Clinical trial NCT04455633
Conditions: Diabetic Peripheral Neuropathy Diabetes
Sponsor: Lexicon Pharmaceuticals
Start date: 2020-09-03; Completion date: 2022-06-28
Enrollment: 319 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluation of the efficacy of a low and high dose of LX9211 compared to placebo in reducing pain related to diabetic peripheral neuropathy (DPNP) over an 11 week assessment period.

Detailed description:

Arms: arm 1: Following a 2-week run-in period, participants were randomized to LX9211 matching placebo received as a single loading dose, orally, on Day 1, followed by maintenance doses of LX9211 matching placebo tablets, orally, once daily (QD) from Day 2 up to Week 6. Following completion of the 6-week treatment, all participants were followed for safety and received single oral tablet of LX9211 matching placebo, QD, for 5 weeks during the safety follow-up. arm 2: Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 milligrams (mg), tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablets, orally, QD from Day 2 up to Week 6. Following completion of the 6-week treatment, all participants were followed for safety and received single oral tablet of LX9211 matching placebo, QD, for 5 weeks during safety follow-up. arm 3: Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 200 mg orally on Day 1, followed by maintenance doses of LX9211, 20 mg, orally, QD from Day 2 up to Week 6. Following completion of the 6-week treatment, all participants were followed for safety and received single oral tablet of LX9211 matching placebo, QD, for 5 weeks during safety follow-up.
Interventions: intervention 1: LX9211 intervention 2: LX9211 Matching Placebo
Intervention descriptions: intervention 1: Oral Tablets intervention 2: Oral Tablets

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of LX9211 in the 
Treatment of Diabetic Peripheral Neuropathic Pain (RELIEF-DPN 1) 
NCT Number: NCT04455633
Document Date: Protocol Amendment 4: 09-September-2021


Lexicon Pharmaceuticals, Inc. 
Confidential 
Page 1 
Clinical Study Report 
03 April 2023 
LX9211.1-201-DPN 
16.1.1 
Protocol and Protocol Amendments 
Clinical Study Protocol LX9211.1-201-DPN Amendment 4 (09 September 2021) 
Clinical Study Protocol LX9211.1-201-DPN Amendment 3 (18 November 2020) 
Clinical Study Protocol LX9211.1-201-DPN Amendment 2.0.1 – PK Substudy Sites Only 
(09 October 2020) 
Clinical Study Protocol LX9211.1-201-DPN Amendment 2 (28 August 2020) 
Clinical Protocol LX9211.1-201-DPN – Amendment 1 (17 March 2020) 
Clinical Study Protocol LX9211-201-DPN (05 December 2019) 


Protocol No. LX9211.201 
09 September 2021 
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CLINICAL STUDY PROTOCOL AMENDMENT 4 
SUMMARY OF CHANGES 
Protocol Number:
LX9211.1-201-DPN 
LX9211.201 (Abbreviated number) 
Investigational Phase:
2 
Protocol Title:
A Phase 2, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of LX9211 in 
the Treatment of Diabetic Peripheral Neuropathic Pain 
(RELIEF-DPN 1) 
Amendment 4 Date: 
09 September 2021 
Amendment 3 Date:
18 November 2020 
Protocol Amendment 2.0.1 Date: 
09 October 2020 
Amendment 2 Date:
28 August 2020 
Amendment 1 Date:
17 March 2020
Original Version Date:
05 December 2019
Sponsor:
Lexicon Pharmaceuticals, Inc.
2245 Technology Forest Blvd, Level 11 
The Woodlands, TX 77381-5261 
Telephone: (281) 863-3000 
Safety Data Facsimile: (832) 442-5462 
 
 MD 
 Clinical Development 
Lexicon Pharmaceuticals, Inc. 
Telephone: 
 


 
 
Protocol No. LX9211.201  
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Rationale for Amendment
Protocol Amendment 4 includes the following changes to the protocol:
 Modification to plans for interim analyses and their implications
 Modification of the time window allowed for assessment of Orthostatic Vital Signs  
 Increase to the number of study sites from 30 to 45  
 Change in physical address of Lexicon Pharmaceuticals, Inc.
 Specified temporary dose interruptions are allowed based on tolerability issues at the 
Investigators consideration. Time limits to temporary dose interruptions have been 
included (no less than 3 days but no more than 5 days) 
 
 Qualitative Patient Interview substudy will increase number of interviews to capture 
patients in the last part of the trial and look at the distribution 
Attached is a detailed summary of each change included in this amendment.  
















 
Protocol No. LX9211.201  
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CLINICAL STUDY PROTOCOL 
Protocol Number:
LX9211.1-201-DPN
LX9211.201 (Abbreviated number) 
Investigational Phase:
Phase 2 
Protocol Title:
A Phase 2, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of LX9211 in 
the Treatment of Diabetic Peripheral Neuropathic Pain 
(RELIEF-DPN 1) 
Amendment 4:
09 September 2021
Amendment 3:
18 November 2020  
Protocol Amendment 2.0.1 
09 October 2020  
Amendment 2:
28 August 2020  
Amendment 1:
17 March 2020  
Original Version Date:
05 December 2019
Sponsor:
Lexicon Pharmaceuticals, Inc.
2245 Technology Forest Blvd, Level 11 
The Woodlands, TX 77381-5261
Telephone: (281) 863-3000
Safety Data Facsimile: (832) 442-5462 
 
 
 MD 
 Clinical Development 
Lexicon Pharmaceuticals, Inc. 
Telephone: 
 
 


Protocol No. LX9211.201
09 September 2021
CONFIDENTIAL
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Investigator Signature Page
Protocol Number:
LX9211.1-201-DPN
Protocol Title:
A Phase 2, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of LX9211 in 
the Treatment of Diabetic Peripheral Neuropathic Pain 
(RELIEF-DPN 1)
Amendment 4
09 September 2021
Amendment 3
18 November 2020
Protocol Amendment 2.0.1
09 October 2020 
Amendment 2:
28 August 2020 
Amendment 1:
17 March 2020 
Original Version Date:
05 December 2019
Sponsor:
Lexicon Pharmaceuticals, Inc.
2245 Technology Forest Blvd, Level 11
The Woodlands, TX 77381-5261
Telephone: (281) 863-3000
By my signature below, I hereby attest that I have read and that I understand and will abide by 
all the conditions, instructions, and restrictions contained in the attached protocol and will 
conduct the study in accordance with International Council for Harmonisation (ICH) E6 Good 
Clinical Practice (GCP) guidance.
Additionally, I will not initiate this study without written and dated approval from the 
appropriate Institutional Review Board (IRB)/Ethic Review Committee (ERC), and I 
understand that any changes in the protocol must be approved in writing by the Sponsor, the 
IRB/ERC, and, in certain cases the US Food and Drug Administration (FDA) or other 
applicable regulatory agencies, before they can be implemented, except where necessary to 
eliminate hazards to patients.
Principal Investigator’s Signature
Date
Principal Investigator’ Name (Print)
(Signature)
Date
 MD
(Printed Name)






 
Protocol No. LX9211.201  
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Screening Period: After signing the Informed Consent Form 
(ICF), all patients will enter a Screening Period of up to 2 weeks. 
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. 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 the 
intensity of their DPNP over the previous 24 hours based on 
Question 5 of the BPI-DPN by answering the question “Please rate 
your pain due to your diabetes by indicating the one number that 
best describes your pain on the average.” (0 [no pain] to 10 [pain as 
bad as you can imagine]) in their daily pain diary and will rate the 
interference of pain with sleep by completing Question 9F of the 
BPI-DPN. The ADPS will be calculated using all available daily 
pain diary data. This derived value of the ADPS over Week 2 will 
serve as the Baseline measure used for analyses. In order to qualify 
for randomization, patients must have completed 7
of the daily 
pain diary entries during the second week of the Run-in Phase, 
meet criteria for moderate to severe pain, and demonstrate 
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 may be rescreened ONCE after 
discussion with the Medical Monitor. Patients who begin the 
Screening period prior to this amendment and who otherwise would 
qualify for the study may be rescreened again so as to allow them 
to begin the Run-in Phase following implementation of this 
amendment.  
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.  
Patients will be randomly assigned in a 1:1:1 ratio among the 
following 3 treatment groups: 
 Group 1: LX9211 100 mg* / 10 mg**, once daily (qd) 
 Group 2: LX9211 200 mg* / 20 mg**, qd  
 Group 3: Placebo, qd  
* Loading dose (Day 1) 


 
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** Maintenance dose (Day 2 – Week 6 Visit) 
Implementation of the treatment randomization schedule will be 
centralized. A 1:1:1 ratio for assigning patients among the treatment 
groups will be accomplished by use of randomly permuted blocks 
of fixed size. 
On Day 1, patients will receive 1 of 2 dose levels of LX9211 or 
placebo, based on their treatment assignment, 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 patients will rate and record the intensity of their 
DPNP over the previous 24 hours based on Question 5 of the BPI-
DPN by answering the question “Please rate your pain due to your 
diabetes by indicating the one number that best describes your pain 
on the average.” (0 [no pain] to 10 [pain as bad as you can 
imagine]), will record the use of rescue medication 
(acetaminophen), and will rate the interference of pain with sleep 
by completing Question 9F of the BPI-DPN. 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 of weekly averages. 
If a patient is unable to tolerate their DPNP, 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 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 every morning taken at home. Each evening 
patients will rate and record the intensity of their DPNP over the 
previous 24 hours based on Question 5 of the BPI-DPN by 
answering the question “Please rate your pain due to your diabetes 
by indicating the one number that best describes your pain on the 
average.” (0 [no pain] to 10 [pain as bad as you can imagine]), will 
record the use of rescue medication (acetaminophen), and will rate 
the interference of pain with sleep by completing Question 9F of 
the BPI-DPN.  


 
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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, 
and 6, just prior to the dosing of study drug on the day of the clinic 
visit. At the Week11 EOT/EW Visit a final sample will be collected. 
During the Screening Visit, patients may choose to participate in 1 
or both of the 2 optional substudies.
The PK substudy will include approximately 30 patients. These 
patients will be confined to a clinical research unit (CRU) twice 
during the study for intensive PK evaluation and biomarker 
evaluation: prior to and following the first dose of study drug and 
prior to and following their final dose of study drug (planned for 
Week 6). 
The second optional substudy is a qualitative patient interview 
following the Week 6 visit (or after early study withdrawal), which 
will include approximately 60 patients. The telephone interview is 
designed to gain insight and understanding of patients’ experiences 
with symptoms of DPNP and to assess relevance and clinical 
meaningfulness of symptom improvements (eg, reduction in pain) 
with LX9211 treatment.
The study design is presented in the diagram below:  






 
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1. Patient has given written informed consent to participate in 
the study in accordance with local regulations  
2.
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.
2 at Screening
4. Diagnosis of T1DM or T2DM with chronic DPNP, (defined 
as distal symmetric polyneuropathy characterized by 
burning pain, paresthesia’s, and numbness with reduced or 
absent deep tendon reflex at both ankles) at Screening
5. Michigan Neuropathy Screening Instrument (MNSI) Part B 
score of 2.5 at Screening based on Items 1-4 
6. Pain from DPN present for at least 6 months  
7. 
11
.
8. 
month prior to Screening, consisting of diet and/or oral or 
injectable antidiabetic therapy. Note: Modifications in 
insulin dose are permitted for patients using insulin. 
9. Moderate to severe pain as confirmed by average pain score 
based on Question 5 of the BPI-DPN recorded in the pain 
diary in the 14 days prior to randomization (Run-in Period) 
10. At least 
-week 
Run-in Period, and 7
with completion of the 
daily diary during the second week of the Run-in Period 


 
Protocol No. LX9211.201  
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11. 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 DPNP: 
a. Patients should not have any other neurological disorder 
or conditions that can cause symptoms that may mimic 
peripheral neuropathy or that might confound 
assessment of distal symmetrical sensory 
polyneuropathy, and especially should not have any 
neuropathy due to nondiabetic causes. Patients with any 
condition that mimics peripheral neuropathy such as: 
stroke with distal neurological deficit; amyotrophy; 
polyradiculopathy; history of transient ischemic attacks; 
multiple sclerosis; mononeuropathy multiplex should be 
excluded. 
b. Other causes of diffuse painful peripheral neuropathy 
such as: paraproteinemia, untreated hypothyroidism 
(previously treated hypothyroidism not excluded if 
treated and euthyroid for at least 6 months), vitamin B12 
deficiency, neurologically-evident vasculitis, 
malignancy, amyloidosis, renal insufficiency, 
connective tissue disease (eg, Sjogren's, systemic lupus 
erythematosus), porphyria, hereditary motor sensory 
neuropathy, postherpetic neuralgia, 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. Patients 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 


 
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3. Mood and anxiety disorder scores defined by Hospital
Anxiety and Depression Scale (HADS) 
 
4. History of neurolytic or neurosurgical therapy for DPNP  
5. Use of opioid medications for management of DPNP within 
the 2 months prior to the Screening Visit. Note:  Brief use 
(<1 week) of opioid medication for management of non-
DPNP acute pain (eg, tooth extraction/acute injury) at least 
1 month prior to Screening Visit is permitted. 
6. Use of NSAIDs less than 2 weeks prior to the Screening 
Visit 
7. A positive urine drug test for drugs of abuse and 
cannabinoids. Note: Cannabidiol, if used for mood or sleep, 
is acceptable. If used for DPNP, it would be allowed if it is 
the only concomitant medication being taken for DPNP. If it 
is not the only medication being taken for DPNP, it should 
be withdrawn at least 1 month prior to Screening. 
8. Patients with 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. 
9. Patients with abnormal kidney function test (glomerular 
filtration rate [GFR] <60 mL/min as calculated using the 
Cockcroft-Gault equation) at Screening or renal dysfunction 
requiring hemodialysis 
10. Patients with a history of epilepsy or seizure disorder 
requiring treatment with antiepileptic drugs 
11. Presence of clinically significant physical examination (PE) 
findings other than DPNP, 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 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 


 
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history of NYHA class III/IV heart failure or 
structural heart disease) 
12. Receipt of any investigational agent or study drug within 30 
days or 5 half-lives, whichever is longer, prior to Screening 
13. 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:  Prophylactic vaccines, such as influenza, 
pneumococcal, or TDAP vaccine will be allowed if 
administered >7 days prior to randomization. 
14. Prior exposure to LX9211 
15. 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 
16. Presence of any skin condition such as ulcers, lower 
extremity amputations, etc., which interferes with 
assessment of DPNP 
17. Existence of any surgical 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 (eg, bariatric surgery) 
18. History of any major surgery within 3 months prior to 
Baseline or surgery that is anticipated to be performed 
during the study period 
19. History of any active infection within 30 days prior to 
Baseline, if deemed clinically significant by the 
Investigator, Medical Monitor, and/or the Sponsor 
20. 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 
that in the opinion of the Investigator and the Medical 
Monitor are considered cured, may participate. 
21. Donation or loss of >500 mL of blood or blood product 
within 3 months prior to Baseline 
22. Inability or difficulty swallowing whole tablets 
23. Any other condition that compromises the ability of the 
patient to provide informed consent or to comply with the 


Protocol No. LX9211.201  
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objectives and procedures of this protocol, as judged by the 
Investigator, Medical Monitor, and/or the Sponsor 
24. 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 
25. Patients who refuse to participate in processes established 
by the Sponsor, to minimize duplicate patients  
26. 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 
Statistical Methods
A sample size of 75 patients per treatment group who complete the 
6-week Double-
detect a true mean difference of 1 unit between at least 1 LX9211 
treatment group and placebo in ADPS change from Baseline to 
Week 6, assuming a common standard deviation of 2 and an overall 
significance level of 
(2-sided Dunnett’s test). Accounting 
for a uniform dropout rate of 20
patients per treatment group) will be enrolled and randomly 
assigned to treatment in a 1:1:1 ratio. This sample size is adjusted 
for the multiple comparisons of each LX9211 treatment group with 
placebo (Westfall, 1999). The sample size can be increased to a 
maximum of 351 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. 
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 at least 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 


 
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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: BPI-
DPN score and NPSI score, measured at multiple time points, a 
similar modeling strategy used for the primary endpoint will be 
applied. PGIC and the proportion of responders based on Question 
5 of the BPI-DPN, 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 
analysis methods will be detailed in a separate statistical analysis 
plan and will be reported separately.  
Pharmacokinetic 
Substudy Assessments 
The Pharmacokinetic (PK) Population for the PK Substudy patients 
who receive a dose of study drug and who have a predose sample 
and at least the minimum number of samples required to estimate 
the PK parameters. 
For the PK substudy (approximately 30 patients), patients will be 
admitted to the CRU either the day before the first dose (Day -1) or 
prior to the first dose of study drug (Day 1). Blood samples will be 
collected at the following time points: 
 Day 1: predose (0 hr), and 0.5, 1, 2, 4, 6, 8, 10, 12, 14, and 
16 hours postdose; 
 Day 2: predose (24 hrs post Day 1 dose)




 
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Safety Data Analysis
Safety analyses, based on the Safety Population, will involve 
examination of the descriptive statistics and individual patient 
listings for any effects of study treatment on clinical tolerability and 
safety. Summaries will be prepared by treatment group (ie, placebo 
and LX9211 dose level) and, by study visit where applicable. The 
incidence of AEs will be presented by severity and by relatedness 
as assessed by the Investigator. All safety data will be provided in 
listings. 
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, TEAEs by relationship to study treatment, events leading 
to discontinuation of study drug, deaths, and SAEs. 
Vital signs, ECGs findings, PE findings, clinically significant PE 
findings, weight, and laboratory parameters (chemistry, 
hematology, and urinalysis) will be summarized descriptively at 
each time point. Actual and change from Baseline data will be 
calculated and summarized. In addition, shift table analyses will be 
presented for the laboratory 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
3.2.5
LX9211 Toxicology .................................................................................. 28
3.2.6
Preclinical GLP-Compliant Toxicology Studies in Rats .......................... 28
3.2.7
Preclinical GLP-Compliant Toxicology Studies in Dogs ......................... 29
3.2.8
Embryo-Fetal Development Study in Rats ............................................... 30
3.2.9
Embryo-Fetal Development Study in Rabbits ......................................... 30
3.3
Clinical Trials of LX9211 in Humans .................................................................... 31
3.4
Rationale for Current Study ................................................................................... 32
3.4.1
Rationale for Selection of Dose ............................................................... 32
3.5
Rationale for Study Design and Control Groups ................................................... 33
4.
Study Objectives ............................................................................................................. 33
4.1
Primary Objective .................................................................................................. 33
4.2
Secondary Objective(s) .......................................................................................... 33
4.3
Other Objective(s).................................................................................................. 33
5.
Investigational Plan ........................................................................................................ 34
5.1
Overall Study Design ............................................................................................. 34
Figure 5.1–1
Treatment Schema ........................................................................................... 35
5.1.1
Screening Period ...................................................................................... 36
5.1.2
Run-in Period ........................................................................................... 36
5.1.3
Randomization/Treatment Period ............................................................. 36
5.1.4
Safety Follow-up Period ........................................................................... 38
5.1.5
Optional Substudies .................................................................................. 38
6.
Study Population ............................................................................................................. 39
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 ..................................................................................... 43


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6.4
Criteria for Termination of the Study..................................................................... 43
6.4.1
Termination of the Study Based on Planned Interim Analysis ................. 44
6.5
Clinical Stopping Rules ......................................................................................... 44
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 and Matching Placebo ............................................................................. 46
7.1.1
Identity of Active Drug ............................................................................ 46
7.1.2
Packaging, Labeling, and Storage ............................................................ 46
7.2
Prior and Concomitant Medications ...................................................................... 47
7.2.1
Prior Medication ....................................................................................... 47
7.2.2
Concomitant Medication .......................................................................... 47
7.3
Prohibited Medication............................................................................................ 47
7.4
Administration of Study Drug ............................................................................... 48
Table 7.4-1 
Study Drug Administration .............................................................................. 49
7.4.1
Treatment Compliance ............................................................................. 49
7.5
Dose Adjustment .................................................................................................... 50
8.
Study Procedures ............................................................................................................ 50
8.1
Description of Study Assessments ......................................................................... 50
8.1.1
Clinical Laboratory Assessment ............................................................... 50
8.1.2
Pharmacokinetic Assessments .................................................................. 50
8.1.3
Safety Assessments .................................................................................. 51
8.1.3.1
Vital Sign Measurements ......................................................... 51
8.1.3.2 
Physical Examinations, Height, and Weight ............................ 51
8.1.3.3 
Electrocardiograms .................................................................. 52
8.1.4
Patient Reported Outcomes ...................................................................... 52
8.1.5
Qualitative Patient Interview .................................................................... 52
9.
Safety Reporting ............................................................................................................. 53
9.1
Definitions and Special Considerations ................................................................. 53
9.1.1
Adverse Events ......................................................................................... 53
9.1.1.1 
Special considerations for bladder dysfunction-related adverse 
events ....................................................................................... 54
9.1.2
Serious Adverse Events ............................................................................ 54
9.1.3
Unexpected Adverse Events ..................................................................... 55


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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 .................................................................................................... 60
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
10.2.4.1 Pharmacokinetics Population (PK) – Substudy ....................... 61
10.2.4.2 Pharmacokinetics Population (PK) – Ctrough............................ 61
10.2.5
Safety Population ..................................................................................... 61
10.3 Study Endpoints ..................................................................................................... 62
10.3.1
Primary Efficacy Endpoint ....................................................................... 62
10.3.2
Secondary Efficacy Endpoints ................................................................. 62
10.3.3
Other Efficacy Endpoints ......................................................................... 63
10.3.4
Pharmacokinetic (PK) Endpoints ............................................................. 63
10.3.5
Safety Endpoints ...................................................................................... 64
10.4 Statistical Methods ................................................................................................. 64
10.4.1
Extent of study drug exposure and compliance ....................................... 64
10.4.1.1 Extent of study drug exposure ................................................. 64
10.4.1.2 Compliance .............................................................................. 64
10.4.2
Analyses of efficacy endpoints................................................................. 65
10.4.2.1 Analysis of primary efficacy endpoint ..................................... 65
10.4.2.2 Analysis of secondary and other efficacy endpoints ............... 65
10.4.3
Pharmacokinetic (PK) Analyses ............................................................... 66
10.4.4
Subgroup Analyses ................................................................................... 66
10.4.5
Safety Analyses ........................................................................................ 66


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10.4.5.1 Adverse Events ........................................................................ 67
10.4.5.2 Deaths, Serious and Other Significant Adverse Events ........... 67
10.4.5.3 Clinical Laboratory Parameters ............................................... 67
10.4.5.4 Vital Signs ................................................................................ 68
10.4.5.5
Physical Examination Findings ............................................... 68
10.4.5.6
Electrocardiogram (ECG) ........................................................ 68
10.4.5.7
Interim Analysis ....................................................................... 68
10.4.6
Baseline Characteristics and Other Summaries ....................................... 69
10.4.6.1 Protocol Deviations.................................................................. 69
11.
Study Management ......................................................................................................... 69
11.1 Monitoring ............................................................................................................. 70
11.2 Protocol Deviations................................................................................................ 70
11.3 Audits and Inspections ........................................................................................... 71
11.4 Amendments .......................................................................................................... 71
11.5 Record Keeping ..................................................................................................... 71
11.5.1
Drug Accountability ................................................................................. 71
11.5.2
Health Insurance Portability Accountability Act of 1996 and Subsequent 
Updates  ................................................................................................. 71
11.5.3
Financial Disclosure ................................................................................. 72
11.5.4
Access to Original Records ...................................................................... 72
11.5.5
Retention of Study Documents ................................................................ 72
12.
Administrative Structure of the Study ............................................................................ 73
13.
Appendix A – Schedule of Events .................................................................................. 74
14.
Appendix B – Substudy of PK on Day 1, Day 2, and Week 6 Visits: Procedure Listing ... 
 
 ......................................................................................................................... 77
15.
Appendix C –Biomarker Collections for Patients Participating in Substudy of PK:  
Procedure Listing ............................................................................................................ 78
16.
Appendix D – Amount of Blood to be Collected from Each Patient ............................. 79
17.
Appendix E – Ethical Standards ..................................................................................... 80
18.
Appendix F – Investigator Obligations........................................................................... 82
19.
Appendix G – Calculations ............................................................................................. 87
20.
Appendix H – Human Anxiety and Depression Scale (HADS) ..................................... 88
21.
Appendix I – Michigan Neuropathy Screening Instrument (MNSI-Part B)................... 90
22.
Appendix J – Brief Pain Inventory Short Form for Diabetic Peripheral Neuropathy 
(BPI-DPN) ...................................................................................................................... 91
23.
Appendix K – Patient Global Impression of Change (PGIC)......................................... 93
24.
Appendix L – Neuropathic Pain Symptom Inventory (NPSI) ........................................ 94
25.
References....................................................................................................................... 97


 
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2.
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
A1C
hemoglobin A1c / glycosylated hemoglobin (previously HbA1c) 
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
BPI 
Brief Pain Inventory
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI 
confidence intervals
CMP 
comprehensive metabolic panel 
CRO 
contract research organization 
DPN
diabetic peripheral neuropathy
DPNP
diabetic peripheral neuropathic pain
eCRF 
electronic Case Report Form 
ECG 
electrocardiogram 
EMG
electromyogram
EOT
end of treatment 
ERC
Ethics Review Committee 
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 


 
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Abbreviation
Definition
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
MedDRA
Medical Dictionary for Regulatory Activities 
MNSI 
Michigan Neuropathy Screening Instrument 
NFR
nociceptive flexion reflex
NOAEL
no observable adverse effect level
PBMC
peripheral blood monocytes
PD
pharmacodynamic
PE
physical examination
PK
pharmacokinetic(s)
PHN
postherpetic neuralgia 
PRO 
patient reported outcome 
RBC
red blood cells
SAE
serious adverse event
SOP 
standard operating procedure 
SD
standard deviation
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
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 
 


 
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Definitions of Pharmacokinetic Terms
Parameter
Definition
AUC
Area under the concentration-time curve 
AUC0-24
area under the concentration-time curve from time 0 to 
24 hours 
AUC0-tlast
area under the concentration-time curve from time 0 to 
time tlast, where tlast is the last time point with a 
measurable concentration 
AUC0–
area under the concentration-time curve from time 0 to 
infinity 
Cmax  
maximum plasma concentration
Ctrough
trough plasma concentrations
Css
plasma concentration at steady state
tmax 
time to maximum plasma concentration 
t1/2
apparent terminal elimination half-life 
z 
apparent terminal phase elimination rate constant
Vz/F 
apparent volume of distribution 
CL/F 
apparent total body clearance 
CL/F/kg 
weight adjusted clearance 


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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 
ction 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 
projected human maximum free plasma concentration (Cmax values 16.6 ng/mL corrected for 
cted efficacious clinical dose is 1.28 ng/mL (ie, 
16.6x [1-
50 
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 2 neuropathic pain models in rats (CCI and 
STZ 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-
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. Separate studies confirmed that 




 
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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.
3.2.5
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. In embryo-fetal development 
studies, the NOAEL for LX9211 phosphate was determined to be 10 mg/kg/day in the rat and 4 
mg/kg/day in the rabbit. 
Additional details can be found in the IB. 
3.2.6 
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 3630 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 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 


 
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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 1370 ng/mL for males and females, respectively 
(mean of 1090 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 high dose in the current DPN study. 
3.2.7
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 
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 1860 and 1090 ng*hr/mL, respectively (mean 1470 
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-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 


 
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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 et al, 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).
3.2.8
Embryo-Fetal Development Study in Rats 
In the rat embryo-fetal development study, doses of LC9211 phosphate 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. 
3.2.9
Embryo-Fetal Development Study in Rabbits
In the rabbit embryo-fetal development study, 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 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. 


 
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3.3
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 (IV) 
Administration in Healthy Male Subjects. A cohort of 6 male subjects were exposed to a single 
oral dose of 14C-LX9211 (nominal 50 mg free drug). Drug-related material in urine and feces 
was recovered for up to 34 days. The mean recovery percentage of drug-related material was 
 
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 addition, a separate cohort of 6 subjects underwent an evaluation to establish the absolute oral 
bioavailability of LX9211. A single oral dose of 50 mg was administered, followed by an IV 
microdose (14C-9211 50 g). 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.  
Both 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 randomized to 
receive LX9211.  
The results from the LX9211-101 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 of 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 


 
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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 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 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. 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,  
3.4 
Rationale for Current Study 
3.4.1 
Rationale for Selection of Dose 
The doses of LX9211 selected for evaluation in the current study were 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 levels selected in this study, 100 mg and 200 mg 
loading doses followed by 10 mg and 20 mg maintenance doses, respectively, are expected to be 
well tolerated and represent an adequate range for dose exploration. 


 
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3.5
Rationale for Study Design and Control Groups
The randomized, placebo-controlled, double-blind clinical design allows for unbiased 
comparison of efficacy and safety between 2 different dose levels of 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 doses of 100 mg and 200 mg, which were 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 provide guidance in early stopping for futility. The option of sample size 
reestimation (SSR) allows the study to maintain statistical power at the original specified value, 
and guard against its reduction due to an unexpected increase in the dropout rate or variability 
associated with the primary endpoint measure.
4.
Study Objectives 
4.1
Primary Objective 
 To evaluate the efficacy of LX9211 in reducing pain related to diabetic peripheral 
neuropathy (DPN)
4.2 
Secondary Objective(s)
To assess other effects and patient reported outcomes of LX9211 versus placebo 
following the 6-week double-blind Treatment Period
4.3
Other Objective(s)
Change from Baseline in the Neuropathic Pain Symptom Inventory (NPSI) and to each 
week in the average daily pain score (ADPS), based on Question 5 of the Brief Pain 
Inventory - DPN (BPI-DPN)
To evaluate plasma Ctrough levels of LX9211 at 2 oral dose levels in patients with type 1 
diabetes mellitus (T1DM) and/or type 2 diabetes mellitus (T2DM) with chronic diabetic 
peripheral neuropathy pain (DPNP) over a 6-week period 


 
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The full PK profile of LX9211 will be evaluated in an optional substudy conducted in patients 
who consent to intensive PK sampling over the course of the treatment period. 
Safety will be assessed by AEs, vital signs, ECG findings, and laboratory parameters. 
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 DPNP.
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 at Week 11 (Week 5 of the single-blind Safety Follow-up 
Period). 
Male and female patients of nonchildbearing potential, age 18 years and above, diagnosed with 
T1DM or T2DM and with chronic DPNP, and who meet all inclusion and no exclusion criteria 
are eligible for enrollment. 
Eligible patients may continue use of medications prescribed for DPNP including pregabalin, 
gabapentin, and antidepressant medications, as long as they have been at stable doses for at least 
1 month prior to Screening and are willing to maintain their doses for the duration of the study. 
Use of any opioid medications for the management of DPNP 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. Following confirmation of eligibility criteria, patients will enter the Run-in Period. 
Note:  Patients who fail Screening may be rescreened ONCE after discussion with the Medical 
Monitor. Patients who begin the Screening Period prior to this amendment and who otherwise 
would qualify for the study may be rescreened again so as to allow them to begin the Run-in 
Phase following implementation of this amendment. 
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 in the morning. Each evening patients will rate and record the intensity of 
their DPNP over the previous 24 hours based on Question 5 of the BPI-DPN by answering the 
question “Please rate your pain due to your diabetes by indicating the one number that best 
describes your pain on the average.” (0 [no pain] to 10 [pain as bad as you can imagine]) in their 
daily pain diary and will rate the interference of pain with sleep by completing Question 9F of 
the BPI-DPN. The ADPS will be calculated using all available daily pain diary data. In order to 
qualify for randomization, patients must have completed 7
of the daily pain diary entries 
during the week prior to randomization, meet criteria for moderate to severe pain, and 
demonstrate 
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 may be rescreened ONCE after discussion with the 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 1:1:1 ratio among the following 3 treatment groups: 
 Group 1: LX9211 100 mg* / 10 mg**, once daily (qd)  
Group 2: LX9211 200 mg* / 20 mg**, qd 


 
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 Group 3: Placebo, qd  
* Loading dose (Day 1) 
** Maintenance dose (Day 2 – Week 6 Visit)
Implementation of the treatment randomization schedule will be centralized. A 1:1:1 ratio for 
assigning patients among the treatment groups will be accomplished by use of randomly 
permuted blocks of fixed size.
On Day 1, patients will be assigned to 1 of 2 dose levels of LX9211 or placebo, based on their 
treatment assignment, 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.
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 patients will rate and record the intensity of their DPNP over the previous 24 hours 
based on Question 5 of the BPI-DPN by answering the question “Please rate your pain due to 
your diabetes by indicating the one number that best describes your pain on the average.” (0 [no 
pain] to 10 [pain as bad as you can imagine]), record the use of rescue medication 
(acetaminophen), and rate the interference of the patient’s pain with sleep based on Question 9F 
of the DPI-PHN. 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 of weekly averages. 
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 


 
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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.
Blood samples for the determination of LX9211 trough levels (Ctrough) will be collected predose 
on Day 1, and at Weeks 2, 4, and 6 clinic visits, just prior to the dosing of study drug on the day 
of the visit. At the Week 11 EOT/EW Visit, a final sample will be collected.
On the day of randomization, patients will also receive a bottle of acetaminophen. If a patient is 
unable to tolerate their DPNP, 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 also 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 and take 1 tablet of single-blind study drug each 
morning during this period. 
During the 5-week single-blind Safety Follow-up Period, patients are allowed use of rescue 
medication (acetaminophen) if needed.
5.1.5
Optional Substudies
During the Screening Visit, patients may choose to participate in 1 or both of the 2 optional 
substudies. 
The first substudy will include approximately 30 patients for intensive blood sampling for 
determination of LX9211 plasma concentrations to allow for PK parameter estimation, and 
additional samples for possible biomarker analyses. The PK intensive sampling will occur on 
Days 1 and 2 and at the Week 6 clinic visit. These patients will be confined to a clinical research 
unit (CRU) twice during the study for intensive PK evaluation and biomarker evaluation: prior to 


 
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and following the first dose of study drug and prior to and following their final dose of study 
drug (planned for Week 6).  
The second optional substudy, a qualitative patient interview, will include approximately 60 
patients. The telephone interview will be designed to gain insight and understanding of patients’ 
experiences with symptoms of DPNP and to assess relevance and clinical meaningfulness of 
symptom improvements (eg, reduction in pain) with LX9211 treatment.
6.
Study Population
Up to 282 patients (94/treatment group) are expected to enroll in this study in order to complete 
225 (75/treatment group). The sample size may be increased to a maximum of 351 patients based
on a planned interim analysis that allows for conduct of a sample size reestimation procedure.
A subset of approximately 30 patients will be recruited to participate in the PK and biomarker 
analyses optional substudy. 
A second substudy will enroll a minimum of 60 patients and not to exceed 85 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 and fem
 
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®.  




 
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or other systemic disease associated with a secondary painful neuropathy should 
be excluded.
c.
Patients 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 
criteria (DSM-5) 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) 
 
4. History of neurolytic or neurosurgical therapy for DPNP
5. Use of opioid medications for management of DPNP within the 2 months prior to the 
Screening Visit Note:  Brief use (<1 week) of opioid medication for management of non-
DPNP acute pain (eg, tooth extraction/ acute injury) at least 1 month prior to screening is 
permitted. 
6. Use of chronic NSAIDs less than 2 weeks prior to the Screening Visit.
7. A positive urine drug test for drugs of abuse and cannabinoids. Note:  Cannabidiol, if 
used for mood or sleep, is acceptable. If used for DPNP it would be allowed if it is the 
only concomitant medication being taken for DPNP. If it is not the only medication being 
taken for DPNP, it should be withdrawn at least 1 month prior to Screening  
8. Patients with 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. 
9. Patients with significant abnormal kidney function test (glomerular filtration rate [GFR] 
<60 mL/min as calculated using the Cockcroft-Gault equation) at Screening or renal 
dysfunction requiring hemodialysis 
10. Patients with epilepsy or seizure disorder requiring treatment with antiepileptic drugs 
11. Presence of clinically significant physical examination (PE) findings other than DPNP, 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 rate or rhythm  
b. other ECG abnormalities that are clinically relevant 
c. BP >160/100 mm Hg or <90/50 mm Hg


 
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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 (Martin, 1994) or 
structural heart disease)
12. Receipt of any investigational agent or study drug within 30 days or 5 half-lives, 
whichever is longer, prior to Screening
13. 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:  Prophylactic vaccines, such as influenza, pneumococcal, or TDAP vaccine 
will be allowed if administered >7 days prior to randomization. 
14. Prior exposure to LX9211 
15. 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 
16. Presence of any skin condition such as ulcers, lower extremity amputations, etc., which 
interferes with assessment of DPNP 
17. Existence of any surgical 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 (eg, bariatric surgery) 
18. History of any major surgery within 3 months prior to Baseline or surgery that is 
anticipated to be performed during the study period 
19. History of any active infection within 30 days prior to Baseline, if deemed clinically 
significant by the Investigator, Medical Monitor, and/or the Sponsor 
20. 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 that in the opinion of the Investigator and the Medical Monitor are 
considered cured, may participate. 
21. Donation or loss of >500 mL of blood or blood product within 3 months prior to Baseline 
22. Inability or difficulty swallowing whole tablets 
23. 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 
24. 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 
25. Patients who refuse to participate in processes established by the Sponsor, to minimize 
duplicate patients  
26. 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 


 
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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. 
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 
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 


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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 
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 141 patients have been randomized and 
followed to the Week 6 visit, or dropped out earlier, whichever time is sooner. Enrollment will 
not be temporarily halted while data for the interim analysis is being reviewed. Details of 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 meet every 2 months, plus at the time of 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. 


 
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6.6
Method of Assigning Patients to Treatment  
Patients will be randomly assigned among 3 parallel treatment groups in a 1:1:1 manner. A 
randomization schedule will be centralized and stratified by the ADPS during the Run-in period 
based on moderate or severe pain. The randomization schedule will also account for the optional 
PK and biomarkers substudy. 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-blinded study, the designated treatment assigned to each patient will not be 
revealed to the Investigator, the patient, or the Sponsor or their designee, until the formal 
unblinding of 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. 
During the study, the blind is to be broken only when the safety of a patient is at risk and the 
treatment plan is dependent on the study treatment received. If the unblinding occurs without the 
knowledge of the Sponsor and/or designee, the Investigator must notify the Sponsor and/or 
designee as soon as possible and no later than 24 hours from the unblinding. All circumstances 
surrounding a premature unblinding must be clearly documented in the source records.  
The Sponsor’s designee performing IXRS will not release the randomization schedule to any 
party except upon formal written request by the Sponsor at study end. The request must be 
approved by the appropriate Sponsor personnel, according to the Sponsor’s standard operating 
procedures (SOPs). Details of any disclosure of the randomization schedule will be recorded in 
the site’s study files and the electronic Trial Master File (eTMF). A copy of the randomization 
schedule will also be sent to the Sponsor and/or designee. The blinding of the study will be 
broken after the database has been locked. To maintain continuous blinding and study integrity, 
analysis will be conducted by an independent statistician, and measures will be taken to ensure 
the validity of the data.  




 
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LX9211 20-mg and 10-mg tablets (and matching placebo) are packaged in 30 cc HDPE bottles 
containing pharma coil and a child resistant polyethylene screw cap with induction seal. Each 
bottle contains 20 tablets. 
LX9211 and matching 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 of all the strength tablets 
LX9211 (50-mg, 20-mg, and 10-mg) and matching placebo 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. 
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 of diabetes, 
and the patients' DPNP (ie gabapentin, pregabalin, and antidepressant medications).
7.3
Prohibited Medication
 Use of NSAIDS on chronic basis within 2 weeks prior to Screening or at any time for the 
duration of the study for treatment of DPNP is not permitted.  
Use of opiates in the 2 months prior to Screening or at any time for the duration of the 
study for treatment of DPNP is not permitted Note: Brief use (<1 week) of opioid 
medication for management of non-DPNP acute pain (eg, tooth extraction/acute injury) at 
least 1 month prior to the Screening Visit is permitted.  
 Cannabidiol, if used for mood or sleep, is acceptable. If used for DPNP it would be 
allowed if it is the only concomitant medication being taken for DPNP. If it is not the 
only medication being taken for DPNP, it should be withdrawn at least 1 month prior to 
Screening.
 Patients may not use additional medications for DPNP other than those medications 
prescribed for DPNP including pregabalin, gabapentin, and antidepressant medications, 
which have been taken at stable doses for at least 1 month prior to Screening.


 
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 Note:  At the Investigator’s discretion, patients may take up to 3 grams of acetaminophen 
per day as rescue medication for DPN pain.  
Patients must not have received any investigational agent or study drug within 30 days or 5 half-
lives, whichever is longer, prior to Screening or at any time for the duration of the study. 
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, 20 mg, and 10 mg) will be supplied in tablet form to be taken orally. A placebo, 
identical 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 study facility, 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. 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 study facility, 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 study facility on Day 1.
On Day 2 - 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 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.
The Study schema is presented in Figure 5.1-1. Details of study drug administration are provided 
in Table 7.4-1.


 
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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 100 mg/10 mg
2 x 50-mg LX9211
tablets
+
2 x Placebo tablets
1 x 10-mg LX9211
tablet, qd 
Group 2:
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 3: 
Placebo 
2 x Placebo tablets
+
2 x Placebo tablets
1 x Placebo
tablet, qd 
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 percentage 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 
taking 1 tablet each morning per protocol. Patients will be deemed “compliant” if their calculated 
complian
-
compliance with the dosing instructions, and clearly record the reason(s) in the source documents 
and on the eCRF.  
If a patient’
visits, the patient should be counseled by study personnel, and the Sponsor/designee should be 
contacted to determine study continuation. 


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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. In the case of tolerability issues, the investigator can consider a temporary dose 
interruption of no less than 3 days, but no more than 5 days. If  adverse event continues once 
study drug has been reinitiated then patient’s continued participation needs to be assessed.  
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 
Clinical Laboratory Assessment 
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. 
8.1.2 
Pharmacokinetic Assessments 
Blood samples for the determination of plasma LX9211 trough levels (Ctrough) will be drawn 
predose on Day 1 and at Weeks 2, 4, and 6, just prior to the dosing of study drug on the day of 
the clinic visit. At the Week 11 visit a final sample will be collected.  


 
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The PK substudy will include approximately 30 patients. These patients will be confined to a 
clinical research unit (CRU) twice during the study for intensive PK evaluation and biomarker 
evaluation: prior to and following the first dose of study drug and prior to and following their 
final dose of study drug (planned for Week 6). Pharmacokinetic assessments will be performed at 
time points indicated in the schedule of events (Appendix B).
Plasma samples will be analyzed by a central bioanalytical laboratory (Covance Laboratories 
Inc., Madison, WI) under a separate protocol. Detailed procedures for the drawing, preparation, 
storage, and shipping of samples will be provided to the study site. 
8.1.3 
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 
adverse events 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 with the Medical Monitor.  
8.1.3.1 
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. 
8.1.3.2 
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.  


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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.
8.1.3.3 
Electrocardiograms
Electrocardiograms (ie, 12-lead ECGs) will be performed as specified in Appendix A.
8.1.4 
Patient Reported Outcomes 
Three patient-reported outcomes (PROs), BPI-DPN, 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 BPI-DPN, is a 9-item questionnaire assesses the severity of pain and its impact on 
functioning in patients with DPN. The full questionnaire will be completed at Visit 3 
(Baseline) and at Visit 4, 5, 6, and 7. Question 5 (average pain of prior 24 hours) and 
Question 9 F (interference of pain with sleep) will be completed daily from Run-in 
through the end of the Safety Follow-up Period.  
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 will be performed at 
Week 6. 
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. This will 
be completed at Visit 3 (Baseline), and at Visits 6 and 7. 
8.1.5
Qualitative Patient Interview
A telephone qualitative patient interview substudy will be conducted for approximately 60 
patients within 2 weeks following the Week 6 Visit or following premature withdrawal.  


 
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The purpose of the phone interview will be to gain insight and understanding of patients’ 
experiences with symptoms of DPNP 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.
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.  


 
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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. 
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. 


 
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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; 
 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 


 
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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.
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. 


 
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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  
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. 


 
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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.  
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.com 
In case of failure of/lack of access to both email and fax, the event should be reported using 
Physician On-Call Hotline: (877) 372-3597. 


 
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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
Drug Safety Physician
Email: 
Phone: 
For questions on study patient management related to AE, the Medical Monitor of the study 
should be contacted. 
 MD 
 Clinical Development 
Email: 
 
Phone: 
  
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 at least 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. 




 
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the maximum total number of patients (E[Max]) equal to 351 patients and, specification that the 
reestimation rule is the Exact E method. The Exact E method increases the patient number total 
until the desired conditional power is achieved. 
nQuery Advisor Advanced Pro software (v8.5.2.0) (Statsols, Rathmaculling West, Cork, Ireland) 
was used to estimate the sample sizes.
10.2
Analysis Populations
Analysis of the primary and secondary 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 at least 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. 
10.2.4 
Pharmacokinetics Population (PK)  
10.2.4.1 
Pharmacokinetics Population (PK) – Substudy 
The PK Population for the PK Substudy will include patients who receive a dose of study drug 
and who have a predose sample and at least the minimum number of samples required to 
estimate the PK parameters. 
10.2.4.2 
Pharmacokinetics Population (PK) – Ctrough  
The PK Population for evaluation of Ctrough will include all patients who received at least 1 dose 
of study drug and at least 1 Ctrough 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 Brief Pain Inventory - DPN (BPI-DPN) , 
the 11-point scale (0 [no pain] to 10 [pain as bad as you can imagine])
10.3.2 
Secondary Efficacy Endpoints 
 Proportion of patients with 
reduction in pain intensity in ADPS based on Question 
5 of the Brief Pain Inventory - DPN (BPI-DPN) from Baseline to Week 6 
 Proportion of patients with 
reduction in pain intensity in ADPS based on Question 
5 of the Brief Pain Inventory - DPN (BPI-DPN) from Baseline to Week 6 
 Change from Baseline to Week 6 in the severity of pain and interference of pain with 
sleep and other aspects of the patient’s life based on the Brief Pain Inventory (BPI) Short 
Form for diabetic peripheral neuropathy (BPI-DPN) including the following: 
o Pain at its worst 
o Pain at its least 
o Pain right now 
o
Total interference score 
o
General activity 
o
Mood 
o
Walking ability 
o
Normal work 
o Relations with other people  
o
Sleep 
o
Enjoyment of life
Proportion of patients discontinuing treatment due to lack of efficacy defined as increase 
in ADPS based on Question 5 of the Brief Pain Inventory - DPN (BPI-DPN) from 
PGIC at Week 6 
Time to loss of efficacy from Week 6 to Week 11 among pa
reduction in pain intensity in ADPS based on Question 5 of the Brief Pain Inventory -
DPN (BPI-DPN) at Week 6


 
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10.3.3 
Other Efficacy Endpoints
Other efficacy endpoints are:
1.
Change from Baseline to Week 6 in the Neuropathic Pain Symptom Inventory (NPSI) 
2.
Change from Baseline to each week in ADPS, based on Question 5 of the BPI-DPN
3.
Proportion of patients with 
reduction from Baseline in ADPS, based on Question 5 
of the BPI-DPN by week
4. 
Proportion of patients with 
reduction from Baseline in ADPS, based on Question 5 
of the BPI-DPN by week 
5. 
Cumulative distribution function of percent change in ADPS based on Question 5 of the 
BPI-DPN from Baseline to Week 6 comparing each LX9211 treatment group to placebo 
6.
Cumulative distribution function of percent change in ADPS based on Question 5 of the 
BPI-DPN from Week 6 to Week 11 comparing each LX9211 treatment group to placebo
10.3.4 
Pharmacokinetic (PK) Endpoints
Pharmacokinetic endpoints from the optional PK substudy may include, but are not limited to:
AUC
 AUC0-24
 AUC0-tlast
 AUC0–
AUC0-  
 CL/F 
 CL/F/kg 
 Cmax 
 Css 
 tmax
 t1/2 
 Vz/F 
 
z




 
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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 the rescue 
medications. 
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 BPI-DPN 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 
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: BPI-DPN scores and NPSI, measured at 
multiple time points, will be analyzed using a similar modeling strategy as used for the primary 
endpoint.  
Categorical secondary endpoints: PGIC, Proportion of responders based on Question 5 of BPI-
DPN 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 


 
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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 
reduction 
in ADPS based on Question 5 of the BPI-DPN 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. 
Multiplicity
The 2 pairwise comparisons of each LX9211 dose levels vs placebo will be performed using 
Dunnett’s test. 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. Adjusted and unadjusted p-values will be presented. 
10.4.3 
Pharmacokinetic (PK) Analyses 
If quantifiable plasma concentrations are available, PK parameters will be derived using non-
compartmental techniques, and their summarization will be based on descriptive and graphical 
methods and summarized for each dose level. 
Plasma concentrations and time deviation data will be presented in the data listings by treatment, 
patient, and nominal time point. Plasma concentration data will be summarized descriptively by 
dose and nominal time point. Individual and mean plasma concentration versus nominal time 
profiles will be displayed graphically. All PK data will be presented in the data listings. 
After the first 10 PK substudy patients complete the study, a blinded PK analysis may be done to 
confirm exposure following oral tablet administration.  
10.4.4 
Subgroup Analyses 
The primary endpoint will be analyzed by the following patient subgroups: 
 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.  


 
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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 22.1.
Treatment emergent adverse events (TEAEs) are defined as events that first occur or worsen 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.  
10.4.5.3 
Clinical Laboratory Parameters 
Laboratory results will be reported in Conventional units and Systeme International (SI). 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 into Low, 
Normal, and 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 


 
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number of patients with both non-missing baseline and relevant postbaseline results. A by-patient 
data listing of all clinical laboratory test results will be provided. 
10.4.5.4 
Vital Signs 
Vital signs values, and changes from Baseline to each time point will be summarized using 
descriptive statistics and presented by treatment group. In addition, vital signs categorized as 
“Clinically significant” or” Not clinically significant” 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 at least 1 post Baseline 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 
planned information has been accrued. This will occur when the first 141 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. 
A non-blinding futility  boundary will be used to test treatment group differences in the primary 
by using a beta spending function and specification of a power famil
monitoring boundary is constructed by assuming a 1-sided test with a per comparison Type I 
(or a two-sided 
for the two LX9211 
versus placebo comparisons. Use of this beta spending function for futility testing is conservative 
and results in cumulative beta error rates of 0.015 and 0.197 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). 


 
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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 
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.
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.


 
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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.
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. 


 
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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 
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 


 
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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.
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.


 
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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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15.
Appendix C –Biomarker Collections for Patients Participating in Substudy of PK: Procedure Listing
Week/Visit 
Day 1 
(Baseline) 
Day 2 
Week 2 
Week 4 
Day prior to
Week 6
Or 
EOT / EW
Week 6
Or
EOT / 
EW 
Week 11
Or 
35 Days after 
EOT / EW
Whole blood for biomarker/target 
engagement [a] 
X
X
X
X
 
X
X
Sample for cytokine/chemokine 
analysis 
X
X
X
X
X
X
 
a.  Whole blood for biomarker/target engagement and cytokine/chemokine substudy samples will be collected at the following time points: Day 1 
predose (0 hr), Day 2 predose (0 hr), Week 2 predose (0 hr), Week 4 predose (0 hr); Week 6 predose (0 hr), and Week 11 predose (0 hr).  


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16.
Appendix D – 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 
Volum
e/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 
TOTAL
49
PK and biomarker 
substudy blood 
collection 
Wee
k -4
Week -2
Day 1
(Baseline)
Day 2
Week 
2
Week 
4
Week 6
Or
EOT / 
EW 
Week 11
Or 
35 Days 
after 
EOT / 
EW
Total # 
of Tests 
Volume
/Test 
(mL) 
Total 
Volume 
(mL) 
PK sample collection
11
1
12
24
4
96
Whole blood for 
possible 
biomarker/target 
engagement  
1
1
1
1
1
1
6
3
18
Sample for 
cytokine/chemokine 
analysis 
1
1
1
1
1
1
6
4
24
TOTAL
138


 
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17.
Appendix E – 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; 


 
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 the study is conducted with diligence and in conformance with the protocol in such a way 
as to ensure the integrity of the findings;
 the potential benefits of the research justify the risks. 
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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18.
Appendix F – 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 subInvestigator 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 


 
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involved, a parent or guardian should sign the consent form. If the minor is an adolescent, 
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 


 
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 A description of any benefits to the subject or to others that may reasonably be expected 
from the research
 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


 
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 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. 
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. 


 
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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 
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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19.
Appendix G – Calculations
Cockcroft-Gault equation:
The equation for calculation of creatinine clearance, as an estimation of glomerular filtration 
rate, 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_cal
culator.html for feet, inches, and pounds and 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/metric_bmi_calculator/bmi_cal
culator.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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22.
Appendix J – Brief Pain Inventory Short Form for Diabetic Peripheral 
Neuropathy (BPI-DPN)


 
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23.
Appendix K – Patient Global Impression of Change (PGIC)
 


 
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24.
Appendix L – Neuropathic Pain Symptom Inventory (NPSI)
 


 
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25.
References
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous 
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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.
Westfall PH, Tobias RD, Rom D, Wolfinger RD, Hochberg Y. Multiple Comparisons and 
Multiple Tests Using the SAS® System, Cary, NC SAS Institute Inc., 1999: 141-142.
 




 
 
 
Protocol No. LX9211.201  
18 November 2020 
CONFIDENTIAL 
Page 2 of 5 
Rationale for Amendment 
Protocol Amendment 3 includes modifications to inclusion criteria with regards to the study 
patients’ A1C and history of DPN pain. Of note, this protocol amendment provides information 
about the study’s interim analysis and its timing. Additionally, this amendment provides the 
opportunity to perform administrative changes (typos, etc). The following is a summary of the 
major changes and the rationale for them.  
• 
Increased allowable A1C value at Screening Visit to 11% to improve patient recruitment  
• 
Broadened the allowable duration of DPN pain to be at least 6 months, with no upper limit 
of duration to improve recruitment 
• 
Added information with regard to termination of the study based on the interim analysis 
• 
Provided information on when the interim analysis should take place 
• 
Safety Physician contact information has been updated.  
• 
Clarification has been provided regarding when a patient’s weight can be taken in relation to 
their first meal. 
Attached is a detailed summary of each change included in this amendment.  
 








 
 
 
 
CONFIDENTIAL 
Page 2 of 7 
Rationale for Amendment 
Protocol Amendment 2.0.1 includes a number of modifications to properly outline the PK, whole 
blood for possible biomarker/target engagement, and cytokine/chemokine sample collection. Of 
note, this protocol amendment reduces the number of total samples and total volume of blood to 
be collected from a patient during their participation in the PK substudy. Additionally, the patient 
is given the option to potentially reduce the number of days they are to stay at the site s Clinical 
Research Unit (CRU). This amendment only applies to sites participating in the PK substudy for 
LX9211.201. The following is a summary of the major changes and the rationale for them. 
Attached is a detailed summary of each change included in this Amendment.  
 
Provided patients participating in PK substudy the opportunity to reduce their duration of 
stay giving them the option to be admitted to the CRU either the day before the first dose 
(Day -1) or prior to the first dose of study drug (Day 1). In the same manner, patients can be 
admitted to the CRU either the day before their Week 6 or EOT/EW visit or prior to 
administration of study drug (LX9211) dose the day of their Week 6 or EOT/EW visit. 
 
Modified required PK sample collection time points in the Treatment Schema to align with 
Appendices A and C 
 
Removed collection of samples for PK time points: 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 24 hours 
postdose for Day 2 and Day 3 predose as samples will not provide added scientific benefit to 
the study 
 
Appendix B: revised table to included option for predose check-in to CRU on Day 1 
(Baseline) Visit and Week 6 or EOT/EW visit.  
 
Appendix C: Included sample collections for whole blood for biomarker/target engagement 
and cytokine/chemokine on Day 2, Week 2, Week 4, and Week 11 or  35 Days after 
EOT/EW visits to align with PK collections time points 
 
Appendix D: Clarification to the collection of necessary samples on Day 2; updated to 
reflect reduction in sample collections; and updated volume to reflect reduction in sample 
collection  
 












Protocol No. LX9211.201 
28 August 2020
CONFIDENTIAL
Page 1 of 27
CLINICAL STUDY PROTOCOL AMENDMENT 2
SUMMARY OF CHANGES
Protocol Number:
LX9211.1-201-DPN
LX9211.201 (Abbreviated number)
Investigational Phase:
2
Protocol Title:
A Phase 2, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of LX9211 in 
the Treatment of Diabetic Peripheral Neuropathic Pain 
(RELIEF-DPN 1)
Original Version Date:
05 December 2019
Amendment 1 Date:
17 March 2020
Amendment 2 Date
28 August 2020
Sponsor:
Lexicon Pharmaceuticals, Inc.
8800 Technology Forest Place
The Woodlands, TX 77381-1160
Telephone: (281) 863-3000
Safety Data Facsimile: (832) 442-5917
 MD
 Clinical Development
Lexicon Pharmaceuticals, Inc.
Telephone: 


Protocol No. LX9211.201 
28 August 2020
CONFIDENTIAL
Page 2 of 27
Rationale for Amendment
Protocol Amendment 2 includes a number of modifications to inclusion/exclusion criteria, 
endpoints, prior and concomitant medications, corrects a number of inconsistencies, and includes 
a number of administrative changes. The following is a summary of the major changes and the
rationale for them. Attached is a detailed summary of each change included in this Amendment is 
attached.
The name of the Lexicon Medical Director has been changed due to departure of the 
prior Medical Director from the company.
The Introduction was updated to include results of Segment 2 reproductive toxicology 
studies, which support inclusion of women of childbearing potential in the study 
provided they are using adequate contraception.
The primary endpoint was modified to be based on the average pain experienced by 
the patient over the prior 24 hours as measured by the Brief Pain Inventory-Diabetic 
Peripheral Neuropathy (BPI-DPN) scale, question 5, rather than the Numerical Rating 
Scale (NRS scale), which was a single item scale that collected the worst pain level 
over the prior 24 hours. This also changed the basis upon which the Average Daily 
Pain Score (ADPS) was defined from the NRS to the BPI-DPN. Many other 
endpoints, which had been based on the worst pain measure in the NRS scale, were 
also modified to reflect the new measure based on the BPI-DPN. This was done to 
reduce the amount of variability expected in the scores and provide a better measure 
of overall potential impact the drug on pain levels.
Clarified secondary outcome measure to specify that change from Baseline to Week 6 
in interference of pain with sleep and other aspects of patients life would be assessed 
based on the BPI-DPN, rather than stating the analysis would be of “severity and pain 
interference based on the BPI-DPN”. Specified that Question 9F of the BPI-DPN 
would be administered daily to assess interference of pain with sleep. 
Allowed patients to be removed from Screening and then rescreened in order to begin 
the Run-in Phase under the revised protocol. This is necessary to ensure that the 
primary question being asked daily is consistent in the Run-in and randomized 
treatment period, and that patients are provided the same scales during the Run-in and 
Randomized treatment periods.
Clarified that Baseline ADPS would be based on the average scores during the second 
week of the Run-in Phase (previous protocol version implied that it was a single day 
score – day before randomization)
Modified required compliance with diary completion to qualify for randomization 
during the Run-in Phase from 80% (no more than 1 missed entry per week) to 70% 
(allowing up to 2 missed entries per week) to facilitate patient enrollment.


Protocol No. LX9211.201 
28 August 2020
CONFIDENTIAL
Page 3 of 27
Removed the exclusion criteria for high or low variability in pain scores during the 
Run-in Phase based on rereview of references and assessment that there are no data to 
support the benefit of this exclusion in patients with DPNP.
Allowed inclusion of women of childbearing potential using adequate contraception 
based on new toxicology data.
Removed upper age limit for entry to allow elderly patients greater than 75 years to 
enroll. 
Removed exclusion criterion that prevented enrollment of patients who had greater 
than 1% change in A1C value over prior 6 months based on lack of evidence that 
such a change could significantly impact pain and response to study drug.
Increased allowable A1C value at randomization to 10.5% to improve patient 
recruitment. 
Revised and clarified allowed medications for DPNP prior to, and during the study 
(opioids, NSAIDs, over-the-counter medications and herbal supplements, 
cannabinoids), and vaccinations prior to the study in order to better accommodate 
patient needs.
Clarified that biomarker assay was to be performed only in patients participating in 
intensive PK sampling substudy in order to ensure that samples could be collected, 
processed, and shipped under required conditions.
Added to the text that Interview Substudy would be performed in patients who 
completed the study or who discontinued treatment prematurely. In the prior version, 
this was only stated in the Schedule of Events in the Appendix.
Specified that time to loss of efficacy measure was to be analyzed among patients 
who achieved a 30% reduction in pain from Baseline in order to ensure a meaningful 
analysis.
Clarified that no adjustment for pair-wise comparisons would be applied to the 
secondary outcome measures, and hence these analyses would be considered 
exploratory.
Included analysis of percent change in the primary outcome measure from Baseline to 
Week 6 and from Week 6 to Week 11 using cumulative distribution functions.
Updated the Treatment Schema in the text and the Schedules of Events in the 
Appendices to be consistent with the design changes and administrative changes in 
the protocol.


















































Protocol No. LX9211.201 
17 March 2020
CONFIDENTIAL
Page 1 of 3
CLINICAL STUDY PROTOCOL AMENDMENT 1
SUMMARY OF CHANGES
Protocol Number:
LX9211.1-201-DPN
LX9211.201 (Abbreviated number)
Investigational Phase:
2
Protocol Title:
A Phase 2, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Efficacy, Safety, and Pharmacokinetics of LX9211 in 
the Treatment of Diabetic Peripheral Neuropathic Pain 
(RELIEF-DPN 1)
Original Version Date:
05 December 2019
Amendment 1 Date:
17 March 2020
Sponsor:
Lexicon Pharmaceuticals, Inc.
8800 Technology Forest Place
The Woodlands, TX 77381-1160
Telephone: (281) 863-3000
Safety Data Facsimile: (832) 442-5917
 MD 
Lexicon Pharmaceuticals, Inc.
Office: ((281) 863-3000


Protocol No. LX9211.201 
17 March 2020
CONFIDENTIAL
Page 2 of 3
Rationale for Amendment
Protocol Amendment 1 addresses the following:
a) Added RELIEF-DPN 1 study name reference
b) Synopsis – remove restriction of no rescreening of patients who fail the Run-in Period; 
Section 5.1 added missing statement from synopsis indicating patients who fail Screening 
may be rescreened ONCE after discussion with the Medical Monitor
c) Pharmacokinetic Substudy - change from enroll “up to” 30 patients to enroll 
“approximately” 30 patients
d) Inclusion criterion #7 – change upper limit of A1C to 10.5%; clarify no more than a 1% 
absolute change in A1C (eg, from 8% to 9%) in the previous 6 months
e) Exclusion criterion #5 - clarify brief use of opioids to be allowed at least 1 month prior to 
Screening 
f)
Exclusion criterion #6 – modify to align with Section 7.3 Prohibited Medications 
g) Add Exclusion Criterion #27 for unacceptable high or low variability in subject reported 
pain scores during the Run-in period
h) Section 3.2.6 preclinical GLP-Compliant Toxicology Studies in Rats - Per FDA 
nonclinical review request, provide additional information from 13-week rat toxicology 
study 
i)
Section 3.2.7 Preclinical GLP-Compliant Toxicology Study in Dogs – update section 
describing 13-week study to include information regarding findings of muscle 
degeneration in the urinary bladder per FDA request.
j)
Section 3.3 Clinical Trials of LX9211 in Humans – add statement of no clinically 
significant comprehensive metabolic panel (CMP) or urinalysis findings, or bladder 
dysfunction-related AEs were reported in any subject treated with LX9211 in the SAD or 
MAD studies.
k) Figure 5.1-1 Treatment Schema moved from Section 5.1.5 Optional Substudies to Section 
5.1 Study Design
l)
Section 5.1.4 Safety Follow-up Period – Clarify rescue medication to be acetaminophen
m) Section 7.1.2 Packaging, Labeling, and Storage – Remove statement “Study drug supply 
for the Run-in, Treatment and Safety Follow-up Periods will be labeled accordingly.” as 
labels do not include study periods
n) Section 7.3 Prohibited Medication – added “Note: Brief use (<1 week) of opioid 
medication for management of non-DPNP acute pain (eg, tooth extraction/acute injury) at 
least 1 month prior to Screening Visit is permitted.” to align with Exclusion criteria #5
o) Section 8.1.3.1 Vital Sign Measurements – clarify vital signs should be collected with the 
patient in a seated position; also added to Schedule of Events (Appendix A)
p) Sections 9.1.1 and 9.3.2 Adverse Events – updated to include monitoring for AEs 
suggesting bladder dysfunction
q) Appendix A Schedule of Events 
1. Added Visit names (ie Visit 1, Visit 2, Visit 3, etc) for referencing each visit to 
help in maintaining blind
2. Allow for extending the Run-in Period by up to 3 days 
r)
Appendix C – add collection of cytokine/chemokines sample as part of biomarkers


Protocol No. LX9211.201 
17 March 2020
CONFIDENTIAL
Page 3 of 3
s) Appendix D
1. Corrected number of PK samples to be collected on Day 1 (11 not 9), Day 2 (11 
not 10), and Week 6 (12 not 10) visit; total PK blood samples (35 not 30); and 
total volume of PK blood draw (140 mL not 120 mL)
2. Added samples for cytokine/chemokine analysis (5 samples x 4 mL each = 20 mL 
total)
t)
Add Appendix M for Numerical Rating Scale (NRS)

SAP_001.pdf: 


Lexicon Pharmaceuticals, Inc. 
Confidential 
Page 1 
Clinical Study Report 
03 April 2023 
LX9211.1-201-DPN 
16.1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan – Version 3.0 (07 June 2022) 
Qualitativie Report (02 April 2020) 


CONFIDENTIAL 
Page 1 of 55 
Document Date: 07JUN2022
ST-AD-008 version 05 
Statistical Analysis Plan 
Lexicon Pharmaceuticals, Inc. 
Protocol No.: LX9211.1.201-DPN 
A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of LX9211 in the Treatment of Diabetic Peripheral 
Neuropathic Pain (RELIEF-DPN 1) 
Covance Study ID: 000000198624 
Document Version: Final v3.0 
Document Date: 07-JUN-2022 
Labcorp CDCS 
Clinical Development Commercialization Services 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 2 of 55 
Document Date: 07JUN2022
 
ST-AD-008 version 05 
 
 
Table of Contents 
1. 
Source Documents ................................................................................. 7 
2. 
Protocol Details ..................................................................................... 7 
2.1 
Study Objectives................................................................................. 7 
2.2 
Overall Study Design ........................................................................... 8 
2.3 
Sample Size and Power ..................................................................... 11 
3. 
Efficacy and Safety Variables................................................................. 12 
3.1 
Primary Efficacy Endpoint .................................................................. 12 
3.2 
Secondary Efficacy Endpoints ............................................................. 12 
3.3 
Other Efficacy Endpoints .................................................................... 13 
3.4 
Safety Variables................................................................................ 14 
4. 
Pharmacokinetic (PK) Variables ............................................................. 14 
5. 
Analysis Populations ............................................................................. 15 
5.1 
Intent-to-Treat (ITT) Population ......................................................... 15 
5.2 
Modified Intent-to-treat (mITT) Population ........................................... 15 
5.3 
Per Protocol (PP) Population ............................................................... 15 
5.3.1 
Important Protocol Deviations Leading to Exclusion from the PP 
Population Analysis ................................................................................. 15 
5.4 
PK Populations .................................................................................. 17 
5.4.1 
PK Population - Ctrough .................................................................. 17 
5.4.2 
PK Population - Substudy ............................................................. 17 
5.5 
Safety Population .............................................................................. 17 
6. 
Data Handling ..................................................................................... 18 
6.1 
Time Points and Visit Windows ............................................................ 18 
6.1.1 
Primary efficacy, secondary efficacy, and other efficacy endpoints based 
on daily pain diary data ........................................................................... 18 
6.1.2 
Secondary efficacy and other efficacy endpoints based on data collected 
at clinic visits ......................................................................................... 19 
6.1.3 
Safety analyses ........................................................................... 20 
6.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 20 
6.2.1 
Observed Cases Datasets ............................................................. 21 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 3 of 55 
Document Date: 07JUN2022
 
ST-AD-008 version 05 
 
 
6.2.2 
Pattern-mixture Model ................................................................. 21 
7. 
Statistical Methods ............................................................................... 22 
7.1 
General Principles ............................................................................. 22 
7.2 
Patient Disposition and Data Sets Analyzed .......................................... 23 
7.3 
Protocol Deviations ........................................................................... 24 
7.4 
Demographics and Other Baseline Characteristics ................................. 24 
7.4.1 
Medical History ........................................................................... 25 
7.4.2 
Prior and Concomitant Medications ................................................ 26 
7.5 
Measurements of Treatment Compliance .............................................. 26 
7.6 
Efficacy ............................................................................................ 27 
7.6.1 
Primary Efficacy Analysis .............................................................. 27 
7.6.2 
Secondary Efficacy Analysis .......................................................... 28 
7.6.3 
Sensitivity Analysis ...................................................................... 32 
7.6.4 
Subgroup Analysis ....................................................................... 33 
7.6.5 
Other Efficacy Analysis ................................................................. 34 
7.6.6 
PK Analysis ................................................................................. 36 
7.7 
Safety ............................................................................................. 37 
7.7.1 
Extent of Exposure ...................................................................... 37 
7.7.2 
Adverse Events ........................................................................... 38 
7.7.3 
Laboratory Evaluations ................................................................. 40 
7.7.4 
Vital Signs .................................................................................. 41 
7.7.5 
Electrocardiograms ...................................................................... 42 
7.7.6 
Physical Examination ................................................................... 42 
7.8 
Interim Analysis................................................................................ 43 
8. 
Changes in Planned Analysis ................................................................. 44 
9. 
Data Issues......................................................................................... 44 
10. 
References .......................................................................................... 44 
11. 
Appendices ......................................................................................... 44 
 






Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 6 of 55 
Document Date: 07JUN2022
 
ST-AD-008 version 05 
 
 
PGIC 
Patient Global Impression of Change 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PMM 
pattern-mixture model 
PP 
Per Protocol  
PRO 
patient-reported outcome 
PT 
Preferred Term 
QTcF 
Fridericia corrected QT interval 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SE 
standard error 
SOC 
System Organ Class 
SSR 
sample size reestimation 
TEAE 
treatment-emergent adverse event 
TFL 
tables, figures, and listings 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
WHO 
World Health Organization 
 
 




Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
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Document Date: 07JUN2022
 
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The full pharmacokinetic (PK) profile of LX9211 will be evaluated in an optional 
substudy conducted in patients who consent to intensive PK sampling over the 
course of the treatment period. 
Safety will be assessed by adverse events (AEs), vital signs, electrocardiogram 
(ECG) findings, and laboratory parameters. 
 
2.2 Overall Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in patients with DPNP. Up to 282 patients are expected to 
enroll in this study.  
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 of age 18 years and above, diagnosed with T1DM or T2DM 
and with chronic DPNP, and who meet all inclusion and no exclusion criteria are 
eligible for enrollment.  
Eligible patients may continue use of 1 medication prescribed for DPNP including 
pregabalin, gabapentin, and antidepressant medications, as long as they have been 
at stable doses for at least 1 month prior to screening and are willing to maintain 
their doses for the duration of the study. Use of any opioid medications for the 
management of DPNP within the 2 months prior to Screening is not permitted.  
Screening Period: After signing the Informed Consent Form (ICF), all patients will 
enter a Screening Period of up to 2 weeks. 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. On Day 1 of the Run-in period, patients will be 
administered 4 tablets of single blind study drug at the site. For the remainder of 
the Run-in Period, patients will take a single tablet of study drug in the morning. 
Each evening patients will rate and record the intensity of their DPNP over the 
previous 24 hours based on Question 5 of the BPI-DPN by answering the question 
“Please rate your pain due to your diabetes by indicating the one number that best 
describes your pain on the average.” (0 [no pain] to 10 [pain as bad as you can 
imagine]) in their daily pain diary and will rate the interference of pain with sleep 
by completing Question 9F of the BPI-DPN. The ADPS will be calculated using all 
available daily pain diary data. In order to qualify for randomization, patients must 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 9 of 55 
Document Date: 07JUN2022
 
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complete ≥70% of the daily pain diary entries during the week prior to 
randomization, 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 may be rescreened ONCE after discussion with 
the 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.  
 
Patients will be randomly assigned in a 1:1:1 ratio among the following 3 treatment 
groups:  
• Group 1: LX9211 100 mg* / 10 mg**, once daily (qd)  
• Group 2: LX9211 200 mg* / 20 mg**, qd  
• Group 3: Placebo, qd  
 
* Loading dose (Day 1)  
** Maintenance dose (Day 2 – Week 6 Visit)  
 
Implementation of the treatment randomization schedule will be centralized. A 
1:1:1 ratio for assigning patients among the treatment groups will be accomplished 
by use of randomly permuted blocks of fixed size.  
On Day 1, patients will receive 1 of 2 dose levels of LX9211 or placebo, based on 
their treatment assignment, 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 ± 10 
minutes, orthostatic vital signs will be obtained (heart rate and blood pressure) 
after which time patients may be released. The loading dose will be followed by a 
daily maintenance dose taken at home on Day 2 through the Week 6 Visit. Note: 
On days of the 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 severity of their DPNP over the previous 24 hours based on 
Question 5 of the BPI-DPN by answering the question “Please rate your pain due to 
your diabetes by indicating the one number that best describes your pain on the 
average.” (0 [no pain] to 10 [pain as bad as you can imagine]), record the use of 
rescue medication (acetaminophen), and rate the interference of the patient’s pain 
with sleep based on Question 9F of the BPI-DPN. The ADPS will be calculated using 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 10 of 55 
Document Date: 07JUN2022
 
ST-AD-008 version 05 
 
 
all available data, however a minimum of 4 days (consecutive or non-consecutive) 
from the last week prior to each clinic visit is required for the calculation of weekly 
averages.  
On the day of randomization, patients will also receive a bottle of acetaminophen. If 
a patient is unable to tolerate their DPNP, 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 also complete the Safety Follow-up Visit 5 weeks later.   
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 and take 1 tablet of single-blind study drug each morning during this period. 
During the 5-week single-blind Safety Follow-up Period, patients are allowed use of 
rescue medication (acetaminophen) if needed. Each evening patients will continue 
to rate and record the average severity of their DPNP over the previous 24 hours 
using Question 5 of the BPI-DPN and record the use of rescue medication 
(acetaminophen). 
Blood samples for the determination of plasma LX9211 trough levels (Ctrough) will be 
collected predose on Day 1, and at Weeks 2, 4, and 6 clinic visits, just prior to the 
dosing of study drug on the day of the visit. At the Week 11 EOT/EW Visit, a final 
sample will be collected.  
Optional Substudies: During the Screening Visit, patients may choose to 
participate in 1 or both of 2 optional substudies.  
The first substudy will include approximately 30 patients for intensive blood 
sampling for determination of LX9211 plasma concentrations to allow for PK 
parameter estimation, and additional samples for possible biomarker analyses. The 
PK intensive sampling will occur on Days 1 and 2 and at the Week 6 clinic visit. 
These patients will be confined to a clinical research unit (CRU) twice during the 
study for intensive PK evaluation and biomarker evaluation: prior to and following 
the first dose of study drug and prior to and following their final dose of study drug 
(planned for Week 6). 
The second optional substudy is a qualitative patient interview, which will include  
60 to 85 patients. The interview will be conducted over the telephone and is 
designed to gain insight and understanding of patients’ experiences with symptoms 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 11 of 55 
Document Date: 07JUN2022
 
ST-AD-008 version 05 
 
 
of DPNP and to assess the relevance and clinical meaningfulness of symptom 
improvements (eg, reduction in pain) with LX9211 treatment.  
The study design is presented in the diagram below:  
 
2.3 Sample Size and Power 
A sample size of 75 patients per treatment group who complete the 6-week 
double-blind Treatment Period will yield 80% power to detect a true mean 
difference of 1 unit between at least 1 of LX9211 treatment groups and placebo in 
ADPS change from Baseline, assuming a common standard deviation of 2 and an 
overall significance level of α=0.05 (2-sided Dunnett’s test). Accounting for a 
dropout rate of 20%, a total of 282 patients (94 patients per treatment group; 75 
patients x 1/(1-0.20)) will be enrolled and randomly assigned to treatment in a 
1:1:1 ratio. This sample size is adjusted for the multiple comparisons of each 
LX9211 treatment group with placebo (Westfall, 1999). 
Sample Size Reestimation  
Due to the uncertainty in the outcome for the primary endpoint analysis secondary 
to potential variations in some of the key design parameters such as the dropout 
rate and standard deviation associated with the targeted treatment group 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
  
  
 
  
 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
CONFIDENTIAL 
Page 12 of 55 
Document Date: 07JUN2022
 
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difference, an unblinded SSR adaptation will be implemented at the time of the 
interim analysis testing for futility. This will occur when the first 141 patients 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 two 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 80.3% (the 
original specified power under the group sequential design). 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.  
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, a value for the maximum total number of patients (E[Max]) 
equal to 351 patients and, specification that the reestimation rule is the Exact E 
method. The Exact E method increases the patient number total until the desired 
conditional power is achieved.  
nQuery Advisor Advanced Pro software (v8.5.2.0) (Statsols, Rathmaculling West, 
Cork, Ireland) was used to estimate the sample sizes. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline (Week 2 of the Run-in 
Period) to Week 6 in ADPS, based on Question 5 of the Brief Pain Inventory - DPN 
(BPI-DPN), the 11-point scale (0 [no pain] to 10 [pain as bad as you can imagine]).  
3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are to be assessed in each LX9211 dose group 
versus placebo comparison for each of the following variables listed below:  


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 
Proportion of patients with ≥30% reduction in pain intensity in ADPS based 
on Question 5 of the Brief Pain Inventory - DPN (BPI-DPN) from Baseline to 
Week 6   
 
Proportion of patients with ≥50% reduction in pain intensity in ADPS based 
on Question 5 of the Brief Pain Inventory - DPN (BPI-DPN) from Baseline to 
Week 6 
 
Change from Baseline to Week 6 in the severity of pain and interference of 
pain with sleep and other aspects of the patient’s life based on the Brief Pain 
Inventory (BPI) Short Form for diabetic peripheral neuropathy (BPI-DPN) 
including the following: 
 
Pain at its worst  
 
Pain at its least  
 
Pain right now  
 
Interference score averaged over Questions 9A-G  
 
General activity  
 
Mood  
 
Walking ability  
 
Normal work 
 
Relations with other people  
 
Sleep  
 
Enjoyment of life  
 
Proportion of patients discontinuing treatment due to lack of efficacy defined 
as increase in ADPS based on Question 5 of the Brief Pain Inventory - DPN 
(BPI-DPN) from Baseline of 30%  
 
Patient Global Impression of Change (PGIC) at Week 6  
 
Time to loss of efficacy from Week 6 to Week 11 among patients achieving at 
least 30% reduction in pain intensity in ADPS based on Question 5 of the 
Brief Pain Inventory - DPN (BPI-DPN) at Week 6 
3.3 Other Efficacy Endpoints 
The other efficacy endpoints are to be assessed in each LX9211 dose group versus 
placebo comparison for each of the following variables listed below: 
 
Change from Baseline to Week 6 in the NPSI  
 
Change from Baseline to each week in ADPS, based on Question 5 of the BPI-
DPN  
 
Proportion of patients with ≥30% reduction from Baseline, based on Question 
5 of the BPI-DPN by week  
 
Proportion of patients with ≥50% reduction from Baseline, based on Question 
5 of the BPI-DPN by week 


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 
Cumulative percentage of percent change in ADPS based on Question 5 of 
the BPI-DPN from Baseline to Week 6 comparing each LX9211 treatment 
group to placebo   
 
Cumulative percentage of percent change in ADPS based on Question 5 of 
the BPI-DPN from Week 6 to Week 11 comparing each LX9211 treatment 
group to placebo  
3.4 Safety Variables 
Safety endpoints are as follows:  
 
Incidence of treatment-emergent adverse events (TEAEs), suspected adverse 
reaction, AEs leading to discontinuation from the study, serious adverse 
events (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 physical examination (PE) 
findings  
 
Actual and change from Baseline in ECG findings   
4. Pharmacokinetic (PK) Variables 
PK endpoints from the optional PK substudy may include, but are not limited to:  
 
AUC0-24  
 
AUC0-tlast  
 
AUC0–∞  
 
AUC0-τ  
 
CL/F  
 
CL/F/kg  
 
Cmax 
 
Css 
 
tmax 
 
t1/2 
 
Vz/F  
 
λz  
 
Biomarker samples will be collected for patients participating in the PK substudy. 
 


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5. Analysis Populations
Analysis of the primary and secondary efficacy endpoints will be based on the 
Modified Intent-to-Treat (mITT) population. Safety endpoints analyses will be based 
on the Safety population. 
5.1 Intent-to-Treat (ITT) Population
The ITT population will include all randomized patients. 
5.2 Modified Intent-to-treat (mITT) Population
The mITT population will include all randomized patients who take at least 1 dose of 
study drug. mITT patients will be analyzed according to their randomized 
treatment. 
5.3 Per Protocol (PP) Population
The PP population will include patients in the mITT population who complete 
treatment through the primary assessment of the first 6 weeks, and did not have 
any important protocol deviations that would interfere with the collection or 
interpretation of the efficacy data.   
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol. Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being. Section 5.3.1 details the types of 
deviations. 
5.3.1 Important Protocol Deviations Leading to Exclusion from the PP 
Population Analysis 
Only those important protocol deviations considered to have a major effect on 
efficacy will lead to complete exclusion of the patient from the PP population. For 
the purposes of this study, the following criteria have been identified as important 
protocol deviations leading to exclusion from the PP population as it is considered 
that the occurrences of any of these criteria might have an important influence on 
the primary efficacy endpoint.  




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Incorrect 
Stratum used 
in 
Randomization 
Patients were randomized 
using an incorrect stratum 
Programmatic check of IRT database 
compared to ADPS from Run-in 
Clinical Trial 
Management 
System 
Labcorp Clinical will provide 
the list of protocol 
deviations based on the 
clinical monitoring. 
Non-programmable: The list will be 
reviewed prior to database lock and 
unblinding, and the important protocol 
deviations leading to exclusion from the 
PP population will be identified.  
 
As defined in the table, a set of the important protocol deviations leading to 
exclusion from the PP population will be determined programmatically from the 
data.  Those criteria which require clinical or medical monitoring interpretation will 
be reviewed prior to database lock. 
All important protocol deviations occurring during the study will be reviewed and 
approved by Lexicon Pharmaceuticals, prior to database lock unblinding. Should 
additional important protocol deviations leading to exclusion from the PP 
population, not anticipated at the time of preparing this SAP, be identified during 
the study (and prior to unblinding), they will be provided in a separate document 
and included in all relevant protocol deviation reviews and approvals. 
5.4 PK Populations 
There are 2 PK populations as defined below. 
5.4.1 PK Population - Ctrough 
The PK population for evaluation of Ctrough will include all patients who receive at 
least 1 dose of study drug and have at least 1 Ctrough sample collected. 
5.4.2 PK Population - Substudy 
The PK population for the PK Substudy will include patients who receive at least 1 
dose of study drug and who have a predose sample and have at least the minimum 
of samples required to estimate the PK parameters. 
5.5 Safety Population 
The Safety population is defined as those randomized patients who take at least 1 
dose of study drug during the double-blind Treatment Period. Safety patients are 
analyzed according to their actual treatment received on Study Day 1. 


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6. Data Handling 
6.1 Time Points and Visit Windows 
Day 1 is defined as Baseline/Randomization visit, is also the first day that study 
treatment during the double-blind Treatment Period is planned to be started. 
Should study treatment start at a later date, Day 1 will be defined as the date that 
study treatment during the double-blind Treatment Period is initiated. Relative days 
after Day 1 are calculated as (assessment date – Day 1 date) + 1.  Relative days 
prior to Day 1 are calculated as (assessment date – Day 1 date).  The day prior to 
Day 1 is Day -1; there is no Day 0.  
6.1.1 Primary efficacy, secondary efficacy, and other efficacy endpoints 
based on daily pain diary data 
The following visit windows defined in Table 1.1 will be used for the analyses of the 
primary efficacy endpoint, the secondary efficacy and other efficacy endpoints 
based on the ADPS as well as for the secondary endpoint on pain interfering with 
sleep.  
Table 1.1 
Definition of time point windows for analyses based on ADPS and sleep 
interference rated each evening 
Time point 
 
Time point window a 
Baseline 
 
Day -7 to Day -1  
Week 1 
 
Days 1 to 7  
Week 2 
 
Days 8 to 14  
Week 3 
 
Days 15 to 21  
Week 4 
 
Days 22 to 28  
Week 5 
 
Days 29 to 35  
Week 6 
 
Days 36 to 42  
Week 7 
 
Days 43 to 49  
Week 8 
 
Days 50 to 56  
Week 9 
 
Days 57 to 63  
Week 10 
 
Days 64 to 70  
Week 11 
 
Days 71 to 77  
a relative to the date of first dose of study drug during the double-blind Treatment 
Period/date of Randomization/date of Baseline Visit (Day 1) 
 
The Baseline value for ADPS based on Question 5 of the BPI-DPN will be calculated 
as the mean value of the corresponding question over Week 2 of the single-blind 
Run-in Period, provided that ≥5 days with non-missing data from that period are 
available for analysis. The Baseline value for the interference with sleep using 
Question 9F of the BPI-DPN will be calculated as the mean value of the 


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corresponding question over Week 2 of the single-blind Run-in Period, provided that 
≥5 days with non-missing data from that period are available for analysis.  
The post-Baseline values will be calculated as the mean value of the corresponding 
question, ie, Question 5 for ADPS and Question 9F for interference with sleep of the 
BPI-DPN, rated by patients each evening in the daily pain diary and collected 
during the target week period. A minimum of 4 non-missing data points within the 
target week period is required for the calculation of the mean value for that 
particular week. 
6.1.2 Secondary efficacy and other efficacy endpoints based on data 
collected at clinic visits 
The rest of the efficacy endpoints based on data collected at clinic visits will follow 
the visit windows defined in Table 1.2. 
Table 1.2 
Definition of visit windows for efficacy data collected at each visit 
Visit 
Target Day of Visita 
Acceptable visit window 
Screening 
Day –28 
NA 
Run-in b 
Day –14 
NA 
Baseline 
Day 1 
Day 1 to Day 4 
Week 2 
Day 15 
Day 5 to Day 22  
Week 4 
Day 29 
Day 23 to Day 36  
Week 6 
Day 43 
Day 37 to Day 60  
Week 11 
Day 78 
Day 61 to 35 days after the last 
treatment dose during the double-blind 
Treatment Period  
a relative to the date of first dose of study drug during the double-blind Treatment 
Period/date of Randomization/date of Baseline Visit (Day 1) 
b weight is collected 
 
In general, the Baseline value for a variable is defined the last value collected or 
taken on or before Day 1 and prior to the first dose of double-blind study drug. In 
cases where there are multiple such values, the non-missing value closest to the 
start of study treatment is selected. If time is available for an assessment on Day 
1, it will be compared with dosing time on Day 1 to define the Baseline value. 
Multiple visits within the same window will be dealt with as follows: 
 
If both scheduled and unscheduled visits fall within the same visit window, the 
scheduled visit will be used for analysis. 
 
If multiple scheduled visits occur within a single visit window, then the visit 
closest to the target day of the visit window will be used in the analysis.  If 
there is a tie, the later visit will be used in the analysis. 


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 
If multiple unscheduled visits occur within a single visit window (with no 
scheduled visit within the window) then the unscheduled visit closest to the 
target day of the visit window will be used in the analysis.  If there is a tie, the 
later unscheduled visit will be used in the analysis. 
6.1.3 Safety analyses  
Safety analyses for the laboratory assessments, vital signs, ECG and physical exam 
data will use the study visit window rules used to assign observations to visits as 
defined above in Table 1.2. 
6.2 Handling of Dropouts, Missing Data, and Outliers 
Missing data will not be imputed for safety analyses. The safety evaluations will be 
performed on observed data only. 
For AEs with partial or missing onset or stop dates: 
AE stop date will be imputed first as: 
 
If stop date is completely missing, assume it is ongoing (no imputation); 
 
For a partial AE stop date: 
o day is missing, then take the last day of the month 
o both day and month are missing, then take the last day of the last month 
that the patient was on study 
Then AE onset date will be imputed as: 
 
If onset date is completely missing: the first dose date 
 
For a partial AE onset date: 
o day is missing: 
. 
Partial date < the first dose date: last day of the month 
. 
Partial date = the first dose date: the first dose date 
. 
Partial date > the first dose date: first day of the month 
o both day and month are missing ie only the year is available: 
. 
Partial date < the first dose date: December 31st 
. 
Partial date = the first dose date: the first dose date 
. 
Partial date > the first dose date: January 1st 
If the imputed AE onset date is after the AE stop date/imputed AE stop date, then 
the onset date will be set to the AE stop date/imputed AE stop date. 
The imputed dates will not be listed. Study day relative to the first dose of 
double-blind study drug associated with missing or partial dates will not be 
displayed in AE listings. 


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In the event that a partial date (month/year or year) for concomitant medication is 
available, this information will be used as follows: 

When both month and year are available – first day of the month will be used
for start date and the last day of the month will be used for the stop date.

When only year is available – January 1st will be used for the start date and
December 31st will be used for the stop date.
The imputed dates will only be used to determine whether a concomitant 
medication will be classified as prior medication or concomitant medication. 
For patients who complete the NPSI assessment, but have 1 incomplete answered 
question, the total score will be computed as 10 times sum of scores of 9 
descriptors divided by 9. If more than 1 question is missing, then the total score 
will be missing. Missing questions will not be imputed for the subscores. 
For patients who complete the BPI-DPN assessment Questions 9A-G and have less 
than 4 missing questions, the Interference score averaged Questions 9A-G will be 
computed as the mean of the answered questions. If 4 or more questions are 
missing, then the Interference score will be set to missing.  
The Hospital Anxiety and Depression Scale (HADS) is collected only at Screening 
and imputation of missing data are not critical for this assessment.   
No rules for outlier detection are planned. 
6.2.1 Observed Cases Datasets
The mixed-effects model for repeated measurements (MMRM) will be performed 
based on a missing at random (MAR) assumption using data actually observed - 
observed cases (OC) dataset. The OC datasets will be used for analysis of the 
primary efficacy as well as all secondary efficacy and other efficacy endpoints. This 
dataset will not impute any values for missing observations, unless mentioned 
otherwise.  
6.2.2 Pattern-mixture Model 
As a sensible sensitivity analysis to the MMRM, a method for missing value 
imputation based on pattern-mixture model (PMM) will be used to analyze the data 
under the assumption that the data is missing not at random (MNAR): missingness 
depends on the unobserved values and cannot be predicted solely based on a 
patient’s observed data. It is assumed that the great majority of missing data are 
caused by patients discontinuing prior to the study visit at which primary endpoint 
data are collected and the resulting missing data will have a monotone pattern. 
There may also be some small amount of non-monotone missing data when 
patients skip intermediate visits but return for evaluations at subsequent visits. 






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 
Included in each study population (ITT, mITT, PP, PK – Substudy, PK - Ctrough and 
Safety) 
The number and percentage of patients who complete the study and who 
discontinue early (including a breakdown of the primary reasons for 
discontinuation), will be presented for the ITT population. In addition, the number 
of patients who discontinue from the double-blind Treatment Period and single-blind 
Safety Follow-up Period will be summarized by treatment group, respectively. 
A summary of patient enrollment by site will also be provided by treatment group 
and overall for the ITT population.  A summary of patient enrollment by 
randomization strata of baseline pain severity (moderate or severe pain, based on 
ADPS) will also be provided by treatment group, respectively. 
Randomization strata will be collected in the Interactive Voice/Web Response 
System (IXRS) and it is defined as the average of the scores recorded in the pain 
diary, ie, Question 5 of the BPI-DPN, during the 2-week single-blind Run-in Period. 
The rounded average score will be classified as below: 
 
Moderate: [5-7]  
 
Severe: [8-9]  
A summary of the reasons for screen failure as well as the number of patients 
screened but not randomized will be produced.  No other information for screen 
failures will be presented.  
7.3 Protocol Deviations 
All-important protocol deviations leading to exclusion from the PP population (see 
Section 5.3.1) will be listed and summarized by study drug group for the mITT 
population. 
The deviations will be identified before data are unblinded. 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by 
treatment group and overall for the mITT population. Standard descriptive statistics 
will be presented for the continuous variables of: 
 
Age at time of Informed Consent (years) 
 
Weight (kg), to convert pounds (lbs) to kilograms, multiply the pound value 
by 0.45359237 
 
Height (cm), to convert inches (in) to centimeters, multiply the inches value 
by 2.54 


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 
Body mass index (BMI) (kg/m2) 
 
Sitting systolic blood pressure (BP) (mm Hg) 
 
Sitting diastolic BP (mm Hg) 
 
Pulse rate (beats per minute [bpm]) 
 
Respiration rate (breaths/min) 
 
Temperature (C), to convert Fahrenheit (F) to Celsius, (Fahrenheit value (F) 
– 32) * 5/9 
 
HADS-Depression and HADS-Anxiety subscores  
The total counts and percentages of patients will be presented for the categorical 
variables of: 
 
Age at time of Informed Consent (grouped as <75 years, ≥ 75 years) 
 
Sex 
 
Race 
 
Ethnicity 
 
Fertility status (females only) 
 
Method of contraception 
 
Baseline pain severity categorized by randomization strata (as derived using 
average pain scores collected during the 14-day Run in data) 
 
Baseline ADPS (as derived using week 2 of Run-in data) 
 
DPNP drug use (Yes, No) 
A summary of Baseline physical examination data will be presented by treatment 
group and overall for the mITT population. 
Other baseline measurements, such as laboratory evaluations and ECG, will be 
summarized by treatment group with the post-Baseline measurements. 
No formal tests of statistical significance will be performed on the demographic and 
Baseline characteristics data.   
7.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 23 (or a later version if updated during the study)].  All medical 
history will be listed, and the number and percentage of patients with any medical 
history will be summarized for the mITT population by System Organ Class (SOC) 
and Preferred Term (PT) for each treatment group and overall.   


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7.4.2 Prior and Concomitant Medications 
Medications received prior to or concomitantly with study drug will be coded using 
the World Health Organization (WHO) Drug Dictionary [Version B3 Sep2020 (or a 
later version if updated during the study)], Anatomical Therapeutic Chemical (ATC) 
Classification codes.  
Prior medications and concomitant medications are defined as follows: 
 
Prior medications are those taken prior to the first dose date of double-blind 
treatment, and have a stop date before first dose date of double-blind 
treatment. 
 
Concomitant medications are those with a start date on or after the first dose 
date of double-blind treatment, or those with a start date before the first 
dose date of double-blind treatment and a stop date on or after the first dose 
date of double-blind treatment. 
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 
Prior medications, concomitant medications taken during double-blind Treatment 
Period (excluding prohibited and rescue concomitant medications), prohibited 
concomitant medications taken during double-blind Treatment Period, and 
concomitant medications started during Safety Follow-up Period (those medications 
starting after the last dose of double-blind study drug and through the end of the 
patient's Safety Follow-up Period) will be summarized separately by treatment 
group and overall for the mITT population. 
The number and percentage of patients using each medication will be displayed 
together with the number and percentage of patients using at least 1 medication 
within each therapeutic class (ATC-Level 2), chemical subgroup (ATC-Level 4), and 
generic term. 
The percentage of patients who need rescue medication during the double-blind 
Treatment Period will be summarized descriptively by treatment group and overall 
for the mITT population. 
Prior medications, concomitant medications and rescue concomitant medications will 
be listed separately. 
7.5 Measurements of Treatment Compliance 
Percentage compliance in the double-blind Treatment Period will be calculated as: 
 
(number of actual tablets taken) * 100 / Number of tablets expected to be taken 


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Where actual tablets taken will be defined as the total number of tablets dispensed 
minus the total number of tablets returned during the double-blind Treatment 
Period. The number of tablets expected to be taken will be defined as the number 
of days within the double-blind Treatment Period. 
Percentage compliance will be summarized descriptively by treatment group and 
overall for the Safety population. 
The number and percentage of compliant patients will be presented by treatment 
group and overall for the Safety population, where compliant is defined as 
percentage compliance between 80.0% and 100.0% inclusive. The following 
percentage compliance categories will also be presented: 
 
<80.0% 
 
80.0-100.0% 
 
>100.0% 
7.6 Efficacy 
The 6-week double-blind Treatment Period will provide the main dataset for 
inferential analyses.  
All efficacy analyses will be performed on the mITT population. Supportive analyses 
will be performed on the PP population. 
The 2 pairwise comparisons of each LX9211 dose levels vs placebo will be 
performed using Dunnett’s test. 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. Adjusted and 
unadjusted p-values will be presented. 
7.6.1 Primary Efficacy Analysis 
The primary endpoint is the change from Baseline to Week 6 in ADPS, based on 
Question 5 of the BPI-DPN, the 11-point scale (0 [no pain] to 10 [pain as bad as 
you can imagine]). 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 collected by 
patients in the daily pain diary, provided that ≥5 days from that period are 
available for analysis. The post-Baseline values will be calculated by week as the 
mean value of the Question 5 for ADPS of the BPI-DPN, rated by patients each 
evening and collected during the target week period. A minimum of 4 non-missing 
data within the target week period is required for the calculation. The change from 


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Baseline values at post-Baseline weeks will be calculated as the absolute difference 
between the Baseline value and post-Baseline values, ie 
change from Baseline = post-Baseline value – Baseline value 
The ADPS calculated for each post-Baseline week until Week 6, and the change 
from Baseline in ADPS at post-Baseline weeks until Week 6 will be summarized by 
Week using standard descriptive statistics. Data from all study visits, scheduled and 
unscheduled, and from the daily pain diary will be listed. 
A restricted maximum likelihood-based, 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 BPI-DPN instrument). The MMRM model will include fixed effects of 
treatment, week, treatment-by-week interaction, the randomization stratum of 
Baseline pain severity (moderate, severe), and Baseline ADPS score as a covariate. 
An unstructured covariance structure will be used to model the within-patient error. 
Other covariance structures will be explored should convergence not be met. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom.  
The adjusted mean change in ADPS from baseline to Week 6 for each treatment 
group and the 95% confidence intervals (CIs) will be estimated in the framework of 
this model, as well as the between-group differences (comparing each LX9211 
treatment group to placebo) and the 95% CIs for the difference.  
Summarization of the inferential statistics will include the Least Squares means (LS 
means), standard error (SE) of the estimates, p-values, and 2-sided 95% CIs. 
These statistics will be provided for the within treatment group changes from 
Baseline and for the comparison of each dose level of LX9211 (100 mg/10 mg or 
200 mg/20 mg) versus placebo for the change from Baseline scores. Tabulation of 
the inferential results (CIs and p-values) will include the observed finds from the 
statistical model.  
The same analysis will be performed using the PP population. 
Figures displaying the arithmetic mean change from Baseline in ADPS by week as 
well as LS mean change by week, including Week 6, will be presented by treatment 
group for the mITT population. 
7.6.2 Secondary Efficacy Analysis 
Analysis of the secondary efficacy endpoints will be based on the mITT population. 
Descriptive statistics for all the secondary efficacy endpoints will be presented by 
treatment group and by study visit/week where appropriate. Data from all study 


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visits, scheduled and unscheduled, and from the daily pain diary will be listed. Post-
Baseline data through Week 6 will be used in the analyses where inferential 
statistics are presented, including observations occurring after discontinuation of 
study drug. Figures displaying mean change from Baseline, LS mean change at 
Week 6, and bar charts displaying proportions, will be presented by treatment 
group. 
Continuous secondary efficacy endpoints: BPI-DPN scores, measured at multiple 
time points, will be analyzed using a similar modeling strategy as for the primary 
endpoint.  
The ordinal secondary endpoint, PGIC response at Week 6, will be analyzed using 
an analysis of variance (ANOVA) model to test and estimate the treatment effect. 
Categorical secondary endpoints: the proportion of responders based on Question 5 
of BPI-DPN and the proportion of patients discontinuing study treatment due to lack 
of efficacy will be compared between treatments using a Cochran-Mantel-Haenszel 
(CMH) test stratified by the randomization factor of Baseline pain severity 
(moderate, severe). Patients with missing measurement at Week 6 will be 
considered non-responders. In general, a non-responder imputation (NRI) rule will 
be applied to assign outcomes to all study weeks with missing observations.  
The Kaplan-Meier (KM) method 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 BPI-DPN from Week 6 to Week 11.  
The qualitative patient interview substudy will be managed by a separate vendor 
(RTI-Health Solutions, Research Triangle Park, NC). The data analysis methods they 
employ will be detailed in a separate statistical analysis plan and the results will be 
reported separately by them.  
7.6.2.1 
Proportion of patients with ≥30% reduction in pain intensity 
in ADPS based on Question 5 of the BPI-DPN from Baseline to 
Week 6 
Baseline and Week 6 ADPS scores will be based on the same mean values as 
derived for the primary endpoint. The frequency and percentage of patients with 
≥30% reduction in pain intensity from Baseline at Week 6 will be presented by 
treatment group. Response/Non-response categories will be defined as: 
 
If % change from Baseline ≤ (-30)  Response 
 
If missing % change from Baseline or > (-30)  Non-response 
Where % change from Baseline = 100*(post-Baseline value – Baseline value)/ 
Baseline value. 




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substituted by Visit instead of Week. The Baseline covariate included in the model is 
the Baseline value of the dependent variable under analysis.   
In addition, the change from Baseline to Week 6 in pain interference with sleep 
based on Question 9F, rated by patients and collected each evening in the daily 
pain diary will be summarized using standard descriptive statistics and the 
treatment effect will be evaluated using a similar MMRM method as specified for the 
primary efficacy analysis of change from Baseline to Week 6 in ADPS. In this case, 
the Baseline value for the interference with sleep using Question 9F of the BPI-DPN 
is defined as the value collected at the time of the clinic visit on Day 1. The post-
Baseline values will be calculated by week as the mean value of the Question 9F of 
the BPI-DPN, rated by patients each evening and collected during the acceptable 
week period. A minimum of 4 non-missing data within the target week period is 
required for the calculation. 
7.6.2.4 
Proportion of patients discontinuing treatment due to lack of 
efficacy based on data collected for Question 5 of the BPI-DPN  
This endpoint will be derived as follows: 
1. Condition on the eCRF item if the patient stopped study treatment with reason of
Lack of Efficacy.
2. If "Yes" to the above, calculate the % change from Baseline of ADPS based on
Question 5 of the BPI-DPN during the double-blind Treatment Period, starting at
Baseline and ending on the last assessment before the patient stopped study
treatment. No minimum number of assessments is required.
3. If the derived value in #2 >= 30%, then the patient is classified as a
"responder". If otherwise (including all mITT patients), then the patient is classified
as a "non-responder".
Where % change from Baseline = 100*(last week of treatment value – Baseline 
value)/ Baseline value. 
The frequency and percentage of patients discontinuing treatment during the 
double-blind Treatment Period due to lack of efficacy will be presented by treatment 
group. Similarly, this endpoint will be analyzed as described in for Section 7.6.2.1. 
7.6.2.5 
Patient Global Impression of Change (PGIC) at Week 6 
The PGIC, a 7-point rating scale, will assess the patient's belief about their overall 
improvement experienced at the end of treatment.  
The frequency and percentages of patients within each category at Week 6 will be 
presented by treatment group. The treatment effect will be evaluated using an 


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ANOVA model with treatment and randomization stratum of Baseline pain severity 
(moderate, severe) as independent variables. Least-square means of PGIC in each 
treatment group and the difference between LX9211 and placebo for each 
comparison, along with their 95% CIs and p-value will be presented. 
7.6.2.6 
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 BPI-DPN at Week 6 
Time to loss of efficacy is defined as the time from the date of Week 6 visit to the 
date of termination of safety follow-up due to lack of efficacy. Termination of safety 
follow-up due to other reasons and death are competing risk. Patients who have 
terminated the safety follow-up due to any reason other than lack of efficacy after 
Week 6 visit or have completed the study through Week 11 will be censored at the 
date of the last ADPS assessment based on Question 5 of the BPI-DPN collected by 
patients in the daily pain dairy. 
Time to loss of efficacy (weeks) = (date of termination of safety follow-up due to 
lack of efficacy or censoring – date of Week 6 visit + 1) / 7. 
Only patients who achieved ≥30% reduction in pain intensity in ADPS based on 
Question 5 of the BPI-DPN from Baseline to Week 6 will be included in the analysis 
of time to loss of efficacy. 
Kaplan-Meier estimates and the associated 95% CIs of the median, 25th, and 75th 
percentile will be presented. The 2-sided 95% CIs will be computed using the 
log-log transformation. 
The minimum and maximum time to loss of efficacy (using censored and event 
times) will also be presented.  
The survivor function will be displayed graphically by treatment group using a KM 
curve. 
7.6.3 Sensitivity Analysis 
In the event that rescue medication is used, a supplementary MMRM model will be 
applied to the primary endpoint dataset that excludes data collected after the 
initiation of the rescue medication using the mITT population. This model will be 
parameterized in the same manner as will be used for the primary analysis of this 
endpoint.   
In addition, to assess the robustness of the MMRM analyses performed under the 
MAR assumption, and given the long half-life of LX9211, PMMs with copy reference-
based imputation methods will be applied on both datasets (with and without data 
collected after the initiation of the rescue medication) using the mITT population. 


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Methods will be adopted to estimate for both non-monotone and monotone missing 
data patterns. Imputations for the non-monotone missing data pattern will be the 
initial step. The imputation algorithm based on Monte Carlo Markov Chain 
methodology will be used assuming a MAR mechanism for the missing data; 100 
imputations will be used. Then multiple imputations will be performed to assign the 
response variable at consecutive study weeks in a sequential manner for the 
monotone missing data pattern. For this chain-based method, control-based 
imputation will be applied so that there is no direct use of observed data from the 
LX9211 treatment groups in estimating the imputation model. The method is 
derived such that it builds its imputation only on the placebo group data. 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 the Baseline pain severity (moderate, severe), and the 
continuous fixed covariate of Baseline score. The ANCOVA analysis will be 
performed at Week 6 only. Summary statistics from applying the ANCOVA model 
across the multiple imputed datasets will be combined to obtain an overall estimate 
of the treatment group differences.  
Sensitivity analyses are not planned for analyses of the secondary or other efficacy 
endpoints. 
7.6.4 Subgroup Analysis 
The primary endpoint will be analyzed using the mITT population for the following 
subgroups:  
• Baseline pain severity based on the actual stratum, moderate or severe  
• Sex, male or female  
• DPNP drug use, yes or no 
• Subjects who experience the 5 specific TEAEs, yes or no 
DPNP drug use subgroup is defined as those who took concomitant DPNP 
medications including the following: pregabalin, gabapentin, duloxetine, 
amitriptyline, venlafaxine, desvenlafaxine, valproic acid. 
The 5 specific TEAEs refer to the AEs: dizziness, headache, nausea, somnolence, 
and balance disorder, which usually occur more frequently than other AEs.  
The same MMRM covariates used for the primary endpoint analysis will be used for 
the subgroup analyses except that for the Baseline pain severity subgroup analysis, 
the randomization stratum of Baseline pain severity (moderate, severe) will not be 
included as a covariate. A forest plot of the LS Means difference and 95% CI for the 


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comparison of LX9211 versus placebo with the change from Baseline scores will be 
presented for all subgroups. 
All subgroup analyses will be exploratory. 
7.6.5 Other Efficacy Analysis 
Descriptive statistics for the other efficacy endpoints will be presented by treatment 
group and by study visit/week where appropriate. Data from all study visits, 
scheduled and unscheduled, will be listed. 
7.6.5.1 
Change from Baseline to Week 6 in the NPSI 
The NPSI, a 12-item questionnaire, assesses the different components of 
neuropathic pain syndromes (ie, spontaneous ongoing and paroxysmal pain, 
evoked pain, paresthesia/dysesthesia). 10-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. 
The total intensity score and the 5 subscores (burning spontaneous pain, pressing 
spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) will 
be calculated as: 
 
Total intensity score: Q1+Q2+Q3+Q5+Q6+Q8+Q9+Q10+Q11+Q12 
 
(Superficial spontaneous) Burning pain: Q1 
 
(Deep spontaneous) Pressing pain: (Q2+Q3)/2 
 
Paroxysmal pain: (Q5+Q6)/2 
 
Evoked pain: (Q8+Q9+Q10)/3 
 
Paresthesia/dysesthesia: (Q11+Q12)/2 
Baseline will be the data collected on Day 1 at Visit 3. The change from Baseline to 
Week 6 in total intensity score and the 5 subscores will be summarized using 
standard descriptive statistics and the treatment effect will be evaluated using an 
ANCOVA model fitted for the fixed effects of treatment, the randomization stratum 
of Baseline pain severity (moderate, severe), and the continuous fixed covariate of 
Baseline score. The ANCOVA analysis will be performed at Week 6 only. 
The adjusted mean change from Baseline to Week 6 for each treatment group and 
the 95% CIs will be estimated in the framework of this model, as well as the 
between-group differences (comparing each LX9211 treatment group to placebo) 
and the 95% CIs for the difference.  
Summarization of the inferential statistics will include the LS means, SE of the 
estimates, p-values, and 2-sided 95% CIs. These statistics will be provided for the 


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within treatment group changes from Baseline and for the comparison of LX9211 
versus placebo for the change from Baseline scores. Tabulation of the inferential 
results (CIs and p-values) will include the observed model findings.  
7.6.5.2 
Change in Question 5 of the BPI-DPN from Baseline to each 
post-Baseline visit 
Baseline will be the data collected on Day 1 at Visit 3. For this endpoint, we will use 
the Question 5 of the BPI-DPN, collected at clinic visits and visit windows defined in 
section 6.1.2. The values collected for each post-Baseline visit and the change from 
Baseline at post-Baseline visits will be summarized by visit and treatment group 
using standard descriptive statistics. The treatment effect will be evaluated using a 
similar MMRM method as specified for the primary efficacy analysis of change from 
Baseline to Week 6. 
The change from Baseline values at post-Baseline visits will be calculated as the 
absolute difference between Baseline value and post-Baseline values, ie, 
Change from Baseline = post-Baseline value – Baseline value 
7.6.5.3 
Proportion of patients with ≥30% reduction from Baseline in 
ADPS, based on Question 5 of the BPI-DPN by week 
Baseline and weekly ADPS scores will be based on the mean values as described in 
the primary efficacy analysis. Missing ADPS scores derivations at any week will be 
imputed as non-response. The frequency and percentages of patients with ≥30% 
reduction in pain intensity from Baseline, based on Question 5 of DPI-BPN collected 
each evening on the e-diary, will be presented by Week and treatment group.  
7.6.5.4 
Proportion of patients with ≥50% reduction from Baseline in 
ADPS, based on Question 5 of the BPI-DPN by week 
Baseline and weekly ADPS scores will be based on the mean values as described in 
the primary efficacy analysis. Missing ADPS scores derivations at any week will be 
imputed as non-response. The frequency and percentages of patients with ≥50% 
reduction in pain intensity from Baseline, based on Question 5 of BPI-DPN collected 
each evening on the e-diary, will be presented by Week and treatment group.  
7.6.5.5 
Cumulative distribution function of percent change in ADPS 
based on Question 5 of the BPI-DPN from Baseline to Week 6 
comparing the LX9211 treatment group to placebo  
Baseline and Week 6 ADPS scores will be based on the same mean values as 
derived for the primary endpoint. A descriptive plot of the cumulative distribution 
function of percent change from Baseline to Week 6 in ADPS based on Question 5 of 


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the BPI-DPN collected each evening on the e-diary will be presented by treatment 
group.  
% change from Baseline to Week 6 = 100*(Week 6 value – Baseline value)/ 
Baseline value. 
7.6.5.6 
Cumulative distribution function of percent change in ADPS 
based on Question 5 of the BPI-DPN from Week 6 to Week 11 
comparing the LX9211 treatment group to placebo  
Week 6 and Week 11 ADPS scores will be based on the mean weekly values as 
described in the primary efficacy analysis. A descriptive plot of the cumulative 
distribution function of percent change from Week 6 to Week 11 in ADPS based on 
Question 5 of the BPI-DPN collected each evening on the e-diary will be presented 
by treatment group. Where percent change from Week 6 to Week 11 will be defined 
as: 
% change from Week 6 to Week 11 = 100*(Week 11 value – Week 6 value)/Week 
6 value. 
7.6.5.7 
Change in Question 8 of the BPI-DPN from Baseline to each 
post-Baseline visit 
Baseline will be the data collected on Day 1 at Visit 3. For this endpoint, we will use 
the Question 8 of the BPI-DPN, collected at clinic visits and visit windows defined in 
section 6.1.2. The values collected for each post-Baseline visit and the change from 
Baseline at post-Baseline visits will be summarized by visit and treatment group 
using standard descriptive statistics. The treatment effect will be evaluated using a 
similar MMRM method as specified for the primary efficacy analysis of change from 
Baseline to Week 6. 
The change from Baseline values at post-Baseline visits will be calculated as the 
absolute difference between Baseline value and post-Baseline values, ie, 
Change from Baseline = post-Baseline value – Baseline value 
7.6.6 PK Analysis 
Ctrough values will be summarized at Weeks 2, 4, 6, and 11 using descriptive 
statistics by treatment group.  
For the PK substudy, if quantifiable plasma concentrations are available, PK 
parameters will be derived using non-compartmental techniques, and their 
summarization will be based on descriptive and graphical methods and summarized 
for each dose level.  


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Plasma concentrations and time deviation data will be presented in the data listings 
by treatment, patient, and nominal time point. Plasma concentration data will be 
summarized descriptively by dose and nominal time point. Individual and mean 
plasma concentration versus nominal time profiles will be displayed graphically. All 
PK data will be presented in the data listings. 
After the first 10 PK substudy patients complete the study, a blinded PK analysis 
may be done to confirm exposure following oral tablet administration.  
As part of the PK substudy, additional samples will be collected for possible 
biomarker analyses. The actual and change from Baseline in biomarker/target 
engagement and chemokine/cytokine levels will be summarized descriptively at 
Weeks 2, 4, 6, and 11, by treatment group. Analyses will be performed on the 
mITT population with a Baseline and at least 1 valid post-Baseline data point. 
7.7 Safety 
7.7.1 Extent of Exposure 
Duration of exposure to study drug in the double-blind Treatment Period will be 
defined as the total number of days of administration of the study drug: 
(Date of last dose of double-blind study drug taken – date of first dose of 
double-blind study drug taken) + 1 
Duration of exposure to study drug (days) in the double-blind Treatment Period will 
be summarized using descriptive statistics for each treatment group and overall for 
the Safety population.  
The number and percentage of patients randomized and exposed to the study drug 
will also be presented by double-blinded treatment duration categories for each 
treatment group and overall for the Safety population.  
 
<7 days 
 
≥7 and <14 days 
 
≥14 and <21 days 
 
≥21 and <28 days 
 
≥28 and <35 days 
 
≥35 and <42 days 
 
≥42 days 


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7.7.2 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary (Version 
23 [or a later version if updated during the study]) and classified as TEAEs as 
follows: 
 
TEAEs are events with start date and time on or after the date and time of 
first dose of study drug during the double-blind Treatment Period or single-
blinded Safety Follow-up Period, or events with start date and time prior to 
the date and time of first dose of study drug during the double-blind 
Treatment Period whose severity worsens on or after the date and time of 
first dose of study drug during the double-blind Treatment Period or single-
blind Safety Follow-up Period.  
All AE data will be listed by treatment group with TEAE status flagged in the listing.  
In addition, listings of treatment-emergent SAEs, TEAEs leading to discontinuation 
of study drug during the double-blind Treatment Period and TEAEs resulting in 
death will be produced. 
Summary tables of TEAEs by treatment group and overall will be produced for the 
double-blind Treatment Period and the single-blind Safety Follow-up Period for the 
Safety population. 
The relationship between an AE and study drug is assessed as definite, probable, 
possible, unlikely, or not related.  A drug-related AE is an AE considered by the 
investigator as definitely, possibly, or probably related to study drug or with 
unknown/missing relationship to study drug.   
An overview table will summarize the number and percentage of patients with at 
least 1 of the following TEAEs, where patients with more than 1 TEAE in a particular 
category are counted only once in that category: 
 
Any TEAE  
 
Drug-related TEAE 
 
Severe drug-related TEAE 
 
Treatment-emergent SAEs  
 
Drug-related treatment-emergent SAEs 
 
TEAE leading to study drug discontinuation  
 
Drug-related TEAE leading to study drug discontinuation 
 
TEAE leading to death 
The number and percentage of patients reporting each AE will be summarized by 
SOC and PT for the Safety population. Tables will be sorted alphabetically by SOC. 


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Preferred terms will be sorted by descending overall total. The following summaries 
will be produced: 
 
TEAEs by SOC and PT 
 
TEAEs by PT 
 
TEAEs reported by at least 5% of patients in any treatment group, by SOC 
and PT 
 
TEAEs related to study drug, by SOC and PT 
 
TEAEs related to study drug, by PT 
 
TEAEs by relationship (related, or unrelated) to study drug, by SOC and PT 
 
TEAEs by severity, by SOC and PT 
 
TEAEs related to study drug by severity, by SOC and PT 
 
TEAEs causing discontinuation from study drug, by SOC and PT 
 
TEAEs related to study drug causing discontinuation from study drug, by SOC 
and PT 
 
Treatment-emergent SAEs, by SOC and PT 
 
Treatment-emergent SAEs related to study drug, by SOC and PT   
 
TEAEs leading to death, by SOC and PT 
 
SAEs during Screening or Run-in Periods leading to death, by SOC and PT 
 
The five Specific TEAEs and time to onset, by PT 
 
The five Specific TEAEs and AE duration, by PT 
 
The five Specific TEAEs and DPNP drug use, by PT  
 
The five Specific TEAEs and age category, by PT 
 
The five Specific TEAEs and sex, by PT 
 
The five Specific TEAEs and race, by PT 
 
The five Specific TEAEs and country, by PT 
In the above summaries, patients with more than 1 AE within a particular SOC are 
counted only once for that SOC. Similarly, patients with more than 1 AE within a 
particular PT are counted only once for that PT. For summaries by severity, patients 
with multiple AEs within a particular SOC or PT will be counted under the category 
of their most severe AE within that SOC or PT. In a similar manner, summaries 
prepared by drug relationship will select the event with the greatest degree of 
relationship when a patient reports multiple occurrences of the same event.  




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All laboratory data will be reported in International System of Units and 
conventional units. Out-of-reference-range values will be flagged as high (H) or low 
(L) in the listings.  
For analysis purposes, values preceded by a “<” or a “>” sign (ie, those below or 
above the limits of quantification) will be considered equal to the lower or upper 
limit of quantification, respectively. 
Laboratory data will be summarized by visit using standard descriptive statistics by 
treatment group and overall for the Safety population. Changes from Baseline will 
also be summarized. 
For hematology and serum chemistry, shift tables presenting movement in and out 
of reference range from Baseline to each scheduled post-Baseline visit will be 
provided by treatment group and overall for the Safety population. Percentages will 
be based on the number of patients with both non-missing Baseline and relevant 
post-Baseline results. 
For each laboratory analyte, the Baseline value will be defined as last scheduled or 
unscheduled value collected prior to the first dose of study drug during the 
double-blind Treatment Period. Assessments carried out on the day of first study 
drug administration are considered to have taken place before the study drug 
administration, if the corresponding times have not been recorded.  
7.7.4 Vital Signs 
The following vital signs and weight (kg) will be listed and summarized by 
treatment group and visit. 
 
Systolic and diastolic BP (mm Hg) 
 
Pulse rate (beats/min [BPM]) 
 
Respiration rate (breaths/min) 
 
Body temperature (°C) 
Vital signs and weight data and changes from Baseline in vital signs and weight will 
be summarized by visit using standard descriptive statistics by treatment group and 
overall for the Safety population.  The Baseline value will be defined as last 
scheduled or unscheduled value collected prior to the first dose of study drug 
during the double-blind Treatment Period. Assessments carried out on the day of 
first study drug administration are considered to have taken place before the study 
drug administration, if the corresponding times have not been recorded.  


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In addition, for vital signs, shift from Baseline (normal vs. abnormal, not clinically 
significant vs. abnormal, clinically significant) at each post-Baseline visit will be 
provided by treatment group and overall for the Safety population.  
7.7.5Electrocardiograms 
The following quantitative ECG measurements will be taken during the study: 
 
Heart rate (beats/min) 
 
PR interval (msec) 
 
QRS duration (msec) 
 
QT interval (msec) 
 
QTc interval (msec) 
 
Fridericia corrected QT (QTcF) interval (msec) 
 
RR interval (msec) 
The ECG measurements and changes from Baseline in ECG will be listed and 
summarized by visit using standard descriptive statistics by treatment group and 
overall for the Safety population. 
The Baseline value will be defined as last scheduled or unscheduled value collected 
prior to the first dose of study drug during the double-blind Treatment Period.  
Assessments carried out on the day of first study drug administration are 
considered to have taken place before the study drug administration, if the 
corresponding times have not been recorded.  
An overall Investigator assessment of ECG will be provided (categories “normal”, 
“abnormal, not clinically significant”, “abnormal, clinically significant”, 
“indeterminate”, “not evaluable”, and “unknown”). 
The Investigator assessment will be listed and the number and percentage of 
patients within each assessment category will be tabulated by visit, treatment 
group and overall for the Safety population. Shifts from Baseline (normal vs. 
abnormal, not clinically significant vs. abnormal, clinically significant) at each post-
Baseline visit will be presented by treatment group and overall for the Safety 
population. 
7.7.6 Physical Examination 
Physical examination results (normal/abnormal) and details of abnormalities will be 
listed for each patient. 


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7.8 Interim Analysis 
Enrollment will not be temporarily halted while data for the interim analysis is being 
reviewed. 
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 141 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, the Week 6 data 
will be used in the analysis.  
To maintain continuous blinding and study integrity, analysis will be conducted by a 
separate unblinded team. Details of the unblinding process for the interim analysis 
and the resulting controlled dissemination of interim analysis data will be detailed in 
the Data Monitoring Committee (DMC) Charter document. 
A non-binding futility boundary will be used to test treatment group differences in 
the primary endpoint at 50% 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 a per comparison Type I error rate = 0.0141, assuring 
an overall α= 0.025 (or a two-sided α = 0.05) for the two LX9211 versus placebo 
comparisons. Use of this beta spending function for futility testing is conservative 
and results in cumulative beta error rates of 0.015 and 0.197 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).  
In addition to the above planned interim analysis, 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 based on fractions of patient accrual (eg, 25% 
and 75% of the sample size).  A final DMC meeting is planned when the study 
completes. The DMC will develop a charter and establish criteria 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 an 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 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
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summaries of serious adverse events on a monthly basis to review potential 
emerging safety trends. 
8. Changes in Planned Analysis 
For NPSI, an ANCOVA model will be used to evaluate the treatment effect instead of 
a MMRM since the statistical analysis is conducted for the change scores at Week 6 
only. 
9. Data Issues 
Not applicable. 
10. 
References 
Cleeland CS The Brief Pain Inventory User Guide 1991 
 
Westfall PH, Tobias RD, Rom D, Wolfinger RD, Hochberg Y. Multiple Comparisons 
and Multiple Tests Using the SAS® System, Cary, NC SAS Institute Inc., 1999: 
141-142. 
11. 
Appendices 
Appendix 1: 
Document History 
Document Version, Status, Date
Summary/Reason for Changes
Version 1, Final, 23 FEB 2021 
Not applicable; the first version 
Version 2, Final, 23 SEP 2021 
Update according to protocol amendment 4 
Version 3, Final, 07 JUN 2022 
Update according to dry run comments 
 
 
 


 
 
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Appendix 2: 
Schedule of Events 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
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Appendix 3: 
Brief Pain Inventory – DPN (BPI-DPN) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
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Labcorp Study ID: 000000198624 
 
 
 
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Lexicon Pharmaceuticals, Inc. 
Protocol ID: LX9211.1.201-DPN 
 
Labcorp Study ID: 000000198624 
 
 
 
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Appendix 4: 
Patient Global Impression of Change (PGIC) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Final v3.0 
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Labcorp Study ID: 000000198624 
 
 
 
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Appendix 5: 
Neuropathic Pain Symptom Inventory (NPSI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
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Statistical Analysis Plan Final v3.0 
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Statistical Analysis Plan Final v3.0 
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Labcorp Study ID: 000000198624 
 
 
 
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Appendix 6: 
Hospital Anxiety and Depression Scale (HADS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan Final v3.0 
Lexicon Pharmaceuticals, Inc. 
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Labcorp Study ID: 000000198624 
 
 
 
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2 
TABLE OF CONTENTS 
1 
STUDY BACKGROUND AND DESIGN ............................................................ 3 
2 
ANALYSIS OBJECTIVES ................................................................................. 4 
2.1 
Background Information and Prestudy Experiences ..................................................... 4 
2.2 
Experiences During Treatment ..................................................................................... 5 
3 
ANALYSIS DATA SET AND SOFTWARE ........................................................ 5 
3.1 
Data Transcription ........................................................................................................ 6 
4 
ANALYTICAL METHODS ................................................................................. 6 
4.1 
Codebook Development ............................................................................................... 6 
4.2 
Transcript Coding ......................................................................................................... 6 
4.3 
Qualitative Data Analysis .............................................................................................. 6 
4.4 
Quantitative Data Analysis ........................................................................................... 7 
5 
REPORTING ...................................................................................................... 9 
6 
REFERENCES ................................................................................................... 9 
APPENDIX A. FINAL INTERVIEW GUIDE ......................................................... A-1 
APPENDIX B. ATLAS CODEBOOK (DRAFT 1; 17 FEBRUARY 2020) ............. B-1 
APPENDIX C. ANTICIPATED TABLE SHELLS FOR FINAL REPORT ............. C-1 
 
 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
3 
RTI Health Solutions (RTI-HS) is pleased to deliver this qualitative analysis plan for the 
interviews planned with patients enrolled in the LX9211-102 DPN1 (RELIEF-DPN 1) clinical 
trial in the United States. The purpose of this document is to provide a detailed and 
comprehensive description of the qualitative and, when applicable, quantitative analytic 
methods that will be used to summarize the patient interview data. 
1 STUDY BACKGROUND AND DESIGN 
Lexicon Pharmaceuticals, Inc. (Lexicon) is conducting a phase 2 clinical trial1 to evaluate the 
efficacy of LX9211, an oral product for the treatment of diabetic peripheral neuropathic pain 
(DPNP). As part of the clinical trial, RTI-HS, in collaboration with Lexicon, plans to conduct 
qualitative interviews with a subset of patients from the study that will supplement the 
patient-reported data gathered in the clinical trial and help to further understand and 
describe patients’ experiences with DPNP and LX9211. 
Data collected during in-depth qualitative interviews will provide a deeper understanding of 
patients’ perceptions of and experiences with DPNP and LX9211 and the relevance and 
clinical meaningfulness of symptom improvements (e.g., reduction in pain) to patients. The 
semistructured telephone interviews will be conducted with a subset of English-speaking 
clinical trial participants (up to 60 patients) who complete or terminate early from the 
6-week double-blind treatment phase of the trial. 
The overall objective of the qualitative interviews is to gain a more comprehensive 
understanding of patient experiences with DPNP and LX9211 treatment by collecting 
information that may not be captured adequately via traditional clinical outcomes 
assessments. Specifically, the objectives of the qualitative interviews are to obtain a better 
understanding of the perspectives of patients with DPNP on the following: 
 
Disease-related burden 
 
Impact of the disease on patients’ lives before starting the clinical trial 
 
Satisfaction with DPNP treatments used prior to the clinical trial 
 
Most important to treat and most bothersome aspects of DPNP 
 
Expectations of study drug 
 
General experiences with study drug 
 
Benefits and impact of those benefits 
 
Importance of improvements experienced during the clinical trial (if experienced) 
 
Impact of the study drug on daily life/functioning 
 
1 A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of LX9211 in the Treatment of Diabetic Peripheral Neuropathic Pain 
(Protocol Number LX9211.201) 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
4 

How well the study drug addresses most important/bothersome symptoms

Satisfaction with and reason(s) for satisfaction or dissatisfaction (if applicable) with
the study drug
2 ANALYSIS OBJECTIVES 
Analysis of the interview data will focus on answering the research questions (described in 
Sections 2.1 and 2.2), which expand on the study objectives described above and form the 
conceptual basis for the interview guide (Appendix A). Additionally, selected research 
questions will be further analyzed within the context of clinical trial treatment groups (to be 
provided by Lexicon). This process and the anticipated analysis by treatment group are 
further described in Section 4.3. 
Analysis for the initial draft of the summary report will be based on blinded data. The final 
summary report will present the analysis of unblinded data (LX9211 treatment groups and 
placebo). 
2.1 
Background Information and Pre-Study Experiences 

Describe study participants (sex, age, age when first diagnosed with diabetes, age at
onset of DPNP symptoms)

Summarize satisfaction with DPNP treatment(s) and difficulty managing DPNP before
clinical trial

Identify DPNP symptoms2 before the clinical trial
–
Spontaneous descriptions of pain/sensations

The presence of specific symptoms/sensations (i.e., numbness/dead feeling,
tingling/pins and needles, weakness, very sensitive/heightened sensitivity to
touch and pressure) will be probed (if not spontaneously reported by the
interview participant) per the interview guide (Appendix A)
–
Location of DPNP and severity of DPNP in each location
–
Most bothersome symptom(s)/sensations

Describe the impact of DPNP on patients before participating in the clinical trial
–
What impacts associated with DPNP (e.g., on daily activities, mobility,
mood/emotions, self-care, sleep) are reported most frequently by patients?

The presence of specific impacts will be probed (if not spontaneously reported
by interview participants) (daily activities at work and/or home, mobility,
mood/emotions, self-care, sleep)
2 List of symptoms anticipated are included in interview guide and codebook. Note: codes will be modified as 
needed based on content reported in patient interviews. 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
5 
– 
What about DPNP and/or its treatment is most bothersome to the interview 
participants (e.g., if the most bothersome issues are symptom related or 
treatment related)? 
 
Identify interview participants’ expectations of treatment 
– 
Reasons for participating in the clinical trial 
– 
What symptoms do interview participants most want to see treated with the study 
drug? 
 
Perceived importance of each symptom improvement 
2.2 
Experiences During Treatment 
 
What improvements did interview participants see in their DPNP symptoms during 
clinical trial? 
– 
The presence of specific symptoms will be probed (if not spontaneously reported 
by interview participants) per the interview guide (Appendix A) 
 
If improvements were noticed, summarize when interview participants first reported 
experiencing these changes and which change was noticed first (if more than one 
improvement) 
 
Summarize the improvements identified as the most important as well as importance 
ratings 
 
Summarize the impact of improvements noticed as a result of study drug 
– 
Specific impacts will be probed (if not spontaneously reported by the interview 
participant) (daily activities at work and/or home, mobility, mood/emotions, self-
care, sleep) 
 
Summarize the drug’s ability to treat those symptoms identified as the most 
bothersome or important to treat 
 
Assess interview participants’ clinical trial treatment satisfaction 
– 
What factors or considerations influenced satisfaction ratings? 
– 
How many interview participants expressed a desire to continue taking the study 
drug and why? 
– 
How many interview participants expressed a preference for the study drug over 
previous medication(s) for DPNP and why? 
3 ANALYSIS DATA SET AND SOFTWARE 
Interview data analysis will be performed using anonymized interview transcripts. The 
majority of the planned analyses will be conducted using ATLAS.ti version 7.5 qualitative 
data analysis software. Other software will also be used as appropriate for the generation of 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
6 
descriptive analyses, including SAS for Windows (version 9.4 or higher) and Microsoft Excel 
2017. 
3.1 
Data Transcription 
Upon interview completion, each interview will be transcribed and prepared in a 
standardized, quality-checked manner with each transcription undergoing multiple levels of 
review. First, the interviews will be transcribed by a qualified medical transcriptionist. All 
personally identifying data will be removed from the transcript at this stage. Next, a second 
medical transcriptionist will review the draft, typed transcript while listening to the recorded 
interview and will implement any necessary corrections or edits. A review of the transcripts 
by the technical team will occur during the coding process. Before delivery to the client, all 
transcripts will also be reviewed by RTI-HS editors to check for any spelling and/or 
punctuation errors prior to finalization of the transcripts for analysis. 
4 ANALYTICAL METHODS 
4.1 
Codebook Development 
Thematic analysis methods will be used to analyze the interview transcript data (Braun and 
Clarke, 2006). An initial coding framework (Draft 1; 25 February 2020) based on the final 
interview guide is presented in Appendix B. Finalization of the codebook will be an iterative 
process based on the interview data. Specifically, it is anticipated that new codes will be 
added to the codebook as new concepts (e.g., potential DPNP symptoms, impacts) are 
identified during transcript review. 
4.2 
Transcript Coding 
Each interview transcript will be coded in accordance with the codebook. To ensure 
consistency in coding, approximately 10% (n = 6) of the transcripts will be double coded, 
meaning that two different people will code these transcripts. Any discrepancies found 
between these codes will be resolved by the two coders and in discussion with the Project 
Director. 
4.3 
Qualitative Data Analysis 
Standardized qualitative research methods will be applied during the conduct of each 
interview (Willis, 1999; Boeije, 2002). Specifically, immediately following the receipt of each 
transcript, RTI-HS will begin the thematic analysis process. Using field notes and 
transcripts, thematic analysis methods will be used to analyze the interview transcript data. 
Important concepts and dominant trends will be identified in each interview. These 
individual interview results will then be compared across interviews to allow for the 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
7 
generation of themes or patterns in interview participants’ responses. As noted above, the 
qualitative data analyses will be facilitated through the use of ATLAS.ti and other software 
(e.g., Microsoft Excel). 
4.4 
Quantitative Data Analysis 
The ATLAS codebook (Appendix B) includes codes to facilitate quantitative summarization 
(descriptive analysis) of interview participants’ reports related to DPNP symptoms and 
impacts. In the analysis and reporting of frequencies or counts of these concepts, only 
unique mentions per code per patient will be counted. 
 
Frequency and percentage of interview participants reporting each DPNP 
symptom/sensation before the clinical trial 
 
Frequency and percentage of interview participants reporting pain in specific 
locations (e.g., hands, arms, feet) 
 
Frequency and percentage of interview participants reporting a specific location 
(e.g., hands, arms, feet) as the location where their pain is most severe 
 
Frequency and percentage of interview participants reporting a specific location 
(e.g., hands, arms, feet) as the most bothersome 
 
Frequency and percentage with which each symptom or sensation was reported as 
the most bothersome 
 
Frequency and percentage of DPNP impacts reported before the clinical trial 
 
Frequency and percentage of a DPNP symptom being reported as the most important 
to treat prior to starting the clinical trial 
Descriptive statistics (frequencies, mean, range) will be computed for the following 
assessments for the overall interview sample and by treatment assignment, as provided by 
Lexicon (LX9211 treatment [10 mg or 20 mg] or placebo): 
 
Clinical and demographic characteristics reported (e.g., sex, age, age of diagnosis of 
diabetes, age at onset of DPNP symptoms) 
 
Frequency and percentage of interview participants reporting specific symptom 
improvements during the clinical trial 
 
Frequency and percentage of improvement in a symptom (reported during the 
clinical trial) being reported as the most important improvement 
 
Frequency and percentage of specific impacts of symptom improvements being 
reported across interview participants 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
8 
 
Satisfaction with treatment before and after the clinical trial 
– 
0 = not at all satisfied, 1 = a little satisfied, 2 = moderately satisfied, 
3 = quite satisfied, and 4 = very satisfied 
 
Difficulty managing DPNP before the clinical trial 
– 
0 = not at all difficult, 1 = a little difficult, 2 = moderately difficult, 
3 = quite difficult, 4 = very difficult 
 
Ratings for how important it would be for a treatment to improve specific symptoms 
– 
1 = not at all important, 2 = a little important, 3 = moderately important, 
4 = very important, 5 = extremely important 
 
Importance ratings for any symptom reported as improved during the clinical trial 
– 
1 = not at all important, 2 = a little important, 3 = moderately important, 
4 = very important, 5 = extremely important 
 
Preference of study drug or a previous medication 
 
Desire to continue study drug (yes/no) 
As noted previously, analysis will initially be conducted on blinded data, and will be 
presented in aggregate in the first draft of the summary report (Section 5). After provision 
of the treatment assignment data (from Lexicon) RTI-HS will conduct analyses by treatment 
group. 
For the analysis correlating/examining the relationship between selected interview 
(e.g., treatment satisfaction, desire to continue on treatment and treatment preference) 
and clinical trial results (e.g., baseline average daily pain score and the change in average 
daily pain score; up to 5 variables, to be decided in collaboration with Lexicon), it is 
anticipated that Lexicon will provide RTI-HS with clinical data in one of two formats: 
 
Clinical Data Interchange Standards Consortium (CDISC)-compliant data sets in SAS 
Analysis Data Model (ADaM) format 
OR 
 
A SAS data set organized as one row per patient and structured such that a variable 
measured at multiple time points is represented as multiple variables (columns) per 
patient (rather than multiple observations or rows per patient). 
Lexicon will also provide RTI-HS with codebooks and any other relevant data documentation 
and will be available to answer questions regarding the data and appropriate analysis 
variables. 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
9 
5 REPORTING 
RTI-HS will prepare and submit to Lexicon a summary report describing the interview 
methods and results. The draft report will be prepared using blinded data; the final 
summary report will incorporate treatment assignment provided by Lexicon. Specifically, 
this report will include results pertaining to each of the research questions outlined in 
Section 2. Tables will be prepared to summarize the results of the descriptive analyses 
outlined in Sections 4.3 and 4.4. Table shells for use in the final report are provided in 
Appendix C (these same shells will be used to inform the draft report; however, data will be 
presented in aggregate on blinded data). 
Although adverse event elicitation and description are not an objective of this study, any 
adverse events (as described in the study procedure guide) reported in the context of the 
patient interviews will be summarized in tabular format in the summary report. Sites will be 
notified of any reported adverse events, and all reported events will be reconciled by 
Lexicon or their designee with the clinical trial safety database to ensure no new signals 
were detected. 
6 REFERENCES 
Boeije HA. Purposeful approach to the constant comparative method in the analysis of 
qualitative interviews. Qual Quant. 2002;36:391-409. 
Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3(2):77- 
101. 
Willis G. Cognitive interviewing: a "how to" guide. Research Triangle Park, NC: RTI 
International; 1999. 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
A-1 
Appendix A. Final Interview Guide 
 
 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
A-2 
Phase 2 Clinical Trial of LX9211 for the Treatment of Diabetic 
Peripheral Neuropathic Pain 
Exit Interviews 
I. 
Introduction 
~ 5 min 
[Introduce interviewers; confirm participant’s first name before starting the interview; 
confirm with the participant that now is still a convenient time for the interview—if the 
patient expresses any concerns or hesitancy (or based on the interviewer’s judgment), 
reschedule the interview.] 
[Remind participant about key elements listed in consent form] 
The purpose of today’s interview is to learn more about your experiences, specifically: 
 
Your experiences with diabetic peripheral neuropathic pain (we will refer to this 
as neuropathic pain) and its treatments 
 
Any expectations about the study drug you had before starting the clinical trial 
 
Your experiences with the drug you received in the clinical study and 
 
Any improvements you may have noticed from the study drug. 
The information you provide today will be used to help the study sponsor better 
understand people’s experiences with nerve pain associated with their diabetes and 
their experiences with the study drug. 
We invite you to speak openly and share your opinions freely. We value everything you 
tell us and be assured that there are no wrong answers. 
This information is in the study consent form, but as a reminder… 
 
Our discussion today is scheduled to take about 60 minutes. 
 
We are audio recording and transcribing all interviews to make sure we do not 
miss any important information. Also, this will help us write a summary report. 
 
The transcripts from the interviews will be given to the study sponsor at the end 
of this study, with only your study ID number attached. All names mentioned 
during the interview will be removed from the transcript. 
 
Finally, please remember that today’s interview is completely voluntary; you can 
take a break or end the discussion at any time. 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
A-3 
If you report a side effect during today’s call that is potentially related to the study drug, I 
will have to notify your clinical site. They will determine whether your study doctor needs 
to follow-up with you for more information. 
Additionally, the clinical study sponsor will share limited data from the clinical study with 
us so that we can better understand experiences of participants in the study. For 
example, they may share with us scores from some of the questionnaires you 
completed as part of the clinical study and your responses to certain questions about 
how well the drug worked for you. 
Do you have any questions before we begin? [Answer any questions.] 
START RECORDING 
[Once the recording starts, the interviewer will verbally record the participant’s 
clinical study ID and interview date for the audio] 
We have started the audio recording. Do we have your permission to continue 
with the interview? 
 Yes   
CONTINUE 
 No  
 
STOP INTERVIEW 
II. 
Background Information and Prestudy Experiences 
~ 10 min 
[RECORD] 
First, I would like to learn a little more about you and about your experiences with 
diabetic neuropathic pain 
1. 
How old are you? _________ years [Confirm from recruitment grid] 
2. 
About how old were you when you were diagnosed with diabetes? 
_________ (years old) 
3. 
About how long ago did you start to experience neuropathic pain 
associated with your diabetes__________ (months/years) 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
A-4 
4. 
Before starting the study, in your own words, what did this pain feel like? 
[If not reported spontaneously probe for the presence of the following] 
a) Numbness/dead feeling 
b) Tingling/pins and needles 
c) Weakness 
d) Very sensitive/heightened sensitivity to touch and pressure 
5. 
Before starting the study, where did you experience your neuropathic 
pain? 
a) Hands 
b) Arms 
c) Feet 
d) Legs 
e) Other _________________________ 
6. 
[If experienced in more than 1 location] Were there specific locations where 
the pain was more severe than others before starting the clinical trial? [If 
yes] Which ones? 
7. 
[If more than one symptom experienced] Were specific symptoms more 
bothersome to you than others before starting the clinical trial? [If 
necessary, remind patient of the symptoms reported in Q4]. [If yes] Which 
ones? 
8. 
Before starting the clinical trial, overall, how satisfied were you with your 
neuropathic pain treatment(s)? 
 0 = Not at all satisfied 
 1 = A little satisfied 
 2 = Moderately satisfied 
 3 = Quite satisfied 
 4 = Very satisfied 
 
Tell me why you selected that answer. 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
A-5 
9. 
Before starting the clinical trial, how easy or hard was it for you to manage 
your neuropathic pain? 
 0 = Not at all difficult 
 1 = A little difficult 
 2 = Moderately difficult 
 3 = Quite difficult 
 4 = Very difficult 
 
Tell me why you selected that answer. 
III. Prestudy Impact/Burden Of DPNP 
~ 10 min 
10. 
Before starting the study, what impact did diabetic neuropathic pain have 
on your life, if at all? [Allow for spontaneous reports of impacts. Specific 
probes are listed below] 
11. 
How, if at all, did this pain affect your life before the study? [Probe for 
impact areas if not spontaneously reported]… 
a) Daily activities? What kinds of daily activities were impacted? 
 Are there things you could not do because of the pain that you wanted to 
do? 
b) Mobility (e.g., walking; using stairs; getting up/down from chair or toilet) 
c) Mood/emotions (e.g., depressed mood, anxiety, irritability, anger) 
d) Self-care (e.g., bathing or dressing self; using utensils) 
e) Sleep 
12. 
What was it about your neuropathic pain or its treatment that bothered you 
the most before starting the study? [Probe to understand if most 
bothersome issues are issues related to the pain and/or are treatment-
related] 
Why does [repeat most bothersome issue] bother you? 


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IV. Prestudy Treatment Expectations  
~ 5 min 
13. 
Thinking back to before you started the clinical trial, what were some of the 
reasons you decided to participate in the trial? 
a) Were some reasons more important to you than others? [If yes] Which 
ones? 
14. 
Before starting the clinical trial, were there specific symptoms/problems 
that you most wanted the study drug to help? Which ones? Why? 
15. 
How important to you would it be for a neuropathic pain treatment to 
improve? [Use the 1-to-5 rating scale below for each symptom the patient 
reports – examples listed below. Repeat scale as often as needed] 
 1 = Not at all important 
 2 = A little important 
 3 = Somewhat important 
 4 = Very important 
 5 = Extremely important 
a) Pain 
b) Numbness 
c) Tingling/pins and needles 
d) Weakness 


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V. 
During Study Experiences 
~ 15 min 
Now I would like to talk to you about your experiences during the clinical study. 
So, thinking about your experiences while you were taking the study drug…. 
16. 
What were your overall impressions of the study drug? 
17. 
What improvements, if any, did you notice while taking the study drug? 
[Ask the participant to describe each improvement reported. Allow for 
spontaneous reports of improvements in symptoms/pain. If not already 
mentioned, probe to see if the symptoms experienced before the study 
improved, if so, have the participant describe the improvement and rate the 
importance of the improvement below] 
18. 
Please rate the importance of the improvement in [SYMPTOM from Q4] on 
the following scale (from 1 to 5). I will read the scale to you: 
 1 = Not at all important 
 2 = A little important 
 3 = Moderately important 
 4 = Very important 
 5 = Extremely important 
Why? 
[If improvements noticed] How soon after receiving the study drug did you notice 
these improvements? 
a) What, specifically, did you notice first? 


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VI. Impact of Improvements [If no improvements, skip to Q 23] ~ 10 min 
19. 
Thinking about the improvements [Refer back to improvements listed 
above] you noticed as a result of the study drug, which are the most 
important to you? Why? 
20. 
Thinking about the improvements you have seen from the study drug; how 
did these improvements affect you in your daily life? [Allow for 
spontaneous responses] 
[If not reported spontaneously] How, if at all, did these improvements affect 
your… 
a) Daily activities? What kinds of daily activities were impacted? 
 
Are there things you can now do or do better because of improvements in 
neuropathic pain? 
b) Mobility (e.g., walking; using stairs; getting up/down from chair or toilet) 
c) Mood/emotions (e.g., depressed mood, anxiety) 
d) Self-care (e.g., bathing or dressing self; using utensils) 
e) Sleep 
21. 
You mentioned that that [insert response from Q14] bothered you the most. 
How, if at all, did the study drug improve these issues? 
VII. Treatment Satisfaction and Preference 
~ 5 min 
22. 
Overall, how satisfied are you with the study drug as a treatment for 
diabetic neuropathic pain? 
 0 = Not at all satisfied 
 1 = A little satisfied 
 2 = Moderately satisfied 
 3 = Quite satisfied 
 4 = Very satisfied 
a) Tell me why you selected that response. [Probe to better understand what 
specifically influenced participant’s response to this question] 


Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
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23. 
Thinking about the study drug compared to the neuropathic pain 
treatment(s) you had tried before the study, which did you prefer: 
 Study drug 
 A previous medication 
Why? 
24. 
Would you have continued taking the study drug if you could have? 
 Yes 
 No 
Why? 
VIII. Summing Up 
~ 2 min 
Thank you for sharing your thoughts and experiences with us today. This information is 
very valuable and will help the study sponsors understand more about patients with 
diabetic neuropathic pain and the impact of the study drug. 
Is there anything else you think we should know (i.e., anything we should have asked 
but didn’t)? 
[Thank participant again and end call] 


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Appendix B. ATLAS Codebook 
(Draft 1; 17 February 2020) 










Interviews to Assess the Patient Experience With LX9211 for Treatment of DPNP: Qualitative Analysis Plan 
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Appendix C. Anticipated Table 
Shells for Final Report