CirrhosisPhase 2/3NCT02173288
Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites
A Phase 2/3 study testing Standard medical therapy, Tolvaptan and Midodrine in people with Cirrhosis and Refractory/Recurrent Ascites, run by Post Graduate Institute of Medical Education and Research, Chandigarh at 1 site in India.
Trial summary
The development of ascites in the natural history of cirrhosis heralds a worsening of the prognosis to 50% survival at 2 years, and this deteriorates to 30-50% at 1 year when the ascites becomes refractory to medical therapy. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Cirrhosis, Refractory/Recurrent Ascites
- What is being tested?
- Standard medical therapy, Tolvaptan and Midodrine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteIndia
- Study dates
- Jul 2013to Mar 2016
- Phase
- Phase 2/3
- 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
None listed.
Who cannot join
- Presence of gastrointestinal bleeding, HRS, hepatic encephalopathy of grade 2 or higher or infection within 1 month preceding the study or during the study, presence of diabetes, intrinsic renal or cardiovascular disease or arterial hypertension on history and physical examination, abnormal urine analysis, chest radiograph or electrocardiogram, presence of hepatocellular carcinoma or portal vein thrombosis or treatment with drugs with known effects on systemic and renal hemodynamics within 7 days of inclusion .
Trial locations and contacts
1 site in 1 country.
About this study
The development of ascites in the natural history of cirrhosis heralds a worsening of the prognosis to 50% survival at 2 years, and this deteriorates to 30-50% at 1 year when the ascites becomes refractory to medical therapy. Hemodynamic alterations and their relation to neurohumoral systems are essential in pathophysiology of ascites formation. The theory that best explain the ascites formation and sodium retention in cirrhotics is portal hypertension leading to splanchnic arterial vasodilatation leading to underfilling of arterial circulation which is sensed by the arterial and the cardiopulmonary receptors leading to sympathetic nervous system activation and activation of the anti-natriuretic factors (RAAS and arginine vasopressin), resulting in sodium and water retention. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, liver transplantation and transjugular intrahepatic portosystemic shunts.Vasopressin V2 receptor antagonists antagonize the antidiuretic effects of vasopressin at the V2 receptor located in the renal collecting duct, they increase free water clearance, and thus may be helpful in mobilizing excess water in conditions associated with water retention including cirrhosis. The use of V2 receptor antagonists in cirrhosis with ascites has been shown to be safe and efficacious. Midodrine, an alpha adreno receptor agonist by causing splanchnic vasoconstriction has been used in hepatorenal syndrome (HRS) and for control of ascites in patients with refractory or recurrent ascites. It is possible that vasoconstrictors and aquaretics (V2 receptor antagonists) by acting at different sites in combination may reverse some of the pathogenic events that results in refractory or recurrent ascites.There are no reports on the use of combination of midodrine and tolvaptan in the patients with cirrhosis with ascites. Therefore, we plan to study the role of midodrine, tolvaptan and their combination on systemic hemodynamics, renal functions and control of ascites in patients with cirrhosis and refractory or recurrent ascites.
- Conditions
- Cirrhosis, Refractory/Recurrent Ascites
- Being tested
- Standard medical therapy, Tolvaptan, Midodrine
- Medical subject headings
- Fibrosis, Ascites
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard medical therapyDrug
Also called Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide.
TolvaptanDrug
Also called Tolvaptan 15 mg twice a day
MidodrineDrug
Also called Midodrine 7.5 mg thrice a day
| Study group | Role | What they receive |
|---|---|---|
| Standard medical therapy | Active comparator | Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide. Receives: Drug: Standard medical therapy |
| Midodrine group | Active comparator | Standard medical therapy (n-15) with Midodrine 7.5 mg thrice a day Receives: Drug: Standard medical therapy; Drug: Midodrine |
| Tolvaptan group | Active comparator | Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day Receives: Drug: Standard medical therapy; Drug: Tolvaptan |
| Tolvaptan plus midodrine arm | Experimental | Standard medical therapy (n-15) with Tolvaptan 15 mg twice a day and Midodrine 7.5 mg thrice a day Receives: Drug: Standard medical therapy; Drug: Tolvaptan; Drug: Midodrine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with control of ascites
Control of ascites will be defined as:
Complete: defined as the elimination of ascites Partial: presence of ascites not requiring paracentesis Failure: defined as persistence of ascites requiring paracentesis
Measured: 3 months
Secondary outcomes (5)
Number of patients with worsening of encephalopathy
Measured: 3 months
Number of patients with impairment of liver function
Measured: 3 months
Number of patients with variceal bleed
Measured: 3 months
Number of patients developing hepatorenal syndrome
Measured: 3 months
Number of patients with hypernatremia
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2014 (estimated)
- Study startJul 2013
- Primary completionMar 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for CirrhosisStudies of the same condition, open and under way.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, Chandigarh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr.Virendra Singh, Post Graduate Institute of Medical Education and Research, Chandigarh
- Investigators
- Virendra Singh, Study chair, PGIMER, Chandigarh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02173288
- Sponsor's protocol ID
- Mido-tolvaptan 1
- Status last verified
- Sep 2017
- First submitted
- 18 Jun 2014
- Last updated
- 19 Sep 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Rai N, Singh B, Singh A, Vijayvergiya R, Sharma N, Bhalla A, Singh V. Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study. Liver Int. 2017 Mar;37(3):406-414. doi: 10.1111/liv.13250. Epub 2016 Oct 2.
PubMed 27614145
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of Midodrine and Tolvaptan in Patients With Cirrhosis With Refractory or Recurrent Ascites
- ClinicalTrials.gov ID
- NCT02173288
- Acronym / sponsor ID
- Mido-tolvaptan 1
- Conditions
- Cirrhosis, Refractory/Recurrent Ascites
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Post Graduate Institute of Medical Education and Research, ChandigarhUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Mar 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 24 Jun 2014 (estimated)
- 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.
The development of ascites in the natural history of cirrhosis heralds a worsening of the prognosis to 50% survival at 2 years, and this deteriorates to 30-50% at 1 year when the ascites becomes refractory to medical therapy. Hemodynamic alterations and their relation to neurohumoral systems are essential in pathophysiology of ascites formation. The theory that best explain the ascites formation and sodium retention in cirrhotics is portal hypertension leading to splanchnic arterial vasodilatation leading to underfilling of arterial circulation which is sensed by the arterial and the cardiopulmonary receptors leading to sympathetic nervous system activation and activation of the anti-natriuretic factors (RAAS and arginine vasopressin), resulting in sodium and water retention. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, liver transplantation and transjugular intrahepatic portosystemic shunts.Vasopressin V2 receptor antagonists antagonize the antidiuretic effects of vasopressin at the V2 receptor located in the renal collecting duct, they increase free water clearance, and thus may be helpful in mobilizing excess water in conditions associated with water retention including cirrhosis. The use of V2 receptor antagonists in cirrhosis with ascites has been shown to be safe and efficacious. Midodrine, an alpha adreno receptor agonist by causing splanchnic vasoconstriction has been used in hepatorenal syndrome (HRS) and for control of ascites in patients with refractory or recurrent ascites. It is possible that vasoconstrictors and aquaretics (V2 receptor antagonists) by acting at different sites in combination may reverse some of the pathogenic events that results in refractory or recurrent ascites.There are no reports on the use of combination of midodrine and tolvaptan in the patients with cirrhosis with ascites. Therefore, we plan to study the role of midodrine, tolvaptan and their combination on systemic hemodynamics, renal functions and control of ascites in patients with cirrhosis and refractory or recurrent ascites.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Standard medical therapy | Active comparator | Drug: Standard medical therapyStandard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide. |
| Midodrine group | Active comparator | Drug: Standard medical therapy, Drug: MidodrineStandard medical therapy (n-15) with Midodrine 7.5 mg thrice a day |
| Tolvaptan group | Active comparator | Drug: Standard medical therapy, Drug: TolvaptanStandard medical therapy (n-15) with Tolvaptan 15 mg twice a day |
| Tolvaptan plus midodrine arm | Experimental | Drug: Standard medical therapy, Drug: Tolvaptan, Drug: MidodrineStandard medical therapy (n-15) with Tolvaptan 15 mg twice a day and Midodrine 7.5 mg thrice a day |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (1 listed)
- Presence of gastrointestinal bleeding, HRS, hepatic encephalopathy of grade 2 or higher or infection within 1 month preceding the study or during the study, presence of diabetes, intrinsic renal or cardiovascular disease or arterial hypertension on history and physical examination, abnormal urine analysis, chest radiograph or electrocardiogram, presence of hepatocellular carcinoma or portal vein thrombosis or treatment with drugs with known effects on systemic and renal hemodynamics within 7 days of inclusion .
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 |
|---|---|---|
| Standard medical therapyAlso: Standard Medical therapy (n-15) with100 to 400mg spironolactone and/or 40 to 160mg furosemide. | Drug | Midodrine group, Standard medical therapy, Tolvaptan group, Tolvaptan plus midodrine arm |
| TolvaptanAlso: Tolvaptan 15 mg twice a day | Drug | Tolvaptan group, Tolvaptan plus midodrine arm |
| MidodrineAlso: Midodrine 7.5 mg thrice a day | Drug | Midodrine group, Tolvaptan plus midodrine arm |
Primary outcome
Number of patients with control of ascites
Time frame: 3 months
Control of ascites will be defined as: Complete: defined as the elimination of ascites Partial: presence of ascites not requiring paracentesis Failure: defined as persistence of ascites requiring paracentesis
5 secondary outcomes
Number of patients with worsening of encephalopathy
Time frame: 3 months
Number of patients with impairment of liver function
Time frame: 3 months
Number of patients with variceal bleed
Time frame: 3 months
Number of patients developing hepatorenal syndrome
Time frame: 3 months
Number of patients with hypernatremia
Time frame: 3 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2017.
- Derived from this study: PubMed 27614145Rai N, Singh B, Singh A, Vijayvergiya R, Sharma N, Bhalla A, Singh V. Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study. Liver Int. 2017 Mar;37(3):406-414. doi: 10.1111/liv.13250. Epub 2016 Oct 2.
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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.
Virendra Singh study chair
PGIMER, Chandigarh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Standard medical therapy, Tolvaptan and Midodrine in people with Cirrhosis and Refractory/Recurrent Ascites, run by Post Graduate Institute of Medical Education and Research, Chandigarh 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 0 inclusion and 1 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: finished, as of the sponsor's last update on 19 Sep 2017. 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.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with control of ascites (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02173288, which also lists 1 linked publication.
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 19 Sep 2017.