A Mechanism Based Proof of Concept Study of the Effects of Duloxetine in the Treatment of Patients With Osteoarthritic Knee Pain
Condition: Osteoarthritis, Knee
MeSH terms: Osteoarthritis, Knee
Study type: Interventional
Phase: Phase 2

Summary: 
      Background: Duloxetine provides an analgesic effect of patients with OA. The mode of action
      of duloxetine is partly believed to act through modulating the descending inhibitory pain
      pathways from the brainstem towards the spinal cord thereby dampening pain by gating the
      afferent pain signals from the periphery during their passage to the brain. This study aims
      to investigate if the analgesic effect of duloxetine is due to modulation of pain mechanisms.

      Study Rationale: The present study will utilize a set of quantitative pain biomarkers
      developed to assess peripheral and central manifestations in OA and the influence of
      duloxetine on those manifestations.

      Treatment: Patients will be randomized to one of two treatment sequences:

        1. Sequence 1: 20 mg duloxetine QD for 1 week, 40 mg Duloxetine QD for 1 week, 60 mg
           duloxetine QD for 10 weeks, 40 mg duloxetine QD for 1 week, 20 mg duloxetine QD for 1
           week, followed by 14 weeks of corresponding placebo

        2. Sequence 2: 14 weeks of placebo followed by 20 mg Duloxetine QD for 1 week, 40 mg
           duloxetine QD for 1 week, 60 mg duloxetine QD for 10 weeks, 40 mg duloxetine QD for 1
           week and 20 mg duloxetine QD for 1 week.

      The two treatment periods of 14 weeks each are separated by a washout period of two weeks and
      include a two-week titration period.

      Primary Objective: To assess the effect of 60 mg daily maintenance dose administration of
      Duloxetine for 10 weeks compared with placebo on pain mechanisms.

      Sample Size Justification/Statistics: The sample size was calculated to 32 patients providing
      a power of 85% with a significant level of 0.05 to detect a group difference of 1 point in
      the change from baseline of the week 12 mean of 24-hour worst pain between duloxetine and
      placebo treatment.

      Patient Selection: Up to 40 patients with osteoarthritic knee pain will be enrolled in this
      study in order to complete 32 patients.

      Study sites:

      Mech-Sense Aalborg University Hospital, DK-9000 Aalborg, Denmark Study Assessments: As the
      primary objective of this study is the assessment of which pain mechanisms are modulated by
      administration of the study drug, the primary endpoints will be Experimental Mechanism Based
      Pain Measures (EPMs) including 1) Pressure Pain Thresholds (PPTs), Temporal Summation,
      Conditioned Pain Modulation (CPM) and Offset Analgesia. In addition, efficacy will be
      evaluated using 1) pain severity (worst daily pain and night pain), 2) Pittsburgh Sleep
      Quality Index (PSQI), 3) Brief Pain Inventory (BPI), 4) Investigator and Patient Global
      Assessment of Changes (IGIC and PGAC), 5) Western Ontario and MacMaster (WOMAC) OA physical
      function, 6) PainDetect, and 7) Central Sensitization Index (CSI).

      Safety: Discontinuation rates and Treatment Emergent Adverse Events (TEAEs). Key
      Inclusion/Exclusion Criteria: Males or females between 40 and 75 years of age, who are
      postmenopausal or using allowed contraception methods, and have a Body Mass Index (BMI)
      between 20-35 kg/m2 inclusive Patient with unilateral or bilateral OA of knee diagnosed
      according to the American College of Rheumatology (ACR) criteria based on clinical and
      radiographic evidence with pain severity equal to or higher than 5 on a Visual Analogue Scale
      (VAS) assessed as the worst pain within the last 24 hours.
    


Intervention name(s): Duloxetine; Placebo oral tablet
Intervention type(s): Drug; Drug
Intervention description(s): Duloxetine will be administrated with a two weeks up titration followed by a 10 weeks full treatment (60 mg/daily) and finalized by a two weeks discontinuation.; Placebo will act as a control for duloxetine.
Intervention MeSH terms: Duloxetine Hydrochloride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science