Metformin for Fibromyalgia Symptoms (INFORM Trial)

Metformin as a Novel, Mechanistic Treatment of Fibromyalgia; a Proof of Concept RCT

The main purpose of the project is to evaluate the safety and efficacy of low dose metformin for improving symptoms associated with fibromyalgia syndrome (FMS) via modulating neuroinflammatory pathways. The investigators hypothesize that FMS patients in the low-dose metformin conditions will show greater improvement in FMS symptoms than those who are in the placebo group. Further, the investigators hypothesize that metformin will increase phosphorylated AMPK in peripheral immune cells of FMS patients and will decrease the transcription of mTORC1, NLRP3 inflammasome, and nociceptive cytokines interleukin 1beta and interleukin 18.

Study Overview

• Status: Recruiting
• Conditions: Fibromyalgia Syndrome
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

Fibromyalgia syndrome (FMS) is a chronic pain condition that is debilitating to an estimated 10 million Americans and results in high utilization of medical resources with a cost of over $100 billion in health care and lost productivity each year. It is widely accepted that chronic widespread pain is a defining feature of FMS and that it is maintained by central sensitization. Accumulating evidence demonstrates that central sensitization is driven, at least in part, by neuroinflammation. Thus, molecules that ameliorate the causes of neuroinflammation are intriguing candidates to treat FMS symptoms. Current therapies are only partially effective in about 50% of patients. The development of a treatment approach with better efficacy is urgently needed.

The investigators propose to test the use of metformin for FMS. This drug is widely used as a first line treatment for type II diabetes. Metformin causes the phosphorylation of AMP-activated protein kinase (AMPK), which regulates key enzymes and transcription factors that modulate gene expression involved in metabolism and inflammation. Because AMPK acts as a master switch kinase, this target may prove particularly effective in treating the many diverse symptoms of FMS. Indeed, metformin treated hyperalgesia in preclinical models of neuropathic, inflammatory, spinal cord injury and diabetes-induced mechanical hyperalgesia and reduced symptoms of anxiety, depression and cognitive dysfunction. This is of significant relevance because these symptoms contribute greatly to FMS patient disability.

The investigators expect that this study will determine the effectiveness of metformin on pain and comorbidity FMS symptoms and delineate the role that AMPK and its downstream targets play on these phenotypes. The investigators anticipate that these results will demonstrate the efficacy of an intervention not currently used clinically to treat FMS. Understanding these pathways represents a critical step in the development of non-addictive pain treatments and holds enormous potential to reduce disability in the 10 million Americans with FMS.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Reiko Mitsunaga, RN; Phone Number: 801-585-7695; Email: reiko.mitsunaga@hsc.utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah
      • Contact: Reiko Mitsunaga, RN; Phone Number: 801-585-7695; Email: reiko.mitsunaga@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• To be able to follow the protocol in English
• Fibromyalgia Syndrome: Participant must meet the American College of Rheumatology 2016 revised classification criteria for Fibromyalgia
• Ability to take oral medication and be willing to adhere to the metformin regimen (once daily)

Exclusion Criteria:

• Co-occurring progressive disease (self-report, physician-diagnosed)
• Diabetes
• Pregnancy or planning to be pregnant in the next year (all premenopausal participants will be tested)
• Having known cardiovascular, liver, kidney or pulmonary diseases (self-report, physician-diagnosed)
• Having known serious psychopathology (Clinician diagnoses of psychosis, organic mental disorder, or dissociative disorder, self-reported active suicidal intent, self-reported history of inpatient admission to a psychiatric ward in the past year, evidence or self-report of self-injurious behaviors in the past year, reported current or recent history (2years) of non-IV substance abuse, any history of recreational IV drug use)
• Having autoimmune disorder (e.g., rheumatoid arthritis) (self-report, physician-diagnosed)
• Having neuropathic pain (self-report, physician-diagnosed)
• Having pain associated with a terminal illness, acute pain, pain associated with specific organ damage (eg, stomach ulcer) (self-report, physician-diagnosed)
• Concurrent use of weight controlling medications (eg, Xenical)
• Requiring an interpreter to communicate
• Abnormal levels of creatinine, vitamin B12, or hepatic function panel
• eGFR of below 45mL/min/1.73m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1: Metformin Treatment; 500 mg metformin ER tablets once daily in the morning with a glass of water for 8 weeks.	Drug: Metformin; 500 mg Metformin ER tablets once daily in the morning for 8 weeks; Other Names: Glucophage XR (metformin hydrochloride); Glucophage (metformin hydrochloride)
Placebo Comparator: 2: Placebo; Matching metformin ER placebo tablets once daily in the morning with a glass of water for 8 weeks.	Drug: Placebo; Matching tablets once daily in the morning for 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the safety and efficacy of low-dose metformin in improving the symptoms associated with FMS	Safety will be measured by the Fibromyalgia Impact Questionnaire, Revised (FIQ-R score and will measure overall FMS severity. The numeric scale ranges from 0-10 with 0 being "low difficulty" (better outcome) and 10 being "high difficulty" (worse outcome).	12-14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Examine changes in individual FMS symptoms - Fatigue	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of fatigue (PROMIS Fatigue SF7a). The scale ranges from 1-5, 1 being "not at all" (better outcome) and 5 being "very much" (worse outcome).	12-14 weeks
Examine changes in individual FMS symptoms - Sleep Disturbance	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of sleep disturbance (PROMIS Sleep Disturbance SF8b). The scale ranges from 1-5, 1 being "very poor" or "not at all" (worse outcome) and 5 being "very good" or "very much" (better outcome).	12-14 weeks
Examine changes in individual FMS symptoms - Depression	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of depression (PROMIS Depression SF8b). The scale ranges from 1-5, 1 being "never" (better outcome) and 5 being "always" (worse outcome).	12-14 weeks
Examine changes in individual FMS symptoms - Anxiety	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of anxiety (PROMIS Anxiety SF7a). The scale ranges from 1-5, 1 being "never" (better outcome) and 5 being "always" (worse outcome).	12-14 weeks
Examine changes in individual FMS symptoms - Physical Function	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of physical functioning (PROMIS Physical Function SF10a). The scale ranges from 1-5, 1 being "unable to do" (worse outcome) and 5 being "without any difficulty" (better outcome).	12-14 weeks
Examine changes in ecological momentary assessment (EMA) symptoms	EMA will allow us to evaluate symptom variations at home environment	12-14 weeks
Examine patient's global improvement impression	Global impression of improvement scale will be used to assess clinical global impression (CGI). Global impression of improvement scale is a 7-point scale. Scores range from 1 being the better outcome (i.e. "normal", "improved") and 7 being the worse outcome (i.e. "most severely ill", "very much worse").	12-14 weeks
Examine adherence	Pill counts will provide us with a measure of adherence	Week 4 and week 14
Examine changes in individual FMS symptoms - Pain Intensity	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of pain intensity (PROMIS Pain Intensity SF3a). The scale ranges from 0-10, 0 being "no pain" (better outcome) and 10 being "worst pain imaginable" (worse outcome).	12-14 weeks
Examine changes in individual FMS symptoms - Perceived Cognitive Function	Efficacy will be evaluated for a range of symptoms through the PROMIS Short Form measures of perceived cognitive functioning (title: Multiple Ability Self-Report Questionnaire (MASQ)). The scale ranges from 1-5 with 1 being "never" (better outcome) to 5 being "always" (worse outcome).	12-14 weeks

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Akiko Okifuji, PhD, University of Utah; Principal Investigator: Norman Taylor, MD, PhD, University of Utah

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: May 17, 2023
• First Submitted That Met QC Criteria: June 2, 2023
• First Posted (Actual): June 12, 2023

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: FMS
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Fibromyalgia; Myofascial Pain Syndromes; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 00160543; R21AR082574 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes