A Study for Treatment of Pain in Patients With Diabetic Neuropathy.

Study Overview
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Brief Summary
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The purpose of this study is to test whether a new treatment will be safe and effective in treating pain. Patients with diabetic peripheral neuropathy will be included.

Official Title
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A Phase 2 Study of the Effects of LY545694, an iGluR5 Antagonist, in the Treatment of Subjects With Painful Diabetic Neuropathy.

Conditions
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Diabetic Neuropathy, Painful

Intervention / Treatment
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* Drug: Placebo
* Drug: Pregabalin
* Drug: LY545694 21 mg
* Drug: LY545694 49 mg
* Drug: LY545694 105 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have pain due to peripheral neuropathy based on disease diagnostic criteria: must have Type 1 or Type 2 diabetes mellitus, pain must being in the feet, with relatively symmetrical onset, daily pain must be present for at least 6 months, and diagnosis must be confirmed by a score of at least 3 on Part B of the Michigan Neuropathy Screening Instrument. Have stable glycemic control, and glycated hemoglobin (HbA1c) less than or equal to 10% Mean score of at least 4 on the 24-hour average page severity assessment from (from daily diary) Visits 2 to 3. Fully completed daily diaries for at least 70% of the days between Visit 2 and 3. Women must test negative for a serum pregnancy test at Visit 1, and must agree to use medically acceptable and reliable means of birth control as determined by the investigator during the study and for 1 month following the last dose of study drug. Are competent and able to freely give own informed consent. Have an educational level and degree of understanding such that they can communicate intelligible with the investigator and study coordinator. Have been judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol. Exclusion Criteria: Have historical exposure to drugs known to cause neuropathy, or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy. Have pain that cannot be clearly differentiated from or conditions that interfere with the assessment of diabetic neuropathy pain. Have had treatment with any centrally active neuroleptic drug within 30 days of visit 3. Have had intolerance to pregabalin or have frequent and/or severe allergic reactions with multiple medications. Have current or previous (within the past 1 year) Axis 1 diagnosis of major depressive disorder, mania, bipolar disorder, psychosis, dysthymia, generalized anxiety disorder, alcohol or eating disorders according to Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria, as determined by the investigator and confirmed by the Mini-International Neuropsychiatric Interview (MINI). Have a serious of unstable cardiovascular, hepatic, renal, respiratory, ophthalmologic, gastrointestinal, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition that in the opinion of the investigator would compromise participation or be likely to lead to hospitalization during the course of the study. Have alanine aminotransaminase > 2 times upper limit of normal at Visit 1, based on reference ranges of central lab. Have prior renal transplant, current renal dialysis, or serum creatinine laboratory values > 1.5 times upper limit of normal, based on reference ranges of the central lab at Visit 1. Have a diagnosis or history of glaucoma. Are taking excluded medication that cannot be stopped and washed out prior to Visit 2. Have history of substance abuse or dependence within the past year, excluding nicotine and caffeine. Are judged clinically by the investigator to be at suicidal risk in the opinion of the investigator based upon clinical interview and the Columbia Suicide-Severity Rating Scale. Have a positive urine drug screen for any substance of abuse or excluded medication. Are unwilling or unable to comply with the use of a data collection device to directly record data from the subject (daily diary). Are pregnant or breast-feeding. Are investigator site personnel directly affiliated with this study and/or their immediate families. Are Lilly employees. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. Have a history of recurrent seizures other than febrile seizures. Have a history of severe gastroparesis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>LY545694 placebo twice daily (BID) oral (po) for 5 weeks and pregabalin placebo capsules thrice daily (TID) po for 6 weeks | Drug: Placebo<br>* LY545694 placebo BID po for 5 weeks Pregabalin placebo capsules TID po for 6 weeks<br>|
| Active Comparator: Pregabalin<br>Pregabalin thrice daily (TID) oral for 6 weeks: 50 mg TID po for Week 1, 100 mg TID po for Weeks 2 - 5, and 50 mg TID po taper for Week 6 LY545694 placebo BID po for 5 weeks | Drug: Pregabalin<br>* Pregabalin TID po for 6 weeks: 50 mg TID po for Week 1, 100 mg TID po for Weeks 2 - 5, and 50 mg TID po taper for Week 6 LY545694 placebo BID po for 5 weeks<br>|
| Experimental: LY545694 21 mg<br>LY545694 21 milligrams (mg) BID po for 1 week Pregabalin placebo TID po for 6 weeks | Drug: LY545694 21 mg<br>* LY545694 21 mg BID po for 1 week Pregabalin placebo TID po for 6 weeks<br>* Other names: LY545694;|
| Experimental: LY545694 49 mg<br>LY545694 escalated to 49 mg BID po during Week 2; possible titration down to 21 mg BID po within 1 week of escalation for remainder of study treatment. Pregabalin placebo TID po for 6 weeks | Drug: LY545694 49 mg<br>* LY545694 escalated to 49 mg BID po for 1 week during Week 2. Pregabalin placebo TID po for 6 weeks.<br>* Other names: LY545694;|
| Experimental: LY545694 105 mg<br>LY545694 escalated to 105 mg BID po during Week 3 through Week 5; possible titration down to 49 mg BID po within 1 week of escalation for the remainder of study treatment. Pregabalin placebo TID po for 6 weeks | Drug: LY545694 105 mg<br>* LY545694 105 mg BID po for 5 weeks Pregabalin placebo TID po for 6 weeks<br>* Other names: LY545694;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Mean 24-hour Average Pain Severity (APS) Score at 5 Weeks | This scale measured 24-hour APS scores. Data were recorded daily (preferably at bedtime) on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). Least Squares (LS) Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weekly Mean Night Pain Severity Score at 5 Weeks | This scale measured night pain APS scores. Data were recorded daily on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Change From Baseline in Weekly Mean Worst Daily Pain Severity Score at 5 Weeks | This scale measured worst pain APS scores. Data were recorded daily (preferably at bedtime) on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Number of Participants With 30% Reduction in Weekly Mean 24-hour Average Pain Severity (APS) Score | This scale measured the number of participants with a 30% reduction in weekly mean 24-hour APS score from baseline to endpoint. Data were recorded daily (preferably at bedtime) on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). | Baseline through 5 weeks | 
| Change From Baseline in Average Brief Pain Inventory - Interference (BPI-I) Subscale Score at 5 Weeks | Average BPI-I measured self-reported degree of pain interference on function. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference = average of non-missing scores of individual interference items. LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Change From Baseline in Brief Pain Inventory - Severity (BPI-S) Subscale Score at 5 Weeks | BPI-S measured self-reported severity of pain. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessing worst pain, least pain, and average pain in past 24 hours, and current pain. LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 5 Weeks | CGI-S measured severity of illness at the time of assessment compared with start of treatment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Patient Global Impression of Improvement (PGI-I) Score at 5 Weeks | PGI-I measured the participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranged from 1 (very much better) to 7 (very much worse). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Week 5 | 
| Change From Baseline in Short-form McGill Pain Questionnaire (SF-MPQ) Sensory Subscale Score at 5 Weeks | SF-MPQ consisted of 11 sensory descriptors describing pain that were rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or 3 = severe. Three pain scores were derived from the sum of the intensity rank values of the words chosen for sensory descriptors. The SF-MPQ sensory subscale was the sum of the 11 scores (ranged from 0 to 33, with 33 being the worst). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Change From Baseline in Assessment of Sleep Questionnaire (ASQ) Total Score at 5 Weeks | ASQ consisted of 21 items (including a single item to assess overall sleep quality) and 3 subscales: Sleep Onset and Maintenance (items 1-3, 5-6, 9, 11); Sleep Experience (items 4, 7, 8, 10, 12); and Awakening Experience (items 13-20). Each item was scored on a 5-point Likert scale, ranging from 0 (no sleep at all) to 5 (a lot of sleep). Each subscale was calculated as the mean of the individual items comprising the subscale. A total ASQ score was calculated as the mean of the subscale scores; higher scores represent better sleep. | Baseline, 5 weeks | 
| Change From Baseline in Neuropathy-Specific Quality of Life (NeuroQoL) Questionnaire Score at 5 Weeks | NeuroQoL had 29 items: 13 assessed specific somatic experiences (pain, lost/reduced feeling, and diffuse sensory-motor symptoms); 14 assessed specific functional, social, and emotional experiences (restrictions in daily living activities, disruptions in social relationships, and emotional distress); 2 items assessed QoL and overall satisfaction. Items reported on a 5-point scale (never/not at all to all of the time/very much). Higher mean scores=more severe symptoms/greater disruption in functioning. First 27 items also associate with 3-point bothersome/importance scale (1=none to 3=very). | Baseline, 5 weeks | 
| Change From Baseline in Short Form-36 (SF-36) Health Survey Bodily Pain Score at 5 Weeks | The SF-36 Health Status Survey was a generic, health-related scale assessing participants' quality of life on 8 domains (physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional and general health) and 2 summary scores (mental component summary [MCS] and physical component summary [PCS]). MCS and PCS scores=0-100 (higher scores indicate better health status). Domain scores: general health=5-25; physical functioning=10-30; role-physical=4-8; role-emotional=3-6; social functioning=2-10; bodily pain=2-11; vitality=4-24; mental health=5-30. | Baseline, 5 weeks | 
| Change From Baseline of European Quality of Life Scale - 5 Dimensions (EQ-5D) at 5 Weeks: United States Population Based Index Score | The EQ-5D was a generic, multidimensional, health-related, quality-of-life instrument. The profile allowed participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood. A single score between 1 and 3 was generated for each domain. For each participant, the outcome rating on the 5 domains was mapped to a single index through an algorithm. The index ranged between 0 and 1, with the higher score indicating a better health state perceived by the participant. | Baseline, 5 weeks | 
| Change From Baseline in Sheehan Disability Scale (SDS) Global Impairment Score at 5 Weeks | The SDS was completed by the participant and was used to assess the effect of the participant's symptoms on work/social/family life. Total scores ranged from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Number of Participants Who Discontinued Due to Adverse Events (AEs) During the Therapy (Double-blind) Phase and 1-Week Washout (Follow-up) Phase | Participant discontinuation in the study due to serious and other non-serious AEs was measured during both the therapy (double-blind) phase and 1-week washout (follow-up) phase. A listing of serious and other non-serious AEs is located in the Reported Adverse Event module. | Baseline through 6 weeks | 
| Number of Participants With Serious Treatment Emergent Abnormal High or Low Laboratory Values | The number of participants by treatment group who had abnormal high or low laboratory values was reported by the investigator and summarized as serious adverse events (SAEs) from the Investigations system organ class during the treatment phase of the study. A listing of SAEs is located in the Reported Adverse Event module. | Baseline through 5 weeks | 
| Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure at 5 Weeks | Participants' systolic blood pressure and diastolic blood pressure were measured in millimeters of mercury (mmHg). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Change From Baseline in Vital Signs: Pulse Rate at 5 Weeks | Pulse rate was measured in beats per minute (bpm). LS Means were adjusted for baseline, investigator, treatment, visit, a treatment-by-visit interaction, and a baseline-by-visit interaction. | Baseline, 5 weeks | 
| Number of Participants With Electrocardiogram Change in Heart Rate Using Bazett's (QTcB) and Fridericia's (QTcF) Formulas | The number of participants having QTcF and QTcB change ≥ 30 msec was summarized. | Baseline through 5 weeks | 
| Percentage of Participants With Reported Hypoglycemic Events | Percentage of participants who reported hypoglycemic (lower than normal level of blood glucose) episodes was summarized as other non-serious adverse events (AEs) from the Investigations system organ class (preferred term = hypoglycemia). A listing of AEs is located in the Reported Adverse Event module. | Baseline through 5 weeks | 
| Change From Baseline in Overall Total Quick Inventory of Depressive Symptomatology (QIDS) Score | The QIDS was a 16-item patient-rated measure of depressive symptomatology. Each item had a 0 to 3 point scale. The total score ranged from 0 to 27 with higher scores indicative of greater severity. QIDS was calculated by summing the scores from the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) major depressive disorder criteria: depressed mood, loss of interest or pleasure, concentration/decision making, self outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, and psychomotor changes. | Baseline, 5 weeks | 
| Number of Participants With Suicidal Behaviors and Ideations | The Columbia Suicide Severity Rating Scale (C-SSRS) captured occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors and ideations were provided. Suicidal behavior = a yes answer to any 1 of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation = a yes answer to any 1 of 5 suicidal ideation questions, which included the wish to be dead and 4 different categories of active suicidal ideation. | Baseline through week 5 | 
| Number of Participants Reporting Blurry or Hazy Vision Using the Subjective Vision Inventory (SVI) Question 1 (Q1) at 5 Weeks | This scale first asked if the participant was experiencing hazy or blurry vision or if he/she had difficulty focusing. If the answer was yes, follow-up questions rated the degree to which the issue impaired his/her ability to do work or to read. | Week 5 | 
| Pharmacokinetic (PK) Parameter: Clearance of LY545694 (CLp) and Compound 645838 (CLm) | Clearance is the volume of plasma cleared of study drug LY545694 (CLp) and metabolite compound 645838 (CLm) per unit time. The original PK/pharmacodynamic (PD) relationship outcome measure analysis was not conducted; therefore, only PK data were reported. | Baseline through 5 weeks | 
| Time to Response | Time to response=first visit achieving a 30% reduction of weekly mean 24-hour APS score. Data were recorded daily (preferably at bedtime) on an 11-point Likert scale, an ordinal scale ranging from 0 (no pain) to 10 (worst possible pain). The number of days at which 50% of the participants at risk had at least 30% response was reported. | Baseline through 5 weeks | 
| Number of Participants With Neurological Treatment Emergent Adverse Events (TEAEs) | The total number of TEAEs (serious and non-serious) that first occurred or worsened during the treatment period) from the Nervous system disorders system organ class was summarized. A listing of serious AEs (SAEs) and other non-serious AEs is located in the Reported Adverse Event module. | Baseline through 5 weeks |