The purpose of this study is to assess the efficacy of metformin to improve airway ion channel function in those with CF-related diabetes (CFRD)
Up to 30 patients with CFRD on highly effective CFTR modulator therapy who meet criteria and agree to participation in the study will be placed on metformin 500mg twice daily (low) and 1000mg twice daily (normal) in a randomized order (simple randomization). There will be a dose-escalation with each dosing regimen starting with 500mg twice daily for a week, followed by 500mg in the AM and 1000mg in the PM for another week and finally followed by 1000mg twice daily until the end of normal dose cycle (in those in the normal dose portion of the crossover trial). A matching placebo pill will be utilized so participants do not know which dosing regimen, low or normal, they are on during each 14-week period. Participants will continue each dosing regimen of metformin for 14 weeks with a washout period of 2 weeks between dose changes. To minimize risk of B12 deficiency, a known side effect of long-term metformin use, we will also provide a supplement of 1000 µg oral cyanocobalamin daily for the duration of the trial.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
26
500-1000 mg twice daily
University of Kansas Medical Center
Kansas City, Kansas, United States
Change in BK channel gene expression
Levels of LRRC26 (big potassium channel regulatory subunit) mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in BK function, as measured by nasal potential difference testing
Nasal potential difference testing measures direct BK current in the nasal epithelium, with greater current indicating greater BK function
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in receptor for receptor for advanced glycation end products (RAGE) gene expression
Levels of RAGE mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in advanced glycation end products (AGE)
Plasma levels of AGE, receptor for AGE (RAGE), soluble RAGE and S100A12 will be quantified by ELISA
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in sweat chloride
Measured as a secondary marker of CFTR function, with lower levels indicating greater CFTR function
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in lung function
Measured by percent predicted forced expiatory volume in one second captured on spirometry (FEV1)
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
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Change in Quality of Life (CFQ-R)
Measured by Patient Reported Outcome measurement tool called CFQ-R (validated)
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Change in airway inflammatory markers
Inflammatory markers (interleukin-1beta, interleukin-6, interleukin-8, transforming growth factor beta1, tissue necrosis factor-alpha, matrix metalloproteinase-9 and cyclooxygenase-2) collected from nasal fluid will be measured by enzyme linked immunosorbent assay (ELISA)
Time frame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Safety of metformin
Number of adverse events during study period
Time frame: Baseline through week 30 of metformin treatment
Pharmacokinetics of metformin
Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry
Time frame: Week 14 and week 30 of metformin treatment