Skeletal Muscle Dysfunction in Rheumatoid Arthritis (RA)
Condition: Rheumatoid Arthritis; Insulin Resistance
MeSH terms: Arthritis; Arthritis, Rheumatoid; Insulin Resistance
Study type: Interventional
Phase: Phase 1

Summary: 
      Muscle strength helps determine a person's quality of life and functional independence.
      Patients with rheumatoid arthritis often suffer from muscle weakness and a pre-diabetic
      condition called insulin resistance.

      By doing this study, the investigators hope to learn why patients with rheumatoid arthritis
      (RA) suffer from muscle weakness.
    

Detailed description: 
      The investigator plans to enroll 80 participants with RA and 30 non-RA controls between the
      ages of 35 and 65 between August 2015 and December 2018 (arm-1). The investigator plan to
      perform a needle muscle biopsy in a subset of participants who agree to undergo this
      procedure. From the total cohort number of enrolled participants, 36 participants will be
      identified as having insulin resistance and recruit them to participate in the pioglitazone
      study (arm-2). Those patients who elect to participate further in the pioglitazone/ placebo
      study will sign separate consent document during Visit 1.

      Since RA is more common in women, it is anticipated that 2/3 of the participants will be
      women. Children, pregnant or breast-feeding women, adults with impaired consent capacity, or
      vulnerable populations will not be enrolled.

      In the cross-sectional study, after having provided informed consent, participants will
      undergo a history and physical exam by a rheumatologist to verify diagnosis of RA or that
      they are a healthy volunteer. All inclusion and exclusion criteria will be verified by the
      examining physician. During this visit, the participants will complete questionnaires
      including the Brief Pain Inventory (BPI), Health Assessment Questionnaire (HAQ), Patient
      Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-36.
      Participants will undergo dual energy x-ray absorptiometry (DXA) scanning to assess muscle
      mass of the upper leg (dominant and non-dominant sides), as well as computed tomography (CT)
      to assess body composition. Women of child bearing age will undergo urine pregnancy testing.
      Participants will undergo strength testing and a fatiguing bout of knee extension exercise.
      Blood will be drawn for glucose, insulin, liver function tests (LFT), lipid profile,
      rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), insulin like growth
      factor (IGF-1), C-Reactive Protein (CRP), insulin like growth factor binding protein-1
      (IGFBP-1) and insulin like growth factor binding protein-3 (IGFBP-3). All participants will
      be asked to wear an accelerometer for 7 day to measure physical activity. The participants
      will be scheduled to return to Center for Clinical and Translational Science (CCTS) within 7
      days for biopsy of the vastus lateralis muscle.

      In the pioglitazone clinical trial study, 36 participants who have insulin resistance will be
      recruited to receive pioglitazone. After the participants have provided informed consent,
      women of childbearing potential will be given a urine pregnancy test at visits 1, 3 and 6.
      The investigator will review participant eligibility and participants will be randomized to
      receive either pioglitazone 45 mg daily or matching placebo for 15 weeks. Below is the dosing
      schedule.

      Participants will start by taking increasing doses for three weeks as follows: 1 capsule
      (15mg) per day for 7 days, 1 capsule per day (30 mg) for 7 days, and 1 capsule (45mg), if
      tolerated. Participants will continue this dose (45 mg) throughout the 10 weeks of treatment.
      The placebo or non-pioglitazone capsules will look identical to the pioglitazone capsules,
      but will contain inert substances, and the escalating dose schedule will be the same.

      If participants experience difficulty with the drug, the investigators will slow the pace of
      dose escalation. If they cannot take 45 mg/day, then they may be dropped from the study. The
      placebo capsules will look identical to the pioglitazone capsules, but will contain inert
      substances. Drug compounding and dispensing (including blinding) will be handled by the
      University of Kentucky's Investigational Drug Service, which routinely serves this function.
      All participants in the pioglitazone study will undergo a second round of assessments. During
      the 15-week drug trial, participants will receive monthly phone calls to monitor for adverse
      effects. Additionally, participants will be asked to fill out a daily medication diary to
      monitor compliance and adverse effects. A skeletal muscle biopsy will be performed after
      treatment with pioglitazone/ placebo, which will take place within 1-2 weeks after the second
      round of assessments following pioglitazone treatment.
    

Intervention name(s): Pioglitazone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Pioglitazone CT Scan DXA scan Needle muscle biopsy; Placebo CT Scan DXA scan Needle muscle biopsy
Other intervention name(s): Actos
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Rheumatoid Arthritis