A Study in the Treatment of Osteoarthritis Knee Pain

Study Overview
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Brief Summary
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To gather data on whether a new drug for osteoarthritis knee pain will be safe and have an effect on pain levels.

Official Title
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A Phase 2 Study of the Effects of LY545694, an iGluR5 Antagonist, in the Treatment of Subjects With Osteoarthritis Knee Pain

Conditions
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Osteoarthritis Knee Pain

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present with Osteoarthritis (OA) of the knee based on: 1) Knee pain for at least 14 days per month for the last 3 months, 2) Osteophytes (bone spurs), 3) And at least 1 of the following: Over the age of 50, OR morning stiffness in knee for less than 30 minutes, OR crunching sensation as the knee bends back and forth (crepitus). Mean score of 4 or greater on the 24-hour average pain score from Visit 2 to Visit 3. Completion of electronic daily diaries with at least 70% complete between Visit 2 and Visit 3. Taken non-steroidal anti-inflammatory drugs (NSAIDs) less than 15 days over the past month AND not taken NSAIDs at least 1 week prior to Visit 3. Agree to maintain the same activity level throughout the study. Women who can become pregnant must test negative for pregnancy and agree to utilize medically acceptable/reliable birth control during the study and 1 month following the last dose of the study. Competent and freely able to give an informed consent. Ability to understanding and intelligibly communicate with the investigator. Judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol. Exclusion Criteria: Knee arthroscopy within past 3 months or any knee joint replacement. Surgery planned during the trial for the knee to be studied. Prior synovial fluid analysis showing a white blood cell of 2000 cubic millimeters (mm^3) that is indicative of a diagnosis other than OA Are non-ambulatory or require the use of crutches or a walker. Use of a cane in the hand opposite the index knee is acceptable. Body Mass Index over 40. Confounding painful condition that may interfere with assessment of the index knee. (Knee pain should be the predominant pain. Mild OA of the hands is allowed, for instance.) Diagnosis of inflammatory arthritis (rheumatoid arthritis) or an autoimmune disorder (except inactive Hashimoto's thyroiditis). Received intra-articular hyaluronate or steroids, joint lavage, or other invasive therapies to the knee in the past 3 months. Frequent falls that could result in hospitalization or could compromise response to treatment. Current or previous (within the past 1 year) Axis 1 diagnosis of major depressive disorder, mania, bipolar disorder, psychosis, dysthymia, anxiety disorder, alcohol or eating disorders. Serious or unstable cardiovascular, hepatic, renal, respiratory, ophthalmologic, gastrointestinal, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition that in the opinion of investigator would compromise participation or be likely to lead to hospitalization during the course of the study. Alanine transaminase (ALT) > 2.0 times upper limit of normal at Visit 1, based on reference ranges of the central lab. Prior renal transplant, current renal dialysis, or serum creatinine laboratory value >1.5 times upper limit of normal based on the reference ranges of the central lab. Diagnosis or past history of glaucoma. Subjects with intraocular pressure >24 millimeters of mercury (mm Hg). Are taking any excluded medications that cannot be discontinued at Visit 1. History of substance abuse or dependence within the past year, excluding nicotine and caffeine. Have a positive urine drug screen for any substance of abuse or excluded medication. History of recurrent seizures other than febrile seizures. Are judged by the investigator to be at suicidal risk. History of frequent and/or severe allergic reactions with multiple medications. Pregnant or breast-feeding. Are unwilling/unable to comply with the use of a data collection devices. 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. Investigator site personnel directly affiliated with this study, and/or their immediate families, or Lilly employees. History of severe delay in stomach emptying (gastroparesis).

Ages Eligible for Study
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Minimum Age: 40 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>Participants randomized to LY545694 placebo were given LY545694 placebo twice daily (BID) oral (po) for 5 weeks. | Drug: Placebo<br>* LY545694 placebo BID po for 5 weeks<br>|
| Experimental: LY545694 49 mg<br>Participants randomized to LY545694 49 milligrams (mg) BID po were first administered LY545694 21 mg BID po at Visit 3. After 1 week of dosing, participants were escalated to LY545694 49 mg BID po at Visit 4. Participants who were intolerant of this dose were titrated back down to 21 mg BID po for the remainder of study treatment. | Drug: LY545694 49 mg<br>* LY545694 49 mg BID po for 5 weeks.<br>|
| Experimental: LY545694 105 mg<br>Participants randomized to LY545694 105 mg BID po were first administered LY545694 21 mg BID po at Visit 3. After 1 week of dosing, participants were escalated to LY545694 49 mg BID po at Visit 4. At Visit 5, participants were titrated to the final dose of LY545694 105 mg BID po. Participants who were intolerant of this dose were titrated back down to LY545694 49 mg BID po for the remainder of study treatment. | Drug: LY545694 105 mg<br>* LY545694 105 mg BID po for 5 weeks.<br>|

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 From Electronic Diary 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 From Electronic Diary 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 From Electronic Diary 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 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). The 11-point Likert scale was also used for assessment of night pain and worst pain each day, evaluated as weekly means. | Baseline through 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 | 
| Change From Baseline in Average Brief Pain Inventory - Interference (BPI-I) Subscale Score at 5 Weeks | Average BPI-I was a self-reported scale measuring degree of pain interference on function. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessed 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 was a self-reported scale measuring severity of pain. Severity scores: 0 (no pain) to 10 (severe pain) on each question assessed 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 | 
| Patient Global Impression of Improvement (PGI-I) Score at 5 Weeks | PGI-I was a scale that 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 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 represented better sleep. | Baseline, 5 weeks | 
| Change From Baseline in Total Western Ontario and MacMaster (WOMAC) Osteoarthritis Physical Function, Pain, and Stiffness Subscales at 5 Weeks | The Total WOMAC index (pain, stiffness, physical function subscales) was completed by the participant and had 24 questions. Each question was answered using a 5-point Likert scale (0 to 4). The Total score had a range from 0 (none) to 96 (extreme). 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 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 indicated 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 in European Quality of Life Scale - 5 Dimensions (EQ-5D) at 5 Weeks: United States Population Based Index Score | The EuroQoL Questionnaire - 5 Dimension (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 their 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 Treatment Emergent Adverse Events (TEAEs) During the Therapy Phase and 1-Week Washout 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 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 (ECG) Change in Heart Rate Using Bazett's (QTcB) and Fridericia's (QTcF) Formulas | The number of participants having QTcF and QTcB ECG change >450 milliseconds (msec) was summarized. | Baseline through 5 weeks | 
| 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, followup questions rated the degree to which the issue impaired his/her ability to do work or read. | Week 5 | 
| Pharmacokinetic (PK) Parameter: Clearance of LY545694 (CLp) and Compound 645838 (CLm) | Clearance was 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 | 
| Number of Participants With Neurological Treatment Emergent Adverse Events (AEs) | 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 and other non-serious AEs is located in the Reported Adverse Event module. | 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 30% of the participants at risk had at least 30% response was reported. | Baseline through 5 weeks |