A Mechanism Based Proof of Concept Study of the Effects of Duloxetine in the Treatment of Patients With Osteoarthritic Knee Pain

NCT04224584 | Completed Phase 2

• 1 other identifier: DULKOA2019
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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. 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. 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.

Conditions

Osteoarthritis, Knee

Outcome Measures

Primary Outcomes (1)

• Pressure Pain Threshold.

  Assessment of pressure hyperalgesia. The Pressure Pain Threshold is assessed using a Somedic Handheld algometer (Somedic AB, Sösdala, Sweden). The Pressure Pain Threshold is assessed in kPa (kilo pascal).

  Difference between baseline (prior to treatment) compared with 10 weeks of 60 mg/daily duloxetine compared with placebo

Study Arms (2)

Duloxetine

ACTIVE COMPARATOR

Duloxetine is a serotonin-norepinephrine reuptake inhibitor. Duloxetine will be administrated as follows: 20 mg/daily duloxetinefor 1 week, 40 mg/daily duloxetine for 1 week, 60 mg/daily duloxetine for 10 weeks, 40 mg/daily duloxetine for 1 week, 20 mg/daily duloxetine for 1 week.

Drug: Duloxetine

Placebo

PLACEBO COMPARATOR

Placebo will be administrated for 14 weeks.

Drug: Placebo oral tablet

Interventions

Duloxetine DRUG

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.

Duloxetine

Placebo oral tablet DRUG

Placebo will act as a control for duloxetine.

Placebo

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written informed consent and abide by the study restrictions.
• 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
• 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
• Have agreed to maintain the same activity level throughout the course of the study.
• Knee pain for at least 14 days per month for the last three months before study entry.
• Osteophytes (with radiographic evidence).
• At least 1 of the following 3 conditions: Age \>50, or morning stiffness \<30 minutes, or crepitus.
• 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.
• 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.
• 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).

You may not qualify if:

• Have a history of recurrent seizures other than febrile seizures.
• Have a history of frequent and/or severe allergic reactions with multiple medications.
• 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.
• Moderate or great hepatic impairment. Retest of abnormal lab values is allowed once. If still abnormal, the patient will be excluded.
• An alanine aminotransaminase (ALAT) higher than the Upper Limit of Normal (ULN) or explain by obesity
• 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.
• Have uncontrolled hypertension (systolic blood pressure over 160 and diastolic blood pressure over 100)
• Have active peptic ulcer, gastrointestinal (GI) bleeding or previous unexplained bleeding episodes
• Have known inflammatory intestinal disease or gastrointestinal disease which might impact absorption
• Patients with congestive heart failure (NYHA II-IV)
• Bazett's corrected QT (QTcB) interval \> 450 msec for men and \> 470 msec for women
• Patients with diabetes mellitus and documented atherosclerosis
• Patients allergic to the active ingredient of duloxetine or one or more of the excipients
• Pregnancy and breast feeding
• 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

Sponsors & Collaborators

• Kristian Kjær Petersen: lead
• CCBR, Aalborg: collaborator
• Aalborg University Hospital: collaborator

Study Sites (1)

Mech-Sense

Aalborg, 9000, Denmark

Location

Related Publications (1)

• Ammitzboll N, Arendt-Nielsen L, Bertoli D, Brock C, Olesen AE, Kappel A, Drewes AM, Petersen KK. A mechanism-based proof of concept study on the effects of duloxetine in patients with painful knee osteoarthritis. Trials. 2021 Dec 27;22(1):958. doi: 10.1186/s13063-021-05941-y.

  PMID: 34961547 DERIVED

MeSH Terms

Conditions

Osteoarthritis, Knee

Interventions

Duloxetine Hydrochloride

Condition Hierarchy (Ancestors)

Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor, M.Sc., Ph.D.

Study Record Dates

• First Submitted: January 6, 2020
• First Posted: January 13, 2020
• Study Start: January 1, 2020
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: February 16, 2022

Record last verified: 2022-02

Locations

DK (1)