Metformin for Cystic Fibrosis

Overseen By Matthias A Salathe, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Kansas Medical Center

Must be taking: Ivacaftor, Elexacaftor/Tezacaftor/Ivacaftor

Must not be taking: Corticosteroids, NSAIDs, CYP inducers/inhibitors

Disqualifiers: Lung/liver transplant, Oxygen use, BMI<18, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether metformin, a common diabetes medication, can improve lung function in individuals with cystic fibrosis-related diabetes (CFRD). Participants will follow one of two metformin dosing plans to assess its impact while continuing other CF medications. Ideal candidates have cystic fibrosis and diabetes, use medications like ivacaftor, and have experienced blood sugar control issues. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that interact with metformin and those known to be strong CYP inducers or moderate to strong CYP inhibitors. If you are on these medications, you may need to stop them to participate.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that metformin is generally safe for most people, including those without diabetes. Studies indicate it rarely causes low blood sugar, a common concern with diabetes medications. One study involving patients with cystic fibrosis-related diabetes (CFRD) used metformin without major side effects. Participants tolerated it well, and no serious problems occurred.

Another study found that a delayed-release form of metformin can reduce stomach-related side effects, making it easier for people to continue treatment. Overall, these findings suggest that metformin is well-tolerated, with few serious side effects reported. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CF?

Unlike the standard treatments for cystic fibrosis-related diabetes (CFRD), which often include insulin therapy and cystic fibrosis transmembrane conductance regulator (CFTR) modulators like elexacaftor/tezacaftor/ivacaftor, metformin brings a fresh approach. Metformin is a medication typically used for type 2 diabetes that works by improving insulin sensitivity and reducing glucose production in the liver. Researchers are excited about metformin because it may offer additional benefits in managing blood sugar levels in CFRD patients, potentially improving outcomes when combined with CFTR modulators. Additionally, metformin might offer a more convenient oral alternative to insulin injections, making it easier for patients to manage their condition.

What evidence suggests that metformin might be an effective treatment for cystic fibrosis-related diabetes?

Research has shown that metformin helps control blood sugar by reducing sugar production in the liver. It is often used to treat diabetes and might also benefit people with cystic fibrosis-related diabetes (CFRD). Some studies suggest that metformin could improve lung function in these patients. Although no specific test measures its effectiveness in CFRD, previous research indicates it may help manage blood sugar levels. In this trial, participants will receive different metformin dose regimens to evaluate its effects. It is important to note that metformin carries risks, such as lactic acidosis (a build-up of acid in the body), especially for those with liver or kidney problems. ^{1 2 6 7 8}

Who Is on the Research Team?

Matthias A Salathe, M.D.

Principal Investigator

Professor

Are You a Good Fit for This Trial?

Adults over 18 with Cystic Fibrosis (CF) and CF-related diabetes, using specific CF medications for at least 30 days. They must show signs of glucose intolerance despite treatment. Excluded are those on certain other drugs, with recent severe illness or lung/liver transplants, pregnant or breastfeeding women, and individuals unable to follow the study's contraception guidelines.

Inclusion Criteria

I am over 18 and have been diagnosed with cystic fibrosis.

I have been taking ivacaftor or elexacaftor/tezacaftor/ivacaftor for the last 30 days.

I have diabetes due to cystic fibrosis and still have high blood sugar after 6 months of specific treatment.

Exclusion Criteria

I do not have heart, kidney, nerve, mental health, hormone, or cancer conditions that could affect my study participation.

Your liver enzymes or bilirubin levels are higher than they should be.

I use supplemental oxygen.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive metformin 500 mg twice daily, with dose escalation to 1000 mg twice daily over 14 weeks

14 weeks

Regular visits for dose adjustment and monitoring

Washout

Participants undergo a washout period between treatment phases

2 weeks

Treatment Phase 2

Participants resume metformin treatment with dose adjustments similar to Phase 1

14 weeks

Regular visits for dose adjustment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Metformin Hydrochloride

Trial Overview The trial is testing if Metformin Hydrochloride can improve airway ion channel function in patients with CF who also have diabetes related to their condition. It aims to see if this medication can help alleviate some of the complications associated with CF.

How Is the Trial Designed?

Group I: Metformin dose regimen B Experimental Treatment 1 Intervention

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).

Group II: Metformin dose regimen A Experimental Treatment 1 Intervention

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).

Metformin Hydrochloride is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in United States as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome
• Gestational diabetes

Approved in Canada as Metformin Hydrochloride for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in Japan as Metformin Hydrochloride for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Published Research Related to This Trial

In a study involving 40 patients with type 2 diabetes, the combination tablet of glibenclamide and metformin (Glucovance) led to significantly lower postprandial glucose excursions compared to taking glibenclamide and metformin separately, indicating better blood sugar control after meals.

The combination formulation resulted in a higher peak concentration and greater overall exposure of glibenclamide in the bloodstream, which may explain its enhanced effectiveness in managing post-meal blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of glyburide/metformin tablets (Glucovance) versus equivalent doses of glyburide and metformin in patients with type 2 diabetes. Donahue, SR., Turner, KC., Patel, S.[2021]

In a study of 40 type 2 diabetic patients, it was found that good glycometabolic control could be maintained by replacing phenformin with the sulphonylurea gliclazide, even at lower doses of glibenclamide.

Patients on higher doses of glibenclamide and phenformin showed improved metabolic control when switched to a combination of gliclazide and benfluorex, suggesting that phenformin can be safely withdrawn or replaced without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of sulfonylurea and sulfonylurea-benfluorex therapy in patients with type 2 diabetes treated with commercial sulfonylurea-biguanide combinations]. Di Cianni, G., Benzi, L., Ciccarone, AM., et al.[2013]

In a study of 126 overweight and obese patients with type 2 diabetes, dulaglutide (DU) showed a significant and sustained reduction in HbA1c levels over 18 months, with a mean decrease of -0.85% at 6 months, indicating its effectiveness as an add-on therapy to metformin.

Dulaglutide was associated with a higher percentage of patients achieving glycemic targets (HbA1c ≤ 7.0%) compared to liraglutide (LIRA) at 18 months, with 64.8% of DU patients reaching this target versus 42.6% for LIRA, highlighting its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes. Mirabelli, M., Chiefari, E., Tocci, V., et al.[2021]

In a study involving 24 healthy male volunteers, the bioavailability of two metformin tablet formulations was compared, showing that both formulations had equivalent absorption when taken after fasting.

Key pharmacokinetic parameters, such as maximum concentration and area under the curve, were similar for both formulations, indicating that they can be considered equivalent in their effectiveness for delivering metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of two metformin formulations. Al Hawari, S., AlGaai, E., Yusuf, A., et al.[2013]

In a 52-week study involving 939 patients with type 2 diabetes, dapagliflozin plus saxagliptin and dapagliflozin alone were more effective than glimepiride in lowering HbA1c levels, with changes of -1.20% and -0.82% respectively, compared to -0.99% for glimepiride.

Both dapagliflozin regimens led to significant weight loss and reductions in systolic blood pressure, while also having a lower incidence of hypoglycemia compared to glimepiride, although there was a higher occurrence of genital infections with dapagliflozin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes. Müller-Wieland, D., Kellerer, M., Cypryk, K., et al.[2021]

In a study of 130 patients with type 2 diabetes treated with Metformin Hydrochloride, gastrointestinal adverse effects were the most common, with diarrhea affecting 30.77% of patients and leading to treatment discontinuation in 3.85%.

No cases of serious complications like lactic acidosis or allergic reactions were reported, indicating that while Metformin is generally safe, monitoring for digestive issues is important in managing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cross-Sectional Study on Adverse Effects of Metformin Hydrochloride on 130 Patients Type 2 Diabetic Admitted to Medical Center and Diabetes Home of Sidi Bel-Abbès]. Sakouhi, M., Matmour, D., Belakhdar, K., et al.[2023]

A retrospective chart review of 471 patients showed that those switched from immediate-release metformin to extended-release metformin (metformin-XR) experienced significantly fewer gastrointestinal side effects, including diarrhea, indicating better tolerability of the extended-release formulation.

The study found that while the overall frequency of gastrointestinal adverse events was similar between both formulations, patients who switched to metformin-XR reported a reduction in gastrointestinal issues, with diarrhea rates dropping from 18.05% to 8.29%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Blonde, L., Dailey, GE., Jabbour, SA., et al.[2021]

In a 52-week study involving 477 patients with high blood sugar despite sulphonylurea therapy, the combination of metformin and glibenclamide (Glucovance) maintained a significant reduction in HbA1C levels by an average of -1.7%.

The combination therapy was well tolerated, with only 11.1% of patients experiencing mild to moderate hypoglycemic symptoms, and no patients required withdrawal or additional treatment for hypoglycemia, indicating its safety for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable efficacy of metformin/glibenclamide combination tablets (Glucovance) during 52 weeks of open-label treatment in type 2 diabetic patients with hyperglycaemia despite previous sulphonylurea monotherapy. Blonde, L., Joyal, S., Henry, D., et al.[2022]

In two studies involving a total of 982 patients, metformin XR significantly reduced HbA1C levels compared to placebo, demonstrating its efficacy in improving glycemic control in patients with inadequate management despite diet and exercise.

A clear dose-response relationship was observed, with higher doses of metformin XR leading to greater reductions in HbA1C, and the medication was well tolerated, with minimal withdrawals due to gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Fujioka, K., Brazg, RL., Raz, I., et al.[2022]

A systematic review of 1,662 patients from five randomized control trials and 10,909 patients from one observational study found that both metformin immediate-release (IR) and extended-release (XR) formulations have similar effectiveness and safety profiles in managing blood glucose levels.

Patients showed better compliance with metformin XR due to its once-daily dosing, making it a more convenient option for long-term treatment compared to the IR formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Acting Metformin Vs. Metformin Immediate Release in Patients With Type 2 Diabetes: A Systematic Review. Tan, J., Wang, Y., Liu, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04530383

NCT04530383 | Effects of Metformin on Airway Ion ... 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 ...

2. ctv.veeva.com ctv.veeva.com/study/effects-of-metformin-on-airway-ion-channel-dysfunction-in-cystic-fibrosis-related-diabetes

Effects of Metformin on Airway Ion Channel Dysfunction in ... The purpose of this study is to assess the efficacy of metformin to improve airway ion channel function in those with CF-related diabetes ...

3. researchgate.net researchgate.net/publication/375439131_P110_Metformin_in_patients_with_cystic_fibrosis-related_diabetes_CFRD_outcomes_from_a_single_UK_centre

P110 Metformin in patients with cystic fibrosis-related ... The main effect of metformin is to suppress glucose production in the liver; however, there is no reliable biomarker to assess the effectiveness ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7171946/

Optimization of Metformin in the GRADE Cohort: Effect on ... In this study, we report the impact of optimizing metformin dose during the run-in phase of the GRADE study on glycemic control and body weight and evaluate ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6139848/

Cystic Fibrosis Related Diabetes: a Unique Challenge in ... Treatment with metformin may be unsafe due to the increased risk of lactic acidosis in patients with frequent hypoxia and underlying liver and chronic kidney ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8102119/

Metformin and Fibrosis: A Review of Existing Evidence and ... In this study, researchers found that metformin treatment effectively prevented and slowed the progression of fibrosis, and impressively, it was ...

7. diabetesjournals.org diabetesjournals.org/care/article/43/5/940/35701/Optimization-of-Metformin-in-the-GRADE-Cohort

Optimization of Metformin in the GRADE Cohort: Effect on ... Metformin, when used alone, rarely causes hypoglycemia and is generally safe even in patients who do not have diabetes (8,9). Therefore, in most ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8266931/

Efficacy and Side Effect Profile of Different Formulations of ... Metformin delayed release was associated with reduced gastrointestinal side effects compared to immediate release, which could improve drug compliance. Further ...