To Study Effect of the Combination of Midodrine and Tolvaptan (drug) Versus Tolvaptan Alone in Patients With Severe Hyponatremia in Cirrhosis (Liver Disease).

Recruiting

• Conditions: Liver disease, unspecified,

• Registration Number: CTRI/2021/09/036265
• Lead Sponsor: Institute of Liver and Biliary Sciences

Brief Summary

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.

(a)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



(b) Methodology:

•Study Definitions:

In this study we classified 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

Detailed Description

Not available

Study Timeline

• Study Start: 2021-10-09
• Last Update Posted: 2021-10-21

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 220

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; Pseudohyponatremia.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Improvement in Na+ to 125meq/L	1 week

Secondary Outcome Measures

Name	Time	Method
Reduction in clinical complications(AKI,HE) in patients with hyponatre	1 week, 1 month
Development of AKI	7 days
Mean Arterial pressure	Day 1,7,14, and 30]
Improvement in sodium (120 -125 meq/L)	3,5 days
Changes in osmolality , urine volume,urinay sodium excretion in body	0,1day,3day,1week ,2 week,1 month
Failure to achieve sodium concentration to 125 meq/L	7 days
RBC water and sodium concentration in RBC cell	Day 7 and day 30
Maintenance of sodium concentration	Day 14 and 30
Improvement in sodium concentration from base line to 130 meq/l	day 7
Improvement in ascites	Day 7 and 30
Change in body weight	Day 7 and 30

Trial Locations

Locations (1)

Institute of Liver and Biliary Sciences; 🇮🇳 South, DELHI, India

Institute of Liver and Biliary Sciences

🇮🇳South, DELHI, India

Dr GSrinivasa Reddy

Principal investigator

01146300000

srinivasareddygolamari@gmail.com