1.3 
Clinical Laboratory Assessments  
Clinical laboratory assessments will include, at a minimum, blood chemistry (albumin, alkaline 
phosphatase, alanine transaminase [ALT], amylase, aspartate transaminase [AST], total bilirubin, 
glucose, blood urea nitrogen [BUN], calcium, carbon dioxide, chloride, creatinine, magnesium, 
phosphorus, potassium, sodium, total protein, and uric acid), lipid panel (high-density lipoprotein 
(HDL), low-density lipoprotein (LDL), total cholesterol, triglycerides, creatinine phosphokinase 
[CPK]), hematology (complete blood count [CBC] with differential, and platelet counts), and 
urinalysis (including appearance, color, glucose, ketones, nitrite, pH, protein, specific gravity, 
occult blood, leukocyte esterase, bilirubin, and urobilinogen). Urine microscopy will only be 
performed if any of the following are present in the urine sample: occult blood, leukocyte 
esterase, protein, or nitrite. The microscopy will include analysis for the presence of WBC, red 
blood cells, epithelial cells, bacteria, casts, and crystals. 
Additional assessments such as: pregnancy tests [females only]), and a urine screen (drugs of 
abuse and THC) will be done at time points specified in Appendix A. 
The incidence of clinically significant laboratory values, as well as clinically significant shifts in 
laboratory values, should be reported as an AE (Section 9.1.1) and followed as described in 
Section 9.5; retests should be performed as frequently as clinically indicated. 
8.1.4 
Pharmacokinetic Assessments 
Plasma samples from all patients will be analyzed for LX9211 Cp2hr and Ctrough  levels. Blood 
draws will be performed at time points indicated in the schedule of events (Appendix A). 
 
 
 
 
 
 

  
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8.1.5 
Safety Assessments 
In addition to the clinical laboratory assessments described in Section 8.1.1, monitoring of AEs 
is also considered a safety assessment and is described in detail in Section 9. Clinically 
significant changes compared with Baseline findings for these variables may be reported as AEs 
on the eCRF. Clinically significant changes compared with Baseline values, which are 
determined to be AEs should be followed until the event has resolved, the condition has 
stabilized, etiology of the event is determined to be not related to study drug, or the patient is lost 
to follow-up. In case a patient reports an AE, study drug may be held for up to 3 days to assess 
resolution, rather than discontinuing patient permanently from study participation. If the AE 
improves or resolves, study drug may be resumed. Prior to discontinuing a patient permanently 
from study participation, the Investigator should discuss the case with the Medical Monitor.  
8.1.5.1 Vital Sign Measurements 
Measurement of vital signs will include assessment of blood pressure, respiratory rate, pulse rate, 
and temperature as specified in Appendix A. Vital sign measurements should not be conducted 
within the 15 minutes immediately following any phlebotomy. Vital signs should be collected 
with the patient in a seated position. 
On Day 1 all patients will have orthostatic BP and HR measured 2 hours after administration of 
loading dose while in the clinic. 
8.1.5.2  Physical Examinations, Height, and Weight 
Complete physical examinations will be performed as outlined in Appendix A. A complete 
physical examination will include, at minimum, a review of the patient’s general appearance, 
head, eyes, ears, nose and throat, neck, heart, lungs, abdomen, back and extremities, skin, and 
general neurological system.  
A symptom-related brief physical exam will only occur if the patient is experiencing symptoms 
or AEs. If a symptom-related brief physical exam is required, it should include a review of all 
body systems that relate to the symptoms and/or AE the patient is experiencing. 
Height and weight (without shoes) will be measured as outlined in Appendix A. Patients may 
consume a light meal prior to the visit.  
All weights can be taken prior to or after the patient’s first meal of the day.  
8.1.5.3 Electrocardiograms 
Electrocardiograms (ie, 12-lead ECGs) will be performed as specified in Appendix A. 
 

  
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9. 
Safety Reporting 
It is the responsibility of the Investigator to document all AEs and special situations that occur 
during the study. 
Adverse events will be collected at all study visits as outlined in the Schedule of Study 
Assessments. Each AE should be recorded using the medical diagnosis; if a diagnosis is not 
established at the time of the reporting, a symptom or sign in standard medical terminology 
should be used. 
Adverse events should not be solicited with leading questions that suggest specific signs or 
symptoms. Rather, AEs should be solicited by asking the patient a non-leading question such as: 
“Do you feel different in any way since receiving the dose or since the last assessment?”  
Adverse events that occur after the signing of the informed consent and before the first dose of 
study drug should be recorded as medical history unless the event is a serious adverse event 
(SAE) that could be associated with the trial procedures and, which could modify the conduct of 
the trial, or otherwise specified. 
9.1 
Definitions and Special Considerations 
9.1.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
Non-serious AE collection will be initiated after the first dose of double-blind study drug. 
Any sign, symptom, or illness occurring prior to the first dose of double-blind study drug will be 
captured in the medical history. Treatment-emergent adverse events are defined as any AEs 
reported after the first dose of double-blind study drug. 
An AE includes any noxious, pathological, or unintended change in anatomical, physiological, or 
metabolic functions as indicated by physical signs or symptoms occurring after a patient has 
provided informed consent, whether or not considered related to the study medication.  
This definition includes an exacerbation of preexisting medical conditions or events, historical 
conditions not present prior to study treatment, which reappear following study treatment, 
intercurrent illnesses, hypersensitivity reactions, drug-drug or drug-food interactions, medication 
errors, overdose (both intentional or unintentional), drug misuse/abuse, false positive laboratory 
test, or the significant worsening of the disease under investigation.  
 

  
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Anticipated day-to-day fluctuations of preexisting conditions that do not represent a clinically 
significant exacerbation or worsening need not be reported as AEs. 
Treatment-emergent AEs are defined as any AEs reported after the first dose of double-blind 
study medication on study Day 1. 
Any treatment-emergent abnormal laboratory result should be reported as an AE if it meets 1 or 
more of the following conditions: 
• 
Fulfills any of the criteria for an SAE (Section 9.1.2), 
• 
Results in discontinuation of study treatment, 
• 
Requires treatment,  
• 
Is considered by the Investigator to be clinically significant. 
9.1.1.1 
Special Considerations for Bladder Dysfunction-related Adverse Events 
In studies with LX9211 in dogs, changes to the urinary bladder (including minimal 
inflammation, slight urothelial hyperplasia, minimal focal ulceration, and minimal muscle 
degeneration) were noted. The doses used in these animal studies were much higher than what 
will be used in this Phase 2. In the Phase 1 SAD and MAD studies with LX9211, no clinically 
significant CMP, UA findings, or bladder dysfunction-related AEs were reported in any subject. 
In this study, bladder dysfunction-related AEs will be closely monitored on an ongoing basis. In 
addition, an unscheduled visit may be conducted in case of a reported AE suspicious for urinary 
bladder abnormalities, where additional labs and follow-up may be obtained, as deemed 
necessary. 
9.1.2 
Serious Adverse Events 
All SAEs will be collected starting with signing informed consent and continue until 35 days 
after the last dose of study drug. 
An SAE is defined as any AE that results in any of the following outcomes: 
• 
Death; 
• 
A life-threatening AE - defined as an event, in the view of the Investigator, the 
occurrence of which places the patient or patient at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death; 
• 
Hospitalization or prolonging of an existing hospitalization; 
 

  
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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or, 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
Hospitalization is defined as any inpatient overnight stay in a hospital. This does not include an 
emergency room visit or admission to an outpatient facility. 
A hospitalization in and of itself should not be reported as an SAE. 
Hospitalizations for preplanned or elective surgery or routine clinical procedures without 
worsening of the underlying condition, or for administrative/social reasons (such as convenience, 
logistics) should not be reported as SAEs. However, if an elective procedure has to be performed 
sooner than planned due to a worsening of the underlying medical condition and the patient is 
hospitalized for the procedure, the worsening medical condition should be reported as an SAE. 
Any laboratory abnormality fulfilling any of the criteria for an SAE should be reported as such. 
9.1.3 
Unexpected Adverse Events 
An unexpected AE is an AE that is not listed in the Reference Safety Information (eg, the IB) or 
is not listed at the specificity or severity that has been observed. “Unexpected” also refers to the 
AEs that are mentioned in the Reference Safety Information as occurring with the class of study 
medication or as anticipated from the pharmacological properties of the study medication, but are 
not specifically mentioned as occurring with the study medication. 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the IB listed only cerebral vascular accidents. 
It the responsibility of the Sponsor to assess whether an AE is expected or unexpected. 
 

  
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9.2 
Assessment of Adverse Events 
The Investigator will evaluate all AEs with regard to the severity and relationship to study drug. 
9.2.1 
Severity 
The Investigator will assess the severity of each AE using their clinical expertise and judgment 
using 1 of the following 3 severity grades: 
• 
Mild: event is transient and easily tolerated, and requires no or minimal treatment 
• 
Moderate: event causes limited interference with usual daily activity and requires simple 
therapeutic intervention 
• 
Severe: event causes marked interference with usual daily activities and requires 
systemic drug therapy or other therapeutic intervention 
Changes in the severity of an AE should be documented as separate AEs to allow an assessment 
of the duration of the event at each level of severity. 
9.2.2 
Causality 
Causality assessment is a determination of whether there is a reasonable possibility that the study 
medication caused an AE. Factors that should be considered in causality assessment include, but 
are not limited to, temporal relationship, dechallenge/rechallenge information, association (or 
lack of association) with underlying disease or concomitant medication, biological plausibility, 
and previous observation or lack of with the study medication or other medication(s) in the same 
class as the study medication. 
For each AE, the Investigator will assess the causal relationship between the study medication 
and the AE using their clinical expertise and judgment according to the most appropriate 
description as follows: 
• 
Not related: The AE does not follow a reasonable temporal relationship to administration 
of the study medication, or an alternative etiology (eg, underlying disease, complications, 
concomitant drugs, or concurrent treatment) is much more likely 
• 
Unlikely related: The AE has an improbable temporal relationship to administration of 
the study medication, or an alternative etiology (eg, underlying disease, complications, 
concomitant drugs, or concurrent treatment) is more likely  
 

  
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• 
Possibly related: The AE follows a reasonable temporal relationship to administration of 
the study medication (including the course after withdrawal of the drug), and an 
alternative etiology (eg, underlying disease, complications, concomitant drugs, or 
concurrent treatment) is equally or less likely 
• 
Probably related: The AE follows a reasonable temporal relationship to administration 
of the study drug (including the course after withdrawal of the drug), and an alternative 
explanation (eg, underlying disease, complications, concomitant drugs, or concurrent 
treatment) is unlikely 
• 
Definitely related: The AE follows a plausible temporal relationship to administration of 
the study medication (including the course after withdrawal of the drug) and alternative 
etiology (eg, underlying disease, complications, concomitant drugs, or concurrent 
treatment) can be ruled out. Positive rechallenge (ie, reappearance or worsening of the 
AE after the study drug is reintroduced) or a response pattern known to be associated 
with administration of the study drug provides further evidence of a definitive causality 
assessment. 
9.3 
Special Situations 
Unless otherwise defined, events described below should be reported in the manner and 
timeframe as SAEs (Section 9.4) 
9.3.1 
Pregnancy 
Any patient who becomes pregnant during the study must be discontinued from the study 
immediately. 
Any pregnancy during the study that occurs after administration of the study medication, where 
the embryo or fetus may have been exposed to the study medication (either through maternal 
exposure or transmission of a medicinal product via semen following paternal exposure), should 
be followed-up in order to collect information on the outcome of the pregnancy and development 
of the child after birth.  
The pregnancy exposure should be reported on the Pregnancy Form (initial notification form) 
and captured on the eCRF page for AEs. The pregnant woman should be followed for pregnancy 
outcome through delivery or termination of the pregnancy. In pregnancies that progress to term, 
the infants should be followed till 6 months after birth and any congenital abnormalities/birth 
defects in the infants should be reported as an SAE.  
 

  
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The outcome of a pregnancy, and the presence or absence of a congenital abnormality should be 
reported on the Pregnancy Form (outcome form).  
After the study period, pregnancies should be collected by requesting study patients notify the 
Investigator if a female patient or a female partner of a male patient becomes pregnant within 35 
days after last dose of study medication. These pregnancies should be reported and followed in 
the same manner as pregnancies occurring during the study. 
9.3.2 
Adverse Events of Special Interest 
No AEs of special interest have been defined for this study. 
9.4 
Reporting of Serious Adverse Events and Pregnancies 
All SAEs, regardless of causal relationship to the study medication, and pregnancies must be 
reported to the Sponsor within 24 hours of investigational site awareness of the event. 
Investigators should not wait for complete information on an event before notifying the Sponsor 
(or designee) of an SAE. 
Investigational site personnel must use the SAE Report form and Pregnancy form provided by 
the Sponsor to report these events.  
The SAE form should be sent to: 
Safety Data Facsimile: (832) 442-5462 or  
Email address (in case of fax failure): drugsafetygeneral@LexPharma.comm 
In case of failure of/lack of access to both email and fax, the event should be reported using 
Safety Hotline: (877) 372-3597. 
If an SAE is reported via telephone, the telephone report should be followed by a completed 
SAE Report form.  
For questions on safety reporting, the Safety Physician of the study should be contacted at: 
 MD  
 
Email: 
 
Telephone: 
 
For questions on study patient management related to AEs, the Medical Monitor of the study 
should be contacted. 
, MD 
 

  
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Email: 
 
Telephone: 
 
Where applicable, information from relevant hospital records and autopsy reports should be 
obtained. 
Additional information received after the initial SAE has been reported to the Sponsor should be 
reported as follow-up information following the same procedure and timeline as the initial SAE. 
All SAEs, pregnancies, and other special situations should also be recorded on the study patient’s 
eCRF page for AEs. 
An SAE that occurs after completion of the study and in the opinion of the Investigator, is related 
to the study medication should be reported following the same procedure and timeline as an SAE 
that occurs during the study. 
9.5 
Follow-up of Adverse Events 
All AEs should be followed until the event has resolved, the condition has stabilized, the patient 
is lost to follow-up, or ≥35 days following the last dose of study drug, whichever comes first. 
Final known outcome must be reported whenever possible.  
Medically significant abnormal laboratory test results should be repeated and followed until the 
test results have returned to the normal range or Baseline value, and/or an adequate explanation 
of the abnormality is determined. 
9.6 
Safety Oversight 
A DMC will be utilized for this study.  
 

  
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10. 
Statistical Methodology 
10.1 
Determination of Sample Size 
Proposed Sample Size 
The proposed sample size is derived by satisfying the original design assumptions made for the 
primary efficacy endpoint. It is assumed that the difference in treatment group means is 0 under 
the null hypothesis (H0) and is unequal to 0 under the alternative hypothesis (H1); a 2-sided 
hypothesis under test. Under the H1, the difference in group means of LX9211 minus placebo is 
expected to be -0.8 units with a common standard deviation of 1.0 units. These assumptions yield 
an effect size of 0.8. The effect size is the absolute value of the difference in treatment group 
means divided by the common standard deviation of that difference. A uniform dropout rate of 
0.15 is anticipated, and adjustment of the effect size for this rate results in an estimate 0.68; the 
adjusted difference in group means is equal to -0.8 units x 0.85 = -0.68. For a 2-sided test sized 
at α = 0.05, 37 patients per treatment group are required under a 1:1 randomization ratio to detect 
the stated treatment difference under H1 with statistical power equal to 82.27% under a single 
stage design. The total planned N = 74 patients. 
This study is designed as a group sequential trial with 1 interim look at approximately the 50% 
information time and a final analysis at 100%. A non-binding futility boundary will be used to 
test for futility of the primary endpoint. The futility boundary is 1-sided with α = 0.025 and for 
the parameters specified, a power estimate of 82.53% is derived. 
Sample Size Reestimation 
Due to the uncertainty in the outcome for the primary endpoint analysis in this population, an 
unblinded SSR adaptation will be implemented at the time of the efficacy interim analysis. This 
will occur when the first 38 patients (rounded up from 37) have been accrued and followed thru 
Week 6 or dropped out early from the trial (whichever event happens first). Should a patient drop 
out early in the study, but return for the Week 6 visit, the Week 6 data will be used in the 
analysis. The Chen-DeMets-Lan method will be used for the unblinded SSR since it requires 
minimal change from a group sequential test. This method requires specification for a number of 
criteria related to the allowable conditions for increasing the sample size that ensures that 
ordinary group sequential methods can be applied while seeing that the overall error is not 
inflated compared to the original group sequential design. The 2 primary conditions which are 
required and satisfied in the SSR for this study are that (a) the SSR is made at the penultimate 
look, and (b) the conditional power at the penultimate look occurs between 50% and 82.53% (the 
original specified power). The SSR is linked to the projected effect size falling within this 
“promising” or “favorable” range of conditional power. Having satisfied these 2 main conditions, 
the Type I error rate after increasing the sample size until the conditional power equals the 
original target power will not be greater than the Type I error from the originally proposed 
design.  
 

  
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To derive the reestimated number of patients at the interim analysis, a simulation will be made 
that: inputs the observed group mean difference and its common standard deviation, input a value 
for the maximum total number of patients (E[Max]) equal to 148 patients and, specify a 
reestimation rule as the Exact E method. The Exact E method increases the patient number total 
until the desired conditional power is achieved.  
 
 
10.2 
Analysis Populations 
Analysis of the primary, secondary, and other efficacy endpoints will be based on the Modified 
Intent-to-Treat (mITT) population. Safety endpoints analyses will be based on the Safety 
population. 
10.2.1 
Intent-to-Treat (ITT) Population 
The ITT population will include all randomized patients. 
10.2.2 
Modified Intent-to-Treat (mITT) Population 
The mITT population will include all randomized patients who have taken ≥1 dose of study drug.  
10.2.3 
Per Protocol (PP)  
The PP population will include patients in the mITT population who did not have any major 
deviations that would interfere with the collection or interpretation of the efficacy data. 
10.2.4 
Pharmacokinetics Population (PK)  
10.2.4.1 
Pharmacokinetics Population (PK) – Ctrough  
The PK population for evaluation of Cp2hr and Ctrough will include all patients who received ≥1 
dose of study drug and ≥1 sample collected. 
10.2.5 
Safety Population 
The Safety Population is defined as those patients who received any exposure to study drug. 
 

  
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10.3 
Study Endpoints 
10.3.1 
Primary Efficacy Endpoint 
The change from Baseline (Week 2 of the Run-in Period) to Week 6 in Average Daily Pain 
Score (ADPS), based on Question 5 of the ZBPI, the 11-point numerical rating scale (0 [No 
Pain] to 10 [Pain as bad as you can imagine])  
10.3.2 Secondary Efficacy Endpoints 
• Change from Baseline to Week 6 in pain interfering with sleep based on Question 9F of the 
ZBPI “Indicate the one number that describes how, in the past 24-hours shingles pain has 
interfered with your: Sleep (0 [Does not interfere] to 10 [Completely interferes])” 
• Proportion of patients with ≥30% reduction in pain intensity in ADPS based on Question 5 
of the ZBPI from Baseline to Week 6 
• Proportion of patients with ≥50% reduction in pain intensity in ADPS based on Question 5 
of ZBPI from Baseline to Week 6 
• Change from Baseline to Week 6 in interference in General Activity, Mood, Walking 
Ability, Normal Work (includes both outside the home and housework), Relations with 
other people, Sleep, and Enjoyment of Life interference based on the Questions 9A-G of 
the ZBPI 
• Proportion of patients discontinuing treatment due to lack of efficacy defined as increase in 
ADPS from Baseline of ≥30% based on Question 5 of the ZBPI  
• Patient Global Impression of Change (PGIC) at Week 6 
• Time to loss of efficacy from Week 6 to Week 11 among patients achieving ≥30% 
reduction in pain intensity in ADPS based on Question 5 of the ZBPI at Week 6.  
10.3.3 
Other Efficacy Endpoints 
Other efficacy endpoints are: 
• Change from Baseline to Week 6 in the Neuropathic Pain Symptom Inventory (NPSI) 
• Change from Baseline to each week in ADPS, based on Question 5 of the ZBPI. 
• Proportion of patients with ≥30% reduction from Baseline in ADPS, based on Question 5 
of the ZBPI by week 
• Proportion of patients with ≥50% reduction from Baseline in ADPS, based on Question 5 
of the ZBPI by week 
• Cumulative distribution function of percent change in ADPS based on Question 5 of the 
ZBPI from Baseline to Week 6 comparing each LX9211 treatment group to placebo 
 

  
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• 
Cumulative distribution function of percent change in ADPS based on Question 5 of the 
ZBPI from Week 6 to Week 11 comparing the LX9211 treatment group to placebo 
10.3.4 
Pharmacokinetic (PK) / Pharmacodynamic (PD) Endpoint 
The PK endpoints are the plasma Cp2hr and Ctrough levels of LX9211 in patients with postherpetic 
neuralgia. 
 
 
10.3.5 
Safety Endpoints 
Safety endpoints are as follows:  
• 
Incidence of treatment-emergent AEs, suspected adverse reaction, AEs leading to 
discontinuation from the study, SAEs, and deaths 
• 
Actual and change from Baseline in clinical laboratory results  
• 
Actual and change from Baseline in vital signs results, including weight  
• 
Clinically significant change from Baseline in PE findings 
• 
Actual and change from Baseline in ECG findings 
10.4 
Statistical Methods 
Continuous variables (including Ctrough) will be summarized by the mean, standard deviation, 
median, minimum, and maximum values for all patients with non-missing data. Categorical 
variables will be summarized by their counts and associated percentages. All data will be 
provided in individual patient listings. A formal SAP with more details on the statistical methods 
will be completed prior to database lock and unblinding of the study data. 
10.4.1 
Extent of Study Drug Exposure and Compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received in the safety population. 
10.4.1.1 
Extent of Study Drug Exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. The duration of treatment exposure will be the total number of days of 
administration of the study drug, regardless of unplanned intermittent discontinuations. The 
 

  
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duration of study drug exposure will be calculated as: (Date of the last study drug taken – Date of 
the first study drug taken) + 1. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) will be presented by treatment group. The number and percentage (%) of patients 
randomized and exposed to the study drug will be presented by visit/week for each treatment 
group.  
10.4.1.2 
Compliance 
A patient will be considered noncompliant if they did not take the planned dose of treatment as 
required by the protocol. Treatment compliance will be summarized descriptively (number, 
mean, SD, median, minimum, and maximum). The percentage of patients with overall 
compliance <80% will be summarized descriptively by treatment group.  
10.4.2 
Analyses of Efficacy Endpoints 
All efficacy analyses will be performed on the mITT population as defined in Section 10.2.2. 
Supportive analyses will be performed on the PP population.  
10.4.2.1 
Analysis of Primary Efficacy Endpoint 
The primary endpoint is the change from Baseline to Week 6 in ADPS. The primary analysis will 
be based on observed data including data measured after the initiation of rescue medications. 
Baseline is defined as the average of the Week 2 Run-in period data, provide that ≥5 days from 
that period are available for analysis. The Week 6 mean value will be derived from the 7-day 
period immediate to the endpoint, provided that ≥4 days of non-missing data are collected. 
A restricted maximum likelihood-based, mixed-effects model repeated measures (MMRM) 
approach will be used to assess the difference between LX9211 and placebo in the primary 
endpoint (ie, change from Baseline to Week 6 in the ADPS derived from data collected daily 
from Question 5 of the ZBPI instrument). The MMRM model will include fixed effects of 
treatment, week, treatment-by-week interaction, the randomization stratum of Baseline pain 
severity, and the Baseline score as covariate. An unstructured covariance structure will be used to 
model the within-patient error. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. Other covariance structures will be explored should 
convergence not be met. In the event that a rescue medication is used, a supplementary MMRM 
model will be applied to a dataset that excludes data collected after the initiation of the rescue 
medication. To assess the robustness of the MMRM analyses performed under the missing at 
random (MAR) assumption, and given the long half-life of LX9211, pattern mixture models 
(PMM) with copy reference-based imputation methods will be applied to both datasets (with and 
 

  
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without data collected after the initiation of the rescue medication). The imputed datasets will be 
combined by use of Rubin's rule and analyzed using an analysis of covariance (ANCOVA) model 
fitted for the fixed effects of treatment, the randomization stratum of Baseline pain severity, and 
the continuous fixed covariate of Baseline score.  
10.4.2.2 
Analysis of Secondary and Other Efficacy Endpoints 
Continuous secondary and other efficacy endpoints: ZBPI scores, PGIC scores and NPSI scores, 
measured at multiple time points, will be analyzed using a similar modeling strategy as used for 
the primary endpoint.  
Categorical secondary endpoints: The proportion of responders based on Question 5 of ZBPI will 
be compared between treatment groups using a Cochran-Mantel-Haenszel test stratified by the 
randomization factor of Baseline pain severity. Patients with missing measurement at Week 6 
will be considered non-responders. A nonresponder imputation (NRI) rule will be applied for all 
analyses based on categorical variables to assign outcomes to missing observations. The 
percentage of patients who need rescue medication and prematurely dropout will be summarized 
descriptively. The Kaplan-Meier methods will be used to generate statistical summaries of the 
time to loss of efficacy variable among patients who achieve ≥30% reduction in ADPS based on 
Question 5 of the ZBPI from Week 6 and Week 11. 
The qualitative patient interview substudy will be managed by a vendor (RTI-Health Solutions, 
Research Triangle Park, NC). The data analysis methods will be detailed in a separate statistical 
analysis plan and results will be reported separately. 
10.4.2.3. 
Multiplicity 
Testing among the secondary endpoints will not be adjusted for multiplicity, and hence, the 
analyses will be exploratory. Other endpoints will likewise not be adjusted for multiple testing. 
Unadjusted p-values will be presented for all analysis results. 
10.4.3 
Pharmacokinetic (PK)/ Pharmacodynamic (PD) Analyses 
PK plasma concentration data will be summarized descriptively by dose and nominal time point. 
All PK data will be presented in the data listings. 
 
  
10.4.4 
Subgroup Analyses 
The primary endpoint will be analyzed by the following subgroup of population 
 

  
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• 
Baseline pain severity moderate or severe  
• 
Sex 
Additional subgroup analyses may be conducted and will be described in the SAP. All subgroup 
analyses will be exploratory. 
10.4.5 
Safety Analyses 
All safety analyses will be performed on the Safety population as defined in Section 10.2.5.  
Safety will be assessed by evaluating all reported adverse events, actual and changes in clinical 
laboratory values, vital signs, and ECGs. Baseline for computing the change in safety variables 
will be the observation measured before the first dose (Day 1). No formal statistical significance 
tests will be performed on safety data. 
10.4.5.1 
Adverse Events 
Adverse events verbatim descriptions (Investigator terms from the eCRF) will be coded using the 
Medical Dictionary for Regulatory Activities MedDRA, Version 23. 
Treatment emergent adverse events (TEAEs) are defined as events that first occurred or 
worsened after the first dose (Day 1). Treatment-related adverse events are defined as events that 
are indicated on the CRF by the Investigator to be treatment related. 
Incidence of TEAEs will be summarized descriptively by PT within each SOC and presented by 
treatment group and as needed, by study time point. Treatment-emergent adverse event (TEAE) 
summaries will include the overall incidence of TEAEs, Incidence of TEAEs (by System Organ 
Class [SOC] and Preferred Term [PT]), TEAEs by maximum intensity (mild, moderate, or 
severe), TEAEs by relationship to study treatment (related, or unrelated). In addition, events 
leading to discontinuation of study drug, deaths, and SAEs will also be summarized and/or listed 
by patient. If a patient reports the occurrence of a particular event more than once, the most 
severe of that event will be counted in the summary of the TEAEs, and the greatest degree of 
relationship to treatment will be included in the summary of treatment-related events. Patients 
will be counted only once within a SOC and PT, even if the patient experienced more than 1 
TEAE within a specific SOC or PT. A by-patient data listing of all AEs will be provided. 
10.4.5.2 
Deaths, Serious and Other Significant Adverse Events 
Listings of all deaths, SAEs, and AEs leading to discontinuation from study treatment will be 
provided.  
 

  
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10.4.5.3 
Clinical Laboratory Parameters 
Laboratory results will be reported in conventional units and Systeme International (SI) units. 
Clinical laboratory value observed at Baseline (predose), at each time point, and changes from 
Baseline to each assessment time point will be summarized using descriptive statistics and 
presented by treatment group. Additionally, each patient’s laboratory results will also be 
classified as low, normal, or high according to standard normal ranges and summarized using 
shift tables, comparing the Baseline and each assessment time point. Percentages will be based 
on the number of patients with both non-missing Baseline and relevant postBaseline results. A 
by-patient data listing of all clinical laboratories will be provided. 
10.4.5.4 
Vital Signs 
Vital signs values, and changes from Baseline will be summarized using descriptive statistics and 
presented by treatment group. In addition, vital signs categorized as “clinically significant (CS)” 
or “not clinically significant (NCS)” will be summarized descriptively and presented by 
treatment group in shift tables. A by-patient data listing of all vital signs’ parameters will be 
provided. 
10.4.5.5 
Physical Examination Findings 
Physical examination findings will be listed for each patient. 
10.4.5.6 
Electrocardiogram (ECG) 
The actual values of the 12-lead ECG parameters at Baseline, at each time point, and change 
from Baseline will be summarized using descriptive statistics. The number and percentage of 
patients with ≥1 postBaseline abnormal ECG result will be summarized using descriptive 
statistics and presented by treatment group.  
10.4.5.7 
Interim Analysis 
An interim analysis of the primary endpoint will be performed to test for futility when 
approximately 50% of the planned information has been achieved. This will occur when the first 
38 patients have been accrued and followed to endpoint at Week 6 or dropped out from the trial 
earlier, whichever event occurs first. Should a patient drop out early in the study, but return for 
the Week 6 visit, that Week 6 data will be used in the analysis. The patient number for the 
interim analysis has been rounded upward from 37 to 38 patients to yield the minimum number 
of patients exceeding the 50% information fraction that preserves the 1:1 randomization ratio. 
 

  
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A non-blinding futility boundary will be used to test treatment group differences in the primary 
endpoint at 51.4% of the original planned information. The set of boundary values will be 
derived by using a beta spending function and specification of a power family with value = 
3.672. The monitoring boundary is constructed by assuming a 1-sided test with an overall Type 1 
error rate = 0.025 (or a two-sided α = 0.05). Use of this beta spending function for futility testing 
is conservative and results in cumulative beta error rates of 0.015 and 0.175 at the interim and 
final analyses, respectively. Application of the futility analysis is to serve as a guideline and is 
not the only source of information used to evaluate the trial for a negative finding. Assessment of 
other data available at the interim analysis will be used to qualify the trial for a recommendation 
of futility (eg, secondary and other efficacy variables, safety data). 
Details of the futility analysis will be described in the SAP and DMC Charter documents. 
10.4.6 
Baseline Characteristics and Other Summaries 
Treatment group differences will be summarized descriptively for demographic data, prior and 
concomitant medications, treatment compliance, and final disposition. 
10.4.6.1 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Study 
Manual requirements. The noncompliance may be either on the part of the patient, the 
Investigator, or the study site staff.  
Significant deviations (ie, those categorized as critical or major) will be provided as listings in 
the final report. 
11. 
Study Management 
The Investigator is responsible for completing and maintaining adequate and accurate eCRFs and 
source documentation. Source documentation constitutes original records, which may include: 
progress notes, medication administration records, laboratory reports, ECG tracings, discharge 
summaries, etc.  
It is the responsibility of the Investigator and site staff to use continuous vigilance to identify and 
report deviations. In addition to notifying the Sponsor, protocol deviations are to be reported to 
the Institutional Review Board (IRB) as per applicable guidelines. The Investigator and site study 
staff are responsible for knowing and adhering to their IRB requirements.  
All data and corrections, if applicable, entered on to the eCRF must meet minimum requirements 
as specified in the case report form guidelines. All eCRFs should be completed in their entirety 
 

  
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and stored in accordance with ICH GCP guidelines. The Investigator must sign the Investigator’s 
statement in each patient’s eCRF indicating that the data reported are accurate. 
At the study site, clinical research associates will verify up to 100% of eCRFs in their entirety 
against source documentation. Computer programmed edit checks will be run against the 
database to check for discrepancies and reasonableness of the data, and the safety database will 
be reconciled with the clinical database. All issues resulting from the computer-generated checks 
and the safety database reconciliation will be resolved according to standard data management 
practices in conjunction with the Sponsor, clinical study personnel, and the study Investigators. 
11.1 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or regulations. 
At regular intervals during the study and following completion of the study, the Sponsor’s study 
monitors will contact the study site via visits to the site, telephone calls, and/or letters in order to 
review study progress, eCRF completion, and address any concerns or questions regarding the 
study conduct. During monitoring visits, the following aspects of study conduct will be carefully 
reviewed: informed consent of patients, patient recruitment, patient compliance with the study 
procedures, source data verification, drug accountability, use of concomitant therapy by patients, 
AE and SAE documentation and reporting, and quality of data. Records pertaining to these 
aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to other authorized 
representatives of the Sponsor, and to regulatory inspectors. 
11.2 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Study 
Manual requirements. The noncompliance may be either on the part of the patient, the 
Investigator, or the study site staff. 
It is the responsibility of the Investigator and site staff to use continuous vigilance to identify and 
report deviations. In addition to notifying the Sponsor, protocol deviations are to be reported to 
the Institutional Review Board (IRB) as per applicable guidelines. The Investigator and site 
study staff are responsible for knowing and adhering to their IRB requirements.  
Study clinical research associates will record deviations identified by the site and those identified 
during their review of study documentation in a tracking system for assessment and for ensuring 
proper follow-up and remediation, as required. 
 

  
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In the case of certain deviations, including those that are deemed to be Critical or Major, 
corrective actions may need to be developed by the site (with the input of the Sponsor/CRO), and 
implemented promptly. Prospective requests to deviate from the protocol (ie, waivers) will not 
be approved unless the approval is required to protect the health or welfare of the patients 
enrolled in the study. 
11.3 
Audits and Inspections 
The Sponsor, regulatory authority, or IRB may visit the study site at any time during the study or 
after completion of the study to perform audits or inspections. The purpose of a Sponsor audit or 
regulatory inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted according to the protocol, 
GCP, ICH guidelines, and any other applicable regulatory requirements. Investigators should 
contact the Sponsor immediately if contacted by a regulatory agency about an inspection at their 
site. 
11.4 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All amendments 
must be submitted to the IRB for approval prior to implementing the changes. In some instances, 
an amendment may require changes to the informed consent form, which also must be submitted 
for IRB approval prior to administration to patients. If any changes to the eCRF are required, the 
Sponsor will issue supplemental or revised eCRF pages. 
11.5 
Record Keeping 
11.5.1 
Drug Accountability  
The Investigator must maintain accurate records of study drug receipt, dispensing information, 
and disposition. If the Investigator cannot account for all clinical supplies at the termination of 
the study, a written explanation must be provided. 
11.5.2 
Health Insurance Portability Accountability Act of 1996 and Subsequent 
Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 (the 
Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation and any 
applicable updates). The Investigator shall ensure that study patients authorize the use and 
 

  
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disclosure of protected health information in accordance with HIPAA Privacy Regulation and in 
a form satisfactory to the Sponsor. 
The Department of Health and Human Services updated a final rule to modify HIPAA. The new 
rule has been in effect since 26 Mar 2013, and strengthens the privacy and security protection for 
individual’s health information; modify the rule for Breach Notification for Unsecured Protected 
Health Information (Breach Notification Rule) under the HITECH Act to address public 
comment received on the interim final rule; modify the HIPAA Privacy Rule to strengthen the 
privacy protections for genetic information by implementing section 105 of Title I of the Genetic 
Information Nondiscrimination Act of 2008 (GINA); and make certain other modifications to the 
HIPAA Privacy, Security, Breach Notification, and Enforcement Rules (the HIPAA Rules) to 
improve their workability and effectiveness and to increase the flexibility for and decrease 
burden on the regulated entities. 
The full text of the rule can be found at: 
https://www.federalregister.gov/documents/2013/01/25/2013-01073/modifications-to-the-hipaa-
privacy-security-enforcement-and-breach-notification-rules-under-the 
11.5.3 
Financial Disclosure 
The Investigator shall provide to the Sponsor sufficient accurate financial information to allow 
the Sponsor to submit complete and accurate financial certification or disclosure statements to 
the FDA. The Investigator shall promptly update this information if any relevant changes occur 
in the course of the study or for 1 year following completion of the study. 
11.5.4 
Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original source 
documentation (see examples in Section 11) to ensure data integrity. “Original” in this context is 
defined as the first documentation of an observation and does not differentiate between hard 
copy and electronic records. 
11.5.5 
Retention of Study Documents 
The EU clinical trial regulation (Regulation (EU) No 536/2014 of the European Parliament and 
of the Council of 16 April 2014 (Article 58) mandates a minimum retention period for the trial 
master file of “25 years after the end of the clinical trial”. This establishes a more specific time 
period than with internationally accepted practice of ICH GCP. 
 

  
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The Investigator must not destroy any study-related records without receiving approval from the 
Sponsor. The Investigator must notify the Sponsor in the event of accidental loss or destruction 
of any study records. If the Investigator leaves the institution where the study was conducted, the 
Sponsor must be contacted to arrange alternative record storage options. 
12. 
Administrative Structure of the Study 
The study will be monitored by Sponsor personnel or Sponsor representative. The following 
functions including, but not limited to data management, statistical analysis, including PK 
analysis, and reporting may be performed by organizations designated by the Sponsor. Specific 
functions designated by the Sponsor to an organization are to be defined via a formal transfer of 
obligations document.  
 

  
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14. 
Appendix B – Amount of Blood to be Collected from Each Patient 
Estimated Amount of Blood Volume to be Collected from Each Patient 
Procedure 
Screening 
 
 
Single-blind 
Placebo Run-in 
Period 
 
 
Double-blind Treatment Period 
Follow-up 
Total # 
of 
Tests 
Volume/Test 
(mL) 
Total 
Volume 
(mL) 
Week -4 
Week -2 
Day 1 
Week 2 
 
Week 4 
Week 6 
Week 11 
 
 
 
Serum pregnancy  
1 
 
 
 
 
 
 
 
1 
2  
2  
Hematology and 
chemistry 
1 
 
1 
 
 
 
1 
 
3 
9 
27 
Ctrough blood samples 
 
 
1 
1 
 
1 
1 
1 
5 
4 
20 
Cp2hr  blood samples 
 
 
1 
 
 
 
 
 
1 
4 
4 
 
TOTAL 
88 
 

  
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15. 
Appendix C – Ethical Standards 
Ethics and Regulatory Considerations 
This study will be conducted according to GCP, 21 CFR Part 50, (Protection of Human 
Subjects), 21 CFR Part 56 (Institutional Review Boards), International Conference on 
Harmonisation Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance, 
the Nuremberg Code, and the Declaration of Helsinki.  
General Instructions 
The FDA regulates studies of drugs, biologics, and medical devices. Consequently, these 
studies are subject to GCP regulations and guidance issued by the FDA and are included in, 
but not limited to, the following parts of the CFR and guideline document: 
• 
21 CFR Part 11 – Electronic Records 
• 
21 CFR Part 50 – Protection of Human Subjects 
• 
21 CFR Part 54 – Financial Disclosure 
• 
21 CFR Part 56 – Institutional Review Boards 
• 
21 CFR Part 312 – Investigational New Drug Application 
• 
Current FDA Guideline for the Monitoring of Clinical Investigations 
• 
Current Guidance for Institutional Review Boards and Clinical Investigators 
• 
ICH E6 – Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance 
Copies of these materials are available from the Sponsor upon request. The purpose of these 
regulations and legal obligations is to define the standards and principles for the proper 
conduct of clinical trials that have been developed by the medical, scientific, and regulatory 
communities. They are not intended to impede or restrict clinical research.  
The ethical standards defined within GCP are intended to ensure that: 
• 
human subjects are provided with an adequate understanding of the possible risks of their 
participation in the study, and that they have a free choice to participate or not; 
• 
the study is conducted with diligence and in conformance with the protocol in such a way 
as to ensure the integrity of the findings; and 
• 
the potential benefits of the research justify the risks. 
 

  
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Lexicon Pharmaceuticals, Inc., is the Sponsor of the Investigational New Drug Application 
(IND). The Sponsor is responsible for the following: 
• 
selecting qualified Investigators, 
• 
providing Investigators with the information they need to properly conduct an 
investigation, 
• 
ensuring proper monitoring of the investigation, 
• 
ensuring that the study is conducted according to the general investigational plan and 
protocols contained in the IND, 
• 
maintaining the IND, and  
• 
ensuring that FDA and all participating Investigators are properly informed of significant 
new information regarding adverse effects or risks associated with the drug being studied. 
 
 
 

  
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16. 
Appendix D – Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the subject informed consent form will be 
approved by the institutional review board (IRB) before enrollment of any subjects. The 
opinion of the IRB will be dated and given in writing. A copy of the letter of approval from 
the IRB and a copy of the approved informed consent form will be received by the Sponsor 
prior to shipment of study drug supplies to the Investigator. 
The Investigator will ensure that the IRB will be promptly informed of all changes in the 
research activity and of all unanticipated problems including risk to subjects. The 
Investigator will also ensure that no changes will be made to the protocol without IRB 
approval. 
As a part of the IRB requirement for continuing review of approved research, the Investigator 
will be responsible for submitting periodic progress reports to the IRB at intervals 
appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the most 
important considerations and should prevail over interests of science and society. 
As described in GCP guidelines, study personnel involved in conducting this trial will be 
qualified by education, training, and experience to perform their respective task(s). Study 
personnel will not include individuals against whom sanctions have been invoked after 
scientific misconduct or fraud (eg, loss of medical licensure, debarment). Quality assurance 
systems and procedures will be implemented to assure the quality of every aspect of the 
study. 
Principal Investigators in the US must provide the Sponsor with a fully executed Form FDA 
1572 (statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide the Sponsor with their own curriculum vitae and current 
curriculum vitae for each sub Investigator listed on the Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50)  
Informed consent must be obtained from every subject before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an IRB-
approved consent form and signed by the subject or the subject’s legally authorized 
representative. The Department of Health and Human Services suggests that when minors are 
involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
 

  
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their signature should also be included. Non-English-speaking subjects must be presented 
with a consent form written in a language that they understand. A copy of the signed consent 
form must be given to the subject signing it. Another copy must be kept in the Investigator’s 
files and made available to FDA representatives upon request. If, for any reason, subject risk 
is increased as the study progresses, a revised, IRB-approved consent form must be signed by 
the subject. Before the study begins, a sample of the consent form must be provided to the 
Sponsor for review. The FDA may reject otherwise scientifically valid studies if proper 
informed consent has not been obtained from all subjects. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB within 5 working 
days. In this situation, the Investigator may not administer any subsequent product to that 
subject until informed consent and IRB approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study. One 
copy of the signed informed consent document will be given to the subject, and another will 
be retained by the Investigator. Additionally, the patient must be allowed adequate time to 
consider the potential risks and benefits associated with their participation in the study.  
In situations where the patient is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor and 
by the Investigator’s IRB prior to the initiation of the study. The document must contain the 8 
basic elements of informed consent and may contain the 6 additional elements described in 
21 CFR Part 50. Every consent form must include the following 8 elements: 
• 
A statement that the study involves research, an explanation of the purpose of the 
research and the expected duration of the subject’s participation, a description of the 
procedures to be followed, and identification of any procedures that are experimental 
• 
A description of any reasonably foreseeable risks or discomforts to the subject 
• 
A description of any benefits to the subject or to others that may reasonably be expected 
from the research 
 

  
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• 
A disclosure of appropriate alternative procedures or course of treatment, if any, that 
might be advantageous to the subject 
• 
A statement describing the extent, if any, to which confidentiality of records identifying 
the subject will be maintained and noting the possibility that the FDA and representatives 
may inspect the records 
• 
An explanation as to whether any compensation or medical treatments are available if 
injury occurs for research involving more than minimal risk. The explanation should 
involve a description of the compensation or treatment available, or a statement 
describing where further information may be obtained 
• 
An explanation of whom to contact for answers to pertinent questions about the research 
and the subject’s rights and whom to contact in the event of a research related injury 
• 
A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which the 
subject is otherwise entitled. 
When appropriate, 1 or more of the following elements of information shall also be included 
in the consent form: 
• 
A statement that the particular treatment or procedure may involve risks to the subject (or 
to the embryo or fetus, if the subject is or may become pregnant), which are currently 
unforeseeable 
• 
Anticipated circumstances under which the subject’s participation may be terminated by 
the Investigator without regard to the subject’s consent 
• 
Any additional costs the subject may incur from participation in the research 
• 
The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject 
• 
A statement that significant new findings developed during the course of the research that 
may relate to the subject’s willingness to continue participation will be provided to the 
subject 
• 
The approximate number of subjects involved in the study 
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
 

  
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Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective. Some states, such as California and Oregon, 
require further action on the Investigator’s part concerning subject consent. 
Study Documentation 
Institutional Review Board (IRB) Ethic Review Committee (ERC) Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
patients, must be reviewed and approved by an appropriate IRB/ERC prior to enrollment of 
patients in the study. It is the responsibility of the Investigator to assure that all aspects of the 
ethical review are conducted in accordance with the current Declaration of Helsinki, ICH, 
GCP, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval, which specifically identifies the study/protocol and a 
list of the committee members must be received by the Sponsor prior to initiation of the 
study. Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
A progress report with a request for reevaluation and reapproval will be submitted by the 
Investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor provides the Investigator with a Safety Report, the Investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB/ERC and to the Sponsor, if required. This report should include: deviations from the 
protocol, the number and types of patients evaluated, the number of patients who 
discontinued (with reasons), results of the study, if known, and significant AEs, including 
deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study. Study 
documents include, but are not limited to, the Investigator’s Brochure, drug accountability 
 

  
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records, Sponsor/Investigator correspondence, IRB correspondence, protocol and 
amendments, information regarding monitoring activities, subject exclusion records, CRFs, 
and data queries. 
Confidentiality 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents submitted to the 
clinical monitor. Documents that will be submitted to the clinical monitor and that identify 
the subject (eg, the signed informed consent document) must be maintained in strict 
confidence by the Principal Investigator, except to the extent necessary to allow auditing by 
the FDA, the clinical monitor, or Sponsor personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor to 
the Investigator (with the exception of information required by law or regulations to be 
disclosed to the IRB, the subject, or the FDA) must be kept in confidence by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each subject, and return to the Sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol. 
 
 

  
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17. 
Appendix E – Calculations 
Cockcroft-Gault equation: 
The equation for calculation of creatinine clearance, as an estimation of glomerular filtration rate 
(eGFR), using the method of Cockcroft and Gault is: 
     [(140-age) x weight (in kg)]
            
[72 x serum creatinine (in mg/dL)]  
If the patient is female, multiply the above by 0.85  
For an online calculator, please use: http://www.nephron.com/cgi-bin/CGSI.cgi 
Source:  Cockcroft D, Gault MD. Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron. 1976;16:31-41. 
Body Mass Index equation: 
 
For an online calculator, please use: 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/bmi_calcula
tor.html for feet, inches, and pounds and 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/metric_bmi_calculator/bmi_calcula
tor.html for meters and kilograms 
From the Centers for Disease Control and Prevention site: 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html#Interpreted 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

  
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19. 
Appendix G – Zoster Brief Pain Inventory (ZBPI) 
   
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Appendix H – Patient’s Global Impression of Change (PGIC) Scale 
 
 
 
 
 
  
 
 

  
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Appendix I – Neuropathic Pain Symptom Inventory (NPSI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 

  
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22. 
References 
American Psychiatric Association. DSM-5 Criteria for Substance-Related Disorders. Criteria 
for Substance Dependence Use (LEVEL 2 – Substance Abuse – Adult). 2016. 
http://www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures. Accessed June 
17, 2014. 
Cain GR, Tsai K, Pulley LT, Taylor M. Detrusor myopathy in young beagle dogs. Toxicol 
Pathol. 2000;28 (4): 565-567. 
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous 
system to damage. Annu Rev Neurosci. 2009;32: 1-32.  
Fairbanks CA, Stone LS, Wilcox GL. Pharmacological profiles of alpha 2 adrenergic 
receptor agonists identified using genetically altered mice and isobolographic analysis. 
Pharmacol Ther. 2009;123: 224-238.  
Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of 
neuropathic pain. Pain. 2010;150: 573-581.  
Kostich W, Hamman BD, Li Y-W, et al. Inhibition of AAK1 kinase as a novel therapeutic 
approach to treat neuropathic pain. J Pharmacol Exp Ther. 2016;358: 371-386.  
Martin D. The Criteria Committee of the New York Heart Association. Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: 
Little, Brown & Co; 1994: 253-256. 
Sandrini G, Serrao M, Rossi P, et al. The lower limb flexion reflex in humans. Prog 
Neurobiol. 2005;77: 353-395.  
Snedecor SJ, Sudharshan L, Cappelleri JC, et al. Systemic review and meta-analysis of 
pharmacological therapies for pain associated with postherpetic neuralgia and less common 
neuropathic conditions. Int J Clin Pract. 2014;68: 900-918. 
 
 

 
 
 
 
Protocol No. LX9211.202  
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Rationale for Amendment 
Protocol Amendment 3 includes the following changes to the protocol:  
• Modification to plans for interim analysis and their implications 
• The exclusion of patients with facial PHN are eligible for participation if trigeminal 
neuralgia has been excluded as a cause 
• Change in the physical address of Lexicon Pharmaceuticals, Inc.  
 
Attached is a detailed summary of each change included in this Amendment.