Effects of Metformin on Airway Ion Channel Dysfunction in Cystic Fibrosis-related Diabetes

Cystic Fibrosis Clinical Trial

Official title:

A Randomized, Double-blind, Crossover Clinical Trial of Metformin in Those With CFRD on CFTR Modulator Therapy to Improve Ion Channel Function

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04530383
• Other study ID #: STUDY00146063
• Status: Recruiting
• Phase: Phase 2
• Start date: February 14, 2022
• Est. completion date: October 1, 2025

Study information

• Verified date: June 2024
• Source: University of Kansas Medical Center
• Contact: Matthias A Salathe, M.D.
• Phone: 9135886000
• Email: msalathe[@]kumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: October 1, 2025
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Cystic Fibrosis-related Diabetes
• Fibrosis

Intervention

Drug:
• Metformin Hydrochloride
500-1000 mg twice daily

Locations

Country	Name	City	State
United States	University of Kansas Medical Center	Kansas City	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
University of Kansas Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	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	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	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	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	Change in advanced glycation end products (AGE)	Plasma levels of AGE, receptor for AGE (RAGE), soluble RAGE and S100A12 will be quantified by ELISA	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	Change in sweat chloride	Measured as a secondary marker of CFTR function, with lower levels indicating greater CFTR function	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	Change in lung function	Measured by percent predicted forced expiatory volume in one second captured on spirometry (FEV1)	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	Change in Quality of Life (CFQ-R)	Measured by Patient Reported Outcome measurement tool called CFQ-R (validated)	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	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)	Baseline through week 14 and week 16 through week 30 of metformin treatment
Secondary	Safety of metformin	Number of adverse events during study period	Baseline through week 30 of metformin treatment
Secondary	Pharmacokinetics of metformin	Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry	Week 14 and week 30 of metformin treatment