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

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

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)

Study Overview

• Status: Recruiting
• Conditions: Cystic Fibrosis; Cystic Fibrosis-related Diabetes
• Intervention / Treatment: Drug: Metformin Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthias A Salathe, M.D.; Phone Number: 9135886000; Email: msalathe@kumc.edu
• Study Contact Backup: Name: Carolina Aguiar; Phone Number: 9139459295; Email: caguiar@kumc.edu

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Recruiting
      • University of Kansas Medical Center
      • Contact: Matthias A Salathe, M.D.; Phone Number: 913-588-6000; Email: msalathe@kumc.edu
      • Contact: Carolina Aguiar; Phone Number: 9139459295
      • Sub-Investigator: Charles D Bengtson, M.D.
      • Sub-Investigator: Andreas Schmid, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin dose regimen A; Participants with CFRD on elexacaftor/tezacaftor/ivacaftor who meet criteria and agree to participation in the study will be placed on metformin 500 mg twice daily on study week 0 after undergoing study procedures through week 14. They will then undergo a two week washout period. For the second half of the study metformin will be resumed and, if tolerated, dose will be increased by 500mg on weeks 17 and 18 to a final dose of 1000 mg twice daily through end of study (week 30).	Drug: Metformin Hydrochloride; 500-1000 mg twice daily; Other Names: Glucophage
Experimental: Metformin dose regimen B; Participants with CFRD on elexacaftor/tezacaftor/ivafactor who meet criteria and agree to participation in the study will be placed on metformin 500 mg twice daily on study week 0 after undergoing study procedures. If tolerated, dose will be increased by 500mg on weeks 1 and 2 to a final dose of 1000 mg twice daily through week 14.They will then undergo a two week washout period. For the second half of the study metformin will be resumed at a dose of 500 mg twice daily through the end of study (week 30).	Drug: Metformin Hydrochloride; 500-1000 mg twice daily; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CFTR function, as measured by nasal potential difference testing	Nasal potential difference testing measures direct CFTR current in the nasal epithelium, with greater current indicating greater CFTR function	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	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	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	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	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)	Baseline through week 14 and week 16 through week 30 of metformin treatment
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
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
Safety of metformin	Number of adverse events during study period	Baseline through week 30 of metformin treatment
Pharmacokinetics of metformin	Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry	Week 14 and week 30 of metformin treatment

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center
• Investigators: Principal Investigator: Matthias A Salathe, M.D., Professor

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2022
• Primary Completion (Anticipated): May 1, 2025
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: August 24, 2020
• First Submitted That Met QC Criteria: August 24, 2020
• First Posted (Actual): August 28, 2020

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Metformin
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: STUDY00146063

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No