Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Pivotal, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Milnacipran for the Treatment of Fibromyalgia
Brief Summary: Antidepressants of all varieties represent a common form of therapy for many chronic states including fibromyalgia. The majority of antidepressants increase the levels of serotonin or norepinephrine in the central nervous system. Milnacipran is a dual norepinephrine and serotonin reuptake inhibitor and may be effective in the treatment of fibromyalgia.


Options:
A: Inclusion Criteria:

* Diagnosis of fibromyalgia defined by 1990 American College of Rheumatology (ACR) Criteria

Exclusion Criteria:

* Psychiatric illness
* Depression
* Suicidal risk
* Substance abuse
* Pulmonary dysfunction
* Renal impairment
* Active cardiac disease
* Liver disease
* Autoimmune disease
* Cancer
* Sleep apnea
* Inflammatory bowel disease
B: Inclusion Criteria:

* Participants fulfilling the following criteria in the American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia
* Participants with pain rated severity 4 or over by Brief Pain Inventory (BPI) - average pain severity item (Question 3)

Exclusion Criteria:

* Participants with serious cardiovascular, hepatic, renal, respiratory, or hematological disease, or clinically significant laboratory or electrocardiogram abnormality which indicate a serious medical problem or require significant intervention in the judgment of the investigators
* Participants with alanine aminotransferase/aspartate aminotransferase of not less than 100 international units per liter (IU/L) or total bilirubin of not less than 1.6 milligrams per deciliter (mg/dL)
* Participants with serum creatinine level of not less than 2.0 mg/dL, participant who has undergone kidney transplantation or hemodialysis
* Participants with pain difficult to discriminate from pain associated with fibromyalgia or disease which disturbs the assessment
* Participants with treatment-refractory fibromyalgia
* Participants with thyroidal dysfunction, excluding those assessed by the investigator that the disorder is controlled as appropriate by 3-month or longer drug therapy
* Participants with present or past history of rheumatoid arthritis, inflammatory arthritis, infectious arthritis, or auto immune disease rather than thyroid deficiency
* Participants with an axis I condition according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), currently or within the past year, except for major depressive disorders
* Participants with a lifetime diagnosis of bipolar disorder or schizoaffective disorder; or any other disorder with psychotic symptoms - based on the clinical opinion of the investigator
* Participants with personality disorder or mental retardation
* Participants with uncontrolled angle closure glaucoma
* Participants with present or past history of uncontrolled seizures or convulsion disorders
* Participants with suicidal ideation within past 6 months, with suicidal attempt within past 1 year
* Participants answering "yes" to any of the questions about active suicidal ideation/intent/behaviors occurring within the past 6 months (Columbia Suicide Severity Rating Scale, Suicide Ideation section - Questions 4 and 5; Suicidal Behavior section)
* Participants with past history of multiple episodes of drug allergy
* Female participants who are pregnant, lactating, or who want to get pregnant during the study period. Male participants who want his partner to get pregnant
* Females of child-bearing potential who can't agree to utilize medically. acceptable and reliable means of birth control during the study and for 1 month following the last dose of the study
* Participants with a history of alcohol or any psychoactive substance abuse or dependence (including alcohol, but excluding nicotine and caffeine) within the past 1 year
* Participants who have a positive urine drug screen for any substance of abuse (phencyclidine, cocaine, antihypnotic agent, or cannabis)
* Participants previously treated with duloxetine
C: Inclusion Criteria:

* Age: 45-80 years
* ACR criteria for OA including Kellgren-Lawrence radiographic OA grades II-IV
* VAS pain score \>5/10 within 48 hrs of the phone screen and visit 1 (Screening)
* Knee OA for a minimum of 12 months
* Need for daily pain medication to manage symptoms of OA

Exclusion Criteria:

Currently taking MAO inhibitors or any centrally acting drug for analgesia, depression

* Narrow angle glaucoma
* Uncontrolled hypertension
* Co-existing inflammatory arthritis, fibromyalgia or other chronic pain state.
* If a female, pregnant, trying to become pregnant, or lactating
* Major depressive disorder
* Substantial alcohol use or history of significant liver disease
* Use of MAO inhibitors, triptans, serotonin precursors (tryptophan)
* Use of potent CYP1A2 inhibitors, Thioridazine, and anti-depressants
* Diabetes, type 1 or type 2
* Condition in which the Investigator believes would interfere with the subject's ability to comply with study instructions, or might confound the interpretation of the study results or put the subject at undue risk
* MRI safety necessitates the exclusion of subjects having one or more of the following:

  * Metal fragments in the eye or face, or having worked previously in the metal industry
  * Implantation of any electronic devices such as (but not limited to) cardiac pacemakers, cardiac, defibrillators, and cochlear implants or nerve stimulators.
  * Surgery on the blood vessels of the brain
  * Claustrophobia (fear of enclosed places)
  * Piercings or tattoos
  * More than 250 lbs in weight
  * Obvious brain abnormalities
D: 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.

Answer: A