OsteoarthritisPhase 4IPRONCT02208778
Imaging Pain Relief in Osteoarthritis
A Phase 4 study testing Duloxetine and Remifentanil in people with Osteoarthritis and Chronic Pain, run by University of Nottingham at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 years and older
- Conditions the study is for
- Osteoarthritis, Chronic Pain
- What is being tested?
- Duloxetine and Remifentanil
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 77 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Dec 2014to Jun 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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;
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- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
University of Nottingham - School of Medicine - Radiological Sciences
Nottingham, Nottinghamshire, NG7 2UH
About this study
Official title: Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis
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
Read more
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.
- Conditions
- Osteoarthritis, Chronic Pain
- Being tested
- Duloxetine, Remifentanil, Placebo (for Remifentanil), Placebo (for Duloxetine)
- Keywords
- Osteoarthritis, Chronic Pain, Pain relief
- Medical subject headings
- Osteoarthritis, Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DuloxetineDrug
Also called Cymbalta
54 participants will be allocated for duloxetine treatment
RemifentanilDrug
Also called Remifentanil hydrochloride
27 participants will be allocated to Remifentanil infusion
Placebo (for Remifentanil)Drug
Also called Sodium chloride, Normal saline
Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm
Placebo (for Duloxetine)Drug
Also called Sugar pill
Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention
| Study group | Role | What they receive |
|---|---|---|
| Duloxetine | Experimental | Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth Receives: Drug: Duloxetine |
| Placebo (for Duloxetine) | Placebo comparator | Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth Receives: Drug: Placebo (for Duloxetine) |
| Remifentanil | Experimental | Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes Receives: Drug: Remifentanil |
| Placebo (for Remifentanil) | Placebo comparator | Intravenous infusion of normal saline, during less than 20 min Receives: Drug: Placebo (for Remifentanil) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction in nociceptive brain response after duloxetine
Measured: Baseline, week six
Neural network change (resting condition) induced by duloxetine
Measured: Baseline, week six
Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis
Measured: Baseline, week six
Differences in brain response and network change between responders and non-responders
Measured: Baseline, week six
Secondary outcomes (3)
Identification of QST and questionnaire parameters that predict response to duloxetine
Measured: Baseline, week six
Correlation between baseline CPM and TS with brain activity and connectivity changes
Measured: 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
Measured: Baseline, week six
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2014 (estimated)
- Study startDec 2014
- Primary completionJun 2016
- Study completionJun 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for OsteoarthritisStudies of the same condition, open and under way.
- More trials run by University of NottinghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Nottingham
- Sponsor type
- University, hospital or other
- Collaborators
- Arthritis Research UK
- Responsible party
- Sponsor
- Investigators
- Dorothee P Auer, PhD, Principal investigator, University of Nottingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02208778
- Sponsor's protocol ID
- 13124
- Acronym
- IPRO
- Status last verified
- May 2017
- First submitted
- 4 Aug 2014
- Last updated
- 27 Nov 2017
- Results posted
- No
- Data monitoring committee
- No
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.
PubMed 28652290
Study at a glance
From the registry record, last updated by the sponsor on 27 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis
- ClinicalTrials.gov ID
- NCT02208778
- Acronym / sponsor ID
- IPRO / 13124
- Conditions
- Osteoarthritis, Chronic Pain
- Keywords
- Osteoarthritis, Chronic Pain, Pain relief
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- University of NottinghamUniversity, hospital or other
- Collaborators
- Arthritis Research UK
- Study start
- Dec 2014
- Primary completion
- Jun 2016 (actual)
- Study completion
- Jun 2016 (actual)
- First posted
- 5 Aug 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Duloxetine | Experimental | Drug: DuloxetineDuloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth |
| Placebo (for Duloxetine) | Placebo comparator | Drug: Placebo (for Duloxetine)Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth |
| Remifentanil | Experimental | Drug: RemifentanilIntravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes |
| Placebo (for Remifentanil) | Placebo comparator | Drug: Placebo (for Remifentanil)Intravenous infusion of normal saline, during less than 20 min |
Who may qualify
- Ages
- 35 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (32 listed)
- People with any known contraindication to MRI like
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DuloxetineAlso: Cymbalta54 participants will be allocated for duloxetine treatment | Drug | Duloxetine |
| RemifentanilAlso: Remifentanil hydrochloride27 participants will be allocated to Remifentanil infusion | Drug | Remifentanil |
| Placebo (for Remifentanil)Also: Sodium chloride, Normal salinePlacebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm | Drug | Placebo (for Remifentanil) |
| Placebo (for Duloxetine)Also: Sugar pillSugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention | Drug | Placebo (for Duloxetine) |
Primary outcome
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
3 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Nov 2017.
- Derived from this study: PubMed 28652290Reckziegel 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Dorothee P Auer, PhD principal investigator
University of Nottingham
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Duloxetine and Remifentanil in people with Osteoarthritis and Chronic Pain, run by University of Nottingham at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction in nociceptive brain response after duloxetine (time frame: Baseline, week six). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02208778, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Nov 2017.