Stress urinary incontinence helped with Yentreve(reg) combined with pelvic floor training

Main Category: Urology / Nephrology
Article Date: 13 Apr 2005 - 0:00 PDT


New data published in the May 2005 issue of The Journal of Urology show that the combination of Yentreve(reg) (duloxetine hydrochloride) and pelvic floor muscle training (PFMT) decreased the frequency of incontinence episodes (IEF) by up to 76 percent for women who completed a 12-week course of combined treatment.1

The millions of women worldwide who experience accidental leaks during physical activities such as sneezing, coughing, laughing, lifting or exercising, suffer from a medical condition known as stress urinary incontinence, or SUI.2 These women are greatly impacted by their condition often avoiding social activities and exercise for fear of triggering accidental leaks. They also are significantly preoccupied with trying to hide the leaks even from their friends and families and mask the odor that may result from them.

"This study shows that combining medication and pelvic floor exercises can substantially decrease the number of leakages and improve the quality of life in many women with stress urinary incontinence. Improving muscle strength takes time to achieve and duloxetine can help improve incontinence very early in treatment while the exercises are taking effect. The results will be encouraging to those women with stress urinary incontinence who might think there is no alternative to surgery," said Robert Freeman, M.D.

FRCOG, a lead investigator of the study and Consultant Gynecologist and Obstetrician, Urogynecology Unit, Directorate of Obstetrics and Gynecology, Derriford Hospital, Plymouth, United Kingdom.

The study included 201 women with SUI ranging in age from 29-75 years old and was conducted in 17 continence centers in the Netherlands, the United Kingdom and the United States. The women enrolled in the study experienced an average of at least two incontinence episodes per day. The primary efficacy measure used in the study was the reduction of IEF, calculated from information recorded by patients in a self-completed diary format. A unique feature of this randomized 12-week double-blind placebo-controlled study was that it included a blinded, imitation PFMT control treatment. This is important because an inactive control for both duloxetine and PFMT is the most scientifically accurate way to detect the true effect of the active treatments. The study was designed with the following combinations of treatments: Yentreve(reg) 40mg twice daily plus PFMT (number of patients=52); PFMT plus placebo (n=50); Yentreve(reg) plus imitation PFMT (n=52); and placebo plus imitation PFMT (n=47).1

The results of the study found:

Of all the women who completed the 12 weeks of the study, results demonstrate that Yentreve(reg) combined with PFMT was more effective than either treatment alone.

-- There was a 75.8 percent decrease in IEF for participants using combination therapy compared with 61.1 percent for Yentreve(reg) alone, 46.8 percent for PFMT alone (p=.01) and 42.7 percent for no active therapy (p<.001).1 The enhanced effect of the combination of Yentreve(reg) and PFMT could be explained by their complementary mechanisms of action (Yentreve(reg) is believed to tone the sphincter muscle while PFMT enhances pelvic floor activity).

-- Yentreve(reg) combined with PFMT was significantly more effective in reducing continence pad usage (54.5 percent) than using no treatment at all (13 percent, p<.01). This was possibly due to the complementary clinical effects of Yentreve(reg) (reduction in number of incontinence episodes) and PFMT skill training (reduction in leakage volume with each episode).

-- The combination of Yentreve(reg) and PFMT resulted in significant improvements in patients` quality of life, as assessed by the Incontinence Quality of Life questionnaire compared with no active treatment. Quality of life improvements were greater with combined treatment than with either single treatment or with no treatment.

An analysis of the intent-to-treat population (all randomized participants including those who did not complete the entire 12 weeks of the study or follow the study protocol) demonstrated the superiority of Yentreve(reg), with or without PFMT, compared with either no treatment or with PFMT alone.

-- In this patient group, there was a 57.4 percent reduction in IEF using a combination of Yentreve(reg) and PFMT compared with 56.5 percent reduction with Yentreve(reg) alone, a 34.7 percent reduction with PFMT alone (p<.001) and a 28.9 percent reduction with no treatment (p<.001).1 This analysis included all diary data collected after the randomization (after 4, 8, and 12 weeks of treatment), and represents an assessment of the benefits throughout the 12-week trial

-- The results of the intent-to-treat population reflect the more rapid onset of action of Yentreve(reg) (within 3 days up to 2 weeks)3 combined with PFMT skill training4 as opposed to the more gradual efficacy of PFMT strength training which is achieved over time.*

-- In this patient population, Yentreve(reg) combined with PFMT was significantly more effective in reducing continence pad usage (45.7 percent) than using no active treatment (10.5 percent, p=.001).

-- Quality of Life findings were similar in this patient population to those described in the completer analysis.

*Note: PFMT skill training is believed to result in a reduction in leakage volume very soon after the patient is instructed to contract her muscles in anticipation of an event (such as a cough) that causes leakage. In contrast, PFMT strength training's goal is to make the muscles stronger and this effect occurs over a period of time, usually weeks to months. Once adequate strength improvement is realized, this results in a reduction in leakage frequency.

In this study, the most common side effect reported with Yentreve(reg) was nausea, occurring with an incidence of 38.5 percent compared with 5.2 percent with placebo. However, of the patients being treated with Yentreve(reg) who experienced nausea, the majority (83 percent) completed the study. Generally, nausea is known to be mild to moderate and transient.

Other common side effects (defined with an incidence of at least 5 percent and twice that of placebo) were dizziness, dry mouth, constipation, insomnia, somnolence, and asthenia. The side effect profile from this study was very similar to that observed in other clinical studies of duloxetine for the treatment of SUI.

Yentreve(reg) for the Treatment of SUI

Yentreve(reg) is a balanced dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine,5 based upon pre-clinical data; these neurotransmitters are believed to play key roles in the normal closure of the urethral sphincter, the muscle that if weakened can contribute to SUI.5,6

By increasing neurotransmitter concentration, Yentreve(reg) is believed to increase the tone and contraction of the urethral sphincter, which helps prevent accidental urine leakage due to physical activities such as sneezing, coughing, laughing, lifting or exercising.

In four multicenter clinical trials involving nearly 2,000 women performed in Africa, Australia, Europe, North America, and South America, Yentreve(reg) reduced the number of leakages by 50 percent to 100 percent in more than half of women with SUI as compared with 33 percent in placebo-treated patients. Yentreve(reg) also helped improve their quality of life, and was generally well tolerated with mild and manageable side effects, the most common of which was transient nausea.6 Other common adverse events observed in the clinical studies of duloxetine from the treatment of SUI (incidence of greater than 5 percent and significantly more common than placebo) were dry mouth, fatigue, insomnia, constipation, headache, dizziness, somnolence and diarrhea.6

Yentreve(reg) has been studied in more than 10,000 patients and is now approved throughout the 25 European Union countries, Mexico, Switzerland, Norway and Israel. Duloxetine for SUI is now marketed in Austria, Denmark, Finland, Germany, Ireland, Norway, Sweden, Switzerland and the United Kingdom under the trade name Yentreve(reg) and in Greece and Italy under the trade name AriClaim(reg). Eli Lilly and Company and Boehringer Ingelheim plan to make duloxetine for SUI available in many more countries in the coming months.

Stress Urinary Incontinence (SUI)

SUI, the accidental leakage of urine during physical activities such as sneezing, coughing, laughing, lifting or exercise, affects the social and emotional well being of up to 65 million women worldwide. 2 Yentreve(reg) is the first and only widely approved pharmaceutical treatment for SUI. With nearly twice the prevalence as urge incontinence, SUI is the most common form of urinary incontinence in women. Although common, SUI is a medical condition that should not be considered a normal part of aging. SUI causes embarrassment and even social isolation, which may have a profound negative impact on the quality of life of the affected individuals. Even though many women are bothered by their symptoms of SUI, they often do not seek appropriate medical attention because they are embarrassed or mistakenly believe it is a normal part of aging. Several risk factors or contributing variables to the development of SUI have been suggested over the last decade and include childbirth, obesity, pelvic organ prolapse or chronic coughing.7 Prior to Yentreve(reg)`s availability there were no widely approved pharmaceutical options available for the treatment of SUI. Options were limited to treatments such as behavioral therapy, PFMT and surgery.

About the Yentreve(reg) Clinical Research Program

The Yentreve(reg) clinical research program is striving to improve the lives of millions of women worldwide who suffer from SUI. It is a long-term, extensive and evolving global initiative, sponsored by Eli Lilly and Company and Boehringer Ingelheim, and is designed to investigate SUI, its impact on women's quality of life, and the efficacy and safety of Yentreve(reg) in a wide range of patients and clinical settings. More than ten studies enrolling nearly 2,000 patients were completed prior to the launch of Yentreve(reg). Other studies are planned and new studies will be initiated as the clinical research program evolves.

Eli Lilly and Company and Boehringer Ingelheim

In November 2002, Eli Lilly and Company and Boehringer Ingelheim signed a long-term agreement to jointly develop and commercialize duloxetine hydrochloride. Duloxetine is currently being developed for the treatment of depression, stress urinary incontinence and diabetic peripheral neuropathic pain. This partnership covers most countries worldwide with few exceptions. In the USA, the collaboration excludes neuroscience indications.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers - through medicines and information - for some of the world`s most urgent medical needs.

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 144 affiliates in 45 countries and nearly 36,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2004, Boehringer Ingelheim posted net sales of 8.2 billion euro while spending nearly one fifth of net sales in its largest business segment Prescription Medicines on research and development.

Duloxetine for stress urinary incontinence will be marketed by Lilly and Boehringer Ingelheim in all countries included in the partnership under the brand name Yentreve(reg), except for Greece, Italy, and Spain. In Greece, Italy, and Spain, Lilly will market the product as Yentreve(reg) and Boehringer Ingelheim will market the product as AriClaim(reg).

Boehringer Ingelheim GmbH
Julia Meyer-Kleinmann
55216 Ingelheim am Rhein
GERMANY
Phone: +49/6132/77 82 71
Fax: +49/6132/77 66 01
webmaster@ing.boehringer-ingelheim.com

Eli Lilly and Company
Christine Van Marter
PO Box 23456 Indianapolis, Indiana
USA
Phone: (1)317-655-2249

References:

1 Ghoniem GM et al. A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment, and no active treatment in women with stress urinary incontinence. J of Urology 2005;175(5)

2 Voelker R. International group seeks to dispel incontinence "taboo". JAMA 1998;280(11):951-953

3 Cardozo L et al. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstetrics and Gynecology. 2004;104(No. 3):511-519

4 Miller JM et al. A pelvic muscle precontraction can reduce cough-related urine loss in selected women with mild SUI. J Am Ger Soc 1998;46:870-874

5 Bymaster FP et al. Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors. Neuropsyhcopharmacology2001;25(6):871-880

6 Hurley et al. Duloxetine for Stress Urinary Incontinence (SUI): Meta-Analysis of Safety. Abstract presented at the International Federation of Gynecology and Obstetrics (FIGO) World Congress, Santiago, Chile. 2-7 November 2003

7 Viktrup L. Female stress and urge incontinence in family practice: insight into the lower urinary tract. Int J Clin Prac 2003;56(9):694-700

http://www.boehringer-ingelheim.com

• Additional
• References
• Citations