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CTRI Number  CTRI/2021/09/036265 [Registered on: 06/09/2021] Trial Registered Prospectively
Last Modified On: 21/10/2021
Post Graduate Thesis  Yes 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   To Study Effect of the Combination of Midodrine and Tolvaptan (drug) Versus Tolvaptan Alone in Patients With Severe Hyponatremia in Cirrhosis (Liver Disease).  
Scientific Title of Study   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.  
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
None  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr G Srinivasa Reddy 
Designation  Senior Resident,Department of hepatology 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No 23330, Department of Hepatology, Phase II, 3rd Floor,Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070.

South
DELHI
110070
India 
Phone  01146300000  
Fax    
Email  srinivasareddygolamari@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Shiv Kumar Sarin 
Designation  Senior Professor, Hepatology 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No 23375, Department of Hepatology, Phase II, 3rd Floor,Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070.

South
DELHI
110070
India 
Phone  01146300000  
Fax    
Email  shivsarin@gmail.com  
 
Details of Contact Person
Public Query  
Name  Dr Shiv Kumar Sarin 
Designation  Senior Professor, Hepatology 
Affiliation  Institute of Liver and Biliary Sciences 
Address  Room No 23375, Department of Hepatology, Phase II, 3rd Floor,Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070.


DELHI
110070
India 
Phone  01146300000  
Fax    
Email  shivsarin@gmail.com  
 
Source of Monetary or Material Support  
Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070. 
 
Primary Sponsor  
Name  Institute of Liver and Biliary Sciences 
Address  Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070. 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr GSrinivasa Reddy  Institute of Liver and Biliary Sciences  Room No 23330, Department of Hepatology, Phase II, 3rd Floor,Institute of Liver and Biliary Sciences, D-1, Vasant Kunj New Delhi-110070.
South
DELHI 		 01146300000

srinivasareddygolamari@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional Ethics Committee, ILBS  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: K769||Liver disease, unspecified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  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 Placebo Placebo of tolvaptan 
Intervention  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 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  70.00 Year(s)
Gender  Both 
Details  1) Child B/C cirrhosis
2) Hyponatremia( severe)
3) Written informed consent
4) Age-18-70 years 
 
ExclusionCriteria 
Details  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 
 
Method of Generating Random Sequence   Permuted block randomization, fixed 
Method of Concealment   Sequentially numbered, sealed, opaque envelopes 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Improvement in Na+ to 125meq/L   1 week 
 
Secondary Outcome  
Outcome  TimePoints 
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 
Reduction in clinical complications(AKI,HE) in patients with hyponatre  1 week, 1 month 
Failure to achieve sodium concentration to 125 meq/L   7 days 
Development of AKI   7 days 
Mean Arterial pressure  Day 1,7,14, and 30] 
Improvement in sodium concentration from base line to 130 meq/l  day 7 
RBC water and sodium concentration in RBC cell   Day 7 and day 30 
Improvement in ascites   Day 7 and 30 
Maintenance of sodium concentration   Day 14 and 30 
Change in body weight  Day 7 and 30 
 
Target Sample Size   Total Sample Size="220"
Sample Size from India="220" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   N/A 
Date of First Enrollment (India)   10/09/2021 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   None Yet 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
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

 
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