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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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:

Official Title
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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

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Tolvaptan Tablets
* Drug: Midodrine Oral Tablet
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Child B/C cirrhosis Hyponatremia( severe) Written informed consent Age-18-70 years Exclusion Criteria: AKI(1.5mg/dl) Sepsis Underlyig CKD High risk varices Recent Bleed in 2 weeks Acute Symptomatic hyponatremia SIADH Hypothyroidism Severe cardiopulmonary disease Cerebrovascular accident Multiple strokes; Pseudohyponatremia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |