An Open-Label Comparison of Duloxetine to Other Alternatives for the Management of Diabetic Peripheral Neuropathic Pain

Study Overview
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Brief Summary
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To test the non-inferiority of duloxetine monotherapy as a treatment for the management of diabetic peripheral neuropathic pain as compared to pregabalin treatment among patients who have not had an adequate response to gabapentin.

Official Title
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An Open-Label, Randomized Comparison of Duloxetine, Pregabalin, and the Combination of Duloxetine and Gabapentin Among Patients With Inadequate Response to Gabapentin for the Management of Diabetic Peripheral Neuropathic Pain

Conditions
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Diabetic Neuropathy, Painful

Intervention / Treatment
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* Drug: duloxetine hydrochloride
* Drug: pregabalin
* Drug: gabapentin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: You must have been diagnosed with Diabetic Neuropathic Pain Patient has an average daily pain score greater than or equal to 4 on an 11-point Likert scale, and patient or provider feel that a change from the current gabapentin therapy for pain management is warranted Patient is currently treated with gabapentin greater than or equal to 900 milligram/day, has been prescribed the current dose for at least 4 weeks, and has been at least 80% compliant with dosing, according to patient report Patient must agree not to change dose of gabapentin between Visits 1 and 2 You must have stable glycemic control Exclusion Criteria: Are judged prior to randomization to be at suicidal risk as defined by a score of 2 or greater on question 9 of the Beck Depression Inventory-II (BDI-II) Current diagnosis or history of hemangiosarcoma Patients with New York Heart Association Class III or IV symptoms of congestive heart failure Patients with uncontrolled narrow-angle glaucoma Presence of a current seizure disorder

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pregabalin<br>Pregabalin (PGB) 50 milligram (mg) three times a day (TID) (US & Germany) or 75 mg twice daily (BID) (Canada), orally (PO) for 2 weeks, then PGB 100 mg TID (US & Germany) or 150 mg BID (Canada), PO for 10 weeks. | Drug: pregabalin<br>* Pregabalin (PGB) orally (PO)<br>|
| Experimental: Duloxetine<br>Duloxetine (DLX) 30 milligram (mg) once daily (QD), orally (PO) for 1 week, then DLX 60 mg QD, PO for 11 weeks. | Drug: duloxetine hydrochloride<br>* Duloxetine (DLX) once daily (QD), orally (PO)<br>* Other names: Cymbalta;|
| Experimental: Gabapentin + Duloxetine<br>Stable Gabapentin (GAB) + Duloxetine (DLX) 30 milligram (mg) once daily (QD), orally (PO) for 1 week, then stable GAB + DLX 60 mg QD, PO for 11 weeks. | Drug: duloxetine hydrochloride<br>* Duloxetine (DLX) once daily (QD), orally (PO)<br>* Other names: Cymbalta;Drug: gabapentin<br>* Stable Gabapentin (GAB) (participants will remain on the same dose of gabapentin at which they entered the study)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to 12 Weeks in Weekly Mean of Daily 24 Hour Average Pain Score, Pregabalin Compared With Duloxetine | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the average pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to 12 Weeks in Weekly Mean of Daily 24 Hour Average Pain Score, Duloxetine Compared With Duloxetine+Gabapentin | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the average pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Weekly Mean of Nighttime Pain Severity | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the daily nighttime pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Weekly Mean of the Daily Worst Pain Severity Score | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the daily worst pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Clinical Global Impression of Severity Scale (CGI Severity) | Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Patient's Global Impression of Improvement Scale (PGI - Improvement) at 12 Weeks | A scale that measures the patient's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). | 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: 24-hour Average Pain | A self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Worst Pain | A self-reported scale that measures the severity of pain based on the worst pain experienced over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 Weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Least Pain | A self-reported scale that measures the severity of pain based on the least pain experienced over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Pain Right Now | A self-reported scale that measures the severity of pain based on the pain right now. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference: With General Activity | A self-reported scale that measures the interference of pain in the past 24 hours on general activity. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Mood | A self-reported scale that measures the interference of pain in the past 24 hours on mood. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Walking Ability | A self-reported scale that measures the interference of pain in the past 24 hours on walking ability. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Normal Work | A self-reported scale that measures the interference of pain in the past 24 hours on normal work. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Relations With Other People | A self-reported scale that measures the interference of pain in the past 24 hours on relations with other people. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Sleep | A self-reported scale that measures the interference of pain in the past 24 hours on sleep. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Enjoyment of Life | A self-reported scale that measures the interference of pain in the past 24 hours on enjoyment of life. The Interference scores range from 0 (does not interfere) to 10 (completely interferes). Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Mean Interference Score | The Interference scores range from 0 (does not interfere) to 10 (completely interferes). There are 7 questions assessing the interference of pain in the past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Number of Participants With ≥ 30% Reduction in the Weekly Mean 24 Hour Average Pain Score at 12 Weeks | This is a nominal outcome reflecting whether or not a clinically-important efficacy outcome was achieved at endpoint. It is based on a comparison between baseline and endpoint scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by patients in their diaries. | baseline, 12 weeks | 
| Number of Patients With a Reduction of ≥ 50% in Weekly Mean of 24 Hour Average Pain Score | This is a nominal outcome reflecting whether or not a clinically-important efficacy outcome was achieved at endpoint. It is based on a comparison between baseline and endpoint scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by patients in their diaries. | baseline, 12 weeks | 
| Number of Participants With a ≥ 2-points Reduction on the Weekly Average of the Daily 24-hour Average Pain Scale at 12 Weeks | This is a nominal outcome reflecting whether or not a clinically-important efficacy outcome was achieved at endpoint. It is based on a comparison between baseline and endpoint scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by patients in their diaries. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Leeds Sleep Evaluation Questionnaire (LSEQ) Subscales of Ease of Going to Sleep (GTS), Awakening (AFS), and Behavior Following Wakefulness (BFW), Quality of Sleep (QOS) | The LSEQ assesses the effects of psychoactive compounds on sleep and early morning behavior. Participants mark a series of 100 mm line analogue scales, indicating the direction and magnitude of any changes in behavioral state they experience following administration of the drug. Scores are represented in millimeters, higher scores indicate better sleep and better early morning behavior. Subscale score ranges: GTS=0-300, QOS=0-200, AFS=0-200, BFW=0-300. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Sheehan Disability Scale (SDS) - Total Score and Scores for Items 1 to 3 | The SDS is completed by the patient and is used to assess the effect of the patient's symptoms on their work/social/family life. Total scores range from 0 to 30, higher values indicate greater disruption in the patient's life. Item 1 assesses the effect of the patient's symptoms on their work/school schedule, Item 2 on their social life/leisure activities, and Item 3 on their family life/home responsibilities. Subscales scores range: 0-10, higher values indicate greater disruption in the patient's life. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation |  | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Sexual Functioning Questionnaire (CSFQ) Total Score and Subscale Scores | 14-item subject-rated scale assessing medication related changes in sexual activity + functioning. Structured interview/questionnaire. It measures five dimensions of sexual behavior: pleasure; desire/frequency; desire/interest; arousal; and orgasm. The total score is obtained across all 5 dimensions, ranging from 14 to 70. Subscale score ranges: desire/frequency=2-10; desire/interest=3-15; pleasure=1-5; arousal=3-15; orgasm=3-15. Higher scores = better sexual functioning. Least-squares means: adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Categorical Change From Baseline to 12 Weeks in Sexual Functioning Questionnaire (CSFQ) Total Score and Subscale Scores | 14-item subject-rated scale assessing changes in sexual activity and functioning; structured interview/questionnaire, designed to measure medication related changes in sexual functioning. 5 dimensions of sexual behavior: pleasure; desire/frequency; desire/interest; arousal; orgasm. Total score: obtained across all 5 dimensions, ranges from 14 to 70. Subscale scores: desire/frequency=2-10; desire/interest=3-15; pleasure=1-5; arousal=3-15; orgasm=3-15. Higher scores = better sexual functioning. Categories: better=positive change in score; same=no change in score; worse=negative change in score. | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Portland Neurotoxicity Scale - Total Score and Subscale Scores | The Portland Neurotoxicity Scale is a 15-item, patient-completed questionnaire designed to assess the degree of impact of anti-epileptic drug therapy on a number of cognitive and somatomotor parameters. The total score ranges from 15-135 with higher scores indicating more toxicity. The cognitive toxicity score ranges from 10-90 and the somatomotor toxicity score ranges from 5-45, for both higher scores indicate more toxicity. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Categorial Change From Baseline to 12 Weeks in Portland Neurotoxicity Scale - Total Score and Subscale Scores | The Portland Neurotoxicity Scale is a 15-item, patient-completed questionnaire designed to assess the degree of impact of anti-epileptic drug therapy on a number of cognitive and somatomotor parameters. Categories: better=negative change in score; same=no change in score; worse=positive change in score. | baseline, 12 weeks | 
| Path Analysis of Improvement in Pain Through Improvement in Depressive Symptoms | Contribution to reduction in pain directly by treatment and indirectly by treatment through the reduction of depressive symptoms using path analysis. The direct treatment effect estimates the mean drug difference in pain reduction directly through treatment; the indirect treatment effect estimates the contribution that treatment plays to the mean drug difference in pain reduction indirectly through the reduction in mood symptoms; the total effect estimates the drug difference in reducing pain in sum through the specified path of direct and indirect treatment effects. | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Beck Depression Inventory II (BDI-II) Total Score | A 21-item, patient-completed questionnaire to assess characteristics of depression. Each of the 21 items corresponding to a symptom of depression is summed to give a single score. There is a four-point scale for each item ranging from 0 to 3. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 12 weeks | 
| Categorical Change From Baseline to 12 Weeks in Number of Patients Using Health Care as Measured by the Resource Utilization Scale | The Resource Utilization Scale measures direct and indirect costs (collected only for US sites). Direct costs include inpatient and outpatient costs, while indirect costs include lost days of work and caregiver time spent with patients. Inpatient costs include costs associated with hospitalizations and time spent in emergency rooms and psychiatric rooms. Outpatient costs include costs associated with visits to various health care providers, home health care by health care providers, and partial care. | baseline, 12 weeks | 
| Summary of Number of Participants Who Discontinued | Number of participants who discontinued. The reasons for discontinuation are presented in the participant flow. | baseline through 12 weeks | 
| Time to First ≥ 30% Reduction in Weekly Mean 24 Hour Average Pain Score | This is the number of days required to first achieve a nominal outcome reflecting whether or not a clinically-important efficacy outcome was achieved. It is based on a comparison between baseline and post-baseline scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by patients in their diaries. | baseline through 12 weeks | 
| Time to First ≥ 50 % Reduction in Weekly Mean 24 Hour Average Pain Score | This is the number of days to first achieve ≥50% reduction, baseline to endpoint, in the weekly means of the 24-hour average pain severity via daily patient assessments using an ordinal scale (scores from 0 (no pain) to 10 (worst possible pain). The median time to first ≥50% reduction with some measure of dispersion could not be calculated for each treatment group. The number of patients who reached a ≥50% reduction in weekly mean 24 hour average pain score are presented in outcome measure 20. | baseline through 12 weeks | 
| Time to First Sustained Response in Weekly Mean 24 Hour Average Pain Score | This is the number of days to first achieve an outcome using the weekly means of the 24-hour average pain severity via daily patient assessments using an ordinal scale (scores from 0 (no pain) to 10 (worst possible pain). Sustained response: ≥30% reduction, baseline to endpoint, with 30% reduction from baseline ≥2 weeks prior to endpoint, remaining at ≥20% reduction between. The median time to sustained response with some measure of dispersion could not be calculated for each treatment group. | baseline through 12 weeks | 
| Time to First ≥ 2 Points Reduction in Weekly Mean 24 Hour Average Pain Score | This is the number of days required to first achieve a nominal outcome reflecting whether or not a clinically-important efficacy outcome was achieved. It is based on a comparison between baseline and post-baseline scores on an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Used were the weekly mean of the scores of the average pain severity over the last 24 hours. The weekly averages were based on daily assessments recorded by patients in their diaries. | baseline through 12 weeks | 
| Weekly Mean Change in 24 Hour Average Pain Severity +/- Generalized Anxiety Disorder (GAD) | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the average pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. It was planned to analyze participants stratified by the presence or absence of a co-morbidity with GAD. However, due to the low number of participants with GAD in the study this analysis was not possible. | baseline, 12 weeks | 
| Weekly Mean Change From Baseline to 12 Weeks in 24 Hour Average Pain Severity - Only Participants Who Adhered to Key Protocol Requirements (Per-Protocol Population) | Ordinal scale: 0=no pain, 10=worst possible pain. Data=weekly mean of scores of average pain severity over last 24 hours (h). Scores: daily assessments recorded by patients in diaries. Only patients adhering to key protocol criteria included: baseline Weekly Mean 24h Average Pain Score ≥4; 80-120% compliant with study Drug, each visit; baseline Michigan Neuropathy Screening Instrument Physical Assessment Total Score ≥3; gabapentin taper ≤14 days, no HbA1c ≥12% post randomization; no contraindicated medications used. Least-squares means=adjustment due to baseline severity + investigative site. | baseline, 12 weeks | 
| Weekly Mean Change in 24 Hour Average Pain Severity by Week by Gabapentin Exposure Subgroup (de Novo Versus Prior Use) | This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the average pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries. De novo: use of gabapentin for <56 contiguous days prior to randomization. Prior use: use of gabapentin for >=56 contiguous days prior to randomization. Least-squares means represent adjustment due to baseline severity and investigative site. | baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks | 
| Discontinuations for Abnormal Laboratory Analytes, Vital Signs, Overall and for Each Measure | Presented are numbers of participants who discontinued due to a change from baseline in laboratory analytes or vital signs. | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Blood Pressure | Least-squares means represent adjustment due to baseline severity and investigative site. | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Heart Rate | Least-squares means represent adjustment due to baseline severity and investigative site. | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Body Weight | Least-squares means represent adjustment due to baseline severity and investigative site. | baseline through 12 weeks | 
| Number of Participants With Treatment-emergent Elevated Blood Pressure | Elevated systolic blood pressure: >=130 millimeter mercury (mm Hg) + an increase of >=10 mm Hg if baseline <130 mm Hg. Elevated diastolic blood pressure: >=85 mm Hg + an increase of >=10 mm Hg if baseline <85 mm Hg. | baseline through 12 weeks | 
| Number of Participants With Treatment-Emergent Elevated Heart Rate | Elevated heart rate: >=100 beats per minute (bpm) + an increase of >=10 bpm if baseline <100 bpm. | baseline through 12 weeks | 
| Number of Participants With Treatment-Emergent Changes in Body Weight | Treatment-emergent high body weight: weight at last visit >=107% of baseline weight. Treatment-emergent low body weight: weight at last visit <=93% of baseline weight. | baseline through 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Hepatic Enzyme Serum Levels | Aspartate aminotransferase = AST Alanine aminotransferase = ALT Gamma glutamyl transferase = GGT Alkaline phosphatase = AlkPhos | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Total Bilirubin |  | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Fasting Plasma Glucose |  | baseline, 12 weeks | 
| Mean Change From Baseline to 12 Weeks in Hemoglobin A1C |  | baseline, 12 weeks | 
| Number of Patients With Treatment-Emergent Elevated Laboratory Analytes | Treatment-emergent: within range at baseline, out of range after baseline. Ranges in Units/Liter (U/L). Aspartate Aminotransferase (AST): female (f): >34, male (m): >36. Alanine Aminotransferase (ALT): f:<69 years (yr) >34, ≥69yr >32; m: <69yr >43, ≥69yr >35. Total Bilirubin (TBili): >21. Gamma Glutamyl Transferase (GGT): f: <59yr >49, ≥59yr >50; m: <59yr >61, ≥59yr >50. Fasting Plasma Glucose (FPG): <59yr >6.4, ≥59yr >6.7. Hemoglobin A1C (HbA1C) >6%. Alkaline Phosphatase (AlkPhos): f: 18-50yr >106, 50-70yr >123, 70-80yr >164, ≥80yr >221; m: 18-50yr >129, 50-70yr >131, 70-80yr >156, ≥80yr >187 | baseline through 12 weeks |