Losartan for Cystic Fibrosis

Recruiting in Palo Alto (17 mi)

Overseen by Charles D Bengtson, M.D.

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Kansas Medical Center

Must be taking: Elexacaftor/tezacaftor/ivacaftor

Must not be taking: Corticosteroids, NSAIDs, ARBs, ACE inhibitors

Disqualifiers: Lung transplant, Renal insufficiency, Pregnancy, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test use of losartan in those with cystic fibrosis (CF) on modulator therapy. The main question it aims to answer is if treatment with losartan improves response of the CF transmembrane conductance regulator (CFTR) channel to modulator therapy. Participants will be asked take losartan or placebo for twelve weeks and will have changes in sweat chloride levels measured as a marker of CFTR function.

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, like systemic corticosteroids, non-steroidal anti-inflammatory drugs, and any drugs that interact with losartan, such as aliskiren, at least 30 days before joining. If you're on these medications, you may need to stop them to participate.

Is Losartan safe for humans?

Losartan, also known as Cozaar or Hyzaar, is generally considered safe for humans and is commonly used to treat high blood pressure and other conditions. It has been studied extensively and is known to have a well-established safety profile. ^{1 2 3 4 5}

How does the drug Losartan work differently for cystic fibrosis compared to other treatments?

Losartan is unique for cystic fibrosis because it targets inflammation-related mucociliary dysfunction, improving airway function by restoring the activity of specific channels in the airways, independent of its usual role in blocking angiotensin receptors. ^{6 7 8 9 10}

Research Team

Charles D Bengtson, M.D.

Principal Investigator

University of Kansas Medical Center

Eligibility Criteria

This trial is for individuals with cystic fibrosis who are currently receiving modulator therapy. Specific eligibility details aren't provided, but typically participants must meet certain health criteria and not have conditions that would exclude them from safely participating.

Inclusion Criteria

I am 12 years old or older.

I have been taking elexacaftor/tezacaftor/ivacaftor steadily for 90 days.

I have been diagnosed with cystic fibrosis.

Exclusion Criteria

Pregnancy or lactation

Participation in another interventional trial that, in the opinion of the investigator, has the potential to affect the primary outcome

BMI <18

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive losartan or placebo for twelve weeks to assess changes in CFTR function

12 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Losartan (Angiotensin II Receptor Blocker)

Trial Overview The study is testing whether losartan can improve the effectiveness of modulator therapy in cystic fibrosis patients by measuring changes in sweat chloride levels over twelve weeks. Participants will be randomly assigned to receive either losartan or a placebo.

Participant Groups

Group I: Losartan Experimental Treatment 1 Intervention

Losartan 25mg twice daily for one week followed by 50mg twice daily through week 12.

Group II: Placebo Placebo Group 1 Intervention

Placebo twice daily through week 12

Losartan is already approved in Canada for the following indications:

Approved in Canada as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Dr. Steve Stites

University of Kansas Medical Center

Chief Executive Officer

MD from University of Kansas School of Medicine

Dr. Matthias Salathe

University of Kansas Medical Center

Chief Medical Officer

MD from University of Kansas School of Medicine

Findings from Research

Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) significantly improves lung function and quality of life in cystic fibrosis patients, as shown in a systematic review of 9 clinical trials and 16 observational studies involving participants aged 6-11 and older with specific genetic mutations.

The treatment has a favorable safety profile, with mostly mild to moderate side effects, although its effects on cystic fibrosis-related diabetes remain unclear and further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review. Kapouni, N., Moustaki, M., Douros, K., et al.[2023]

A 7-year-old boy with cystic fibrosis experienced a severe skin reaction to the CFTR modulator elexacaftor/tezcaftor/ivacaftor (Trikafta), highlighting the potential for adverse reactions to these important medications.

Desensitization was successfully implemented, allowing the patient to continue treatment, which underscores the importance of managing drug reactions to maintain access to essential therapies for cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

If At First You Don't Succeed, Trikafta Again. Loyd, I., Papac, N., Hirshburg, J., et al.[2022]

Tezacaftor, a newly approved CFTR corrector, shows improved efficacy and safety when used in combination with ivacaftor compared to the previous combination of lumacaftor-ivacaftor, particularly in increasing lung function (FEV1) and reducing adverse events.

This combination therapy is effective for a broader range of cystic fibrosis mutations, and ongoing research into three-drug combinations and novel treatments suggests a promising future for personalized CF therapies, with many patients expected to have access to effective modulators within the next five years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tezacaftor for the treatment of cystic fibrosis. Sala, MA., Jain, M.[2019]

In a study of 67 children aged 6 to 11 with cystic fibrosis, tezacaftor/ivacaftor significantly improved lung function and CFTR function over 8 weeks, as shown by a reduction in the lung clearance index and decreased sweat chloride levels.

The treatment was found to be safe and well tolerated, with no serious adverse events reported, although common side effects included cough and headache.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. Davies, JC., Sermet-Gaudelus, I., Naehrlich, L., et al.[2021]

In a randomized, double-blind, placebo-controlled phase 3b trial involving 121 children aged 6 to 11 with cystic fibrosis, the triple-combination therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improved lung function, with a mean decrease in lung clearance index of 2.29 units compared to 0.02 units in the placebo group (P < 0.0001).

ELX/TEZ/IVA also led to substantial improvements in secondary outcomes, including a reduction in sweat chloride concentration and enhancements in respiratory symptoms, while being generally safe and well tolerated, with most adverse events being mild or moderate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study. Mall, MA., Brugha, R., Gartner, S., et al.[2022]

Losartan has been shown to effectively reverse mucociliary dysfunction associated with cystic fibrosis (CF) by rescuing the activity of BK channels and improving mucociliary function in both human airway epithelial cells and a sheep model of CF-like airway disease.

The beneficial effects of losartan, including improved mucus transport and reduced inflammation, occur independently of its action on angiotensin receptors, suggesting a novel mechanism for its anti-inflammatory properties in CF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis. Kim, MD., Baumlin, N., Yoshida, M., et al.[2021]

Losartan potassium, an angiotensin II receptor antagonist, shows significant haemodynamic benefits in patients with heart failure, based on extensive clinical trials.

The drug is well tolerated with a low incidence of adverse effects related to kidney function, making it a safe option for treating hypertension and heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan in heart failure: preclinical experiences and initial clinical outcomes. Sweet, CS., Rucinska, EJ.[2019]

The study confirmed that Losartan Potassium Tablets 50 mg from Micro Labs Ltd. are bioequivalent to Cozaar® Tablets 50 mg from Merck Sharp and Dohme Ltd., showing similar absorption rates and extents in a trial with 60 healthy male subjects.

Both formulations were well tolerated, with no significant differences in safety parameters such as blood pressure and heart rate, indicating that they can be considered equally safe for use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of two losartan tablet formulations with special emphasis on cardiac safety. Khandave, SS., Sawant, SV., Sahane, RV., et al.[2019]

Losartan potassium, an angiotensin II receptor antagonist, is effective and well-tolerated for treating hypertension, especially when combined with hydrochlorothiazide (HCTZ) for enhanced efficacy.

A new high-performance liquid chromatography method was successfully developed to simultaneously analyze losartan potassium and HCTZ along with their impurities and degradates, ensuring accurate quantification at very low levels (0.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products. Hertzog, DL., McCafferty, JF., Fang, X., et al.[2019]

Losartan/hydrochlorothiazide (HCTZ) is an effective fixed-dose combination therapy for hypertension, providing greater blood pressure reduction than either medication alone, and is particularly beneficial for patients with severe hypertension and left ventricular hypertrophy (LVH).

In the LIFE study, losartan-based therapy demonstrated a lower incidence of cardiovascular events and new-onset diabetes compared to atenolol, highlighting its safety and efficacy in reducing stroke risk and improving overall cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan/Hydrochlorothiazide: a review of its use in the treatment of hypertension and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy. Keating, GM.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

If At First You Don't Succeed, Trikafta Again. [2022]

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

Tezacaftor for the treatment of cystic fibrosis. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Losartan in heart failure: preclinical experiences and initial clinical outcomes. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of two losartan tablet formulations with special emphasis on cardiac safety. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products. [2019]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Losartan/Hydrochlorothiazide: a review of its use in the treatment of hypertension and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy. [2021]