To Study Effect of the Combination of Midodrine and Tolvaptan Versus Tolvaptan Alone in Patients With Severe Hyponatremia in Cirrhosis(TOLMINA Trial)

To Study Effect of the Combination of Midodrine and Tolvaptan Versus Tolvaptan Alone in Patients With Severe Hyponatremia in Cirrhosis(TOLMINA Trial) - An Open Label Placebo Randomized Control Trial

In this randomized controlled trial , The patients who satisfy the below inclusion and exclusion criteria will be included and they will be randomised, according to 2 groups ( in total 110patients in each group) to receive either Midodrine+Tolvaptan or tolvaptan+placebo for 7 days followed by follow up for 1 month. These patients will be admitted to the hospital from OPD or emergency.

In patients with cirrhosis with Patients with cirrhosis -there are two types of hyponatremia. hyponatremia is due to important losses of extracellular fluid, most commonly from the kidneys (because of overdiuresis due to treatment with excessive doses of diuretics) or from the gastrointestinal tract( hypovolemic hyponatremia) hyponatremia develops in the setting of expanded extracellular fluid volume and plasma volume with ascites and edema.This condition is known as hypervolemic or dilutional hyponatremia.A marked impairment of renal solute-free water excretion, resulting in disproportionate renal retention of water with respect to sodium retention.In SALT trail showed that tolvaptan showed improvement in Na+ concentration from baseline at 4 ,30 day. It acts on by increasing free water generation by blocking ADH receptors in distal convoluted tubule. A study by Patel et al in 2017 showed that midodrine also increasing the Na+ by increasing the free water delivery to distal convoluted tubules(in cirrhosis usually there is less water delivery to distal convoluted tubules in view of less GFR).Till now there is no study has been done as combination of midodrine and tolvaptan whether superior to tolvaptan alone or not .So our aim is to study combination of midodrine and tolvaptan verses tolvaptan alone in patients with hyponatremia.

Study Overview

• Status: Recruiting
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Tolvaptan Tablets; Drug: Midodrine Oral Tablet; Other: Placebo

Detailed Description

1. Aim and Objective -

   AIM:

   • To study effect of the combination of Midodrine and Tolvaptan versus Tolvaptan alone in patients with severe hyponatremia in cirrhosis.

   PRIMARY Objective :

   • To study the Improvement in sodium concentration from base line to target level 125 meq/L in patients with hyponatremia ( Time frame-1 week) SECONDARY Objective :- To study the

   1 The change in Na+ concentration at D2,D4,D5. 2) Maintenance of Na concentration at d14, d30 3) Improvement in Na+ concentration from base line to 130 meq/l at day 7 4) Improvement in ascites at day 7,30 5) Development of AKI, HE [ 1 week,2 weeks,D30] 6) Osmolality changes, urine volume,urinay Na + excretion at D3,D5,D7,D14 D30 7) Mean arterial pressure at D1,D7,D14,D30. 8) RBC water and Na concentration in RBC cell at day 7, 30 9) Change in body weight at day 7, 30 10) The urine metabolomics

2. Methodology:

   • Study Definitions:

Hyponatermia as

Mild-126-130 Moderate-121-125 Severe-<120 Acute-<48 hours Chronic >48 hours - alukal et al 2020 Symptomatic-presence of symptoms Asymptomatic-no symptoms

Study population -All the patients of cirrhosis of liver patients visiting to ILBS and diagnosed to have hyponatremia Study design - Open label Placebo RCT

Assuming that the response rate is 30% in tolvaptan group and 50% in midodrine +tolvaptan group Alpha Error-5%,power 80% we need to enroll 200 cases, 100 each group.Further assuming 10% drop rate, 220 cases-110 in each arm(Allocated each group block randomization method, block size-10)

At baseline, a complete history with clinical and physical examination, a record of demographic profile, standard of care biochemical investigations would be done. All included patients will be evaluated with -

• Etiology of cirrhosis
• Upper GI endoscopy
• Haemogram (including reticulocyte count)
• Liver function tests,Renal function tests
• CBC/LFT/KFT/ELECTOLYTES/URINENa,URINEOsmolality,Sosmolality,thyroidprofile,S Cortisol,S ADH,RBC water,RBC Na
• UGIE endoscopy,Usg Abdomen/IVC and 2D echo,cardichaemodynamics,PRO BNP,PRA, Renal resistivity index
• USG abdomen with Doppler study
• Fibroscan
• Child-Pugh score , MELD The patients will be managed according to randomization. Subsequently, patients would be assessed clinically each day at the baseline and post-treatment at every day for 1 month.

ADVERSE EFFECTS Thirst Dry mouth Hypernatremia Renal dysfunction Abdomnal pain Nasea/Vomitting Muscle cramp

DURATION:

• Study Type: Interventional
• Enrollment (Anticipated): 220
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110070
      • Recruiting
      • Institute of Liver & Biliary Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Child B/C cirrhosis
2. Hyponatremia( severe)
3. Written informed consent
4. Age-18-70 years

Exclusion Criteria:

1. AKI(1.5mg/dl)
2. Sepsis
3. Underlyig CKD
4. High risk varices
5. Recent Bleed in 2 weeks
6. Acute Symptomatic hyponatremia
7. SIADH
8. Hypothyroidism
9. Severe cardiopulmonary disease
10. Cerebrovascular accident
11. Multiple strokes;
12. Pseudohyponatremia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolvaptan with Midodrine	Drug: Tolvaptan Tablets; • Tolvaptan15 mg once a day for 7 days, stat with 7.5 mg and titrate to 15 mg in 24 hours max30 mg; Drug: Midodrine Oral Tablet; • Midodrine 5 mg at "0" hours and then 5 mg every 8 hours to maintain Target MAP-80
Active Comparator: Tolvaptan with Placebo	Drug: Tolvaptan Tablets; • Tolvaptan15 mg once a day for 7 days, stat with 7.5 mg and titrate to 15 mg in 24 hours max30 mg; Other: Placebo; Placebo of Midodrine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Improvement in Na+ to 125meq/L	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Na + (120 -125 meq/L)		3 days
Improvement in Na + (120 -125 meq/L)		5 days
Changes in Serum osmolality	Serum osmolality normal range is 285 to 295 millimol/kg	0,1day,3day,1week ,2 week,1 month
Changes in urine volume		0,1day,3day,1week ,2 week,1 month
Changes in urinay Na + excretion in body		0,1day,3day,1week ,2 week,1 month
Change in clinical complications(AKI,HE) in patients with hyponatremia		1 week,1month
Development of AKI	Changes is serum creatine level more than 0.3 within 24 hours	7 day
Failure to achieve sodium concentration to 125 meq/L		7 day
Improvement in Na+ concentration from base line to 130 meq/l		Day 7
Mean Arterial pressure		Day 1,7,14, and 30
sodium concentration in RBC cell	It is measured by calorimetry	Day 7
sodium concentration in RBC cell	It is measured by calorimetry	Day 30
RBC water concentration in RBC cell	It is measured by calorimetry	Day 7
RBC water concentration in RBC cell	It is measured by calorimetry	Day 30
Improvement in ascites	I t will be measured by ultrasound abdomen and graded as Grade 1 (Mild) , Grade 2 (moderate) & Grade 3 (massisve)	Day 30
Maintenance of sodium concentration		Day 14 and 30
Change in body weight	It is measured by kilograms	Day 7
Change in body weight	It is measured by kilograms	Day 30

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2021
• Primary Completion (Anticipated): September 30, 2022
• Study Completion (Anticipated): September 30, 2022

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: September 18, 2021
• First Posted (Actual): September 29, 2021

Study Record Updates

• Last Update Posted (Actual): November 29, 2021
• Last Update Submitted That Met QC Criteria: November 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Metabolic Diseases; Liver Diseases; Water-Electrolyte Imbalance; Fibrosis; Liver Cirrhosis; Hyponatremia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Natriuretic Agents; Sympathomimetics; Vasoconstrictor Agents; Antidiuretic Hormone Receptor Antagonists; Adrenergic alpha-1 Receptor Agonists; Tolvaptan; Midodrine
• Other Study ID Numbers: ILBS-Cirrhosis-42

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No