- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04043858
Safety and Efficacy of Midodrine Hydrochloride in the Management of Refractory Ascites Due to Cirrhosis in Children
Safety and Efficacy of Midodrine Hydrochloride in the Management of Refractory Ascites Due to Cirrhosis in Children: a Pilot Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Bassam Ayoub, MD
- Phone Number: +201000936418
- Email: bassamayob@yahoo.com
Study Contact Backup
- Name: Mohamed Abdel Hafeez, MD
- Phone Number: +201002362768
- Email: abdelhafeez64@yahoo.com
Study Locations
-
-
Menofiya
-
Shibīn Al Kawm, Menofiya, Egypt, 32511
- Recruiting
- Pediatric Hepatology, Gastroenterology and Nutrition Department, National Liver Institute, Menoufia University
-
Contact:
- Bassam Ayoub, MD
- Phone Number: +201000936418
- Email: bassamayob@yahoo.com
-
Contact:
- Mohamed Abdel Hafeez, MD
- Phone Number: +201002362768
- Email: abdelhafeez64@yahoo.com
-
Sub-Investigator:
- Tahany A Salem, MD
-
Sub-Investigator:
- Marwa S Rizk, MD
-
Sub-Investigator:
- Salma A Nage, MD
-
Sub-Investigator:
- Rasha A Ali, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Midodrine daily
Midodrine hydrochloride 2.5 mg tab once per day
|
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
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Side effect no 1
Time Frame: 3 months
|
number of patients with Elevated BP: ≥90th percentile to <95th percentile
|
3 months
|
Side effect no 2
Time Frame: 3 months
|
number of patients with Stage 1 HTN: ≥95th percentile to <95th percentile + 12 mmHg or 130/80 to 139/89 mm Hg (whichever is lower)
|
3 months
|
Side effect no 3
Time Frame: 3 months
|
number of patients with Stage 2 HTN: ≥95th percentile + 12 mm Hg or ≥140/90 mm Hg (whichever is lower) mmHg or 130/80 to 139/89 mm Hg (whichever is lower)
|
3 months
|
Side effect no 4
Time Frame: 3 months
|
number of patients with low heart rate
|
3 months
|
Side effect no 5
Time Frame: 3 months
|
number of patients with urine retention
|
3 months
|
Side effect no 6
Time Frame: 3 months
|
number of patients with severe itching
|
3 months
|
Side effect no 7
Time Frame: 3 months
|
number of patients with skin rash
|
3 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Complete Response
Time Frame: 12 months
|
absence of ascites by abdominal ultrasound
|
12 months
|
Partial response
Time Frame: 12 months
|
ascites cannot be mobilized completely but not symptomatic or needs paracentesis
|
12 months
|
non-response
Time Frame: 3 months
|
no decrease in ascites which still in need for paracentesis after 3 months of duration
|
3 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Bassam Ayoub, MD, Pediatric Hepatology Dep; National Liver Institute, Menoufia University, Egypt
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- Cardenas A, Arroyo V. Refractory ascites. Dig Dis. 2005;23(1):30-8. doi: 10.1159/000084723.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Ascites
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Adrenergic alpha-Agonists
- Adrenergic Agonists
- Sympathomimetics
- Vasoconstrictor Agents
- Adrenergic alpha-1 Receptor Agonists
- Midodrine
Other Study ID Numbers
- Mid-Asci-Ped
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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