Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Cost-utility and Physiological Effects of LDN in Patients With Fibromyalgia (INNOVA)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04739995
Recruitment Status : Not yet recruiting
First Posted : February 5, 2021
Last Update Posted : February 5, 2021
Sponsor:
Collaborator:
Carlos III Health Institute
Information provided by (Responsible Party):
Fundació Sant Joan de Déu

Brief Summary:

Background: There is growing evidence that 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 (TLR-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 only been evaluated through crossover pilot studies that have yielded highly 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 12 months follow-up. Brain metabolites and systemic inflammatory biomarkers will be included to evaluate neurobiological mechanisms behind LDN therapeutic effects.

Design: Randomized, Controlled Trial (RCT). Centre: Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) Participants: 120 patients with FM meeting elegibility criteria will be randomly assigned to LDN (4.5mg/day) or placebo.

Main outcome measure: Pain severity using Ecological Momentary Assessment with the Pain Monitor© app.

Secondary outcomes: functionality, affective symptoms, fibrofog, quality of life. Costs and quality-adjusted life years 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.


Condition or disease Intervention/treatment Phase
Randomized Controlled Trial Drug: Low-dose naltrexone Phase 4

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, randomized controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effectiveness, Cost-utility and Neurobiological Effects of Low-dose Naltrexone in Patients With Fibromyalgia (INNOVA Project)
Estimated Study Start Date : July 1, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fibromyalgia

Arm Intervention/treatment
Experimental: Low-Dose-Naltrexone (LDN)
The LDN treatment will consist of one 4.5 mg naltrexone tablet (lactose-free) taken daily for 12 months before going to sleep.
Drug: Low-dose naltrexone
4.5 mg LDN/day for 1 year
Other Name: LDN

Placebo Comparator: Placebo
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.
Drug: Low-dose naltrexone
4.5 mg LDN/day for 1 year
Other Name: LDN




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. Revised Fibromyalgia Impact Questionnaire (FIQR) [ Time Frame: Through study completion, an average of 1 year ]
    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)

  2. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Through study completion, an average of 1 year ]
    Scale of 14 items created to assess symptoms of anxiety and depression. The total score ranges from 0 to 42, and each subscale (HADS-Anxiety and HADS-Depression) includes 7 items with scores ranging from 0 to 21. Higher scores indicate higher symptom severity.

  3. Multidimensional Inventory of Subjective Cognitive Impairment (MISCI) [ Time Frame: Through study completion, an average of 1 year ]
    10-item measure of subjective cognitive dysfunction in FM. total score ranges from 10 to 50, where lower scores indicate higher cognitive dysfunction.


Other Outcome Measures:
  1. EuroQoL (EQ-5D-5L) [ Time Frame: Through study completion, an average of 1 year ]
    Instrument for evaluating health-related quality of life. The EQ-5D-5L scores will be used to calculate the QualityAdjusted Life Years (QALYs) for the cost-utility analysis

  2. Client Service Receipt Inventory (CSRI) [ Time Frame: Through study completion, an average of 1 year ]
    The version used in this study is designed to retrospectively collect information on the use of health and social services during the previous 12 months. This instrument does not provide total or sub-scale scores, only collects information about use of services and medication consumption.

  3. Patient Global and Specific Impression of Change (PGIC/PSIC) [ Time Frame: Through study completion, an average of 1 year ]
    Items scored on a 7-point Likert scale (from 1 "much better" to 7 "much worse")

  4. Adverse events linked to the drug/placebo [ Time Frame: Through study completion, an average of 1 year ]
    Qualitative ad hoc measure to check the presence of side effects

  5. The Pain Monitor® app [ Time Frame: Through study completion, an average of 1 year ]
    It was validated in an empirical study for use on Android smartphones. It will be used to assess daily (twice a day) the level of pain, fatigue, etc. during the treatment period.

  6. Socio-demographic questionnaire [ Time Frame: Baseline ]
    Gender, date of birth, marital status, living arrangements, educational level and work status.

  7. Patient Health Questionnaire (PHQ-9) [ Time Frame: Baseline ]
    PRIME-MD module with 9 items adjusted to the DSM-IV criteria for major depression. It can be used algorithmically for the probable diagnosis of a depressive disorder, or as a continuous measure of scores ranging from 0 to 27, with cutoff points of 5, 10, 15 and 20, which set the levels of symptoms of depression as mild, moderate, moderately severe or severe.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

General Inclusion Criteria:

  • 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;
  • Stable pharmacological treatment in the last 2 months;
  • To have a smartphone to complete Ecological Momentary Assessment (EMA) assessments.

General Exclusion Criteria:

  • Treatment with opiates in last 3 months;
  • Taking central anti-hypertensives (α-methyldopa);
  • 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/liver function;
  • Taking anticoagulant medication;
  • Participation in other clinical trials;
  • Ongoing litigation relating to FM.

Additional inclusion criteria for biomarker sub-study:

Women and 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; 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 > 5 cigarettes/day; acute pain not-related to FM on the day of the scan (e.g. headache, back pain).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04739995


Contacts
Layout table for location contacts
Contact: Juan V. Luciano, PhD +34936406350 ext 2540 jvluciano@pssjd.org
Contact: Antoni Rozadilla-Sacanell, MD, PhD +34936615208 a.rozadilla@pssjd.org

Locations
Layout table for location information
Spain
Parc Sanitari Sant Joan de Déu (PSSJD)
Sant Boi De Llobregat, Barcelona, Spain, 08830
Contact: Juan V Luciano, PhD    +34936406350 ext 2540    jvluciano@pssjd.org   
Contact: Antoni Rozadilla-Sacanell, MD, PhD    +34936615208    a.rozadilla@pssjd.org   
Principal Investigator: Juan V Luciano, PhD         
Sub-Investigator: Antoni Rozadilla-Sacanell, MD, PhD         
Sponsors and Collaborators
Fundació Sant Joan de Déu
Carlos III Health Institute
Investigators
Layout table for investigator information
Principal Investigator: Juan V. Luciano, PhD Fundació Sant Joan de Déu
Additional Information:
Layout table for additonal information
Responsible Party: Fundació Sant Joan de Déu
ClinicalTrials.gov Identifier: NCT04739995    
Other Study ID Numbers: ICI20/00080
First Posted: February 5, 2021    Key Record Dates
Last Update Posted: February 5, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Fibromyalgia
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases
Naltrexone
Alcohol Deterrents
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents