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

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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)

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 metformin safe for humans?

Metformin is generally considered safe for humans, with common side effects including stomach issues like diarrhea, nausea, and vomiting. It may also cause a decrease in vitamin B12 absorption and rarely skin reactions. Both immediate-release and extended-release forms have similar safety profiles, but the extended-release form may be better tolerated. ^{1 2 3 4 5}

How is the drug Metformin Hydrochloride unique for treating cystic fibrosis?

Metformin Hydrochloride is unique for treating cystic fibrosis because it is primarily known for managing type 2 diabetes by improving insulin sensitivity and reducing blood sugar levels, which is different from typical cystic fibrosis treatments that focus on lung function and infection control. This novel approach may offer additional benefits by potentially addressing metabolic issues in cystic fibrosis patients. ^{6 7 8 9 10}

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 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]

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 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 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]

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]

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 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 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 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]

Citations

1. France 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]. [2023]

2. England 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. [2021]

4. Switzerland 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. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Long-Acting Metformin Vs. Metformin Immediate Release in Patients With Type 2 Diabetes: A Systematic Review. [2021]

6. Switzerland 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. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of two metformin formulations. [2013]

8. England 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. [2021]

9. India 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. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

[Efficacy of sulfonylurea and sulfonylurea-benfluorex therapy in patients with type 2 diabetes treated with commercial sulfonylurea-biguanide combinations]. [2013]