Symptoms and General Pathology

All Conditions

Nutritional and Metabolic Diseases

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Syndrome

Obesity

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Chronic Graft Versus Host Disease

Micronutrients

All Drugs and Chemicals

Urological Agents

Vitamins

Ascorbic Acid

Adrenergic Agents

Mirabegron

Adrenergic Agonists

Adrenergic beta-3 Receptor Agonists

Adrenergic beta-Agonists

Neurotransmitter Agents

Vitamin C

Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.

Males will be randomized to take placebo versus active drug (mirabegron). Those taking placebo will take 4 tablets each day to mirror to active group (taking 4 tablets of 50 mg each).

B Complex Plus Vitamin C Tablets

Ashley M Schmitz, C.R.N.P.

Aaron M Cypess, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Background:

Brown adipose tissue (BAT) is a type of fat in the body. It may prevent weight gain, improve insulin sensitivity, and reduce fatty liver. Researchers want to see if BAT helps the body burn energy.

Objective:

To learn more about how BAT works to burn energy.

Eligibility:

People ages 18-40 with a body mass index between 18 and 40

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Dietitian interview

Participants will have an overnight baseline visit. This includes:

Repeats of screening tests

Exercise test

Scans. For one scan, a radioactive substance is injected into the arm.

FSIVGIT: An IV is inserted into veins in the right and left arms. Glucose and insulin are injected in one arm. Blood glucose and insulin levels are measured from the other.

Metabolic suite: Participants stay 18 19 hours in a room that measures their metabolic rate. Monitors on the body measure heart rate, movement, and temperature.

Optional fat biopsy: A small piece of tissue is removed with a needle.

Participants will take 2-4 pills daily for 4 weeks. All women will take the drug mirabegron. Men will be randomly get either the drug or a placebo.

All participants will have a visit after 2 weeks of the pills. They will repeat the screening tests.

Participants will have an overnight visit 2 weeks later. They will repeat the baseline tests.

Participants will keep food and medication diaries.

Participants will have a follow-up visit 2 weeks after stopping the pills. This includes heart tests.

Background issues and controversies

More than ever before, there is a rise in the rates of obesity and diabetes. As opposed to white fat which stores excess calories, brown fat - also known as brown adipose tissue or BAT - consumes this energy to generate heat. In settings of increased food consumption and cold-exposure, studies show that human BAT becomes more active, potentially combatting weight gain. Other emerging evidence indicates that human BAT may be an endocrine organ, releasing hormones into the blood and regulating other organs like skeletal muscle, liver, and the insulin-releasing pancreatic Beta-cell. However, alongside these promising studies are those people who believe that there is not enough BAT in humans to be functionally relevant, and it contributes little to heat generation or overall health.

Purpose/Rationale of the proposed study

One of the principal reasons for skepticism about the ability to utilize human BAT is that there is not very much compared to smaller animals in which BAT activation has shown such promise. Therefore, a critical step is to develop medicines that can grow BAT in people and evaluate what kind of health benefits can be achieved.

Specific objectives

This study will administer the clinically-available beta3-AR agonist, mirabegron (Myrbetriq(R), Astellas Pharma). We will determine whether we can increase BAT volume and activity in people after they have taken this medication daily for four weeks. Our current goal is to see if chronic administration of mirabegron leads to an increase in BAT volume and metabolic activity and if it produces health benefits.

Key elements of what is involved

At the beginning of the study, the participants will undergo a series of tests to determine their baseline amounts of BAT, blood sugar status, and levels of specified hormones. The testing will take place over the course of two to three days while an inpatient on the Metabolic Patient Care Unit at the NIH Clinical Center. Depending on the Cohort, participants will then take the medication alone for four weeks or both the medication and placebo for four weeks each, during which time they will continue their standard daily routines. At two weeks after starting placebo or mirabegron, participants will return for one day for the assessment of any interim changes and to validate safety. At the end of each set of four weeks there will be a second set of inpatient testing over two to three days. Participants will be brought back two weeks after finishing the study for a follow-up safety visit, at which time they will receive an ECG and heart rate monitoring.

Primary outcomes

The primary outcome is either the change in BAT metabolic activity as measured by 18FFDG PET/CT or glucose infusion rate as measured by a hyperinsulinemic euglycemic clamp. Secondary endpoints will examine multiple other factors, including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function.

The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

.Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures and appendices).

Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT

Change in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp

Change in metabolic health parameters including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function

Changes in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Blood and Lymph Conditions

Heart and Blood Diseases

Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

Disease Progression

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Bone Marrow Diseases

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Chronic Myeloproliferative Disorders

Essential Thrombocythemia

Mirabegron treatment of at least 24 weeks with an initial dose of 25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.

25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.

Jakob R. Passweg, Prof

Radek Skoda, Prof

The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.

DISEASE BACKGROUND

Myeloproliferative neoplasms (MPN) are clonal stem cell disorders characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They are associated with decreased survival, thromboembolic complications, hemorrhage and an inherent tendency towards leukemic transformation. About 4-6 of 100'000 residents per year are diagnosed with MPN Currently, MPN are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. Between 5-8% of the remaining ET and PMF patients carry mutations in the thrombopoietin receptor (MPL) and in 10-15% of the patient the mutation remains to be determined. Quantitative tests are now available to follow the mutant allele burden of each of the JAK2, CALR and MPL mutant alleles.

THERAPY BACKGROUND

No curative treatment exists for MPN, possibly with the exception of allogeneic hematopoietic stem cell transplantation (HSCT), which is applicable only in a minority of patients. Currently, treatments for MPN are not very effective, or extremely costly. Hydroxyurea has been the standard of care for many decades. A reduction in thrombotic complications can be demonstrated in "high risk" MPN patients (age \>60, presence of a previous thrombotic event), but hydroxyurea has no effect on the course of disease (no remission or substantial reduction of the mutant allele burden). Interferon alpha (IFNα) is a promising treatment for early stage PV and is currently being tested in phase III studies. However, IFNα is not always well tolerated and in phase II studies only a proportion of patients showed a substantial response. Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. Allogeneic HSCT is reserved for patients with PMF with a poor prognostic score. These including the recently developed JAK2 inhibitors reduce the symptoms of the disease, but, with the exception of pegylated interferon alpha (peg-IFNα), have little effect on the size of the neoplastic clone and are unable to induce molecular remissions. Thus, the percentage of mutant allele burden in hematopoietic cells does not change much even with successful treatment when considering symptom reduction. It is generally expected that reduction in the size of the malignant clone, as a surrogate marker of treatment success, will have the potential to reduce morbidity and result in prolonged survival of patients.

NOVEL TREATMENT

The beta-3-sympathicomimetic drug Mirabegron is currently available as Betmiga® and indicated to treat hyperactive bladder. It is available as a slow release tablet in a 25 mg and 50 mg formulation. Sympathicomimetic drugs are known to relax the smooth muscle in several areas of the human body and are therefore used for inhalation in patients with asthma or as described for this drug to relax the smooth muscle of the bladder to treat urge incontinence. β3-Adrenoceptors mediate a negative inotropic effect in human ventricular cardiomyocytes, which is opposite to that of β1- and β2-adrenergic receptors. Unlike beta1/2-mimetics, that have significant cardiovascular side effects (including hypertrophy), beta3-mimetics have been reported to protect from hypertrophy and are only associated with some risk of tachycardia and palpitations in some patients.

Sympathicomimetic agonists in patients with JAK2-mutated MPN

RATIONALE FOR PERFORMING THE TRIAL

MPN is initiated and maintained from a mutated hematopoietic stem cell (HSC). The interplay between the MPN HSCs and the stem cell niche is increasingly recognized as crucial for the biology of the disease. Dr. Simon Méndez-Ferrer et al, previously demonstrated that nestin-positive mesenchymal stem cells (nestin+ MSCs) within the bone marrow niche are innervated by sympathetic nerve fibers and are important in regulating normal HSCs. New findings by Dr. Méndez-Ferrer's laboratory show that these nestin+ MSCs are strongly reduced in bone marrow from patients with MPN.

Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. In vivo depletion of nestin+ cells accelerated MPN progression. Conversely, MPN phenotype could be reversed by compensating for the sympathetic neuropathy by the treatment with a beta-3-sympathicomimetic drug. Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. Thus, treatments with a beta-3 sympathicomimetic agonist corrected the damage inflicted by the MPN clone on the stem cell niche and led to a dramatic improvement of the MPN phenotype. Therefore, beta-3 sympathicomimetic agonists represent a promising novel therapeutic approach to MPN by targeting the stem cell niche rather than the MPN clone itself.

Considering the widely used and established safety track record of beta-3-sympathicomimetic drugs, a phase II study has been selected to test the concept of a beneficial effect of beta sympathicomimetic activity on bone marrow niche cells and through this effect on the disease manifestation in MPN patients.

Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation

Effects of Sympathicomimetic Agonists on the Disease Course and Mutant Allele Burden in Patients With JAK2-mutated Myeloproliferative Neoplasms. A Multicenter Phase II Trial.

Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Reduction in the burden of mutated alleles of ≥50% at 12 weeks (Red-50@12) defined in the same way as the primary endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.

Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.

Swiss Group for Clinical Cancer Research

Behaviors and Mental Disorders

Diseases and Abnormalities at or Before Birth

Prostatic Neoplasms

Erectile Dysfunction

Congenital Abnormalities

Prostatic Hyperplasia

Hyperplasia

Genital Diseases, Male

Sexual Dysfunction, Physiological

Male Urogenital Diseases

Sexual Dysfunctions, Psychological

Mental Disorders

Psychotic Disorders

Genital Neoplasms, Male

Urogenital Neoplasms

Prostatic Diseases

Tamsulosin

oral mirabegron 50 gm plus tamsulosin 0.4 mg once daily for 8 weeks

oral toltordine 4 mg plus tamsulosin 0.4 mg daily for 8 weeks.

oral mirabegron 50 gm plus tamsulosin 0.4 mg once daily for 8 weeks.

placebo

Ahmed Shokeir, PhD

To study the impact of mirabegron, a B3-adrenoceptor agonist, in the treatment of ED in patients with LUTS secondary to BPH and concomitant ED.

Erectile dysfunction (ED) is a major world-wide problem. In United Stated of America, ED affects 26/1000 man yearly (Gonzalgo et al., 2003). The prevalence of ED increases with age from 2-9% in men between 40-49 year, to 20-40% between 60-69 and between 50-100% over 70 years (Gur et al., 2006; Hojanned et al., 2000; Gades et al., 2009; Braun et al., 2000). Many factors may contribute in the occurrence of ED including neuronal, vascular, myogenic and psychological causes (Gur et al., 2016; Johannes et al., 2000, Lewis et al., 2000; Wu et al., 2010; Mallis et al., 2005).

Researchs during the past decade have ﬁrmly established that ED and ejaculatory dysfunction (EJD) are highly prevalent in aging men, particularly those with LUTS of BPH. Furthermore, it has been demonstrated that LUTS of BPH is an independent risk factor for male sexual dysfunction (Hansen BL. et al., 2004).

Although the underlying mechanisms responsible for the relationship between LUTS and male sexual dysfunction are not fully elucidated, possible common links are present including activation of a-adrenergic receptors, endothelial dysfunction, and alterations in sex hormone concentrations and receptor subtypes. Thus, it is now recommended that men presenting with LUTS should be evaluated for sexual dysfunction and those presenting with sexual dysfunction should be evaluated for LUTS (Price DT., et al., 1993).

Also , it is now recognized that certain oral therapies for LUTS/BPH can adversely affect sexual function in patients who are already at increased risk for sexual dysfunction. Moreover, the correction of LUTS was associated with improvement of ED. (De Rose AF., et al., 2002) Healthcare providers should discuss sexual function with BPH patients both before and during treatment. (Raymond C. Rosen et al., 2005) So, use of ED-treating drugs (phosphodiestrase -5 inhibitors) is now a guideline recommendation in the lines of treatment of BPH/LUTS alone or in combination with α blockers. (EUA guidelines, 2015, Gratzke C et., al., 2015).

Phosphodiesterase 5 inhibitors (PDE5i) are effective in treatment of ED. They treat ED through enhancement of the effect of nitric oxide (NO) by inhibition of cyclic guanosin monophosphate (cGMP) breakdown, therefore, increase blood flow through penile arteries. PDE5i are the first-line treatment of ED. Nevertheless, many patients may discontinue the treatment because of side effects, poor response or cost.

It has been shown that B3-adrenoreceptors are mainly localized in the smooth muscle cells of human corpora cavernosa (HCC) (Cirino et al., 2003). The activation of B3-adrenoceptors cause relaxation of the vascular smooth muscle of HCC. Investigators showed that a B3- adrenoreceptors agoinst named "BRL37344" induces relaxation of the HCC. This relaxation has been shown to be linked to inhibition of the RhoA-Rho-associated protein kinase (ROCK) pathway (Cirino et al., 2003). The effect of BRL37344 is mediated by cGMP-dependent but NO-independent mechanisms, altering CC smooth muscle tone and promoting erectile function (Cirino et al., 2003). Thus, b3-adrenoceptor agonists may also serve as potentially useful drugs for the treatment of ED.

Mirabegron is a selective B3-adrenoreceptor agonist and is currently approved in many parts of the world for treatment of overactive bladder (Chapple et al., 2013; Khullar et al., 2013; Chapple et al., 2013; Nitti et al., 2013). Mirabegron displayed 20-200 times higher relative efficacy for human B3-adrenoceptor than that BRL37344 (Takasu et al., 2007). Mirabegron increases intracellular cAMP levels and activates cAMP-dependent protein kinase A resulting in relaxation of the human urinary bladder through a cascade of mechanisms including decrease in intracellular cytoplasmic Ca2+ (Imran et al., 2013; Matanake et al., 2013).

Recently , Gur et al studied the effect of mirabegron on HCC in vitro study and also examined the impact of the drug in vivo, after intracavernosal injection of rats. Authors showed that mirabegron caused marked relaxation of HCC by activating B3-adrenoceptors independently of No pathway. So it appears that mirabegron may be apotential safe and effective therapeutic agent for ED. (Gur et al., 2016) Herein, we designed this protocol to evaluate the role of mirabegron in treating ED in men with BPH/LUTS with concomitant ED.

Mirabegron for Treatment of Erectile Dysfunction in Patients With LUTS Secondry to BPH: A Randomized Study

measured by International Index of Erectile Function (IIEF).

measured by International Prostate Symptom Score (I-PSS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists	NCT03049462	Polycystic Ovar...	Mirabegron B Complex Plus ...	18 Years - 40 Years	National Institutes of Health Clinical Center (CC)
Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation	NCT02311569	Myeloproliferat... Primary Myelofi... Essential Throm... Polycythemia Ve...	Mirabegron	18 Years -	Swiss Group for Clinical Cancer Research
Mirabegron for Treatment of Erectile Dysfunction in Patients With LUTS Secondry to BPH: A Randomized Study	NCT03600766	BPH Erectile Dysfun... Prostate Hyperp... Erectile Abnorm... Prostatic Neopl...	Mirabegron placebo	50 Years - 70 Years	Mansoura University
Sympathicomimetic Agonist in Patients With Myeloproliferative Neoplasms With JAK2-mutation	NCT02311569	Myeloproliferat... Primary Myelofi... Essential Throm... Polycythemia Ve...	Mirabegron	18 Years -	Swiss Group for Clinical Cancer Research

Spots Global Cancer Trial Database for mirabegron

Every month we try and update this database with for mirabegron cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for mirabegron

Every month we try and update this database with for mirabegron cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for mirabegron cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.