Liver CirrhosisNCT05060523
To Study Effect of the Combination of Midodrine and Tolvaptan Versus Tolvaptan Alone in Patients With Severe Hyponatremia in Cirrhosis(TOLMINA Trial)
A study testing Tolvaptan Tablets and Midodrine Oral Tablet in people with Liver Cirrhosis, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Liver Cirrhosis
- What is being tested?
- Tolvaptan Tablets and Midodrine Oral Tablet
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 220 participants
- Where
- 1 siteIndia
- Study dates
- 19 Sep 2021to 30 Sep 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Child B/C cirrhosis
- Hyponatremia( severe)
- Written informed consent
- Age-18-70 years
Who cannot join
- AKI(1.5mg/dl)
- Sepsis
- Underlyig CKD
- High risk varices
- Recent Bleed in 2 weeks
- Acute Symptomatic hyponatremia
Show all 12Show fewer
- SIADH
- Hypothyroidism
- Severe cardiopulmonary disease
- Cerebrovascular accident
- Multiple strokes;
- Pseudohyponatremia
Trial locations and contacts
1 site in 1 country.
India1 site, 1 recruiting
- Recruiting
Institute of Liver & Biliary Sciences
New Delhi, National Capital Territory of Delhi, 110070
Dr G Srinivasa Reddy, MD, 01146300000, srinivasareddygolamari@gmail.com
About this study
Official title: 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.
Read the detailed description
- 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:
- Conditions
- Liver Cirrhosis
- Being tested
- Tolvaptan Tablets, Midodrine Oral Tablet, Placebo
- Medical subject headings
- Liver Cirrhosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tolvaptan TabletsDrug
- Tolvaptan15 mg once a day for 7 days, stat with 7.5 mg and titrate to 15 mg in 24 hours max30 mg
Midodrine Oral TabletDrug
- Midodrine 5 mg at "0" hours and then 5 mg every 8 hours to maintain Target MAP-80
PlaceboOther
Placebo of Midodrine
| Study group | Role | What they receive |
|---|---|---|
| Tolvaptan with Midodrine | Experimental | Not described Receives: Drug: Tolvaptan Tablets; Drug: Midodrine Oral Tablet |
| Tolvaptan with Placebo | Active comparator | Not described Receives: Drug: Tolvaptan Tablets; Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement in Na+ to 125meq/L
Measured: 1 week
Secondary outcomes (18)
Improvement in Na + (120 -125 meq/L)
Measured: 3 days
Improvement in Na + (120 -125 meq/L)
Measured: 5 days
Changes in Serum osmolality
Serum osmolality normal range is 285 to 295 millimol/kg
Measured: 0,1day,3day,1week ,2 week,1 month
Changes in urine volume
Measured: 0,1day,3day,1week ,2 week,1 month
Changes in urinay Na + excretion in body
Measured: 0,1day,3day,1week ,2 week,1 month
Change in clinical complications(AKI,HE) in patients with hyponatremia
Measured: 1 week,1month
Development of AKI
Changes is serum creatine level more than 0.3 within 24 hours
Measured: 7 day
Failure to achieve sodium concentration to 125 meq/L
Measured: 7 day
Improvement in Na+ concentration from base line to 130 meq/l
Measured: Day 7
Mean Arterial pressure
Measured: Day 1,7,14, and 30
sodium concentration in RBC cell
It is measured by calorimetry
Measured: Day 7
sodium concentration in RBC cell
It is measured by calorimetry
Measured: Day 30
RBC water concentration in RBC cell
It is measured by calorimetry
Measured: Day 7
RBC water concentration in RBC cell
It is measured by calorimetry
Measured: 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)
Measured: Day 30
Maintenance of sodium concentration
Measured: Day 14 and 30
Change in body weight
It is measured by kilograms
Measured: Day 7
Change in body weight
It is measured by kilograms
Measured: Day 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Sep 2021
- Study start19 Sep 2021
- Primary completion30 Sep 2022 (estimated)
- Study completion30 Sep 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver CirrhosisStudies of the same condition, open and under way.
- More trials run by Institute of Liver and Biliary Sciences, IndiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 220 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Liver and Biliary Sciences, India
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05060523
- Sponsor's protocol ID
- ILBS-Cirrhosis-42
- Status last verified
- Aug 2021
- First submitted
- 19 Aug 2021
- Last updated
- 29 Nov 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05060523
- Acronym / sponsor ID
- ILBS-Cirrhosis-42
- Conditions
- Liver Cirrhosis
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 220 participants (estimated)
- Lead sponsor
- Institute of Liver and Biliary Sciences, IndiaUniversity, hospital or other
- Study start
- 19 Sep 2021 (actual)
- Primary completion
- 30 Sep 2022 (estimated)
- Study completion
- 30 Sep 2022 (estimated)
- First posted
- 29 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- 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:
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tolvaptan with Midodrine | Experimental | Drug: Tolvaptan Tablets, Drug: Midodrine Oral Tablet |
| Tolvaptan with Placebo | Active comparator | Drug: Tolvaptan Tablets, Other: Placebo |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Child B/C cirrhosis
- Hyponatremia( severe)
- Written informed consent
- Age-18-70 years
Key exclusion criteria (12 listed)
- AKI(1.5mg/dl)
- Sepsis
- Underlyig CKD
- High risk varices
- Recent Bleed in 2 weeks
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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 | Tolvaptan with Midodrine, Tolvaptan with Placebo |
| Midodrine Oral Tablet• Midodrine 5 mg at "0" hours and then 5 mg every 8 hours to maintain Target MAP-80 | Drug | Tolvaptan with Midodrine |
| PlaceboPlacebo of Midodrine | Other | Tolvaptan with Placebo |
Primary outcome
Improvement in Na+ to 125meq/L
Time frame: 1 week
18 secondary outcomes
Improvement in Na + (120 -125 meq/L)
Time frame: 3 days
Improvement in Na + (120 -125 meq/L)
Time frame: 5 days
Changes in Serum osmolality
Time frame: 0,1day,3day,1week ,2 week,1 month
Changes in urine volume
Time frame: 0,1day,3day,1week ,2 week,1 month
Changes in urinay Na + excretion in body
Time frame: 0,1day,3day,1week ,2 week,1 month
Change in clinical complications(AKI,HE) in patients with hyponatremia
Time frame: 1 week,1month
Development of AKI
Time frame: 7 day
Failure to achieve sodium concentration to 125 meq/L
Time frame: 7 day
Improvement in Na+ concentration from base line to 130 meq/l
Time frame: Day 7
Mean Arterial pressure
Time frame: Day 1,7,14, and 30
sodium concentration in RBC cell
Time frame: Day 7
sodium concentration in RBC cell
Time frame: Day 30
RBC water concentration in RBC cell
Time frame: Day 7
RBC water concentration in RBC cell
Time frame: Day 30
Improvement in ascites
Time frame: Day 30
Maintenance of sodium concentration
Time frame: Day 14 and 30
Change in body weight
Time frame: Day 7
Change in body weight
Time frame: Day 30
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2021.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Tolvaptan Tablets and Midodrine Oral Tablet in people with Liver Cirrhosis, run by Institute of Liver and Biliary Sciences, India at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Dr G. Srinivasa Reddy, MD (01146300000, srinivasareddygolamari@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Improvement in Na+ to 125meq/L (time frame: 1 week). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2021.