Knee, Osteoarthritis (OA)NCT05256342
Biomarkers for Prediction of Analgesic Efficacy in Knee OA.
A study testing Duloxetine 60mg, Etoricoxib 60 mg and omeprazol in people with Knee, Osteoarthritis (OA) and Biomarkers for Prediction of OA Treatment Efficacy, run by Rambam Health Care Campus at 2 sites in Israel.
Trial summary
With high NNTs for indiscriminative use in chronic pain, treatment unavoidably entails frustrating long trial and errors. It is timely to identify biomarkers that can predict analgesic efficacy for the individual patient. Read more about this study
- Who is it for?
- Ages 45 to 75 years
- Conditions the study is for
- Knee, Osteoarthritis (OA), Biomarkers for Prediction of OA Treatment Efficacy
- What is being tested?
- Duloxetine 60mg, Etoricoxib 60 mg and omeprazol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 2 sitesIsrael
- Study dates
- 30 Dec 2021to 8 Apr 2024
- Phase
- Interventional
- 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 45 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- males and females
- ages 45 to 75
- radiographic representation of osteoarthritis of the knee
- minimal or moderate OA severity, based on the Kellgren and Lawrence system classification (1-3)
- knee OA pain for more than 3 months, assessed by the patients as being at level 4/10 and above on average at routine daily standing/walking activities during the last week, without medication
Who cannot join
- other more prominent pain
- previous bilateral total knee replacement (TKR) surgery
- secondary OA (post-traumatic or post-infectious, osteochondritis dissecans (OCD) and enteropathic arthritis (EA) deformity)
- significant additional health problems such as substantial painful neuropathy, diabetes above of 5 yrs, renal failure, congestive heart failure, neurological diseases that might mask the pain processing system or reduce patient's cooperation or report capabilities, and significant psychiatric disorders
- use of opioids or cannabis
- known diseases of gastrointestinal tract such as esophagitis, gastritis and duodenitis
- patients that had side effects to the study drugs in the past.
Trial locations and contacts
2 sites in 1 country.
Israel2 sites
Rambam Health Care Campus
Haifa, 31096
Rambam Health Care Campus
Haifa
About this study
Official title: Biomarkers for Prediction of Analgesic Efficacy Based on Interrelations Between Pain Modulation and EEG vs. Drugs' Mode of Action in Knee OA
With high NNTs for indiscriminative use in chronic pain, treatment unavoidably entails frustrating long trial and errors. It is timely to identify biomarkers that can predict analgesic efficacy for the individual patient.
The investigators propose a framework of interrelations between patient's pain modulation profile (PMP) and the drug's mode of action (MOA) based on two principles: (1) 'fix the dysfunction', relevant for drugs whose main mode of action is to modulate central pain processing; the more the dysfunctional the better the modulating drug efficacy. For example, patients with pro-nociceptive PMP due to reduced endogenous pain inhibition, as expressed by less efficient CPM will benefit from drugs that fix this dysfunction such as SNRIs, relative to patients whose pain inhibitory capacity is well functioning. Thus, for the modulating drugs, pro-nociceptivity predicts better efficacy. (2) 'bear with the dysfunction', relevant for drugs which are mostly non-modulating, acting mainly in the periphery; the more dysfunctionalת the less the non-modulating drug efficacy. This is since efficacy is limited by the dysfunctional modulation system, despite the drug's MOA-like reduction of peripheral pain mediators. Thus, for the non-modulating drugs, for example NSAIDs, pro-nociceptivity predicts less good efficacy. The likely protocol suggests that patients with anti-nociceptive PMP should be treated primarily by non-modulating drugs, while pro-nociceptive ones should be given modulating drugs.
Read more
EEG is an additional source of relevant data on brain pain processing. Being objective and stable along time, EEG based parameters are, thus, very attractive candidates to be useful biomarkers for prediction of analgesia efficacy.
This study will focus on the patients with painful knee osteoarthritis.
The aims of this study are:
- To identify psychophysical and neurophysiological biomarkers that can serve as predictors of response to analgesic pain modulating and non-pain modulating drugs.
- To establish a conceptual framework of individualized pain therapy based on inter-relations between patient's parameters of pain modulation and drugs' mode of action.
Read the detailed description
Study design:
The study design includes two experimental meeting sessions (before and at the end / after the treatment) which include clinical and experimental assessments. After the first experimental session, the patients will be asked to rate twice a week their daily pain along two weeks, in order to confirm their OA pain level; the patients with the mean pain score of ≥4 will be supplied with the study medications. Along the 8 weeks-long treatment period, they will provide the rating of OA pain, subjective estimation of pain alleviation and reports of side effects
Clinical assessment: Will be performed by the study physician. The data on OA severity by Kellgren and Lawrence system classification, range of motion and current OA pain (last 48 h) will be collected. In addition, all patients will fill the brief pain inventory questioner (BPI) to assess their pain characteristics. In addition, all patients will be tested for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for assessment of OA pain, stiffness and physical function.
Experimental session:
- At the beginning of pre-treatment experimental session, all patients will fill a following set of psychological pain-related questioners organized in one document: (1) pain catastrophizing scale (PCS), (2) HADS anxiety and depression, (3) short-form health survey (SF-12), (5) pain sensitivity questionnaire (PSQ). In addition, basic assessment of psychomotor attention and cognitive functioning will be performed using (6) Trial making tests A and B (TMT A and B) and (7) Digits symbol substitution test (DSST). All the data will be coded and no personal data will be exposed.
- Resting-state EEG recording. Three minutes of resting-state EEG (eyes closed) will be recorded using the 64-channel EEG recording (Brain Products GmbH, Munich, Germany).
- Psychophysical pain assessment. All tests will be performed remotely from the painful area - on arm or hand. The following tests will be performed:
- Electrical and mechanical temporal summation (TS). For the assessment of electrical TS, a train of 10 electrical stimuli (Digitimer DS7A, Digitimer Ltd, WelWyn Garden City, England) of 2 msec width will be delivered to the non-dominant forearm with ISI of 1 sec. Subject will rate the perceived pain after the 1st and after the 5th stimuli using verbal numerical rating scale (NRS). Mechanical TS with be assessed using ten application of 256mN dull needle (from the DFNS set for quantitative sensory assessment) aimed to evoke slight pricking sensation. The TS responses will be calculated as a difference of the perceived pain between last vs. first pain score.
- CPM. A combination of tonic heat stimulus (up to 50oC, duration up to 20 sec; TSA, Medoc, Israel) and of 3 pressure pain threshold (PPT) measurements performed on the dominant trapezius (Algomed, Medoc, Israel; 3-sec inter-stimulus interval (ISI) will be given. Stimulus heat intensity will be individually adjusted to induce pain at intensity of 50 (on 0 - 100 numerical rating scale, NRS). These stimuli will be delivered to the dominant forearm, serving a 'test-stimulus'. After a 10 min break, the non-dominant hand will be immersed into cold water bath for a period of 60-70 sec (4-10 deg). After 10 sec of the immersion, the 'test-'stimulus' will be delivered again while the hand is still in the water. Along all stimulation period, the subjects will rate their pain perception using numerical pain scale. A CPM response will be calculated as a difference in the pain perception to the 'test-stimulus' during the immersion as compared to the 'test-stimulus' given stand-alone.
Treatment follow-up:
Phone follow-up will be performed: weekly reports at weeks 1-2 and 5-6; twice a week for weeks 3-4 and 7-8. The patients will provide their OA pain score, rating of the pain-relieving drug effect (0-100 scale) and describe the treatment-related side effects for the period of last 48 hours).
Statistical analysis
The classical statistical analysis will be based on correlations between PMP and degree of drug efficacy, represented by percentage pain reduction. We then construct 3 independent model systems, one for each of the 3 PMP parameters (CPM, TS, and EEG based connectivity). Within each model we first test the two correlations, under the presumed pain modulating and non-modulating drugs, between PMP and drug efficacy. A machine learning-based cross-validation and permutation tests will be used in order to access generalizability and statistical significance of the of the findings.
- Being tested
- Duloxetine 60mg, Etoricoxib 60 mg, omeprazol
- Medical subject headings
- Osteoarthritis, Knee
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Duloxetine 60mgDrug
Also called Cymbalta
Eight weeks treatment, one pill daily.
1st week 30mg; weeks 2-7th -- 60 mg daily.
Etoricoxib 60 mgDrug
Also called Arcoxia
One pill daily for 8 weeks
omeprazolDrug
Also called Prilosec, Losec
20 mg daily; will be taken with Etoricoxib from the second week of treatment
| Study group | Role | What they receive |
|---|---|---|
| Duloxetine | Active comparator | Eight weeks treatment, one pill a day. Week 1st - 30 mg a day. Weeks 2nd - 8th - 60 mg a day. Receives: Drug: Duloxetine 60mg |
| Etoricoxib | Active comparator | Eight weeks treatment. 60 mg daily pill ; from the second week adding omeprazol 20 mg daily Receives: Drug: Etoricoxib 60 mg; Drug: omeprazol |
What is being measured
The primary outcome is the main question the study is designed to answer.
CPM, a psychophysical parameter for pain inhibition, NPS
Post vs pre-treatment changes in Conditioned Pain Modulation (CPM)
Measured: up to 2 years
TS, a psychophysical parameter for pain facilitation, NPS
Post vs pre-treatment changes in Temporal Summation of pain (TS)
Measured: up to 2 years
resting-state EEG theta power, microvolts
Post vs pre-treatment changes in the EEG power within theta band
Measured: up to 2 years
resting-state EEG alpha power, microvolts
Post vs pre-treatment changes in the EEG power within alpha band
Measured: up to 2 years
Clincial pain, VAS
Post vs pre-treatment changes in VAS
Measured: up to 2 years
Pain-related disability, numerical scores
Post vs pre-treatment changes (disability score)
Measured: up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2022
- Study start30 Dec 2021
- Primary completion7 Apr 2024
- Study completion8 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Knee, Osteoarthritis (OA)Studies of the same condition, open and under way.
- 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 N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rambam Health Care Campus
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- David Yarnitsky, Prof, Principal investigator, Rambam Health Care Campus
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05256342
- Sponsor's protocol ID
- 0069-21-RMB
- Status last verified
- Apr 2024
- First submitted
- 19 May 2021
- Last updated
- 12 Apr 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biomarkers for Prediction of Analgesic Efficacy Based on Interrelations Between Pain Modulation and EEG vs. Drugs' Mode of Action in Knee OA
- ClinicalTrials.gov ID
- NCT05256342
- Acronym / sponsor ID
- 0069-21-RMB
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Rambam Health Care CampusUniversity, hospital or other
- Study start
- 30 Dec 2021 (actual)
- Primary completion
- 7 Apr 2024 (actual)
- Study completion
- 8 Apr 2024 (actual)
- First posted
- 25 Feb 2022 (actual)
- 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.
With high NNTs for indiscriminative use in chronic pain, treatment unavoidably entails frustrating long trial and errors. It is timely to identify biomarkers that can predict analgesic efficacy for the individual patient.
The investigators propose a framework of interrelations between patient's pain modulation profile (PMP) and the drug's mode of action (MOA) based on two principles: (1) 'fix the dysfunction', relevant for drugs whose main mode of action is to modulate central pain processing; the more the dysfunctional the better the modulating drug efficacy. For example, patients with pro-nociceptive PMP due to reduced endogenous pain inhibition, as expressed by less efficient CPM will benefit from drugs that fix this dysfunction such as SNRIs, relative to patients whose pain inhibitory capacity is well functioning. Thus, for the modulating drugs, pro-nociceptivity predicts better efficacy. (2) 'bear with the dysfunction', relevant for drugs which are mostly non-modulating, acting mainly in the periphery; the more dysfunctionalת the less the non-modulating drug efficacy. This is since efficacy is limited by the dysfunctional modulation system, despite the drug's MOA-like reduction of peripheral pain mediators. Thus, for the non-modulating drugs, for example NSAIDs, pro-nociceptivity predicts less good efficacy. The likely protocol suggests that patients with anti-nociceptive PMP should be treated primarily by non-modulating drugs, while pro-nociceptive ones should be given modulating drugs.
EEG is an additional source of relevant data on brain pain processing. Being objective and stable along time, EEG based parameters are, thus, very attractive candidates to be useful biomarkers for prediction of analgesia efficacy.
This study will focus on the patients with painful knee osteoarthritis.
The aims of this study are:
- To identify psychophysical and neurophysiological biomarkers that can serve as predictors of response to analgesic pain modulating and non-pain modulating drugs.
- To establish a conceptual framework of individualized pain therapy based on inter-relations between patient's parameters of pain modulation and drugs' mode of action.
Detailed description
Study design:
The study design includes two experimental meeting sessions (before and at the end / after the treatment) which include clinical and experimental assessments. After the first experimental session, the patients will be asked to rate twice a week their daily pain along two weeks, in order to confirm their OA pain level; the patients with the mean pain score of ≥4 will be supplied with the study medications. Along the 8 weeks-long treatment period, they will provide the rating of OA pain, subjective estimation of pain alleviation and reports of side effects
Clinical assessment: Will be performed by the study physician. The data on OA severity by Kellgren and Lawrence system classification, range of motion and current OA pain (last 48 h) will be collected. In addition, all patients will fill the brief pain inventory questioner (BPI) to assess their pain characteristics. In addition, all patients will be tested for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for assessment of OA pain, stiffness and physical function.
Experimental session:
- At the beginning of pre-treatment experimental session, all patients will fill a following set of psychological pain-related questioners organized in one document: (1) pain catastrophizing scale (PCS), (2) HADS anxiety and depression, (3) short-form health survey (SF-12), (5) pain sensitivity questionnaire (PSQ). In addition, basic assessment of psychomotor attention and cognitive functioning will be performed using (6) Trial making tests A and B (TMT A and B) and (7) Digits symbol substitution test (DSST). All the data will be coded and no personal data will be exposed.
- Resting-state EEG recording. Three minutes of resting-state EEG (eyes closed) will be recorded using the 64-channel EEG recording (Brain Products GmbH, Munich, Germany).
- Psychophysical pain assessment. All tests will be performed remotely from the painful area - on arm or hand. The following tests will be performed:
- Electrical and mechanical temporal summation (TS). For the assessment of electrical TS, a train of 10 electrical stimuli (Digitimer DS7A, Digitimer Ltd, WelWyn Garden City, England) of 2 msec width will be delivered to the non-dominant forearm with ISI of 1 sec. Subject will rate the perceived pain after the 1st and after the 5th stimuli using verbal numerical rating scale (NRS). Mechanical TS with be assessed using ten application of 256mN dull needle (from the DFNS set for quantitative sensory assessment) aimed to evoke slight pricking sensation. The TS responses will be calculated as a difference of the perceived pain between last vs. first pain score.
- CPM. A combination of tonic heat stimulus (up to 50oC, duration up to 20 sec; TSA, Medoc, Israel) and of 3 pressure pain threshold (PPT) measurements performed on the dominant trapezius (Algomed, Medoc, Israel; 3-sec inter-stimulus interval (ISI) will be given. Stimulus heat intensity will be individually adjusted to induce pain at intensity of 50 (on 0 - 100 numerical rating scale, NRS). These stimuli will be delivered to the dominant forearm, serving a 'test-stimulus'. After a 10 min break, the non-dominant hand will be immersed into cold water bath for a period of 60-70 sec (4-10 deg). After 10 sec of the immersion, the 'test-'stimulus' will be delivered again while the hand is still in the water. Along all stimulation period, the subjects will rate their pain perception using numerical pain scale. A CPM response will be calculated as a difference in the pain perception to the 'test-stimulus' during the immersion as compared to the 'test-stimulus' given stand-alone.
Treatment follow-up:
Phone follow-up will be performed: weekly reports at weeks 1-2 and 5-6; twice a week for weeks 3-4 and 7-8. The patients will provide their OA pain score, rating of the pain-relieving drug effect (0-100 scale) and describe the treatment-related side effects for the period of last 48 hours).
Statistical analysis
The classical statistical analysis will be based on correlations between PMP and degree of drug efficacy, represented by percentage pain reduction. We then construct 3 independent model systems, one for each of the 3 PMP parameters (CPM, TS, and EEG based connectivity). Within each model we first test the two correlations, under the presumed pain modulating and non-modulating drugs, between PMP and drug efficacy. A machine learning-based cross-validation and permutation tests will be used in order to access generalizability and statistical significance of the of the findings.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Duloxetine | Active comparator | Drug: Duloxetine 60mgEight weeks treatment, one pill a day. Week 1st - 30 mg a day. Weeks 2nd - 8th - 60 mg a day. |
| Etoricoxib | Active comparator | Drug: Etoricoxib 60 mg, Drug: omeprazolEight weeks treatment. 60 mg daily pill ; from the second week adding omeprazol 20 mg daily |
Who may qualify
- Ages
- 45 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- males and females
- ages 45 to 75
- radiographic representation of osteoarthritis of the knee
- minimal or moderate OA severity, based on the Kellgren and Lawrence system classification (1-3)
- knee OA pain for more than 3 months, assessed by the patients as being at level 4/10 and above on average at routine daily standing/walking activities during the last week, without medication
Key exclusion criteria (7 listed)
- other more prominent pain
- previous bilateral total knee replacement (TKR) surgery
- secondary OA (post-traumatic or post-infectious, osteochondritis dissecans (OCD) and enteropathic arthritis (EA) deformity)
- significant additional health problems such as substantial painful neuropathy, diabetes above of 5 yrs, renal failure, congestive heart failure, neurological diseases that might mask the pain processing system or reduce patient's cooperation or report capabilities, and significant psychiatric disorders
- use of opioids or cannabis
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 |
|---|---|---|
| Duloxetine 60mgAlso: CymbaltaEight weeks treatment, one pill daily. 1st week 30mg; weeks 2-7th -- 60 mg daily. | Drug | Duloxetine |
| Etoricoxib 60 mgAlso: ArcoxiaOne pill daily for 8 weeks | Drug | Etoricoxib |
| omeprazolAlso: Prilosec, Losec20 mg daily; will be taken with Etoricoxib from the second week of treatment | Drug | Etoricoxib |
Primary outcome
CPM, a psychophysical parameter for pain inhibition, NPS
Time frame: up to 2 years
Post vs pre-treatment changes in Conditioned Pain Modulation (CPM)
TS, a psychophysical parameter for pain facilitation, NPS
Time frame: up to 2 years
Post vs pre-treatment changes in Temporal Summation of pain (TS)
resting-state EEG theta power, microvolts
Time frame: up to 2 years
Post vs pre-treatment changes in the EEG power within theta band
resting-state EEG alpha power, microvolts
Time frame: up to 2 years
Post vs pre-treatment changes in the EEG power within alpha band
Clincial pain, VAS
Time frame: up to 2 years
Post vs pre-treatment changes in VAS
Pain-related disability, numerical scores
Time frame: up to 2 years
Post vs pre-treatment changes (disability score)
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 12 Apr 2024.
- Individual participant dataSharing planned: No
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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.
David Yarnitsky, Prof principal investigator
Rambam Health Care Campus
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Duloxetine 60mg, Etoricoxib 60 mg and omeprazol in people with Knee, Osteoarthritis (OA) and Biomarkers for Prediction of OA Treatment Efficacy, run by Rambam Health Care Campus at 2 sites in Israel.
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 5 inclusion and 7 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 12 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Israel. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
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?
CPM, a psychophysical parameter for pain inhibition, NPS (time frame: up to 2 years). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 12 Apr 2024.