Benefit of the Treatment With Testosterone in Chronic Heart Failure Testosterone Deficiency Subjects

Heart Failure Clinical Trial

— TIC  

Official title:

A Randomized and Double-blind Study to Evaluate the Benefit of the Treatment With Testosterone in Chronic Heart Failure Testosterone Deficiency Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01813201
• Other study ID #: TIC-0911
• Secondary ID: 2009-016498-13
• Status: Completed
• Phase: Phase 4
• First received: June 22, 2011
• Last updated: December 12, 2017
• Start date: March 2011
• Est. completion date: March 2014

Study information

• Verified date: November 2014
• Source: Fundacion para la Formacion e Investigacion Sanitarias de la Region de Murcia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical trial is to determine whether intermittent administration of testosterone against placebo is associated with a reduction of mortality and heart failure hospitalizations at 1 year, in male patients with advanced heart failure and testosterone deficiency.

Description:

Heart Failure (HF) represents one of the major social and health problems, for its high prevalence and its huge economic impact, as well as the elevated morbidity and mortality associated. In Spain, the estimated prevalence is 7% over 45 years old, and it increases until 18% over 75 years old. Currently, HF is the leading cause of hospital admission over 65 years and the mortality for patients with symptomatic HF remains worse than the majority of cancers. The estimated minimum expenditure is 1.1% of total health care costs and 2% of specialized medical care. This accounts for a staggeringly large financial burden on the health care system.

Chronic HF is a complex disease, whose progression involves multiple pathophysiological systems. It is well established the deleterious effect of activation of renin-angiotensin-aldosterone and sympathetic nervous systems. The blockage of these systems by beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and aldosterone antagonists has improved prognosis. However, in spite of these therapies, the prognosis of patients with chronic HF remains poor.

During the HF progression to advanced stages, it has been shown an anabolic and metabolic deterioration, resulting in a predominance of catabolic processes. The deficiency of anabolic hormones correlates with greater severity of symptoms, activation of neuroendocrine and inflammatory systems, insulin resistance, metabolic impairment, exercise intolerance, anemia and cardiac cachexia. All these processes take part of the final progression of the HF disease until death, when HF becomes a systemic disease. In men with HF, levels of testosterone (the main anabolic hormone) are decreased; in fact, 30% of men have levels below the 10th percentile of a reference healthy population adjusted for age. The deterioration of anabolic hormones correlates inversely with the severity of HF disease and it determines a higher mortality. In fact, low testosterone levels are associated with reduced cardiac output, greater symptomatic limitation and higher mortality. Therefore, testosterone deficiency in men with HF has a detrimental impact on symptoms and prognosis.

In addition, testosterone has shown to have beneficial effects on HF patients, such as vasodilatation of coronary and peripheral arteries, inotropic effects, reduction of neurohormonal activation, anti-inflammatory and immunomodulatory actions, reduction of cytokine production and improvement of muscle strength. All these actions have a potential benefit in patients with HF, because they are involved in the progression of the disease, especially at advanced stages.

The rational approach "testosterone replacement for improving the prognosis of patients with advanced HF and testosterone deficiency" has strong pathophysiological plausibility. To date, no other clinical trials have evaluated the effect of testosterone replacement on morbidity and mortality.

However, in the last years, numerous editorials in leading journals have concluded on the need to clarify the effect of testosterone therapy on cardiac function and the morbimortality in patients with advanced HF.

Our group has worked in the last years in this field, confirming the presence of a testosterone deficiency in men with chronic HF, which is associated with a worse prognosis and a greater decline in exercise capacity.

Therefore, the investigators propose a clinical trial of morbimortality in a population with advanced heart failure and associated deficiency on testosterone; in which, the previous background justifies the potential benefit of testosterone replacement therapy. In addition, the large clinical impact of this disease supports the priority need of an independent study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• At least one hospital admission for HF.

• Stable clinical status, New York Heart Association (NYHA) functional class II-IV.

• Left ventricular ejection fraction of less than 40%

• NT-proBNP concentration greater than 1000 pg / ml.

• Total testosterone and free testosterone deficiency measured in the last month

• Age >18 years.

• Patients who have given their written informed consent.

Exclusion Criteria:

• No informed consent.

• Taking oral anticoagulants

• Severe valvular heart disease with an indication for surgical repair.

• Extracardiac disease with an estimated prognosis of less than 1 year.

• History of androgen-dependent prostate cancer, benign prostate hyperplasia treatment or prostate-specific antigen (PSA)> 3 ng / ml.

• History of breast carcinoma or liver tumor

• Severe renal impairment (glomerular filtration rate <30 ml / kg / min).

• Acute coronary syndrome in the last year

• Renal or hepatic failure

• Uncontrolled hypertension

• Erythrocytosis (hematocrit> 5%)

• Hypersensitivity to testosterone or any excipients.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Testosterone undecanoate
Testosterone undecanoate intramuscular long-acting, 1000 mg/dose, administered at inclusion and every 12 weeks for 9 months (4 dose) (testosterone group) against the administration of placebo (saline isotonic solution).
• Saline isotonic solution
Saline isotonic solution (placebo)intramuscular,administered at inclusion and every 12 weeks for 9 months (4 dose)

Locations

Country	Name	City	State
Spain	Cardiology Service, Hospital Universitario Virgen de la Arrixaca	Murcia

Sponsors (3)

Lead Sponsor	Collaborator
Fundacion para la Formacion e Investigacion Sanitarias de la Region de Murcia	Germans Trias i Pujol Hospital, Hospital Universitario Virgen de la Arrixaca

Country where clinical trial is conducted

Spain, 

References & Publications (20)

Anker SD, Al-Nasser FO. Chronic heart failure as a metabolic disorder. Heart Fail Monit. 2000;1(2):42-9. Review. — View Citation

Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997 Jul 15;96(2):526-34. — View Citation

Aukrust P, Ueland T, Gullestad L, Yndestad A. Testosterone: a novel therapeutic approach in chronic heart failure? J Am Coll Cardiol. 2009 Sep 1;54(10):928-9. doi: 10.1016/j.jacc.2009.05.039. — View Citation

Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140-50. — View Citation

Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009 Sep 1;54(10):919-27. doi: 10.1016/j.jacc.2009.04.078. — View Citation

Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006 Oct 24;114(17):1829-37. Epub 2006 Oct 9. — View Citation

Jankowska EA, Filippatos G, Ponikowska B, Borodulin-Nadzieja L, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure. J Card Fail. 2009 Jun;15(5):442-50. doi: 10.1016/j.cardfail.2008.12.011. Epub 2009 Feb 10. — View Citation

Kontoleon PE, Anastasiou-Nana MI, Papapetrou PD, Alexopoulos G, Ktenas V, Rapti AC, Tsagalou EP, Nanas JN. Hormonal profile in patients with congestive heart failure. Int J Cardiol. 2003 Feb;87(2-3):179-83. — View Citation

Malkin CJ, Jones TH, Channer KS. Testosterone in chronic heart failure. Front Horm Res. 2009;37:183-96. doi: 10.1159/000176053. Review. — View Citation

Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail. 2007 Jan;9(1):44-50. Epub 2006 Jul 7. — View Citation

Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J. 2006 Jan;27(1):57-64. Epub 2005 Aug 10. — View Citation

Moriyama Y, Yasue H, Yoshimura M, Mizuno Y, Nishiyama K, Tsunoda R, Kawano H, Kugiyama K, Ogawa H, Saito Y, Nakao K. The plasma levels of dehydroepiandrosterone sulfate are decreased in patients with chronic heart failure in proportion to the severity. J Clin Endocrinol Metab. 2000 May;85(5):1834-40. — View Citation

P Peñafiel, DA Pascual, B. Redondo, P Nicolas, PL Tornel, J Sanchez-Mas, G de la Morena, M Valdés. Anabolic deficiency as determinant of functional impairment and prognosis in heart failure patients. European journal of Heart Failure 2007;6(supl 1):146.

Pascual-Figal DA, Tornel PL, Valdes M. Letter by Pascual-Figal et al regarding article, "Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival". Circulation. 2007 May 29;115(21):e548; author reply e549. — View Citation

Pugh PJ, English KM, Jones TH, Channer KS. Testosterone: a natural tonic for the failing heart? QJM. 2000 Oct;93(10):689-94. Review. — View Citation

Pugh PJ, Jones RD, Jones TH, Channer KS. Heart failure as an inflammatory condition: potential role for androgens as immune modulators. Eur J Heart Fail. 2002 Dec;4(6):673-80. Review. — View Citation

Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart. 2004 Apr;90(4):446-7. — View Citation

Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J. 2003 May;24(10):909-15. — View Citation

Rauchhaus M, Doehner W, Anker SD. Heart failure therapy: testosterone replacement and its implications. Eur Heart J. 2006 Jan;27(1):10-2. Epub 2005 Nov 16. — View Citation

Rodríguez-Artalejo F, Banegas Banegas JR, Guallar-Castillón P. [Epidemiology of heart failure]. Rev Esp Cardiol. 2004 Feb;57(2):163-70. Review. Spanish. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death	Death from any cause or hospitalization for heart failure or decompensation of heart failure requiring intravenous drug for stabilization.	1 year
Secondary	Mortality	Mortality from cardiovascular causes, for HF and other causes.	1 year
Secondary	Hospital readmissions for any reason.		1 year
Secondary	Number of decompensated heart failure who have required intravenous medication for stabilization.		1 year
Secondary	Changes in test quality of life (Minnesota Living Heart Failure) and clinical modified Framingham score.		1 year
Secondary	Changes in cardiac function parameters assessed by echocardiography and natriuretic peptide (NT)-proBNP concentration.		1 year

External Links

•   MeSH Terms
•   Spanish Cardiology Society