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Imaging Pain Relief in Osteoarthritis (IPRO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02208778
Recruitment Status : Completed
First Posted : August 5, 2014
Last Update Posted : November 27, 2017
Sponsor:
Collaborator:
Arthritis Research UK
Information provided by (Responsible Party):
University of Nottingham

Tracking Information
First Submitted Date  ICMJE August 4, 2014
First Posted Date  ICMJE August 5, 2014
Last Update Posted Date November 27, 2017
Study Start Date  ICMJE December 2014
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Reduction in nociceptive brain response after duloxetine [ Time Frame: Baseline, week six ]
  • Neural network change (resting condition) induced by duloxetine [ Time Frame: Baseline, week six ]
  • Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis [ Time Frame: Baseline, week six ]
  • Differences in brain response and network change between responders and non-responders [ Time Frame: Baseline, week six ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 4, 2014)
Demonstration of differences in brain activity during pain perception between pre and post active treatments. [ Time Frame: Baseline, week six ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2016)
  • Identification of QST and questionnaire parameters that predict response to duloxetine [ Time Frame: Baseline, week six ]
  • Correlation between baseline CPM and TS with brain activity and connectivity changes [ Time Frame: Baseline, week six ]
  • Group differences in brain activity and structure in pain processing, limbic and modulatory pathways changes following duloxetine treatment in comparison to placebo [ Time Frame: Baseline, week six ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: August 30, 2016)
Determination of gene variations that can be linked with duloxetine treatment response [ Time Frame: Baseline, week six ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Imaging Pain Relief in Osteoarthritis
Official Title  ICMJE Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis
Brief Summary

Osteoarthritis (OA) is a degenerative joint disease and is the most common form of arthritis. Pain reduction and functional recovery are the key elements of the clinical management of OA. Current treatment guidelines recommend a combination of pharmacological and non-pharmacological treatments. However, these are not always effective, with nearly 20% of patients not responding to any standard therapy, including joint replacement.

The mechanisms of pain relief are not well understood and are complicated by the remarkably large placebo effect, and inter-individual variation. There is no objective criteria for predicting whether a patient will respond to a given treatment

Duloxetine, an antidepressant drug, has proven effectiveness in various chronic pain syndromes including knee OA. The effect is however limited and only clinically relevant in around half of the trial patients. Importantly, it is currently unclear how and in whom duloxetine alleviates chronic pain.

Advanced MRI techniques use strong magnetic fields and radio frequency signals to generate metabolic, anatomical and functional brain images (fMRI).

Remifentanil is a potent analgesic agent whose analgesic effect has been well characterised in healthy volunteers, including fMRI studies showing modulation of activation of regions in the brain related to pain processing. Nevertheless, the neural correlates of remifentanil effects have not yet been investigated in chronic pain patients.

The aim of this research is to use a combination of multimodal MRI, genetic and psychometric assessments to identify the mechanisms of pain relief in knee OA patients, following treatments with duloxetine and remifentanil, in a placebo controlled condition. With this we also aim to identify genetic, anatomical and brain activity predictors of treatment outcomes.

The main hypotheses are:

  • Analgesic response to duloxetine treatment can be predicted using a range of baseline brain imaging markers and QST.
  • Analgesic response to duloxetine is mediated by modulation of neural networks underpinning emotional control.
  • Duloxetine-induced changes in brain activation differ between responders and non-responders.

This study is expected to last for two years. It is funded by Arthritis Research United Kingdom and forms part of a wider scientific investigation, using translational methodologies, to enhance the understanding of arthritis pain and to improve its treatment.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Osteoarthritis
  • Chronic Pain
Intervention  ICMJE
  • Drug: Duloxetine
    54 participants will be allocated for duloxetine treatment
    Other Name: Cymbalta
  • Drug: Remifentanil
    27 participants will be allocated to Remifentanil infusion
    Other Name: Remifentanil hydrochloride
  • Drug: Placebo (for Remifentanil)
    Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm
    Other Names:
    • Sodium chloride
    • Normal saline
  • Drug: Placebo (for Duloxetine)
    Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention
    Other Name: Sugar pill
Study Arms  ICMJE
  • Experimental: Duloxetine
    Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth
    Intervention: Drug: Duloxetine
  • Placebo Comparator: Placebo (for Duloxetine)
    Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth
    Intervention: Drug: Placebo (for Duloxetine)
  • Experimental: Remifentanil
    Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes
    Intervention: Drug: Remifentanil
  • Placebo Comparator: Placebo (for Remifentanil)
    Intravenous infusion of normal saline, during less than 20 min
    Intervention: Drug: Placebo (for Remifentanil)
Publications * Reckziegel D, Bailey H, Cottam WJ, Tench CR, Mahajan RP, Walsh DA, Knaggs RD, Auer DP. Imaging pain relief in osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome. BMJ Open. 2017 Jun 26;7(6):e014013. doi: 10.1136/bmjopen-2016-014013.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 23, 2017)
77
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2014)
93
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Radiographically defined OA knee changes with knee pain
  • Must have self-reported knee pain
  • Able to give informed consent
  • Over 35 years old
  • Male or female
  • Females not pregnant or lactating and using effective contraception

Exclusion Criteria:

  • People with any known contraindication to MRI like

    • Intraocular metallic foreign bodies;
    • Intracranial aneurysm clips;
    • Cardiac pacemakers and defibrillators;
    • Cochlear implants;
  • People with a significant head tremor;
  • People with potential metal foreign bodies due to previous accidents;
  • Breastfeeding or pregnancy, confirmed by pregnancy test;
  • People that are felt to be unfit for the MRI scan according to the judgement of medically qualified personnel, either on the research team, or the patient's clinical team. (eg. due to back pain, claustrophobia, acute sickness etc.) This includes patients with signs of impaired temperature regulation such as an extremely high fever;
  • Patients with large tattoos, specifically in the head, neck or shoulder region;
  • Persons that do not have the capacity to consent;
  • Aged less than 35;
  • Major medical, neurological and psychiatric co-morbidities;
  • Other significant medical condition;
  • Metallic agents embedded within the body (ie. Shrapnel, surgical pins);
  • Refusal by participant to general practitioner (GP) being informed;
  • Have uncontrolled narrow-angle glaucoma;
  • Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);
  • Taking fluvoxamine, ciprofloxacin or enoxacin;
  • Taking St. John's Wort, a herbal treatment (Hypericum perforatum);
  • Taking other medicines containing duloxetine;
  • Have liver disease or severe kidney disease;
  • Currently on antidepressant treatment, including treatment for pain with tricyclic agents such as amitryptiline;
  • Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);
  • Taking tramadol;
  • Known hypersensitivity, allergy or intolerance to one of duloxetine's components;
  • Unwillingness to take caution in relation to use of other centrally active substances such as alcohol and sedative drugs;
  • Current treatment with potent inhibitors of CYP1A2 like fluvoxamine;

Participants undergoing acute treatment (remifentanil or placebo) have, in addition to the stated above, the following exclusion criteria:

  • Taking morphine
  • Known hypersensitivity, allergy or intolerance to one of remifentanil's components or other fentanyl - analogues
  • Current treatment with cardiac depressant drugs such as beta-blockers and calcium channel blocking agents
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02208778
Other Study ID Numbers  ICMJE 13124
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Nottingham
Study Sponsor  ICMJE University of Nottingham
Collaborators  ICMJE Arthritis Research UK
Investigators  ICMJE
Principal Investigator: Dorothee P Auer, PhD University of Nottingham
PRS Account University of Nottingham
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP