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Imaging Pain Relief in Osteoarthritis (IPRO)

Primary Purpose

Osteoarthritis, Chronic Pain

Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Duloxetine
Remifentanil
Placebo (for Remifentanil)
Placebo (for Duloxetine)
Sponsored by
University of Nottingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteoarthritis focused on measuring Osteoarthritis, Chronic Pain, Pain relief

Eligibility Criteria

35 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Nottingham - School of Medicine - Radiological Sciences

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Duloxetine

Placebo (for Duloxetine)

Remifentanil

Placebo (for Remifentanil)

Arm Description

Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth

Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth

Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes

Intravenous infusion of normal saline, during less than 20 min

Outcomes

Primary Outcome Measures

Reduction in nociceptive brain response after duloxetine
Neural network change (resting condition) induced by duloxetine
Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis
Differences in brain response and network change between responders and non-responders

Secondary Outcome Measures

Identification of QST and questionnaire parameters that predict response to duloxetine
Correlation between baseline CPM and TS with brain activity and connectivity changes
Group differences in brain activity and structure in pain processing, limbic and modulatory pathways changes following duloxetine treatment in comparison to placebo

Full Information

First Posted
August 4, 2014
Last Updated
November 23, 2017
Sponsor
University of Nottingham
Collaborators
Arthritis Research UK
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1. Study Identification

Unique Protocol Identification Number
NCT02208778
Brief Title
Imaging Pain Relief in Osteoarthritis
Acronym
IPRO
Official Title
Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
December 2014 (undefined)
Primary Completion Date
June 2016 (Actual)
Study Completion Date
June 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Nottingham
Collaborators
Arthritis Research UK

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteoarthritis, Chronic Pain
Keywords
Osteoarthritis, Chronic Pain, Pain relief

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
77 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Duloxetine
Arm Type
Experimental
Arm Description
Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth
Arm Title
Placebo (for Duloxetine)
Arm Type
Placebo Comparator
Arm Description
Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth
Arm Title
Remifentanil
Arm Type
Experimental
Arm Description
Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes
Arm Title
Placebo (for Remifentanil)
Arm Type
Placebo Comparator
Arm Description
Intravenous infusion of normal saline, during less than 20 min
Intervention Type
Drug
Intervention Name(s)
Duloxetine
Other Intervention Name(s)
Cymbalta
Intervention Description
54 participants will be allocated for duloxetine treatment
Intervention Type
Drug
Intervention Name(s)
Remifentanil
Other Intervention Name(s)
Remifentanil hydrochloride
Intervention Description
27 participants will be allocated to Remifentanil infusion
Intervention Type
Drug
Intervention Name(s)
Placebo (for Remifentanil)
Other Intervention Name(s)
Sodium chloride, Normal saline
Intervention Description
Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm
Intervention Type
Drug
Intervention Name(s)
Placebo (for Duloxetine)
Other Intervention Name(s)
Sugar pill
Intervention Description
Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention
Primary Outcome Measure Information:
Title
Reduction in nociceptive brain response after duloxetine
Time Frame
Baseline, week six
Title
Neural network change (resting condition) induced by duloxetine
Time Frame
Baseline, week six
Title
Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis
Time Frame
Baseline, week six
Title
Differences in brain response and network change between responders and non-responders
Time Frame
Baseline, week six
Secondary Outcome Measure Information:
Title
Identification of QST and questionnaire parameters that predict response to duloxetine
Time Frame
Baseline, week six
Title
Correlation between baseline CPM and TS with brain activity and connectivity changes
Time Frame
Baseline, week six
Title
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
Other Pre-specified Outcome Measures:
Title
Determination of gene variations that can be linked with duloxetine treatment response
Time Frame
Baseline, week six

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dorothee P Auer, PhD
Organizational Affiliation
University of Nottingham
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Nottingham - School of Medicine - Radiological Sciences
City
Nottingham
State/Province
Nottinghamshire
ZIP/Postal Code
NG7 2UH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
28652290
Citation
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.
Results Reference
derived

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Imaging Pain Relief in Osteoarthritis

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