Safety and Efficacy of Midodrine Hydrochloride in the Management of Refractory Ascites Due to Cirrhosis in Children

NCT ID: NCT04043858

Last Updated: 2020-08-24

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-06-05

Study Completion Date

2021-12-01

Brief Summary

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Ascites in liver cirrhosis is explained by increased production of vasoactive substances leading to renal vasoconstriction and salt and water retention. The retained water then accumulates in the peritoneal cavity under the effect of portal hypertension and low albumin. Refractory ascites is defined as ascites that cannot be mobilized or prevented from early recurrence after large-volume paracentesis despite medical therapy and dietary sodium restriction. Midodrine is an α1 receptor agonist that can improve systemic and renal hemodynamics in non-azotemic cirrhotic patients by counteracting mesenteric vasodilatation, which is accentuated in cirrhosis.

Detailed Description

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Ascites in liver cirrhosis is explained by increased production of vasoactive substances, such as nitric oxide, carbon monoxide, and endocannabinoids, which cause splanchnic vasodilatation, increased blood flow through this area, and a decrease in peripheral vascular resistance and the effective arterial volume with resulting reduction in renal blood flow with subsequent activation of rennin-angiotensin-aldosterone system which in turn leads to renal vasoconstriction and salt and water retention. The retained water then accumulates in the peritoneal cavity under the effect of portal hypertension and low albumin.

The International Ascites Club defines refractory ascites as ascites that cannot be mobilized or prevented from early recurrence after large-volume paracentesis despite medical therapy and dietary sodium restriction.

There are two varieties of refractory ascites: diuretic-resistant ascites that is unresponsive to the maximal tolerable dose of diuretic therapy and diuretic-intractable ascites when complications such as hepatic encephalopathy, renal dysfunction, or electrolyte abnormalities limit the use of diuretics in the effective therapeutic dose (Cárdenas and Arroyo, 2005)

The therapeutic options for refractory ascites are serial therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, peritoneovenous shunt, and liver transplantation.

Midodrine is transformed into the active metabolite desglymidodrine, which is an α1 receptor agonist causing an increase in vascular tone and increase in blood pressure without β-adrenergic receptors stimulation so, it can improve systemic and renal hemodynamics in non-azotemic cirrhotic patients by counteracting mesenteric vasodilatation, which is accentuated in cirrhosis. It diffuses poorly across the blood-brain barrier with no central effects.

In a study included 600 adult patients with refractory ascites, midodrine was added to diuretic therapy and lead to enhancement of diuresis with the improvement of systemic, renal hemodynamics and short-term survival. Approximately, the only use of midodrine hydrochloride in children was in postural orthostatic tachycardia syndrome (POTS) which showed a good efficacy and safety profile.

Conditions

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Refractory Ascites Children, Only

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Midodrine daily

Midodrine hydrochloride 2.5 mg tab once per day

Group Type EXPERIMENTAL

Midodrine 2.5 mg tab

Intervention Type DRUG

Patients receive an oral daily dose of 2.5 mg midodrine if age 7-12 years and receive 2.5 mg twice daily of more than 12 years

Interventions

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Midodrine 2.5 mg tab

Patients receive an oral daily dose of 2.5 mg midodrine if age 7-12 years and receive 2.5 mg twice daily of more than 12 years

Intervention Type DRUG

Other Intervention Names

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ProAmatine

Eligibility Criteria

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Inclusion Criteria

* Children aged 7-18 years
* Both sexes
* Having refractory ascites (not responding to maximal dose of diuretics
* Diuretic-induced complications necessitate discontinuation of the drug

Exclusion Criteria

* Non-cirrhotic causes of ascites
* Intrinsic renal disease ( e.g; polycystic kidney disease)
* Active gastrointestinal bleeding or the presence of risky varices
* Patients with Portal vein thrombosis and Budd-Chiari
* Cardiovascular disease
* Systemic hypertension or prehypertension
* Hyperthyroidism
* Patients with narrow-angle glucoma
Minimum Eligible Age

7 Years

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Liver Institute, Egypt

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Bassam Ayoub, MD

Role: PRINCIPAL_INVESTIGATOR

Pediatric Hepatology Dep; National Liver Institute, Menoufia University, Egypt

Locations

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Pediatric Hepatology, Gastroenterology and Nutrition Department, National Liver Institute, Menoufia University

Shibīn al Kawm, Menofiya, Egypt

Site Status RECRUITING

Countries

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Egypt

Central Contacts

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Bassam Ayoub, MD

Role: CONTACT

+201000936418

Mohamed Abdel Hafeez, MD

Role: CONTACT

+201002362768

Facility Contacts

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Bassam Ayoub, MD

Role: primary

+201000936418

Mohamed Abdel Hafeez, MD

Role: backup

+201002362768

References

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Albillos A, Banares R, Gonzalez M, Catalina MV, Molinero LM. A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites. J Hepatol. 2005 Dec;43(6):990-6. doi: 10.1016/j.jhep.2005.06.005. Epub 2005 Jul 5.

Reference Type BACKGROUND
PMID: 16139922 (View on PubMed)

Bes DF, Cristina Fernandez M, Malla I, Repetto HA, Buamscha D, Lopez S, Martinitto R, Cuarterolo M, Alvarez F. Management of cirrhotic ascites in children: Review and recommendations. Part 2: Electrolyte disturbances, nonelectrolyte disturbances, therapeutic options. Arch Argent Pediatr. 2017 Oct 1;115(5):505-511. doi: 10.5546/aap.2017.eng.505. English, Spanish.

Reference Type BACKGROUND
PMID: 28895701 (View on PubMed)

Cardenas A, Arroyo V. Refractory ascites. Dig Dis. 2005;23(1):30-8. doi: 10.1159/000084723.

Reference Type BACKGROUND
PMID: 15920323 (View on PubMed)

Chen L, Wang L, Sun J, Qin J, Tang C, Jin H, Du J. Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. Circ J. 2011;75(4):927-31. doi: 10.1253/circj.cj-10-0514. Epub 2011 Feb 2.

Reference Type BACKGROUND
PMID: 21301135 (View on PubMed)

Dionne JM. Updated Guideline May Improve the Recognition and Diagnosis of Hypertension in Children and Adolescents; Review of the 2017 AAP Blood Pressure Clinical Practice Guideline. Curr Hypertens Rep. 2017 Oct 16;19(10):84. doi: 10.1007/s11906-017-0780-8.

Reference Type BACKGROUND
PMID: 29035421 (View on PubMed)

JCS Joint Working Group. Guidelines for drug therapy in pediatric patients with cardiovascular diseases (JCS 2012). Digest version. Circ J. 2014;78(2):507-33. doi: 10.1253/circj.cj-66-0083. Epub 2013 Dec 26. No abstract available.

Reference Type BACKGROUND
PMID: 24369273 (View on PubMed)

Hanafy AS, Hassaneen AM. Rifaximin and midodrine improve clinical outcome in refractory ascites including renal function, weight loss, and short-term survival. Eur J Gastroenterol Hepatol. 2016 Dec;28(12):1455-1461. doi: 10.1097/MEG.0000000000000743.

Reference Type BACKGROUND
PMID: 27622998 (View on PubMed)

Baker-Smith CM, Flinn SK, Flynn JT, Kaelber DC, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM; SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BP IN CHILDREN. Diagnosis, Evaluation, and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2018 Sep;142(3):e20182096. doi: 10.1542/peds.2018-2096. Epub 2018 Aug 20.

Reference Type BACKGROUND
PMID: 30126937 (View on PubMed)

Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, Angeli P, Porayko M, Moreau R, Garcia-Tsao G, Jimenez W, Planas R, Arroyo V. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology. 2003 Jul;38(1):258-66. doi: 10.1053/jhep.2003.50315.

Reference Type BACKGROUND
PMID: 12830009 (View on PubMed)

Singh V, Dhungana SP, Singh B, Vijayverghia R, Nain CK, Sharma N, Bhalla A, Gupta PK. Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. J Hepatol. 2012 Feb;56(2):348-54. doi: 10.1016/j.jhep.2011.04.027. Epub 2011 Jul 13.

Reference Type BACKGROUND
PMID: 21749847 (View on PubMed)

Tanaka H, Fujita Y, Takenaka Y, Kajiwara S, Masutani S, Ishizaki Y, Matsushima R, Shiokawa H, Shiota M, Ishitani N, Kajiura M, Honda K; Task Force of Clinical Guidelines for Child Orthostatic Dysregulation, Japanese Society of Psychosomatic Pediatrics. Japanese clinical guidelines for juvenile orthostatic dysregulation version 1. Pediatr Int. 2009 Feb;51(1):169-79. doi: 10.1111/j.1442-200X.2008.02783.x.

Reference Type BACKGROUND
PMID: 19371306 (View on PubMed)

Zhang F, Li X, Ochs T, Chen L, Liao Y, Tang C, Jin H, Du J. Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. J Am Coll Cardiol. 2012 Jul 24;60(4):315-20. doi: 10.1016/j.jacc.2012.04.025.

Reference Type BACKGROUND
PMID: 22813609 (View on PubMed)

Other Identifiers

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Mid-Asci-Ped

Identifier Type: -

Identifier Source: org_study_id

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