Randomized Controlled TrialPhase 4INNOVANCT04739995
Cost-utility and Physiological Effects of LDN in Patients With Fibromyalgia
A Phase 4 study testing Low-dose naltrexone in people with Randomized Controlled Trial, run by Fundació Sant Joan de Déu at 1 site in Spain.
Trial summary
Background: Low-dose naltrexone (LDN) may be useful in managing the pathologies that alter inflammatory markers, such as Crohn's disease or fibromyalgia (FM). The anti-inflammatory effect of LDN should be produced through the inhibition of Toll-like receptor 4 activity expressed in the membrane of various immune… Read more about this study
- Who is it for?
- Ages 18 to 70 years, women only
- Conditions the study is for
- Randomized Controlled Trial
- What is being tested?
- Low-dose naltrexone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 99 participants
- Where
- 1 siteSpain
- Study dates
- 1 Jun 2022to 31 Dec 2024
- 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 18 to 70 years
- Women only
- No healthy volunteers
- Adult, Older adult
General Inclusion Criteria:
- Female between 18 and 70 years old
- Patients diagnosed of FM according to ACR 2016 criteria
- Chronic widespread pain for at least 6 months ranked ≥ 4 out of 10;
- Understand Spanish;
- Written informed written consent;
General Exclusion Criteria:
- Treatment with opiates in last 3 months;
- Diagnosis of severe medical/psychiatric disorders (e.g. cancer, severe depression, psychotic disorder, schizophrenia);
- Being pregnant (or planning a pregnancy during the study period) or breastfeeding;
- Known allergy to naltrexone or naloxone;
- Hematological disorders;
- Abnormal hepatic function;
- Taking anticoagulant medication;
- Alcohol consume during the study period
- Participation in other clinical trials;
Additional inclusion criteria for biomarker sub-study:
Right-handed (for the neuroimaging tests)
Additional exclusion criteria for biomarker sub-study:
Comorbid rheumatologic illnesses (e.g. rheumatoid arthritis, lupus); fever (> 38ºC) or infection in the last 2 weeks; vaccination in the last 4 weeks; Take drugs with anti-inflammatory effects in the 72h prior to blood / neuroimaging; taking cortisone or anti-cytokine therapy; needle phobia; inability to be scanned (due to claustrophobia, metal implants, pacemakers, etc.); Body Mass Index (BMI) > 36 kg/m2; consumption of > 8 units of caffeine per day; smoking > 10 cigarettes/day; acute pain not-related to FM on the day of the scan (e.g. headache, back pain).
Trial locations and contacts
1 site in 1 country.
Spain1 site
Parc Sanitari Sant Joan de Déu (PSSJD)
Sant Boi de Llobregat, Barcelona, 08830
About this study
Official title: 12-month Randomized, Double-blind, Placebo-controlled, Pharmacological Clinical Trial to Evaluate the Effectiveness, Cost-utility and Neurobiological Effects of Low-dose Naltrexone in Patients With Fibromyalgia (INNOVA Project)
Background: Low-dose naltrexone (LDN) may be useful in managing the pathologies that alter inflammatory markers, such as Crohn's disease or fibromyalgia (FM). The anti-inflammatory effect of LDN should be produced through the inhibition of Toll-like receptor 4 activity expressed in the membrane of various immune system cells (e.g. microglia). Conversely, due to a rebound effect, LDN could exercise an analgesic effect that strengthens the endogenous inhibitory system. According to this hypothesis, the low-intensity and intermittent blocking of the opioid receptors generated by LDN should induce a compensatory mechanism that should facilitate an increase in the production of endogenous opioids and greater sensitivity of the system to their effects. To date, the effects of LDN in patients with FM have been evaluated through crossover studies that have yielded promising results. Given that the studies conducted up to now have had small sample sizes and crossover designs, and given that there are still no studies in which its potential cost-utility is assessed, studies with greater methodological rigor and larger samples are necessary to confirm the effectiveness of LDN in FM.
Jointly evaluating the effectiveness and cost-utility, the changes in metabolites in certain areas of the brain, and systemic inflammatory markers potentially linked to the etiopathogenesis of FM, should allow us to gain a more detailed knowledge of the neurobiological mechanisms underlying the effectiveness of LDN in this population.
Read more
Objectives: To evaluate the effectiveness and safety of LDN in patients with FM and analyse its cost-utility both from the government and the healthcare perspective at 1-year follow-up. Brain metabolites and systemic inflammatory biomarkers will be included to evaluate neurobiological mechanisms behind LDN therapeutic effects.
Design: Randomized, Controlled Trial. Centre: Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain). Participants: 120 patients with FM will be randomly assigned to LDN (4.5mg/day) or placebo.
Main outcome measure: Pain severity using Ecological Momentary Assessment. Secondary outcomes: functionality, affective symptoms, fibrofog, quality of life. Costs and QALYs will be also calculated. Biomarkers: 50% of the patients will be scanned at baseline and at week 12 for changes in brain metabolites related to neuroinflammation and central sensitization. Immune-inflammatory markers in serum will also be evaluated.
Read the detailed description
Low-dose Naltrexone (LDN): A potential treatment for fibromyalgia (FM)
Naltrexone is an opioid antagonist used for treating opiate and alcohol dependency that blocks the mu receptors and, to a lesser extent, the delta-opioid receptors. There is growing evidence that naltrexone administered in very low doses (i.e. low-dose naltrexone, LDN) -approximately 1/10 of the usual dose, between 1.5-5 mg vs. 50 mg/day- may be useful in managing the various pathologies that alter inflammatory markers, such as Crohn's disease, multiple sclerosis and FM.
The anti-inflammatory effect of naltrexone should be produced through the inhibition of TLR-4 (Toll-like receptor 4) activity expressed in the membrane of various immune system cells (e.g. microglia, macrophages). Conversely, due to a "rebound effect", LDN could exercise an analgesic effect that strengthens the endogenous inhibitory system. According to this hypothesis, the low-intensity and intermittent blocking of the opioid receptors generated by LDN should induce a compensatory mechanism that should facilitate an increase in the production of endogenous opioids and greater sensitivity of the system to their effects. To date, the effects of LDN in patients with FM have only been evaluated through crossover pilot studies and have always produced highly promising results. Thus, in the first study conducted with LDN in FM (N= 10), ameliorations in the daily pain, stress and fatigue levels were observed. In the same vein, in a posterior study (N= 31), significant improvements (vs. Placebo) in daily pain (28% vs. 18%), satisfaction with life and mood were also observed. In another single-blind crossover study (N= 8) the pre and post changes in the levels of cytokines in plasma were evaluated over 8 weeks, with reductions in a wide range of inflammatory markers being observed (e.g. IL-1, sIL-1ra, IL-6, IL-10, TNF-alpha), as well as changes in the levels of pain (-15%) and FM symptoms (-18%). Given that the studies conducted up to now had reduced sample sizes and crossover designs, and given that there are still no studies in which its potential cost-utility is assessed, studies with greater methodological rigor and larger samples are necessary to confirm the clinical effectiveness of LDN in FM. Jointly evaluating the efficacy and cost-utility analyses, the changes in metabolites (i.e. Glu) in certain areas of the brain, and systemic inflammatory markers potentially linked to the etiopathogenesis of FM, should allow us to gain a more detailed knowledge of the neurobiological mechanisms underlying the effectiveness of LDN in this population. The INNOVA project will enable all these factors to be evaluated for the first time.
- Conditions
- Randomized Controlled Trial
- Being tested
- Low-dose naltrexone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low-dose naltrexoneDrug
Also called LDN
4.5 mg LDN/day for 1 year
| Study group | Role | What they receive |
|---|---|---|
| Low-Dose-Naltrexone (LDN) | Experimental | The LDN treatment will consist of one 4.5 mg naltrexone tablet (lactose-free) taken daily for 12 months before going to sleep. Receives: Drug: Low-dose naltrexone |
| Placebo | Placebo comparator | The control group will take the placebo daily (a film-coated tablet, identical to the LDN, filled with a lactose-free excipient), for 12 months, following the same guidelines. Receives: Drug: Low-dose naltrexone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pain intensity
-Numerical Rating Scale-NRS- from 0 (no pain) to 10 (worst possible pain)
Measured: Through study completion, an average of 1 year
Secondary outcomes (3)
Revised Fibromyalgia Impact Questionnaire (FIQR)
21-item questionnaire on physical function, overall impact and severity of the symptoms associated with FM. Total scores can range from 0 (no impairment) to (maximum impairment) memory/attentional problems, quality of sleep)
Measured: Through study completion, an average of 1 year
Depression Anxiety Stress Scale (DASS-21)
Scale of 21 items created to assess symptoms of depression, anxiety and stress. Each subscale (Depressión, Anxiety and Stress) includes 7 items with scores ranging from 0 to 21. Higher scores indicate higher symptom severity.
Measured: Through study completion, an average of 1 year
Multidimensional Inventory of Subjective Cognitive Impairment (MISCI)
10-item measure of subjective cognitive dysfunction in FM. total score ranges from 10 to 50, where lower scores indicate higher cognitive dysfunction.
Measured: Through study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2021
- Study start1 Jun 2022
- Primary completion31 Oct 2024 (estimated)
- Study completion31 Dec 2024 (estimated)
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 Randomized Controlled TrialStudies 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Double-blind, randomized controlled trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 99 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fundació Sant Joan de Déu
- Sponsor type
- University, hospital or other
- Collaborators
- Carlos III Health Institute
- Responsible party
- Sponsor
- Investigators
- Juan V. Luciano, PhD, Principal investigator, Fundació Sant Joan de Déu
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04739995
- Sponsor's protocol ID
- ICI20/00080
- Acronym
- INNOVA
- Status last verified
- Apr 2024
- First submitted
- 1 Feb 2021
- Last updated
- 22 Apr 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Colomer-Carbonell A, Sanabria-Mazo JP, Hernandez-Negrin H, Borras X, Suso-Ribera C, Garcia-Palacios A, Muchart J, Munuera J, D'Amico F, Maes M, Younger JW, Feliu-Soler A, Rozadilla-Sacanell A, Luciano JV. Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost-utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study). BMJ Open. 2022 Jan 6;12(1):e055351. doi: 10.1136/bmjopen-2021-055351.
PubMed 34992118
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 12-month Randomized, Double-blind, Placebo-controlled, Pharmacological Clinical Trial to Evaluate the Effectiveness, Cost-utility and Neurobiological Effects of Low-dose Naltrexone in Patients With Fibromyalgia (INNOVA Project)
- ClinicalTrials.gov ID
- NCT04739995
- Acronym / sponsor ID
- INNOVA / ICI20/00080
- Conditions
- Randomized Controlled Trial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 99 participants (actual)
- Lead sponsor
- Fundació Sant Joan de DéuUniversity, hospital or other
- Collaborators
- Carlos III Health Institute
- Study start
- 1 Jun 2022 (actual)
- Primary completion
- 31 Oct 2024 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 5 Feb 2021 (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.
Background: Low-dose naltrexone (LDN) may be useful in managing the pathologies that alter inflammatory markers, such as Crohn's disease or fibromyalgia (FM). The anti-inflammatory effect of LDN should be produced through the inhibition of Toll-like receptor 4 activity expressed in the membrane of various immune system cells (e.g. microglia). Conversely, due to a rebound effect, LDN could exercise an analgesic effect that strengthens the endogenous inhibitory system. According to this hypothesis, the low-intensity and intermittent blocking of the opioid receptors generated by LDN should induce a compensatory mechanism that should facilitate an increase in the production of endogenous opioids and greater sensitivity of the system to their effects. To date, the effects of LDN in patients with FM have been evaluated through crossover studies that have yielded promising results. Given that the studies conducted up to now have had small sample sizes and crossover designs, and given that there are still no studies in which its potential cost-utility is assessed, studies with greater methodological rigor and larger samples are necessary to confirm the effectiveness of LDN in FM.
Jointly evaluating the effectiveness and cost-utility, the changes in metabolites in certain areas of the brain, and systemic inflammatory markers potentially linked to the etiopathogenesis of FM, should allow us to gain a more detailed knowledge of the neurobiological mechanisms underlying the effectiveness of LDN in this population.
Objectives: To evaluate the effectiveness and safety of LDN in patients with FM and analyse its cost-utility both from the government and the healthcare perspective at 1-year follow-up. Brain metabolites and systemic inflammatory biomarkers will be included to evaluate neurobiological mechanisms behind LDN therapeutic effects.
Design: Randomized, Controlled Trial. Centre: Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain). Participants: 120 patients with FM will be randomly assigned to LDN (4.5mg/day) or placebo.
Main outcome measure: Pain severity using Ecological Momentary Assessment. Secondary outcomes: functionality, affective symptoms, fibrofog, quality of life. Costs and QALYs will be also calculated. Biomarkers: 50% of the patients will be scanned at baseline and at week 12 for changes in brain metabolites related to neuroinflammation and central sensitization. Immune-inflammatory markers in serum will also be evaluated.
Detailed description
Low-dose Naltrexone (LDN): A potential treatment for fibromyalgia (FM)
Naltrexone is an opioid antagonist used for treating opiate and alcohol dependency that blocks the mu receptors and, to a lesser extent, the delta-opioid receptors. There is growing evidence that naltrexone administered in very low doses (i.e. low-dose naltrexone, LDN) -approximately 1/10 of the usual dose, between 1.5-5 mg vs. 50 mg/day- may be useful in managing the various pathologies that alter inflammatory markers, such as Crohn's disease, multiple sclerosis and FM.
The anti-inflammatory effect of naltrexone should be produced through the inhibition of TLR-4 (Toll-like receptor 4) activity expressed in the membrane of various immune system cells (e.g. microglia, macrophages). Conversely, due to a "rebound effect", LDN could exercise an analgesic effect that strengthens the endogenous inhibitory system. According to this hypothesis, the low-intensity and intermittent blocking of the opioid receptors generated by LDN should induce a compensatory mechanism that should facilitate an increase in the production of endogenous opioids and greater sensitivity of the system to their effects. To date, the effects of LDN in patients with FM have only been evaluated through crossover pilot studies and have always produced highly promising results. Thus, in the first study conducted with LDN in FM (N= 10), ameliorations in the daily pain, stress and fatigue levels were observed. In the same vein, in a posterior study (N= 31), significant improvements (vs. Placebo) in daily pain (28% vs. 18%), satisfaction with life and mood were also observed. In another single-blind crossover study (N= 8) the pre and post changes in the levels of cytokines in plasma were evaluated over 8 weeks, with reductions in a wide range of inflammatory markers being observed (e.g. IL-1, sIL-1ra, IL-6, IL-10, TNF-alpha), as well as changes in the levels of pain (-15%) and FM symptoms (-18%). Given that the studies conducted up to now had reduced sample sizes and crossover designs, and given that there are still no studies in which its potential cost-utility is assessed, studies with greater methodological rigor and larger samples are necessary to confirm the clinical effectiveness of LDN in FM. Jointly evaluating the efficacy and cost-utility analyses, the changes in metabolites (i.e. Glu) in certain areas of the brain, and systemic inflammatory markers potentially linked to the etiopathogenesis of FM, should allow us to gain a more detailed knowledge of the neurobiological mechanisms underlying the effectiveness of LDN in this population. The INNOVA project will enable all these factors to be evaluated for the first time.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Double-blind, randomized controlled trial
| Arm | Type | Receives |
|---|---|---|
| Low-Dose-Naltrexone (LDN) | Experimental | Drug: Low-dose naltrexoneThe LDN treatment will consist of one 4.5 mg naltrexone tablet (lactose-free) taken daily for 12 months before going to sleep. |
| Placebo | Placebo comparator | Drug: Low-dose naltrexoneThe control group will take the placebo daily (a film-coated tablet, identical to the LDN, filled with a lactose-free excipient), for 12 months, following the same guidelines. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| Low-dose naltrexoneAlso: LDN4.5 mg LDN/day for 1 year | Drug | Low-Dose-Naltrexone (LDN), Placebo |
Primary outcome
Pain intensity
Time frame: Through study completion, an average of 1 year
-Numerical Rating Scale-NRS- from 0 (no pain) to 10 (worst possible pain)
3 secondary outcomes
Revised Fibromyalgia Impact Questionnaire (FIQR)
Time frame: Through study completion, an average of 1 year
Depression Anxiety Stress Scale (DASS-21)
Time frame: Through study completion, an average of 1 year
Multidimensional Inventory of Subjective Cognitive Impairment (MISCI)
Time frame: Through study completion, an average of 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2024.
- Derived from this study: PubMed 34992118Colomer-Carbonell A, Sanabria-Mazo JP, Hernandez-Negrin H, Borras X, Suso-Ribera C, Garcia-Palacios A, Muchart J, Munuera J, D'Amico F, Maes M, Younger JW, Feliu-Soler A, Rozadilla-Sacanell A, Luciano JV. Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost-utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study). BMJ Open. 2022 Jan 6;12(1):e055351. doi: 10.1136/bmjopen-2021-055351.
- Individual participant dataSharing planned: No
Related trials for Randomized Controlled Trial
Not yet recruitingPhase 3
Efficacy and Safety of Once-Weekly SHR-3167 Compared With Once-Daily Insulin Glargine in Adults With Insulin-Naive Type 2 Diabetes
Type 2 Diabetes
Not yet recruiting
Preventive and Personalized Digital Emotion Regulation Skills Intervention to Reduce Depression and Anxiety in Youths With Adverse Childhood Experiences
Adverse Childhood Experience, Depression / Major Depressive Disorder
Recruiting
Effect of a Brief Daily Digital Meditation on Well-Being in US Young Adults (BEGIN II)
Mental Health and General Well-being
Recruiting
PAW-Hydrogel for Chronic Wound Healing
Diabetic Foot Ulcer (DFU), Pressure Ulcer (PU)
Not yet recruiting
Acupressure as Long-term Intervention to Slow the Progression of Early/Mild Alzheimer's Disease
Alzheimer's Disease
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.
Juan V. Luciano, PhD principal investigator
Fundació Sant Joan de Déu
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 Low-dose naltrexone in people with Randomized Controlled Trial, run by Fundació Sant Joan de Déu at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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: status not confirmed, as of the sponsor's last update on 22 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 1 site in Spain. 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?
Results are not available in the source record.
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?
Pain intensity (time frame: Through study completion, an average of 1 year). 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 NCT04739995, 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 22 Apr 2024.