Clinical trial: A Mechanism Based Proof of Concept Study of the Effects of Duloxetine in the Treatment of Patients With Osteoarthritic Knee Pain (NCT04224584)

Eligibility criteria:
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.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 40 Years old.
Subject must be at most 75 Years

Patient description (medical language): A 66-year-old woman comes to the office due to joint pain in the hands and periodic morning stiffness that lasts less than 15 minutes.  The pain is moderately severe and worsens with daily activity. The patient used Tylenol with minimal relief.  Past medical history is notable for hypertension and hypercholesteremia.  Physical examination shows firm nodules over the distal interphalangeal joints, bilaterally. The patient has pain in her knees as well. The knees are stiff in the morning for less than 30 minutes and become worse with climbing stairs. She has some sensation of bone friction during activity. X-ray shows narrowing of the joint space, subchondral bone sclerosis and osteophyte formation along the joints.

Patient description (patient's own words): I'm a 66-year-old woman and I went to my doctor's office because of a bloody joint pain in my hands that has been lasting for a while. The pain comes and go in the morning usually. I feel like a stiffness that last less than 15 minutes. The pain is moderately severe but it gets worse when I'm using my hands. I used Tylenol which helped a little. Apart from that, I suffer from hypertension and high cholesterol. The doctor made me notice that I have bumps around both of my hand joints. I also suffer from my knees and they are also stiff in the morning for around 30 min. It's even worse when I climb up the stairs! I also feel like my bones are rubbing against each other when I'm moving. The X-ray showed that I have narrow joint space, I have sclerosis, and abnormal growths of bone along my joints.

Does the patient match the trial criteria? 1