Please select the eligibility criteria that correspond to the clinical trial below.
Title: Dose Response Study of Duloxetine Versus Placebo in the Treatment of Fibromyalgia Syndrome
Brief Summary: To assess the efficacy of Duloxetine compared with placebo in the treatment of pain in patients with Fibromyalgia syndrome, with or without major depressive disorder.


Options:
A: Inclusion Criteria:

1. Patients with diagnosis of chronic wide-spread pain for at least 3 months, who fulfill the 1990 ACR Criteria for FM.
2. Patients with mean pain ratings ≥ 4.0 VAS units, at Screening and Baseline visits.
3. Patients, who are able to comprehend and satisfactorily comply with protocol requirements.
4. Patients who have not taken any pain medications except acetaminophen within 3 days prior to the Baseline Visit (these medications if taken prior to the Screening Visit must be discontinued at Screening Visit and the Baseline Visit may be scheduled at least 7 days past the last dose of these medications).
5. All women of childbearing potential (WOCBP) must have a negative urine pregnancy test at the Screening Visit. All women of childbearing potential participating in the study must use a medically acceptable form of contraception

Exclusion Criteria:

1. FM patients unwilling or unable to discontinue analgesics (except Tylenol) for at least 5 drug half-lives prior to enrollment.
2. Patient has previously failed treatment with Milnacipran for FM pain.
3. Patients who have been treated with MAO inhibitors within 30 days prior to the Baseline Visit.
4. Patients who received ECT within 3 months prior to the Screening Visit.
5. Women who are pregnant or nursing, or women of childbearing potential who do not use adequate contraception, or who are judged to be unreliable in their use of contraception.
6. Patients who have participated in any clinical trial within one month prior to the Screening Visit.
7. Patients who have a medical condition that, in the Investigator's opinion, would expose them to an increased risk of a significant adverse event or interfere with assessments of safety and efficacy during the course of the trial.
8. Patients with severe renal insufficiency (Creatinine clearance \< 30 ml/min)
9. Patient has a BDI score \>29
10. Patients with any current malignancy, or any clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal or neurological disease (including any form of epilepsy). If there is a history of such disease but the condition has been stable for at least the past year and is judged by the investigator not to interfere with the patient's participation in the study, the patient may be included.
11. Patients with systolic blood pressure greater than 180 mm Hg or less than 90 mm Hg or diastolic blood pressure greater than 105 mm Hg or less than 50 mm Hg at the Screening visit. Similarly, tachycardia of \>110/min is exclusionary.
12. Patients who require concomitant therapy with any prohibited prescription or over-the-counter medication, including aspirin (except 81 mg for heart disease) or antidepressant medications.
13. Patients who are unable to speak, read, and understand English or are judged by the investigator to be unable or unlikely to follow the study protocol and complete all scheduled visits.
B: Inclusion Criteria:

* Participants present with pain due to bilateral, peripheral neuropathy
* Participants who have hemoglobin A1c (HbA1c) ≤9.4% (National Glycohemoglobin Standardization Program \[NGSP\]) at screening
* Participants who have HbA1c that has been measured 42 to 70 days prior to screening, and the range of variation in the values measured, thereafter, is within ±1.0% of the value measured at screening
* Participants who have a score of at least 4 on the mean of the 24-hour average pain score measured using 11-point NRS (Numeric Rating Scale) in the daily diary (should be calculated from records 7 days immediately prior to randomization)
* Participants who have made complete daily diary entries 80% or more of the time from screening to randomization

Exclusion Criteria:

* Participants who have undergone renal transplant, or are currently undergoing renal dialysis
* Participants who have uncontrolled narrow-angle glaucoma, history of uncontrolled seizures, or uncontrolled or poorly controlled hypertension
* Participants whose glycemic control has been poor within 70 days immediately prior to screening (for example, ketoacidosis requiring hospitalization, or hypoglycemia that may cause consciousness disorder)
* Pregnant or lactating female participants, or male participants who are planning for their partners to be or become pregnant during the timeframe of the study
* Participants who have hypersensitivity to multiple medications
* Participants who answered "yes" to either question 4 (active suicidal ideation with some intent to act, without specific plan) or question 5 (active suicidal ideation with specific plan and intent) on the "suicidal ideation" portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or answered "yes" to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the "suicidal behavior" portion of the C-SSRS; and the ideation or behavior occurred within the past month
* Participants who have past history of psychiatric diseases, such as depression, anxiety disorder, eating disorder, etc., that required drug therapy in the past 1 year, or who are currently having complications of these diseases or any history of manic psychosis or bipolar disorder
* Participants who have major depressive disorder as determined using the depression module of the Mini-International Neuropsychiatric Interview (MINI)
* Participants who have complications of diseases that are considered to affect the assessment of diabetic peripheral neuropathic pain. For example, nerve diseases with pain other than diabetic peripheral neuropathic pain (cervical spondylosis, carpal tunnel syndrome, spinal canal stenosis, and post-herpetic pain), pain diseases other than nerve diseases (collagen diseases, gout, chronic obstructive arteriosclerosis, and arthritis), and other pain at the site of evaluation (skin diseases and traumatic injury) are excluded
* Participants who have neuropathic pain suspected to be caused by alcohol
* Participants who have been treated with a monoamine oxidase (MAO) inhibitor(s) within 14 days immediately prior to randomization. Participants who visited the investigator site 14 days prior to randomization, those who have been treated with MAO inhibitors(s), thereafter, are excluded
* Participants who have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at a level ≥100 units/liter at screening
* Participants who have total bilirubin at a level ≥1.5 milligrams/deciliter (mg/dL) at screening
* Participants who have creatinine clearance (CrCL), calculated by Cockcroft-Gault, that is \<1.0 milliliters/second (mL/s) (\<60 mL/minute) at screening
* Participants who have a white blood cell (WBC) value \<2500/cubic millimeters (mm3), neutrophils \<1500/mm3, or platelets \<100×103/mm3 on their hematology tests at screening
* Participants who are introduced to any treatments for diabetes, or a change in dosing regimen of any treatments for diabetes (exclude insulin treatment), or resumption of insulin treatment after screening
* Participants who have been treated with prohibited concomitant drug(s), or who have undergone prohibited concomitant treatment(s) after screening
* Participants who have taken restricted concomitant drugs 27 days immediately before screening, with continued use of the restricted concomitant drug prior to screening
* Participants who have taken acetaminophen for 4 days or more 7 days immediately prior to randomization
C: Inclusion Criteria:

1. Provide written informed consent and abide by the study restrictions.
2. Males and females between 40 and 75 years of age and body weight \>40 kg and \<150 kg with a body mass index (BMI) between 20-35 kg/m2 inclusive
3. Patients with osteoarthritic knee based on disease diagnostic criteria as presented in section; Inclusion Disease Criteria.
4. Self-reported pain intensities higher or equal to 5 cm on a 0-10 cm visual analog scale when asked to assess the worst pain within the last 24 hours
5. Have agreed to maintain the same activity level throughout the course of the study.
6. Knee pain for at least 14 days per month for the last three months before study entry.
7. Osteophytes (with radiographic evidence).
8. At least 1 of the following 3 conditions: Age \>50, or morning stiffness \<30 minutes, or crepitus.
9. Kellgren and Lawrence grade of I, II or III at the index knee. If the patient has had X-rays of the knee joints within the last year, which can confirm the diagnosis, they may be used. Otherwise, a new posterior-anterior view X-ray of both knees will be conducted by CCBR Aalborg.
10. Worst pain within the last 24-hour must be 5.0cm to 10.0cm (assessed on a 0-10 cm VAS scale anchored at 0cm: no pain and 10cm: worst pain imaginable) prior to enrolment.
11. Discontinued use of all analgesic medications (including over-the-counter \[OTC\] analgesics/ Non-Steroidal Anti-Inflammatory Drug (NSAID) at least three days prior to randomization (patients are allowed limited use of analgesic medications).

Exclusion Criteria:

1. Have a history of recurrent seizures other than febrile seizures.
2. Have a history of frequent and/or severe allergic reactions with multiple medications.
3. Patients with a current or recent history, as determined by the PI or his delegates, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, psychiatric or cerebral disease which could interfere with the patient's participation in the study.
4. Moderate or great hepatic impairment. Retest of abnormal lab values is allowed once. If still abnormal, the patient will be excluded.
5. An alanine aminotransaminase (ALAT) higher than the Upper Limit of Normal (ULN) or explain by obesity
6. Have prior renal transplant, current renal dialysis or severe renal insufficiency (creatinine clearance of \<30 mL/min), or serum creatinine laboratory value \>1.5 times ULN, based on the reference ranges of the central laboratory.
7. Have uncontrolled hypertension (systolic blood pressure over 160 and diastolic blood pressure over 100)
8. Have active peptic ulcer, gastrointestinal (GI) bleeding or previous unexplained bleeding episodes
9. Have known inflammatory intestinal disease or gastrointestinal disease which might impact absorption
10. Patients with congestive heart failure (NYHA II-IV)
11. Bazett's corrected QT (QTcB) interval \> 450 msec for men and \> 470 msec for women
12. Patients with diabetes mellitus and documented atherosclerosis
13. Patients allergic to the active ingredient of duloxetine or one or more of the excipients
14. Pregnancy and breast feeding
15. Non-postmenopausal (defined as the absence of menstruation for at least 12 months and confirmed by assessing the follicle-stimulating hormone (FSH) level) and non-sterile females patients not using fertility control such as either birth control pills, hormonal or copper intrauterine device (IUD), vaginal ring, implant, transdermal release patch, or birth control depot injections
16. Patients with an active malignancy of any type or a history of malignancy within the last five years (except basal cell carcinoma of the skin that has been excised prior to study start)
17. Are taking any excluded medications (analgesic medications) that cannot be discontinued during the study period.
18. Patients in treatment with anticoagulants (with the exception of acetylsalicylic acid)
19. In treatment with a CYP1A2 inhibitors.
20. Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at Visit 1.
21. Have a history of substance abuse or dependence within the past year, excluding nicotine and caffeine
22. Patients at a high risk of infection (e.g. leg ulcers, indwelling urinary catheter and persistent or recurrent chest infections and patients who are permanently bed ridden or wheelchair bound)
23. Patients with a history of, or suspected, demyelinating disease of the central nervous system (e.g. multiple sclerosis or optic neuritis).
24. The investigator experiences that the volunteers do not fully understand the experimental pain procedures.
25. Investigator site personnel directly affiliated with this study and/or their immediate family. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
26. Patients on monoamine oxidase inhibitors (MAOIs), dopamine-antagonists, tricyclic antidepressants (TCAs), selective serotonin re-uptake inhibitors (SSRI)s or SNRIs, as well as use of the supplement St. John's Wort
27. Psychiatric diagnosis or symptoms (e.g. depression or anxiety) that in the opinion of the investigator could interfere with study procedures or participation evaluated using the Mini International Neuropsychiatric Interview (M.I.N.I.).
28. Has answered "yes" in the Columbia-Suicide Severity Rating Scale (C-SSRS) to suicidal ideation items 4 or 5, or any suicidal behaviour within six months before screening, at screening or at randomization visit, or has been hospitalized or treated for suicidal behaviour in the past five years before screening.
29. Patients are not allowed to donate blood or blood products during the study
30. Have secondary causes of arthritis of the knee including septic arthritis, inflammatory joint disease, articular fracture, major dysplasia or congenital abnormality, acromegaly, hemochromatosis, Wilson's disease, and primary osteochondromatosis.
31. Have had lower extremity surgery (including arthroscopy of the index knee) within 3 months prior to Visit 1 or have surgery planned of the index knee at any time.
32. Have had significant prior injury to the index knee within 12 months prior to Visit 1.
33. Use of lower extremity assistive devices other than a cane or knee brace (use of a 'shoe lift' is permitted). 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.
34. Has had a prior synovial fluid analysis showing a White Blood Cell (WBC) ≥2000mm3 that is indicative of a diagnosis other than OA at the index knee.
35. Have a 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).
36. Have any other musculoskeletal or arthritic condition that may affect the interpretation of the clinical efficacy and/or safety data or otherwise contraindicates participation in this clinical study (i.e., currently symptomatic fractures or any concurrent rheumatic diseases such as but not limited to fibromyalgia, rheumatoid arthritis, gout, pseudo-gout or Paget's disease and Reiter's syndrome are excluded).
37. Have used corticosteroids prior to baseline:

    1. Intra-articular injection of steroids to the index knee or into any other site than the index knee within the previous three months.
    2. Intra-muscular corticosteroid injections within the previous three months.
    3. Oral corticosteroids within the previous one month.
38. Have initiated or have changed to an established physiotherapy program within two weeks prior to Visit 2 or during the study period. An established physiotherapy program may be continued throughout the study period if unchanged in frequency and intensity.
D: Inclusion Criteria:

* Meet criteria for primary Fibromyalgia Syndrome as defined by the American College of Rheumatology

Exclusion Criteria:

* Have any current primary Axis I diagnosis other than major depressive disorder
* Have any current or previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder
* Have any primary diagnosis of anxiety disorder within the past year (including panic disorder, agoraphobia, OCD, PTSD, GAD and social phobia)
* Have regional pain syndrome, multiple surgeries or failed back syndrome
* Have a confirmed current or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or infective arthritis, or an autoimmune disease (e.g. lupus)

Answer: D