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

Primary Purpose

Cystic Fibrosis-related Diabetes, Cystic Fibrosis

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Metformin Hydrochloride

About this trial

This is an interventional treatment trial for Cystic Fibrosis-related Diabetes focused on measuring Metformin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Age >18 years with a prior diagnosis of CF.
Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor for 30 days prior to day 0
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:

Prior lung or liver transplant
Use of supplemental oxygen
BMI <18
CF pulmonary exacerbation requiring hospitalization or intravenous antibiotics in the preceding 30 days
Systemic corticosteroid or regular non-steroidal anti-inflammatory use in the preceding 30 days
Cardiac, renal (creatinine clearance <45 mL/minute), neurologic, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in the study
Alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase >1.5X the upper limit of normal; bilirubin >3 mg/dL
Taking medications that interact with metformin.
Vitamin B12 deficiency
Pregnancy or lactation
Inability or unwillingness to comply with an approved contraceptive method during the study period (females of childbearing age)
Use of medications known to be strong CYP inducers or moderate to strong CYP inhibitors
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
Participation in another interventional trial that, in the opinion of the investigator, has the potential to affect the primary outcome

Sites / Locations

University of Kansas Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Metformin dose regimen A

Metformin dose regimen B

Arm 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).

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).

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

Change in advanced glycation end products (AGE)

Plasma levels of AGE, receptor for AGE (RAGE), soluble RAGE and S100A12 will be quantified by ELISA

Change in sweat chloride

Measured as a secondary marker of CFTR function, with lower levels indicating greater CFTR function

Change in lung function

Measured by percent predicted forced expiatory volume in one second captured on spirometry (FEV1)

Change in Quality of Life (CFQ-R)

Measured by Patient Reported Outcome measurement tool called CFQ-R (validated)

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)

Safety of metformin

Number of adverse events during study period

Pharmacokinetics of metformin

Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry

Full Information

NCT ID

NCT04530383

First Posted

August 24, 2020

Last Updated

May 8, 2023

Sponsor

University of Kansas Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT04530383

Brief Title

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

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

February 14, 2022 (Actual)

Primary Completion Date

May 1, 2025 (Anticipated)

Study Completion Date

October 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Kansas Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis-related Diabetes, Cystic Fibrosis

Keywords

Metformin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Metformin dose regimen A

Arm Type

Experimental

Arm Description

Arm Title

Metformin dose regimen B

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Metformin Hydrochloride

Other Intervention Name(s)

Glucophage

Intervention Description

500-1000 mg twice daily

Primary Outcome Measure Information:

Title

Change in BK channel gene expression

Description

Levels of LRRC26 (big potassium channel regulatory subunit) mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Secondary Outcome Measure Information:

Title

Change in CFTR function, as measured by nasal potential difference testing

Description

Nasal potential difference testing measures direct CFTR current in the nasal epithelium, with greater current indicating greater CFTR function

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in BK function, as measured by nasal potential difference testing

Description

Nasal potential difference testing measures direct BK current in the nasal epithelium, with greater current indicating greater BK function

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in receptor for receptor for advanced glycation end products (RAGE) gene expression

Description

Levels of RAGE mRNA will be measured by polymerase chain reaction from nasal cells acquired via brushing

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in advanced glycation end products (AGE)

Description

Plasma levels of AGE, receptor for AGE (RAGE), soluble RAGE and S100A12 will be quantified by ELISA

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in sweat chloride

Description

Measured as a secondary marker of CFTR function, with lower levels indicating greater CFTR function

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in lung function

Description

Measured by percent predicted forced expiatory volume in one second captured on spirometry (FEV1)

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in Quality of Life (CFQ-R)

Description

Measured by Patient Reported Outcome measurement tool called CFQ-R (validated)

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Change in airway inflammatory markers

Description

Time Frame

Baseline through week 14 and week 16 through week 30 of metformin treatment

Title

Safety of metformin

Description

Number of adverse events during study period

Time Frame

Baseline through week 30 of metformin treatment

Title

Pharmacokinetics of metformin

Description

Plasma levels of metformin will be quantified by liquid chromatography-mass spectrometry

Time Frame

Week 14 and week 30 of metformin treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Age >18 years with a prior diagnosis of CF. Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor for 30 days prior to day 0 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: Insulin use Hemoglobin A1C >6.5% Fasting glucose >126 mg/dl Non-fasting glucose >200 mg/dl (random or as part of a 2-hr OGTT) Exclusion criteria: Prior lung or liver transplant Use of supplemental oxygen BMI <18 CF pulmonary exacerbation requiring hospitalization or intravenous antibiotics in the preceding 30 days Systemic corticosteroid or regular non-steroidal anti-inflammatory use in the preceding 30 days Cardiac, renal (creatinine clearance <45 mL/minute), neurologic, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in the study Alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase >1.5X the upper limit of normal; bilirubin >3 mg/dL Taking medications that interact with metformin. Vitamin B12 deficiency Pregnancy or lactation Inability or unwillingness to comply with an approved contraceptive method during the study period (females of childbearing age) Use of medications known to be strong CYP inducers or moderate to strong CYP inhibitors 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 Participation in another interventional trial that, in the opinion of the investigator, has the potential to affect the primary outcome

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Matthias A Salathe, M.D.

Phone

9135886000

msalathe@kumc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Carolina Aguiar

Phone

9139459295

caguiar@kumc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Matthias A Salathe, M.D.

Organizational Affiliation

Professor

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Kansas Medical Center

City

Kansas City

State/Province

Kansas

ZIP/Postal Code

66160

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Matthias A Salathe, M.D.

Phone

913-588-6000

msalathe@kumc.edu

First Name & Middle Initial & Last Name & Degree

Carolina Aguiar

Phone

9139459295

First Name & Middle Initial & Last Name & Degree

Charles D Bengtson, M.D.

First Name & Middle Initial & Last Name & Degree

Andreas Schmid, M.D.

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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