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Fibromyalgia and Naltrexone: The FINAL Study (FINAL)

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ClinicalTrials.gov Identifier: NCT04270877
Recruitment Status : Recruiting
First Posted : February 17, 2020
Last Update Posted : January 13, 2021
Sponsor:
Collaborators:
University of Southern Denmark
University Hospital Bispebjerg and Frederiksberg
Information provided by (Responsible Party):
Karin Bruun Plesner, Odense University Hospital

Tracking Information
First Submitted Date  ICMJE January 30, 2020
First Posted Date  ICMJE February 17, 2020
Last Update Posted Date January 13, 2021
Actual Study Start Date  ICMJE January 6, 2021
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 12, 2020)
Average pain during the last 7 days [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
Assessed by asking the participants about the level of average pain during the last 7 days on a 11 point rating scale, ranging from 0-10 (0 = "no pain" and 10 = "unbearable pain") using the first item from the symptom part of the Fibromyalgia Impact Questionnaire Revised. A lower score indicates lower severity.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2020)
  • Global assessment [ Time Frame: Change in overall fibromyalgia symptoms from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by Patient Global Impression of Change on a 1-7 Verbal Rating Scale. The participants are asked how they rate their overall fibromyalgia symptoms after 4, 8 and 12 weeks of treatment compared with before treatment. A score of 4 indicates "no change", a score of 1 is characterized by "a lot worse" and a score of 7 is characterized by "a lot better." A higher score indicates higher degree of improvement.
  • Impact of fibromyalgia [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the Fibromyalgia Impact Questionnaire Revised (FIQR) total score. The FIQR asks patients to rate how difficult it is to perform a list of 9 common activities over the previous 7 days on an 11 point scale, ranging from 0-10 (0 = "no difficulty" and 10 = "very difficult"). The FIQR then asks patients to indicate how often their fibromyalgia impacts their quality of life over the last 7 days on an 11 point scale, ranging from 1-10 (0 = "never" and 10 = "always"). Finally, the FIQR asks patients to assess the severity of 10 different symptoms on an 11 point scale, ranging from 0-10 (0 = "no symptoms" and 10 = "extreme symptoms"). These three sub-scales are summed to represent an overall FIQR score. A lower score indicates lower severity.
  • Pain distribution [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Widespread Pain Index (WPI) from The American College of Rheumatology 2016 revised criteria for fibromyalgia (ACR-2016). The body is divided into 19 body parts and number of pain full body parts during the last 7 days is counted, giving rise to the WPI. A lower score indicates lower spreading of pain.
  • Level of pain [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of pain" question, asking the participants to rate the average level of pain during the last 7 days on a 11 point rating scale, ranging from 0-10 (0 = "no pain" and 10 = "unbearable pain"). A lower score indicates lower severity.
  • Level of tenderness [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of tenderness to touch" question, asking the participants to rate the average level of tenderness to touch during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "no tenderness" and 10 = "very tender"). A lower score indicates a lower severity. AND Assessed by measurement of pressure pain threshold, using a handheld algometer. Points measured: Right Quadriceps 15 cm proximal of apex patella and left Trapezius 10 cm from acromion. Each point is measured 3 times. Pressure pain threshold is measured in kilopascal (kPa). A higher value indicates a lower severity.
  • Level of fatigue [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of energy" question, asking the participants to rate the average level of energy during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "lots of energy" and 10 = "no energy"). A lower score indicates a lower severity.
  • Level of sleep disturbance [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "quality of sleep" question asking the participants to rate the average quality of sleep during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "awoke well rested" and 10 = "awoke very tired"). A lower score indicates a lower severity.
  • Level of depression [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of depression" question, asking the participants to rate the average level of depression during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "no depression" and 10 = "very depressed"). A lower score indicates a lower severity.
  • Level of anxiety [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of anxiety" question, asking the participants to rate the average level of anxiety during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "not anxious" and 10 = "very anxious"). A lower score indicates a lower severity.
  • Level of cognition [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of memory problems" question, asking the participants to rate the average level of memory problems during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "good memory" and 10 = "very poor memory"). A lower score indicates a lower severity.
  • Level of stiffness [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the Fibromyalgia Impact Questionnaire Revised "level of stiffness" question, asking the participants to rate the average level of stiffness during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = "no stiffness" and 10 = "severe stiffness"). A lower score indicates a lower severity.
  • Level of physical function [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Assessed by the physical function domain of Fibromyalgia Impact Questionnaire Revised; asking participants to rate how difficult it is to perform a list of 9 common activities over the previous 7 days on an 11 point scale, ranging from 0-10 (0 = "no difficulty" and 10 = "very difficult"). The score is characterized by the sum of the 9 scores (0-90). A lower score indicates better function.
  • Health-related quality of life - mobility [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the European Quality of Life 5 Dimensions (EQ-5D) mobility domain; asking the participants to rate their mobility on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity.
  • Health-related quality of life - self care [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the European Quality of Life 5 Dimensions (EQ-5D) self care domain; asking the participants to rate their ability for self care on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity.
  • Health-related quality of life - usual activities [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the European Quality of Life 5 Dimensions (EQ-5D) usual activities domain; asking the participants to rate their ability to perform usual activities on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity.
  • Health-related quality of life - pain/discomfort [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the European Quality of Life 5 Dimensions (EQ-5D) pain/discomfort domain; asking the participants to rate their level of pain or discomfort on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity.
  • Health-related quality of life - anxiety/depression [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the European Quality of Life 5 Dimensions (EQ-5D) anxiety/depression domain; asking the participants to rate their level of anxiety or depression on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity.
  • Health-related quality of life - global [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by European Quality of Life Visual Analogue Scale (EQ-VAS), which asks the participant to rate their overall health 'today' on a 0-100 VAS. A higher score indicates a better quality of life.
  • Number of responders with a more than 15% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    A responder is defined as a subject who reports a more than 15% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group.
  • Number of responders with a more than 30% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    A responder is defined as a subject who reports a more than 30% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group.
  • Number of responders with a more than 50% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    A responder is defined as a subject who reports a more than 50% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 12, 2020)
  • Variation in pain [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    Measured using a diary of daily average pain rated on an 11 point rating scale, ranging from 0-10, during 7 days before visits at baseline, and after 8 and 12 weeks of treatment. The variation in pain is characterized by the highest score minus the lowest score. A lower score indicates a lower variation.
  • Muscle exhaustion [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by an isometric muscle exhaustion test of the deltoid muscle. Measured by asking the participant to complete an isometric muscle exhaustion task by maintaining 90° shoulder abduction (dominant arm) for as long as possible with the elbow extended and the hand pronated (hand facing downwards). Task failure (test position can no longer be maintained) defines the test duration. The participants are instructed to maintain the position until they feel maximal muscle exhaustion (corresponding to a score of 10 on a 0-10 scale with 0 being "no muscle fatigue" and 10 being 'maximal muscle fatigue/exhaustion'). Surface electromyography (EMG) will be recorded from the anterior, middle and posterior deltoid muscle at 3000 Hz during the entire test. A longer duration of test is indicative of lower levels of exhaustion.
  • Physical fitness [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by the 30-second chair stand test. The test starts with the subject seated on a chair with her back touching the backrest. Subjects rise to a full stand with the back straight and then sit down again to regain this cycle as many times as they can within 30 seconds. A higher number of cycles is indicative of better physical fitness.
  • Pain sensitivity [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
    Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs in all patients to assess pressure pain threshold and pressure pain tolerance. Pressure pain threshold and pressure pain tolerance are measured in kilopascal (kPa). A higher value is indicative of lower severity.
  • Inhibition of pain [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by Conditioned pain modulation (CPM). Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs to assess increase in pressure pain threshold during cuff pain conditioning on the contralateral leg. Pressure pain threshold and pressure pain tolerance are measured in kilopascal (kPa). A higher value is indicative of lower severity.
  • Augmentation of pain [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
    Measured by Temporal Summation of Pain (TSP). Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs to assess increase in pain scores to ten repeated stimulations. Pain is rated on a 0-100 Visual Analogue Scale. A lower value indicates a lower severity.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Fibromyalgia and Naltrexone: The FINAL Study
Official Title  ICMJE Fibromyalgia and Naltrexone: The FINAL Study
Brief Summary This study evaluates the effect of low dose naltrexone (LDN) on pain in women with fibromyalgia (FM). The study is designed as a parallel randomized (1:1) double blind, placebo-controlled superiority trial. Half of the participants will receive treatment with LDN while the other half will receive treatment with placebo.
Detailed Description

Low dose naltrexone (LDN) is used widely as off label treatment in patients with fibromyalgia, despite the lack of larger randomized controlled trials (RCT) supporting an effect.

LDN has antagonistic effect on both opioid receptors and on toll-like receptors in glia cells. Mediated via those receptors, LDN can potentially reduce neuroinflammation and induce homeostasis in the endorphin system in patients with fibromyalgia.

The aim of the trial is to investigate whether treatment with LDN has a superior effect compared to placebo on pain among female patients with fibromyalgia, evaluated after 12 weeks of treatment. The study is also exploring secondary aims regarding a possible improvement of other fibromyalgia core symptoms and a possible improvement of global assessment, daily functioning and health-related quality of life. Among the exploratory secondary objectives are changes in muscle exhaustion, physical fitness, pain sensitivity, inhibition of pain, augmentation of pain, and pro-inflammatory cytokines.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
A parallel randomized (1:1) double blind, placebo-controlled superior trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Fibromyalgia
Intervention  ICMJE
  • Drug: Naltrexone Pill
    Treatment with LDN for 12 weeks, including af titration phase of 4 weeks. Initial dosage of 1.5 mg, dose is increased by 1.5 mg every 7th day to 6 mg at week 4. Dosing is increased based on safety and tolerability and delayed increments are allowed. The participants are maintained on the highest tolerable dose for the last 8 weeks of the treatment period.
    Other Name: LDN
  • Drug: Placebo oral tablet
    Treatment with LDN-placebo for 12 weeks, including af titration phase of 4 weeks. Initial dosage of 1.5 mg, dose is increased by 1.5 mg every 7th day to 6 mg at week 4. Dosing is increased based on safety and tolerability and delayed increments are allowed. The participants are maintained on the highest tolerable dose for the last 8 weeks of the treatment period.
    Other Name: LDN-placebo
Study Arms  ICMJE
  • Experimental: Naltrexone

    Low Dose Naltrexone (LDN) is administered for 12 weeks, including a titration phase of 4 weeks.

    Participants will be titrated up to 6 mg following a dose escalation scheme: Initial dosage of 1.5 mg daily, escalated every seventh day by 1.5 mg up to 6 mg at week 4. Dose escalation will be based on safety and tolerability, and if dose escalation is not feasible, delayed increments are allowed. After end of titration (week 4) the subjects will be maintained at the highest tolerated dose level for the last 8 weeks of the treatment period. Subjects are not allowed to change dose during the last 8 weeks of the treatment period.

    The medicine is taken orally as tablets once daily in the evening.

    Intervention: Drug: Naltrexone Pill
  • Placebo Comparator: Placebo

    LDN-placebo is administered for 12 weeks, including a titration phase of 4 weeks.

    Participants will be titrated up to 6 mg following a dose escalation scheme: Initial dosage of 1.5 mg daily, escalated every seventh day by 1.5 mg up to 6 mg at week 4. Dose escalation will be based on safety and tolerability, and if dose escalation is not feasible, delayed increments are allowed. After end of titration (week 4) the subjects will be maintained at the highest tolerated dose level for the last 8 weeks of the treatment period. Subjects are not allowed to change dose during the last 8 weeks of the treatment period.

    The medicine is taken orally as tablets (similar in size, shape and taste to the active medication), once daily in the evening.

    Intervention: Drug: Placebo oral tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 12, 2020)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Women aged 18-64 years
  • Understands and writes Danish
  • Fulfills the American College of Rheumatology 1990 criteria for fibromyalgia
  • A minimum score of 4 in self-reported average pain during the last 7 days on a 0-10 numeric rating scale at baseline
  • All fertile women have to use safe anti conception (Spiral, birth control pills, contraceptive patch, contraceptive vaginal ring or gestagen injections) for 3 weeks before and 1 week after the trial. If the patients' normal lifestyle includes sexual abstinence, they do not have to use anti conception. Instead they can give an oral informed consent, that they will be sexually abstinent during the trial. A woman is considered non-fertile if she is sterilized, hysterectomized, bilateral oophorectomized or is postmenopausal. A woman is considered postmenopausal when vaginal bleeding has been absent for 1 year and is confirmed by measurement of follicle-stimulating hormone.

Exclusion Criteria:

  • Known allergy against naltrexonehydroclorid
  • Pregnancy or breastfeeding. A negative pregnancy test has to be available for all fertile subjects at baseline
  • Use of opioids or NSAIDs during the 4 weeks before inclusion in the trial
  • Abuse of alcohol or other substances
  • Inflammatory rheumatic diseases
  • Demyelinating diseases
  • Active cancer
  • Liver dysfunction
  • Kidney dysfunction
  • Psychotic diseases
  • History of suicide attempts
  • Suicide ideation - evaluated using Patient Health Questionnaire-9 (Item 9 has to be answered "never")
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Karin D Bruun, Consultant +4526183619 karin.due.bruun@rsyd.dk
Contact: Palle Toft, Professor palle.toft@rsyd.dk
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04270877
Other Study ID Numbers  ICMJE 18021
2019-000702-30 ( EudraCT Number )
R177-A6158 ( Other Grant/Funding Number: The Danish Reumatism Association )
A3650 ( Other Grant/Funding Number: The OUH PhD Committee for Operating Costs )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Karin Bruun Plesner, Odense University Hospital
Study Sponsor  ICMJE Odense University Hospital
Collaborators  ICMJE
  • University of Southern Denmark
  • University Hospital Bispebjerg and Frederiksberg
Investigators  ICMJE
Principal Investigator: Karin D Bruun, Consultant Odense University Hospital
PRS Account Odense University Hospital
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP