Efficacy, Safety, and PK of LX9211 in Participants With D... | NCT04455633

ID	Type	Description	Link
LX9211.201	Other Identifier	Lexicon Pharmaceuticals

Efficacy, Safety, and PK of LX9211 in Participants With D... | NCT04455633 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	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.	Drug: LX9211 Matching Placebo
LX9211 100 mg/10 mg	Experimental	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.	Drug: LX9211
LX9211 200 mg/20 mg	Experimental	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.	Drug: LX9211

Name	Type	Description	Arm Group Labels	Other Names
LX9211	Drug	Oral Tablets	LX9211 100 mg/10 mg LX9211 200 mg/20 mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline to Week 6 in ADPS as Measured by the Numerical Rating Scale	ADPS is based on question 5 of Brief Pain Inventory (BPI)-short form for Diabetic Peripheral Neuropathy (BPI-DPN) and is assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average." on a scale of 0 to 10: 0=no pain, and 10=pain as bad as you can imagine. Higher ADPS scores indicate higher pain intensity. Negative change from baseline indicates improvement.	Baseline (Week 2 of the Run-in period) to Week 6

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants With ≥30% Reduction in Pain Intensity in ADPS From Baseline to Week 6	ADPS is based on question 5 of BPI-DPN and assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average." on a scale of 0 to 10 where 0 = No Pain and 10 = pain as bad as you can imagine. If % change from Baseline ≤ (-30) then participant was considered a Responder and if missing % change from Baseline or >(-30) participant is considered a Non-responder. Percentage of participants who were responders (who achieved ≥30% reduction in pain intensity in ADPS from Baseline to Week 6) are reported.

Contacts/Locations Module

Name	Affiliation	Role
Suma Gopinathan, PhD	Lexicon Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Lexicon Investigational Site		Mobile	Alabama	36608	United States
Lexicon Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
35257579	Derived	Luo G, Chen L, Kostich WA, Hamman B, Allen J, Easton A, Bourin C, Gulianello M, Lippy J, Nara S, Maishal TK, Thiyagarajan K, Jalagam P, Pattipati SN, Dandapani K, Dokania M, Vattikundala P, Sharma V, Elavazhagan S, Verma MK, Das ML, Wagh S, Balakrishnan A, Johnson BM, Santone KS, Thalody G, Denton R, Saminathan H, Holenarsipur VK, Kumar A, Rao A, Putlur SP, Sarvasiddhi SK, Shankar G, Louis JV, Ramarao M, Conway CM, Li YW, Pieschl R, Tian Y, Hong Y, Ditta J, Mathur A, Li J, Smith D, Pawluczyk J, Sun D, Yip S, Wu DR, Vetrichelvan M, Gupta A, Wilson A, Gopinathan S, Wason S, Bristow L, Albright CF, Bronson JJ, Macor JE, Dzierba CD. Discovery of (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally Active Adaptor Protein-2 Associated Kinase 1 Inhibitor in Clinical Trials for the Treatment of Neuropathic Pain. J Med Chem. 2022 Mar 24;65(6):4457-4480. doi: 10.1021/acs.jmedchem.1c02131. Epub 2022 Mar 8.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Sep 9, 2021	May 22, 2025

Type	Comment	Reasons
Adverse Event		FG0004 subjects FG00117 subjects FG00228 subjects
Subject Choice Unrelated to Adverse Event/Serious Adverse Event		FG0002 subjects FG0012 subjects FG0026 subjects
Other, not specified		FG0000 subjects FG0012 subjects FG0022 subjects

Follow up Period (Weeks 7 to 11)

Type	Comment	Milestone Data
STARTED	Some of the participants who discontinued in double blind treatment period were also included in safety follow-up.	FG000104 subjects FG00199 subjects FG00292 subjects
COMPLETED		FG000103 subjects FG00199 subjects FG00292 subjects
NOT COMPLETED		FG0001 subjects FG0010 subjects FG0020 subjects

Type	Comment	Reasons
Other, not specified		FG0001 subjects FG0010 subjects FG0020 subjects

Arm/Group Information

ID	Title	Description
BG000	Placebo	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, 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.
BG001	LX9211 100 mg/10 mg	Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 mg tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablet, 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.
BG002	LX9211 200 mg/20 mg	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.
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title	Denominators	Categories
	ParticipantsBG000107 ParticipantsBG001106 ParticipantsBG002106 ParticipantsBG003

Sex: Female, Male

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000107 ParticipantsBG001106 ParticipantsBG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG000107 ParticipantsBG001106 ParticipantsBG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title	Denominators	Categories
American Indian or Alaska Native	ParticipantsBG000107 ParticipantsBG001106 ParticipantsBG002

Average Daily Pain Score (ADPS)

Average Daily Pain Score (ADPS) is based on question 5 of Brief Pain Inventory (BPI)-short form for Diabetic Peripheral Neuropathy (BPI-DPN) and is assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average" on a scale of 0 to 10: 0=no pain, and 10=pain as bad as you can imagine. Higher ADPS scores indicate higher pain intensity.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. "Number analyzed" indicates number of participants with data available for analysis at Baseline.

Mean

Standard Deviation

score on a scale

Title	Denominators	Categories
	ParticipantsBG000106 ParticipantsBG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline to Week 6 in ADPS as Measured by the Numerical Rating Scale

ADPS is based on question 5 of Brief Pain Inventory (BPI)-short form for Diabetic Peripheral Neuropathy (BPI-DPN) and is assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average." on a scale of 0 to 10: 0=no pain, and 10=pain as bad as you can imagine. Higher ADPS scores indicate higher pain intensity. Negative change from baseline indicates improvement.

The modified intent to treat (mITT) population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. 'Overall number of participants analyzed' indicates the number of participants data available for the analysis of this outcome measure.

Posted

Least Squares Mean

95% Confidence Interval

score on a scale

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo	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, 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.
OG001	LX9211 100 mg/10 mg	Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 mg tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablet, 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.
OG002	LX9211 200 mg/20 mg	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.

Units	Counts
Participants	OG00099 OG00187 OG00277

Title

Denominators

Categories

Title	Measurements
	OG000-0.72(-1.08 to -0.36) OG001-1.39(-1.77 to -1.01) OG002-1.27(-1.66 to -0.88)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Mixed model repeated measures (MMRM) model included fixed effects of treatment, visit, treatment-by-week interaction, the randomization stratum of Baseline pain severity (moderate, severe), and the Baseline ADPS score as a covariate.	MMRM model		0.007		LS Mean Difference	-0.67	Standard Error of the Mean	0.249	2-Sided	95	-1.16	-0.18					Superiority

Secondary

Percentage of Participants With ≥30% Reduction in Pain Intensity in ADPS From Baseline to Week 6

ADPS is based on question 5 of BPI-DPN and assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average." on a scale of 0 to 10 where 0 = No Pain and 10 = pain as bad as you can imagine. If % change from Baseline ≤ (-30) then participant was considered a Responder and if missing % change from Baseline or >(-30) participant is considered a Non-responder. Percentage of participants who were responders (who achieved ≥30% reduction in pain intensity in ADPS from Baseline to Week 6) are reported.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. Missing observations at Week 6 are imputed as nonresponses.

Posted

Number

percentage of participants

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo	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, 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.
OG001

Secondary

Percentage of Participants With ≥50% Reduction in Pain Intensity in ADPS From Baseline at Week 6

ADPS is based on question 5 of BPI-DPN and assessed on an 11-point numerical rating scale. Participants were asked to rate their average pain over the past 24 hours, by answering the question 5 "Please rate your pain due to your diabetes by indicating the one number that best describes your pain on the average." on a scale of 0 to 10 where 0 = No Pain and 10 = pain as bad as you can imagine. If % change from Baseline ≤ (-50) then participant is considered a Responder and if missing % change from Baseline or >(-50) then participant is considered a Non-responder. Percentage of participants who were responders (who achieved ≥50% reduction in pain intensity in ADPS from Baseline to Week 6) are reported.

Posted

Number

percentage of participants

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo	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, 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.
OG001

Secondary

Change From Baseline to Week 6 in Severity of Pain and Interference of Pain With Sleep and Other Aspects of the Participant's Life Based on the BPI-DPN

BPI-DPN: questionnaire that assesses severity of pain & its impact on functioning in participants with DPN. It consists of 4 questions that measure pain at its "worst,"least","average","now"(current pain) on 11-point numerical scale 0=no pain;10=worst pain.Score range:0-10 for each of these pain questions, higher scores=greater pain severity. Other 7 questions of BPI evaluate level of interference of pain on daily functioning (general activity,walking,work ability,mood,enjoyment of life,relations,sleep) on 11-point numerical scale, 0=does not interfere;10=completely interferes.Score range:0-10 for each of these intensity questions, higher scores=greater interference. Pain severity & pain interference factors are reported as separate categories. Average interference score= mean of 7 interference categories collected in Questions 9A-G, only if 50% (ie at least 4 of 7) of scores were non-missing. Negative change from baseline=improvement. Score range for average interference score: 0-70.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. Overall number of participants analyzed' indicates the number of participants evaluable for the outcome measure analysis. Number analyzed indicates the number of participants evaluable for the outcome measure for the specified category.

Posted

Least Squares Mean

95% Confidence Interval

score on a scale

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo

Secondary

Percentage of Participants Discontinuing Treatment Due to Lack of Efficacy

Lack of efficacy was defined as an increase of 30% from baseline in ADPS based on question 5 of the BPI-DPN. Baseline was defined as the average of the Week 2 Run-in period data collected by participants in the daily pain diary of BPI-DPN. ADPS is based on question 5 of BPI-DPN and assessed on an 11-point numerical rating scale where 0 = No Pain to 10 = pain as bad as you can imagine, higher score indicates higher pain intensity.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment.

Posted

Number

percentage of participants

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo	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, 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.
OG001	LX9211 100 mg/10 mg	Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 mg tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablet, 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.

Secondary

Patient Global Impression of Change (PGIC) Scale Score at Week 6

PGIC is a 7-point rating scale that assesses participant's belief about the overall improvement experienced after the end of treatment, where 1= very much improved to 7 = very much worse. Higher score indicates worsening.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. Overall number of participants analyzed indicates the number of participants evaluable for the analysis of the outcome measure.

Posted

Least Squares Mean

95% Confidence Interval

score on a scale

Baseline (Week 2 of the Run-in period) to Week 6

ID	Title	Description
OG000	Placebo	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, 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.
OG001	LX9211 100 mg/10 mg	Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 mg tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablet, 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.

Secondary

Time to Loss of Efficacy From Week 6 to Week 11 Among Participants Achieving a ≥30% Reduction in Pain Intensity at Week 6

For participants who achieved ≥30% reduction in ADPS based on Question 5 of the BPI-DPN at Week 6, the time to loss of efficacy was 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. ADPS is based on question 5 of BPI-DPN and assessed on an 11-point numerical rating scale where, 0 = No Pain to 10 = pain as bad as you can imagine.

The mITT population included all randomized participants who took at least 1 dose of study drug; participants were analyzed according to their randomized treatment. Participants who had ≥30% Reduction in Pain Intensity in ADPS at Week 6 were analyzed for this outcome measure.

Posted

Median

Full Range

weeks

Weeks 6 to 11

ID	Title	Description
OG000	Placebo	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, 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.
OG001	LX9211 100 mg/10 mg	Following a 2-week run-in period, participants were randomized to receive a single loading dose of LX9211, 100 mg tablet, orally, on Day 1, followed by maintenance doses of LX9211 10 mg tablet, 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.

Secondary

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Adverse Events (AE) is defined as any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Treatment-emergent AEs are defined as any AEs that occur or worsen after the first dose of study medication.

The safety population included those participants who took at least 1 dose of study drug during the double-blind treatment period. AEs were collected and reported for treatment period and safety follow up period separately.

Posted

Count of Participants

Participants

First dose of study drug after randomization up to the end of study (up to Week 11)

ID	Title	Description
OG000	Placebo (Double-blind Treatment Period)	Following a 2-week single-blind Run-in period, participants were randomized to receive a single loading dose of LX9211 matching placebo tablet, orally, on Day 1 and maintenance doses, orally, once daily from Day 2 to Week 6 during the 6-week double-blind treatment period.
OG001	LX9211 100 mg/10 mg (Double-blind Treatment Period)	Following a 2-week Single-blind Run-in period, participants were randomized to receive a single loading dose of 100 mg tablet, orally, on Day 1 and maintenance doses of 10 mg, orally, once daily from Day 2 to Week 6 during the 6-week double-blind treatment period.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo (Double-blind Treatment Period)	Following a 2-week single-blind Run-in period, participants were randomized to receive a single loading dose of LX9211 matching placebo tablet, orally, on Day 1 and maintenance doses, orally, once daily from Day 2 to Week 6 during the 6-week double-blind treatment period.	1	107	1	107	9	107
EG001	LX9211 100 mg/10 mg (Double-blind Treatment Period)	Following a 2-week Single-blind Run-in period, participants were randomized to receive a single loading dose of 100 mg tablet, orally, on Day 1 and maintenance doses of 10 mg, orally, once daily from Day 2 to Week 6 during the 6-week double-blind treatment period.	0	106	0	106	39	106
EG002	LX9211 200 mg/20 mg (Double-blind Treatment Period)	Following a 2-week Single-blind Run-in period, participants were randomized to receive a single loading dose of 200 mg tablet, orally, on Day 1 and maintenance doses of 20 mg, orally, once daily from Day 2 to Week 6 during the 6-week double-blind treatment period.	1	106	2	106	44	106
EG003	Placebo (Single-blind Follow-up Period)	Following completion of the 6-week double-blind treatment period, all participants entered the 5-week single-blind follow-up period and received a daily dose of LX9211 matching placebo tablet, orally.	0	104	1	104	4	104
EG004	LX9211 100 mg/10 mg (Single-blind Follow-up Period)	Following completion of the 6-week double-blind treatment period, all participants entered the 5-week single-blind follow-up period and received a daily dose of LX9211 matching placebo tablet, orally.	0	99	1	99	2	99
EG005	LX9211 200 mg/20 mg Single-blind Follow-up Period)	Following completion of the 6-week double-blind treatment period, all participants entered the 5-week single-blind follow-up period and received a daily dose of LX9211 matching placebo tablet, orally.	0	92	1	92	6	92

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Oedema peripheral	General disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0021 affected106 at risk EG0030 affected104 at risk EG0040 affected99 at risk EG0050 affected92 at risk
COVID-19	Infections and infestations	MedDRA (23.0)	Systematic Assessment	EG0001 affected107 at risk EG0010 affected106 at risk EG0020 affected106 at risk EG003
Type 1 diabetes mellitus	Metabolism and nutrition disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0021 affected106 at risk EG003
Orthopnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0021 affected106 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0020 affected106 at risk EG003
Supraventricular tachycardia	Cardiac disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0020 affected106 at risk EG003
Abdominal pain lower	Gastrointestinal disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0020 affected106 at risk EG003
Coronavirus infection	Infections and infestations	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0010 affected106 at risk EG0020 affected106 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Dizziness	Nervous system disorders	MedDRA (23.0)	Systematic Assessment	EG0002 affected107 at risk EG00116 affected106 at risk EG00229 affected106 at risk EG0032 affected104 at risk EG0041 affected99 at risk EG0051 affected92 at risk
Headache	Nervous system disorders	MedDRA (23.0)	Systematic Assessment	EG0004 affected107 at risk EG0019 affected106 at risk EG00210 affected106 at risk EG003
Balance disorder	Nervous system disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0016 affected106 at risk EG0025 affected106 at risk EG003
Somnolence	Nervous system disorders	MedDRA (23.0)	Systematic Assessment	EG0000 affected107 at risk EG0017 affected106 at risk EG0022 affected106 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (23.0)	Systematic Assessment	EG0003 affected107 at risk EG0019 affected106 at risk EG00212 affected106 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (23.0)	Systematic Assessment	EG0003 affected107 at risk EG0014 affected106 at risk EG0028 affected106 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (23.0)	Systematic Assessment	EG0002 affected107 at risk EG0012 affected106 at risk EG0027 affected106 at risk EG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Percentage of responders were analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by the randomization factor of Baseline severity score (moderate, severe). The 95% confidence interval (CI) are calculated using the asymptotic Wald method. Missing observations at Week 6 are imputed as nonresponses.	Cochran-Mantel-Haenszel		0.091		Difference in Percentage of Responders	9.6			2-Sided	95	-1.55	20.76					Superiority
OG000 OG002	Percentage of responders were analyzed using the CMH test stratified by the randomization factor of Baseline severity score (moderate, severe). The 95% CI are calculated using the asymptotic Wald method. Missing observations at Week 6 are imputed as nonresponses.	Cochran-Mantel-Haenszel		0.883		Difference in Percentage of Responders	-0.8			2-Sided	95	-10.95	9.40					Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Percentage of responders were analyzed using the CMH test stratified by the randomization factor of Baseline severity score (moderate, severe). The 95% CI are calculated using the asymptotic Wald method. Missing observations at Week 6 are imputed as nonresponses.	Cochran-Mantel-Haenszel		0.289		Difference in Percentage of Responders	4.8			2-Sided	95	-4.11	13.73					Superiority
OG000 OG002	Percentage of responders were analyzed using the CMH test stratified by the randomization factor of Baseline severity score (moderate, severe). The 95% CI are calculated using the asymptotic Wald method. Missing observations at Week 6 are imputed as nonresponses.	Cochran-Mantel-Haenszel		0.837		Difference in Percentage of Responders	-0.8			2-Sided	95	-8.85	7.16					Superiority

Title

Denominators

Categories

Pain at its Worst

Title	Measurements
	OG000-0.69(-1.11 to -0.26) OG001-1.42(-1.87 to -0.97) OG002-1.38(-1.81 to -0.96)

Pain at its Least

Title	Measurements
	OG000-0.69(-1.13 to -0.26) OG001-1.43(-1.89 to -0.98) OG002-1.38(-1.81 to -0.95)

Pain Right Now

Title	Measurements
	OG000-0.55(-1.00 to -0.10) OG001-1.42(-1.89 to -0.95) OG002-1.03(-1.47 to -0.59)

Interference Score Averaged Over Questions 9A - G

Title	Measurements
	OG000-0.74(-1.17 to -0.30) OG001-1.00(-1.46 to -0.53) OG002-0.97(-1.41 to -0.53)

General Activity

Title	Measurements
	OG000-0.77(-1.25 to -0.28) OG001-0.96(-1.48 to -0.44) OG002-0.82(-1.31 to -0.33)

Mood

Title	Measurements
	OG000-0.71(-1.22 to -0.19) OG001-0.72(-1.27 to -0.16) OG002-0.65(-1.18 to -0.13)

Walking Ability

Title	Measurements
	OG000-0.74(-1.24 to -0.24) OG001-1.36(-1.89 to -0.83) OG002-1.22(-1.73 to -0.72)

Normal Work

Title	Measurements
	OG000-1.01(-1.50 to -0.53) OG001-1.07(-1.58 to -0.55) OG002-1.05(-1.54 to -0.56)

Relations with Other People

Title	Measurements
	OG000-0.29(-0.79 to 0.20) OG0010.14(-0.39 to 0.67) OG002-0.09(-0.59 to 0.41)

Sleep

Title	Measurements
	OG000-0.48(-0.96 to -0.01) OG001-1.45(-1.96 to -0.94) OG002-1.52(-2.00 to -1.04)

Enjoyment of Life

Title	Measurements
	OG000-1.03(-1.53 to -0.52) OG001-1.05(-1.59 to -0.50) OG002-1.13(-1.64 to -0.61)

Group IDs	Group Description	Statistical Method	P-Value	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Non-Inferiority Type
OG000 OG001	Pain at its Worst: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain at its worst score as a covariate.	MMRM model	0.014	LS Mean Difference	-0.73	Standard Error of the Mean	0.298	2-Sided	95	-1.32	-0.15	Superiority
OG000 OG002	Pain at its Worst: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain at its worst score as a covariate.	MMRM model	0.017	LS Mean Difference	-0.70	Standard Error of the Mean	0.290	2-Sided	95	-1.27	-0.13	Superiority
OG000 OG001	Pain at its Least: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain at its least score as a covariate.	MMRM model	0.015	LS Mean Difference	-0.74	Standard Error of the Mean	0.302	2-Sided	95	-1.33	-0.15	Superiority
OG000 OG002	Pain at its Least: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain at its least score as a covariate.	MMRM model	0.020	LS Mean Difference	-0.69	Standard Error of the Mean	0.294	2-Sided	95	-1.27	-0.11	Superiority
OG000 OG001	Pain Right Now: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain right now score as a covariate.	MMRM model	0.005	LS Mean Difference	-0.87	Standard Error of the Mean	0.309	2-Sided	95	-1.48	-0.27	Superiority
OG000 OG002	Pain Right Now: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain right now score as a covariate.	MMRM model	0.111	LS Mean Difference	-0.48	Standard Error of the Mean	0.301	2-Sided	95	-1.07	0.11	Superiority
OG000 OG001	Interference score averaged Over Questions 9A - G: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain interference score as a covariate.	MMRM model	0.399	LS Mean Difference	-0.26	Standard Error of the Mean	0.310	2-Sided	95	-0.87	0.35	Superiority
OG000 OG002	Interference score averaged Over Questions 9A - G: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline pain interference score as a covariate.	MMRM model	0.441	LS Mean Difference	-0.23	Standard Error of the Mean	0.302	2-Sided	95	-0.83	0.36	Superiority
OG000 OG001	General Activity: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline general activity score as a covariate.	MMRM model	0.575	LS Mean Difference	-0.19	Standard Error of the Mean	0.346	2-Sided	95	-0.87	0.49	Superiority
OG000 OG002	General Activity: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline general activity score as a covariate.	MMRM model	0.880	LS Mean Difference	-0.05	Standard Error of the Mean	0.337	2-Sided	95	-0.71	0.61	Superiority
OG000 OG001	Mood: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline mood score as a covariate.	MMRM model	0.978	LS Mean Difference	-0.01	Standard Error of the Mean	0.368	2-Sided	95	-0.73	0.71	Superiority
OG000 OG002	Mood: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline mood score as a covariate.	MMRM model	0.877	LS Mean Difference	0.06	Standard Error of the Mean	0.358	2-Sided	95	-0.65	0.76	Superiority
OG000 OG001	Walking Ability: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline walking ability score as a covariate.	MMRM model	0.079	LS Mean Difference	-0.62	Standard Error of the Mean	0.354	2-Sided	95	-1.32	0.07	Superiority
OG000 OG002	Walking Ability: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline walking ability score as a covariate.	MMRM model	0.163	LS Mean Difference	-0.48	Standard Error of the Mean	0.345	2-Sided	95	-1.16	0.20	Superiority
OG000 OG001	Normal Work: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline normal work score as a covariate.	MMRM model	0.875	LS Mean Difference	-0.05	Standard Error of the Mean	0.344	2-Sided	95	-0.73	0.62	Superiority
OG000 OG002	Normal Work: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline normal work score as a covariate.	MMRM model	0.914	LS Mean Difference	-0.04	Standard Error of the Mean	0.335	2-Sided	95	-0.69	0.62	Superiority
OG000 OG001	Relations with Other People: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline relations with other people score as a covariate.	MMRM model	0.219	LS Mean Difference	0.43	Standard Error of the Mean	0.351	2-Sided	95	-0.26	1.12	Superiority
OG000 OG002	Relations with Other People: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline relations with other people score as a covariate.	MMRM model	0.551	LS Mean Difference	0.20	Standard Error of the Mean	0.341	2-Sided	95	-0.47	0.87	Superiority
OG000 OG001	Sleep: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline sleep score as a covariate.	MMRM model	0.005	LS Mean Difference	-0.96	Standard Error of the Mean	0.339	2-Sided	95	-1.63	-0.30	Superiority
OG000 OG002	Sleep: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline sleep score as a covariate.	MMRM model	0.002	LS Mean Difference	-1.04	Standard Error of the Mean	0.329	2-Sided	95	-1.68	-0.39	Superiority
OG000 OG001	Enjoyment of Life: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline enjoyment of life score as a covariate.	MMRM model	0.955	LS Mean Difference	-0.02	Standard Error of the Mean	0.361	2-Sided	95	-0.73	0.69	Superiority
OG000 OG002	Enjoyment of Life: change from baseline was analyzed using MMRM model including fixed effects of treatment, visit, treatment-by-visit interaction, the randomization stratum of baseline pain severity (moderate, severe), and the baseline enjoyment of life score as a covariate.	MMRM model	0.777	LS Mean Difference	-0.10	Standard Error of the Mean	0.351	2-Sided	95	-0.79	0.59	Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Analysis of variance (ANOVA) model was used for the analysis with treatment and the randomization stratum of baseline pain severity (moderate, severe) as fixed covariates.	ANOVA		0.031		LS Mean Difference	-0.35	Standard Error of the Mean	0.163	2-Sided	95	-0.67	-0.03					Superiority
OG000 OG002	ANOVA model was used for the analysis with treatment and the randomization stratum of baseline pain severity (moderate, severe) as fixed covariates.	ANOVA		0.351		LS Mean Difference	-0.15	Standard Error of the Mean	0.165	2-Sided	95	-0.48	0.17					Superiority

Title

Denominators

ID	Term
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases