Clinical trial NCT04530383: Effects of Metformin on Airway Ion Channel Dysfunction in Cystic Fibrosis-related Diabetes
Official title: A Randomized, Double-blind, Crossover Clinical Trial of Metformin in Those With CFRD on CFTR Modulator Therapy to Improve Ion Channel Function
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cystic Fibrosis-related Diabetes
Cystic Fibrosis
Keywords: Metformin
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
First posted: 2020-08-28
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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 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.

Eligibility criteria: Inclusion criteria:

1. Age \>18 years with a prior diagnosis of CF.
2. Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor for 30 days prior to day 0
3. 3. Diagnosis of CFRD with evidence of continued glucose intolerance at least 6 months after starting elexacaftor/tezacaftor/ivacaftor 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

Primary outcomes:
measure: Change in BK channel gene expression
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary outcomes:
measure: Change in BK function, as measured by nasal potential difference testing
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in receptor for receptor for advanced glycation end products (RAGE) gene expression
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in advanced glycation end products (AGE)
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in sweat chloride
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in lung function
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in Quality of Life (CFQ-R)
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Change in airway inflammatory markers
timeFrame: Baseline through week 14 and week 16 through week 30 of metformin treatment
measure: Safety of metformin
timeFrame: Baseline through week 30 of metformin treatment
measure: Pharmacokinetics of metformin
timeFrame: Week 14 and week 30 of metformin treatment
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
Study officials:
affiliation: Professor
name: Matthias A Salathe, M.D.
role: PRINCIPAL_INVESTIGATOR
References: