Extended Release Torsemide for Overactive Bladder in Heart Failure

Overseen By Sophia Shah, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Furosemide

Must not be taking: NSAIDs, Cox-2 inhibitors, Allopurinol

Disqualifiers: Low eGFR, Recent MI or stroke, 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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is being done to compare the effectiveness two drugs: an extended release torsemide (ERT) versus generic immediate release Torsemide (IRT) in reducing the worsening of symptoms of Overactive Bladder (OAB i.e., frequency, urgency, or urgency incontinence) in patients with chronic congestive heart failure (CHF). This study will include CHF patients who experience worsening OAB) symptoms with use of a loop diuretic. The total duration of the study is about eight weeks with a total of nine visits. There will be a screening visit that lasts one to two hours. The screening visit includes history and physical exams, blood draws, and urine analysis. If eligible for the study, participants will receive either generic torsemide or extended release torsemide for the first four weeks. Participants will do a virtual research visit on week one, two and three to submit a symptom diary and answer a questionnaire about urinary symptoms. At four weeks, history and physician exam will be done and blood will be collected. Participants will be assigned to receive either extended release torsemide (if they initially received generic torsemide) and generic torsemide (if they initially received extended release torsemide) for the next four weeks. Participants will attend virtual research visits on week five, six and seven to submit a symptom diary and answer a questionnaire about urinary symptoms. At the end of the study in week eight, they will have history and physical exams and blood draws. Some risks from the study may include side effects of torsemide like acute kidney injury, fluid/electrolyte loss, hypersensitivity reactions and reversible hearing loss/tinnitus.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable dose of furosemide. If you're taking NSAIDs, Cox-2 inhibitors, or Allopurinol, you may need to switch to acetaminophen with the investigator's approval.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like NSAIDs, Cox-2 inhibitors, or Allopurinol. If you're on these, you might switch to acetaminophen if the investigator agrees.

What data supports the idea that Extended Release Torsemide for Overactive Bladder in Heart Failure is an effective drug?

The available research does not provide specific data on the effectiveness of Extended Release Torsemide for Overactive Bladder in Heart Failure. Instead, it focuses on other drugs like fesoterodine, solifenacin, and tolterodine for treating overactive bladder. These studies show that these drugs can reduce symptoms like urinary incontinence and improve bladder function. However, there is no direct comparison or data available for Extended Release Torsemide in the context of overactive bladder in heart failure. ^{1 2 3 4 5}

What safety data exists for Extended Release Torsemide in treating heart failure?

The safety data for Extended Release Torsemide, also known as Demadex, Soaanz, or Torsemide, primarily comes from studies comparing it to furosemide in heart failure patients. These studies indicate that torsemide has a more predictable absorption and may offer better clinical outcomes, such as improved survival rates, left ventricular function, and reduced cardiac remodeling, compared to furosemide. A meta-analysis showed torsemide was associated with improved functional status and lower cardiac mortality, though no significant difference in all-cause mortality or side effects was observed between torsemide and furosemide. Pharmacodynamic studies suggest torsemide has a linear pharmacokinetic profile and a defined dose-response relationship in heart failure patients. ^{6 7 8 9 10}

Is Extended Release Torsemide safe for humans?

Torsemide has been studied in patients with heart failure and is generally considered safe, with no significant difference in side effects compared to furosemide, another common diuretic. It has been shown to improve heart function and reduce cardiac mortality in these patients. ^{6 7 8 9 10}

Is the drug Extended Release Torsemide a promising treatment for overactive bladder in heart failure?

The provided research articles do not mention Extended Release Torsemide or its effects on overactive bladder in heart failure. Therefore, we cannot determine if it is a promising treatment based on this information. ^{4 11 12 13 14}

How does the drug Extended Release Torsemide differ from other treatments for overactive bladder in heart failure?

Extended Release Torsemide is unique because it is primarily a diuretic (a drug that helps remove excess fluid from the body) used for heart failure, and its use for overactive bladder in heart failure patients is novel compared to traditional treatments like antimuscarinics, which directly target bladder muscle activity. ^{4 11 12 13 15}

Research Team

Alvin Chandra

Principal Investigator

University of Texas Southwestern Medical Center

Eligibility Criteria

This trial is for people over 50 with chronic congestive heart failure (CHF) who are in NYHA functional class II-IV. They must be on a stable dose of furosemide and have an eGFR of ≥30 ml/min/1.73 m2, as well as symptoms of overactive bladder.

Inclusion Criteria

I experience symptoms of an overactive bladder.

I have moderate to severe heart condition symptoms.

I am 50 years or older with a diagnosis of heart failure.

Exclusion Criteria

Urinalysis containing white blood cells indicative of urinary tract infection

I have liver cirrhosis.

Any known allergy to diuretics or sulphonamide-derived compounds

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 hours

1 visit (in-person)

Treatment Period 1

Participants receive either extended release torsemide or generic immediate release torsemide for the first four weeks

4 weeks

1 visit (in-person), 3 visits (virtual)

Treatment Period 2

Participants switch treatments and receive the alternative torsemide formulation for the next four weeks

4 weeks

1 visit (in-person), 3 visits (virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Extended Release Torsemide

Trial Overview The study compares extended release torsemide (ERT) to immediate release Torsemide (IRT) for reducing worsening symptoms of Overactive Bladder in CHF patients. It's an eight-week study with nine visits including physical exams, blood tests, and symptom diaries.

Participant Groups

Group I: Investigational product Experimental Treatment 2 Interventions

Extended release torsemide and immediate release torsemide placebo

Group II: Control product Active Control 2 Interventions

Immediate release torsemide and extended release torsemide placebo

Extended Release Torsemide is already approved in United States for the following indications:

Approved in United States as Demadex for:

• Edema associated with congestive heart failure
• Edema associated with renal disease
• Edema associated with hepatic disease
• Hypertension

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Sarfez Pharmaceuticals, Inc.

Lead Sponsor

Trials

6

Recruited

100+

Findings from Research

In a 12-week study involving 794 elderly adults with overactive bladder, fesoterodine significantly reduced urgency episodes and improved overall bladder function compared to placebo, demonstrating its efficacy in this population.

Fesoterodine was generally well tolerated, although it did have higher rates of dry mouth (34%) and constipation (9%) compared to placebo, indicating a need for monitoring side effects in elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. Wagg, A., Khullar, V., Marschall-Kehrel, D., et al.[2015]

In a study of 338 men over 50 with benign prostatic hyperplasia (BPH) and severe overactive bladder (OAB) symptoms, a combination treatment of solifenacin and trospium alongside tamsulosin significantly reduced urinary incontinence episodes from an average of 3.4 to 0.9 per day over two months.

The combination therapy was found to be effective and safe, with side effects comparable to those typically seen with antimuscarinic monotherapy, indicating it is a viable option for managing severe OAB symptoms in BPH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Solifenacin and Trospium for Managing of Severe Symptoms of Overactive Bladder in Patients With Benign Prostatic Hyperplasia. Kosilov, KV., Loparev, SA., Ivanovskaya, MA., et al.[2022]

In a long-term study involving 890 participants (185 men and 705 women), fesoterodine was found to be well tolerated, with 91% of subjects reporting at least 'good' tolerance and low discontinuation rates due to side effects like dry mouth.

Fesoterodine treatment led to significant and sustained improvements in overactive bladder symptoms, such as urgency and urinary incontinence, over a treatment period of up to 24 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety, tolerability, and efficacy of fesoterodine treatment in men and women with overactive bladder symptoms. Scarpero, H., Sand, PK., Kelleher, CJ., et al.[2012]

In a study of 897 patients with overactive bladder, 68% were identified as suboptimal responders to tolterodine ER 4 mg, showing only a 15.3% decrease in urgency urinary incontinence (UUI) episodes, compared to an 80% decrease in responders.

Among those suboptimal responders, nearly 70% experienced a significant UUI response after switching to fesoterodine 8 mg, with predictors for this response including no prior antimuscarinic use and fewer baseline UUI episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms. Grenabo, L., Herschorn, S., Kaplan, SA., et al.[2018]

In a study of 552 vulnerable elderly patients with overactive bladder, those treated with fesoterodine had lower annual healthcare costs (€1,775) compared to those treated with solifenacin (€2,062) and tolterodine (€2,149), indicating a more cost-effective option.

Fesoterodine also showed slightly better persistence to treatment, suggesting it may be a preferable choice for managing overactive bladder in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of health care resources and associated costs in non-institutionalized vulnerable elders with overactive bladder treated with antimuscarinic agents in the usual medical practice. Sicras-Mainar, A., Rejas-Gutiérrez, J., Navarro-Artieda, R., et al.[2018]

In a study of 234 patients with chronic heart failure, those treated with torsemide had significantly lower rates of hospital readmission for heart failure (17% vs. 32% for furosemide) and for all cardiovascular causes (44% vs. 59%).

Patients on torsemide also experienced fewer hospital days for heart failure (106 days vs. 296 days for furosemide) and reported greater improvements in fatigue, suggesting that torsemide may be a more effective diuretic for managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. Murray, MD., Deer, MM., Ferguson, JA., et al.[2019]

In a rat model of chronic heart failure, torasemide significantly improved left ventricular function and survival rates compared to furosemide, indicating its superior efficacy in managing heart failure-related remodeling.

Torasemide also reduced cardiac fibrosis and levels of harmful proteins associated with heart damage, while furosemide did not show these beneficial effects, highlighting torasemide's potential in treating heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effects of torasemide and furosemide in rats with heart failure. Veeraveedu, PT., Watanabe, K., Ma, M., et al.[2018]

In a systematic review of 19 studies involving 19,280 heart failure patients, torsemide was associated with a significant improvement in functional status and a lower risk of cardiac mortality compared to furosemide.

Torsemide also showed a trend towards fewer hospitalizations due to heart failure, although this result was not statistically significant, indicating it may be a more effective diuretic option for heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis Comparing Torsemide Versus Furosemide in Patients With Heart Failure. Abraham, B., Megaly, M., Sous, M., et al.[2020]

In a study of 51 outpatients with symptomatic congestive heart failure, doubling the dose of diuretics (furosemide, torsemide, and metolazone) led to significant weight loss and improved symptoms, as well as increased walking distance over a follow-up period of about 24 days.

Despite these improvements in symptoms and physical capacity, there were no significant changes observed in left ventricular function, indicating that while diuretics can alleviate symptoms, they do not directly improve heart function in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of increased dose of diuretics on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of left ventricular systolic and diastolic function in 51 patients with symptomatic heart failure caused by reduced left ventricular ejection fraction treated with beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Kumar, A., Aronow, WS., Vadnerkar, A., et al.[2013]

In a study involving 16 subjects with compensated congestive heart failure, torsemide showed linear pharmacokinetics up to a dose of 200 mg, with about 20% of the drug excreted unchanged, similar to findings in healthy individuals.

The maximum urinary sodium excretion rate achieved was only about 0.6 mEq/min, indicating diuretic resistance in heart failure patients, and the study found that a 50 mg dose of torsemide reached the ceiling effect for diuretic response, suggesting higher doses may not provide additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pharmacodynamics of torsemide in patients with congestive heart failure. Vargo, D., Kramer, WG., Black, PK., et al.[2019]

In a study involving 293 Japanese patients with overactive bladder, tolterodine ER 4 mg once daily was found to be well tolerated over 12 months, with dry mouth being the most common side effect (33.5%).

The efficacy of tolterodine ER was sustained throughout the year, showing significant reductions in incontinence episodes and improvements in patients' perceptions of their bladder condition, with 78.6% reporting overall treatment benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder in Japanese patients. Takei, M., Homma, Y.[2015]

The oxybutynin extended-release (ER) formulation provides a smoother plasma concentration profile and allows for once-daily administration, improving tolerability and convenience for patients with overactive bladder (OAB).

In clinical trials, oxybutynin ER demonstrated significant reductions in urinary incontinence and micturition frequency, with a better tolerability profile compared to immediate-release formulations and similar efficacy to other treatments like tolterodine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxybutynin extended-release: a review of its use in the management of overactive bladder. Siddiqui, MA., Perry, CM., Scott, LJ.[2019]

In a study of 698 patients with overactive bladder, tolterodine extended release (ER) showed significant reductions in urinary frequency, urgency, and urgency urinary incontinence as early as Day 5 of treatment.

More than half of the patients experienced at least a 50% reduction in urgency or UUI episodes by Day 5, with improvements continuing through Week 12, indicating that tolterodine ER is effective for managing OAB symptoms quickly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Onset of efficacy of tolterodine extended release in patients with overactive bladder. Sussman, DO., Kraus, SR., Carlsson, M., et al.[2019]

In a 12-week study involving 46 patients with neurogenic detrusor overactivity (NDO) and/or low-compliance bladder, extended-release tolterodine (4mg/day) significantly improved bladder capacity and reduced symptoms, with bladder capacity at first sensation increasing by 36.8mL and maximum cystometric capacity by 82.3mL.

The treatment led to a significant decrease in overactive bladder symptoms, including reduced number of voids and leaks, demonstrating tolterodine's efficacy and good tolerance for managing NDO and low-compliance bladder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of extended-release tolterodine for the treatment of neurogenic detrusor overactivity and/or low-compliance bladder. Watanabe, M., Yamanishi, T., Honda, M., et al.[2022]

References

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

Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. [2015]

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

Effectiveness of Solifenacin and Trospium for Managing of Severe Symptoms of Overactive Bladder in Patients With Benign Prostatic Hyperplasia. [2022]

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

Long-term safety, tolerability, and efficacy of fesoterodine treatment in men and women with overactive bladder symptoms. [2012]

4. England pubmed.ncbi.nlm.nih.gov

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms. [2018]

5. Spain pubmed.ncbi.nlm.nih.gov

Use of health care resources and associated costs in non-institutionalized vulnerable elders with overactive bladder treated with antimuscarinic agents in the usual medical practice. [2018]

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

Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure. [2019]

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

Comparative effects of torasemide and furosemide in rats with heart failure. [2018]

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

Meta-Analysis Comparing Torsemide Versus Furosemide in Patients With Heart Failure. [2020]

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

Effects of increased dose of diuretics on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of left ventricular systolic and diastolic function in 51 patients with symptomatic heart failure caused by reduced left ventricular ejection fraction treated with beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. [2013]

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

The pharmacodynamics of torsemide in patients with congestive heart failure. [2019]

11. Australia pubmed.ncbi.nlm.nih.gov

Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder in Japanese patients. [2015]

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

Oxybutynin extended-release: a review of its use in the management of overactive bladder. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Onset of efficacy of tolterodine extended release in patients with overactive bladder. [2019]

14. Australia pubmed.ncbi.nlm.nih.gov

Efficacy of extended-release tolterodine for the treatment of neurogenic detrusor overactivity and/or low-compliance bladder. [2022]

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

Economic impact of extended-release tolterodine versus immediate- and extended-release oxybutynin among commercially insured persons with overactive bladder. [2015]