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

University of Kansas

Status and phase: Enrolling; Phase 2

Conditions: Cystic Fibrosis-related Diabetes; Cystic Fibrosis

Treatments: Drug: Metformin Hydrochloride

Study type: Interventional

Funder types: Other

Identifiers

NCT04530383

STUDY00146063

Details and patient eligibility

About

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)

Full 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.

Enrollment: 36 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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:

   4. Insulin use

   5. Hemoglobin A1C >6.5%

   6. Fasting glucose >126 mg/dl

   7. 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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36 participants in 2 patient groups

Metformin dose regimen A

Experimental group

Description:

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).

Treatment:

Drug: Metformin Hydrochloride

Metformin dose regimen B

Experimental group

Description:

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).

Treatment:

Drug: Metformin Hydrochloride