Duloxetine in Patients With Diabetic in Peripheral Neuropathic Pain With or Without Co-morbid Major Depressive Disorder

Study Overview
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Brief Summary
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The primary objective is to evaluate, separately in diabetic polyneuropathic pain (DPNP) patients with and without co-morbid major depressive disorder (MDD), whether duloxetine given as 60 mg to 120 mg once daily (QD) leads to a clinically relevant improvement as measured by the change in Brief Pain Inventory (BPI) 24 hours average interference score from baseline to after 12 weeks. A clinically relevant improvement will be demonstrated if the confidence interval for the mean change from baseline does not lie above the clinically relevant change of -1.35. If statistically significant results are obtained for the DPNP patients with MDD, then the same evaluation will be performed for the DPNP patients without MDD in another confirmatory analysis. As secondary objectives the study will compare the two groups (MDD+/MDD-) regarding efficacy of duloxetine on BPI severity scales, the distribution of different percentages of pain reduction among the patient population, and the patients and physicians impressions of severity and improvement of pain. The study will also compare treatment outcomes regarding patient-relevant functionality and quality of life (QoL) between the two groups (MDD+/MDD-) by evaluating each single BPI interference item, the Short Form 12 (SF-12) Health Questionnaire and the West Haven Multidimensional Pain Inventory (MPI). As a third group of secondary objectives the efficacy of duloxetine of the psychological symptoms (e.g. depression) of DPNP patients with or without depression will be assessed using the Hamilton depression scale, the Beck Depression Inventory-II and the hospital Anxiety and Depression Scale. Further the effect of duloxetine treatment on fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) will be evaluated. To monitor safety and tolerability, treatment discontinuation rates, treatment emergent adverse events, change in vital signs, laboratory results and suicidal thoughts will be assessed.

Official Title
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A 12 Weeks Open Label Two Parallel Groups Study to Assess the Efficacy of Orally Administered Duloxetine 60 mg and 120 mg Per Day on Treatment Outcomes in Patients With Diabetic Peripheral Neuropathic Pain With and Without Co-morbid Major Depressive Disorder. The Primary Objective of This Study is to Evaluate Whether the Efficacy of Duloxetine Given as 60 mg to 120 mg Once Daily (QD), Measured by the BPI Interference Score After 12 Weeks Shows a Clinically Relevant Improvement in the DPNP Patients With Co-morbid MDD

Conditions
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Diabetic Neuropathies, Depressive Disorder, Major

Intervention / Treatment
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* Drug: Duloxetine 60 mg QD
* Drug: Duloxetine 60 mg QD
* Drug: Duloxetine 30 mg QD
* Drug: Duloxetine 30 mg QD
* Drug: Duloxetine 90 mg QD
* Drug: Duloxetine 90 mg QD
* Drug: Duloxetine 60 mg QD
* Drug: Duloxetine 60 mg QD
* Drug: Duloxetine 120 mg QD
* Drug: Duloxetine 30 mg QD
* Drug: Duloxetine 30 mg QD
* Drug: Duloxetine 120 mg QD


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Present with pain due to bilateral peripheral neuropathy (according to International Statistical Classification of Diseases and Related Health Problems 10 (ICD 10). To qualify for the MDD+ cohort, patients need to meet the ICD-10 criteria for MDD. Furthermore, Hamilton rating scale for depression 17 (HAMD-17) scores need to match with the ICD-10 criteria for qualification of the MDD+ or MDD- groups. Male or female outpatients at least 18 years of age. Females with child bearing potential must test negative for a serum pregnancy test at Visit 1. Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post-menopause) must agree to utilize 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 the study. Examples of reliable methods include use of oral contraceptives or Depo-Clinovir Contraceptive Injection (sterile medroxyprogesterone acetate suspension, Pharmacia), partner with vasectomy, diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, or intrauterine devices. Women who are pregnant or breast-feeding may not participate in the study. Educational level and degree of understanding such that they can communicate intelligibly with the investigator and study coordinator. Judged to be reliable and agrees to keep all appointments for clinic visits, tests, and procedures required by the protocol. Exclusion criteria: Have already a diagnosis of Depression and are currently treated with an antidepressant medication for depression, when entering the study. Suffer from pain that cannot be clearly differentiated from or conditions that interfere with the assessment of DPNPain. Had a historical exposure to drugs known to cause neuropathy, that could have been responsible for neuropathy. Have previously been treated with duloxetine (for DPNP or MDD) Are judged to be at suicidal risk by the clinical investigator or as defined by a score of 2 or greater on question 9 of the Beck Depression Inventory-II (BDI-II). Had a history of substance abuse or dependence within the past year, excluding nicotine and caffeine.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: DPNP with depression (1)<br>Patients that have diabetic polyneuropathy and depression and are responder to 60 mg duloxetine QD (>30% pain reduction after week 6) | Drug: Duloxetine 60 mg QD<br>* given to (1) all patients week 2-6; (2) all responders of both arms week 7-12<br>Drug: Duloxetine 30 mg QD<br>* given to (1) all patients for one week as taper in; (2) all patients for taper down (responder for 2 weeks)<br>|
| Other: DPNP with depression (2)<br>Patients that have diabetic polyneuropathy and depression and are non-responder to 60 mg duloxetine QD (<30% pain reduction after week 6) | Drug: Duloxetine 90 mg QD<br>* given to non-responders of both arms from day of notice that 120 mg is not tolerated to week 12 as 60 mg+30 mg Duloxetine QD<br>Drug: Duloxetine 60 mg QD<br>* given to (1) all patients week 2-6; (2) all non-responders of both arms for first week of taper down<br>Drug: Duloxetine 30 mg QD<br>* given to (1) all patients for one week as taper in; (2) all patients for taper down (non-responder for the second week of taper down)<br>Drug: Duloxetine 120 mg QD<br>* given to non-responders of both arms from week 7-12 as 2x60 mg Duloxetine QD, if tolerated<br>|
| Other: DPNP without depression (1)<br>Patients that have diabetic polyneuropathy and no depression and are responder to 60 mg duloxetine QD (>30% pain reduction after week 6) | Drug: Duloxetine 60 mg QD<br>* given to (1) all patients week 2-6; (2) all responders of both arms week 7-12<br>Drug: Duloxetine 30 mg QD<br>* given to (1) all patients for one week as taper in; (2) all patients for taper down (responder for 2 weeks)<br>|
| Other: DPNP without depression (2)<br>Patients that have diabetic polyneuropathy and no depression and are non-responder to 60 mg duloxetine QD (<30% pain reduction after week 6) | Drug: Duloxetine 90 mg QD<br>* given to non-responders of both arms from day of notice that 120 mg is not tolerated to week 12 as 60 mg+30 mg Duloxetine QD<br>Drug: Duloxetine 60 mg QD<br>* given to (1) all patients week 2-6; (2) all non-responders of both arms for first week of taper down<br>Drug: Duloxetine 120 mg QD<br>* given to non-responders of both arms from week 7-12 as 2x60 mg Duloxetine QD, if tolerated<br>Drug: Duloxetine 30 mg QD<br>* given to (1) all patients for one week as taper in; (2) all patients for taper down (non-responder for the second week of taper down)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Brief Pain Inventory (BPI) Average Interference Score From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI average interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Brief Pain Inventory (BPI) Average Interference Score From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI average interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in BPI Worst Pain During Treatment From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 2 | 
| Change in Worst Pain (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 6 | 
| Change in Worst Pain (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 12 | 
| Change in Least Pain (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 2 | 
| Change in Least Pain During Treatment (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 6 | 
| Change in Least Pain (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 12 | 
| Change in Average Pain (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 2 | 
| Change in Average Pain During Treatment (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 6 | 
| Change in Average Pain (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 12 | 
| Number of Patients With a Reduction in BPI Average Pain at Week 2 |  | Baseline and Week 2 | 
| Number of Patients With a Reduction in BPI Average Pain at Week 6 |  | Baseline and Week 6 | 
| Number of Patients With a Reduction in BPI Average Pain at Week 12 |  | Baseline and Week 12 | 
| Change in Pain During Treatment (BPI) From Baseline to Week 2 | The change from baseline reflects the pain at week 2 minus the pain at baseline. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 2 | 
| Change in Pain (BPI) From Baseline to Week 6 | The change from baseline reflects the pain at week 6 minus the pain at baseline. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 6 | 
| Change in Pain During Treatment (BPI) From Baseline to Week 12 | The change from baseline reflects the pain at week 12 minus the pain at baseline. The BPI pain ranges from 0 (no pain) to 10 (pain as bad as the patient can imagine). | Baseline and Week 12 | 
| Change in Relief of Pain (BPI) From the Week Before Baseline to the Week Before Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The relief of pain ranges from 0% (no relief) to 100% (complete relief). | Baseline and Week 2 | 
| Change in Relief of Pain (BPI) From the Week Before Baseline to the Week Before Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The relief of pain ranges from 0% (no relief) to 100% (complete relief). | Baseline and Week 6 | 
| Change in Relief of Pain (BPI) From the Week Before Baseline to the Week Before Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The relief of pain ranges from 0% (no relief) to 100% (complete relief). | Baseline and Week 12 | 
| Change in Interference of Pain With General Activity (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With General Activity (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With General Activity (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Mood (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Mood (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Mood (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Walking Ability (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Walking Ability (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Walking Ability (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Normal Work (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Normal Work (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Normal Work (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Relations to Other People (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Relations to Other People (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Relations to Other People (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Sleep (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Sleep (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Sleep (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Change in Interference of Pain With Enjoyment of Life (BPI) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 2 | 
| Change in Interference of Pain With Enjoyment of Life (BPI) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 6 | 
| Change in Interference of Pain With Enjoyment of Life (BPI) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BPI interference score ranges from 0 (pain does not interfere) to 10 (pain completely interferes). | Baseline and Week 12 | 
| Patient Global Impression - Improvement (PGI-I) at Week 2 | The investigator judged the improvement of the patient's global impression during treatment. The score ranges from 1 (very much better) to 7 (very much worse). | Baseline and Week 2 | 
| Patient Global Impression - Improvement (PGI-I) at Week 6 | The investigator judged the improvement of the patient's global impression during treatment. The score ranges from 1 (very much better) to 7 (very much worse). | Baseline and Week 6 | 
| Patient Global Impression - Improvement (PGI-I) at Week 12 | The investigator judged the improvement of the patient's global impression during treatment. The score ranges from 1 (very much better) to 7 (very much worse). | Baseline and Week 12 | 
| Change in Beck Depression Inventory Total Score (BDI-II) From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The BDI-II total score ranges from 0 to 63, with a higher score indicating a higher level of depression. | Baseline and Week 2 | 
| Change in Beck Depression Inventory Total Score (BDI-II) From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The BDI-II total score ranges from 0 to 63, with a higher score indicating a higher level of depression. | Baseline and Week 6 | 
| Change in Beck Depression Inventory Total Score (BDI-II) From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The BDI-II total score ranges from 0 to 63, with a higher score indicating a higher level of depression. | Baseline and Week 12 | 
| Change in Hospital Anxiety and Depression Scale (HADS) Anxiety Total Score From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The HADS anxiety total score ranges from 0 (no anxiety) to 21 (extreme anxiety). | Baseline and Week 2 | 
| Change in HADS Anxiety Total Score From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The HADS anxiety total score ranges from 0 (no anxiety) to 21 (extreme anxiety). | Baseline and Week 6 | 
| Change in HADS Anxiety Total Score From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The HADS anxiety total score ranges from 0 (no anxiety) to 21 (extreme anxiety). | Baseline and Week 12 | 
| Change in HADS Depression Total Score From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The HADS depression total score ranges from 0 (no depression) to 21 (extreme depression). | Baseline and Week 2 | 
| Change in HADS Depression Total Score From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The HADS depression total score ranges from 0 (no depression) to 21 (extreme depression). | Baseline and Week 6 | 
| Change in HADS Depression Total Score From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The HADS depression total score ranges from 0 (no depression) to 21 (extreme depression). | Baseline and Week 12 | 
| Change in Short Form Health Survey (SF-12) - Physical Component Summary From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. A lower score corresponds to a lower level of physical health. Values can range from 0 to 100. | Baseline and Week 6 | 
| Change in Short Form Health Survey (SF-12) - Physical Component Summary From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. A lower score corresponds to a lower level of physical health. Values can range from 0 to 100. | Baseline and Week 12 | 
| Change in Short Form Health Survey (SF-12) - Mental Component Summary From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. A lower score corresponds to a lower level of mental health. Values can range from 0 to 100. | Baseline and Week 6 | 
| Change in Short Form Health Survey (SF-12) - Mental Component Summary From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. A lower score corresponds to a lower level of mental health. Values can range from 0 to 100. | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Interference of Pain (With Subjective Well-being) From Baseline to Week 6 | Pain-related life interference (with family and marital functioning, work, social activities). The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (no interference) to 6 (extreme interference). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Interference of Pain From Baseline to Week 12 | Pain-related life interference (with family and marital functioning, work, social activities). The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (no interference) to 6 (extreme interference). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Support From Baseline to Week 6 | Appraisal of support received from spouse, family and significant others. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (no support) to 6 (very much support). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Support Which the Patient Received From Baseline to Week 12 | Appraisal of support received from spouse, family and significant others. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (no support) to 6 (very much support). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Pain Severity From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (not at all strong) to 6 (very strong). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Pain Severity From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (no control) to 6 (extreme control). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Life Control From Baseline to Week 6 | Perceived life control and ability to solve problems and feelings of personal mastery and competence. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (no control) to 6 (extreme control). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Life Control From Baseline to Week 12 | Perceived life control and ability to solve problems and feelings of personal mastery and competence. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (no control) to 6 (extreme control). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Affective Distress From Baseline to Week 6 | Affective distress, including ratings of depressed mood, irritability, and tension. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (no distress) to 6 (extreme distress). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Affective Distress From Baseline to Week 12 | Affective distress, including ratings of depressed mood, irritability, and tension. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (no distress) to 6 (extreme distress). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Negative Responses From Baseline to Week 6 | Degree to which significant others display negative responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Negative Responses From Baseline to Week 12 | Degree to which significant others display negative responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Solicitous Responses From Baseline to Week 6 | Degree to which significant others display solicitous responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Solicitous Responses From Baseline to Week 12 | Degree to which significant others display solicitous responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Degree to Which Significant Others Display Distracting Responses to the Patient's Pain Behaviors and Complaints From Baseline to Week 6 | Degree to which significant others display distracting responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Degree to Which Significant Others Display Distracting Responses to the Patient's Pain Behaviors and Complaints From Baseline to Week 12 | Degree to which significant others display distracting responses to the patient's pain behaviors and complaints. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Household Chores From Baseline to Week 6 | Frequency with which the patient engages in household chores. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Household Chores From Baseline to Week 12 | Frequency with which the patient engages in household chores. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Outdoor Work From Baseline to Week 6 | Frequency with which the patient engages in outdoor work. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Outdoor Work From Baseline to Week 12 | Frequency with which the patient engages in outdoor work. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): Social Activities From Baseline to Week 6 | Frequency with which the patient engages in social activities. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): Social Activities From Baseline to Week 12 | Frequency with which the patient engages in social activities. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Multidimensional Pain Inventory (MPI): General Activities From Baseline to Week 6 | Frequency with which the patient engages in general activities. The change from baseline reflects the week 6 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 6 | 
| Change in Multidimensional Pain Inventory (MPI): General Activities From Baseline to Week 12 | Frequency with which the patient engages in general activities. The change from baseline reflects the week 12 value minus the baseline value. The scores range from 0 (never) to 6 (very frequently). | Baseline and Week 12 | 
| Change in Clinical Global Impression - Severity Pain From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. The score of the Clinical global impression ranges from 1 (not ill at all) to 7 (extremely ill). | Baseline and Week 2 | 
| Change in Clinical Global Impression - Severity Pain From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. The score of the Clinical global impression ranges from 1 (not ill at all) to 7 (extremely ill). | Baseline and Week 6 | 
| Change in Clinical Global Impression - Severity Pain From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. The score of the Clinical global impression ranges from 1 (not ill at all) to 7 (extremely ill). | Baseline and Week 12 | 
| Change in Hamilton Depression Score From Baseline to Week 2 | The change from baseline reflects the week 2 value minus the baseline value. A lower score corresponds to a lower level of depression. The score ranges from 0 to 52. | Baseline and Week 2 | 
| Change in Hamilton Depression Score From Baseline to Week 6 | The change from baseline reflects the week 6 value minus the baseline value. A lower score corresponds to a lower level of depression. The score ranges from 0 to 52. | Baseline and Week 6 | 
| Change in Hamilton Depression Score From Baseline to Week 12 | The change from baseline reflects the week 12 value minus the baseline value. A lower score corresponds to a lower level of depression. The score ranges from 0 to 52. | Baseline and Week 12 | 
| Suicidal Thoughts by BDI-II at Week 2 |  | Week 2 | 
| Suicidal Thoughts by BDI-II at Week 6 |  | Week 6 | 
| Suicidal Thoughts by BDI-II at Week 12 |  | Week 12 | 
| Suicidal Thoughts or Behaviours by HAMD-17 at Week 2 |  | Week 2 | 
| Suicidal Thoughts or Behaviours by HAMD-17 at Week 6 |  | Week 6 | 
| Suicidal Thoughts or Behaviours by HAMD-17 at Week 12 |  | Week 12 | 
| Change of Fasting Blood Glucose From Baseline at Week 12 | Ancova analysis controlling for baseline and insulin intake | Baseline and Week 12 | 
| Change of Glycosylated Hemoglobin A1c (HbA1c) From Baseline at Week 12 | Ancova analysis controlling for baseline and insulin intake | Baseline and Week 12 | 
| Change of Systolic Blood Pressure From Baseline at Week 12 |  | Baseline and Week 12 | 
| Change of Diastolic Blood Pressure From Baseline at Week 12 |  | Baseline and Week 12 | 
| Change of Pulse Rate From Baseline at Week 12 |  | Baseline and Week 12 |