Cystic Fibrosis, Cystic Fibrosis-related Diabetes
Conditions
Keywords
Metformin
Brief summary
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)
Detailed description
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. There will be a dose-escalation 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 for 14 weeks. 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
Interventions
DRUGMetformin Hydrochloride
1000 mg twice daily
Sponsors
University of Kansas Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>18 years with a prior diagnosis of CF. 2. Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor or vanzacaftor/tezacaftor/deutivacaftor for 30 days prior to day 0 3. Diagnosis of CFRD with evidence of continued glucose intolerance at least 6 months after starting qualifying modulator therapy will be based upon one of the following: 1. Insulin use 2. Hemoglobin A1C \>6.5% 3. Fasting glucose \>126 mg/dl 4. Non-fasting glucose \>200 mg/dl (random or as part of a 2-hr OGTT)
Exclusion criteria
1. Prior lung or liver transplant 2. Use of supplemental oxygen 3. BMI \<18 4. CF pulmonary exacerbation requiring hospitalization or intravenous antibiotics in the preceding 30 days 5. Systemic corticosteroid or regular non-steroidal anti-inflammatory use in the preceding 30 days 6. Cardiac, renal (creatinine clearance \<45 mL/minute), neurologic, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in the study 7. Alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase \>1.5X the upper limit of normal; bilirubin \>3 mg/dL 8. Taking medications that interact with metformin. 9. Vitamin B12 deficiency 10. Pregnancy or lactation 11. Inability or unwillingness to comply with an approved contraceptive method during the study period (females of childbearing age) 12. Use of medications known to be strong CYP inducers or moderate to strong CYP inhibitors 13. In the opinion of the investigator any severe or acute or chronic condition or laboratory abnormality that may increase the risk associated with trial participation or make the subject inappropriate for enrollment 14. Participation in another interventional trial that, in the opinion of the investigator, has the potential to affect the primary outcome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BK channel gene expression | Baseline through week 14 of metformin treatment | Levels of LRRC26 (big potassium channel regulatory subunit) mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in BK function, as measured by nasal potential difference testing | Baseline through week 14 of metformin treatment | Nasal potential difference testing measures direct BK current in the nasal epithelium, with greater current indicating greater BK function |
| Change in receptor for receptor for advanced glycation end products (RAGE) gene expression | Baseline through week 14 of metformin treatment | Levels of RAGE mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing |
| Change in advanced glycation end products (AGE) | Baseline through week 14 of metformin treatment | Plasma levels of AGE, receptor for AGE (RAGE), soluble RAGE and S100A12 will be quantified by ELISA |
| Change in sweat chloride | Baseline through week 14 of metformin treatment | Measured as a secondary marker of CFTR function, with lower levels indicating greater CFTR function |
| Change in lung function | Baseline through week 14 of metformin treatment | Measured by percent predicted forced expiatory volume in one second captured on spirometry (FEV1) |
| Change in Quality of Life (CFQ-R) | Baseline through week 14 of metformin treatment | Measured by Patient Reported Outcome measurement tool called CFQ-R (validated) |
| Change in airway inflammatory markers | Baseline through week 14 of metformin treatment | 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) |
| Safety of metformin | Baseline through week 14 of metformin treatment | Number of adverse events during study period |
| Pharmacokinetics of metformin | Week 14 of metformin treatment | Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry |
Countries
United States
Contacts
CONTACTMatthias A Salathe, M.D.
CONTACTCarolina Aguiar
PRINCIPAL_INVESTIGATORMatthias A Salathe, M.D.
Professor
Outcome results
None listed