Danazol for Low Blood Counts in Liver Cirrhosis

Overseen By Caitlin O'Neill, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Southern California

Must not be taking: Hormone stimulants, Bone marrow stimulants

Disqualifiers: Hepatitis B, HIV, Hormone-sensitive malignancy, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing danazol, a medication taken by mouth, to see if it can help people with liver disease and low blood cell counts. Danazol may work by changing hormone levels to increase blood cell production. It has been used to treat certain bleeding conditions, showing long-term benefits.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as hormone stimulants, hormone blockers, bone marrow stimulants, and systemic immunosuppressive medications. If you are on corticosteroids, you must be on a stable dose of 5 mg or less of prednisone (or equivalent) for at least 8 weeks before joining the trial.

What data supports the effectiveness of the drug Danazol for low blood counts in liver cirrhosis?

There is no direct data on Danazol for low blood counts in liver cirrhosis, but similar treatments like anabolic steroids have shown to improve albumin turnover in cirrhosis, which might suggest potential benefits. ^{1 2 3 4 5}

How is the drug Danazol unique in treating low blood counts in liver cirrhosis?

Danazol is unique because it is a synthetic steroid that can increase blood cell production, which may help address low blood counts in liver cirrhosis, a condition where traditional treatments are limited. Unlike other treatments that focus on managing symptoms or complications, Danazol directly influences blood cell production, potentially offering a novel approach for patients with this condition. ^{6 7 8 9 10}

Research Team

Casey O'Connell, MD

Principal Investigator

Keck Hospital of USC

Eligibility Criteria

Adults over 18 with compensated liver cirrhosis (Child-Pugh class A/B) and low blood counts, who can consent to treatment. They must not be pregnant or breastfeeding, agree to use effective contraception if of childbearing potential, and have no history of certain conditions like heart failure or uncontrolled diseases. Excludes those with hepatitis B, recent liver decompensation events, HIV infection, high bilirubin levels, or on specific medications.

Inclusion Criteria

- Thrombocytopenia defined as platelet count ≤ 100,000/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment

I am 18 or older and can give my consent.

I do not have telomere mutations that increase their function.

Exclusion Criteria

I have cirrhosis due to chronic hepatitis B or have had hepatitis B.

Alanine aminotransferase and/or aspartate aminotransferase >3x upper limit of normal

Total bilirubin or direct bilirubin >2.5 x upper limit of normal

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive danazol 600 mg per day by mouth for treatment of cytopenias in patients with cirrhosis

24 months

Visits every 3 months for blood tests and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Danazol (Androgen)

Trial Overview The trial is testing the safety and effectiveness of a drug called Danazol at a dose of 600 mg daily for two years in patients with liver cirrhosis experiencing low blood cell counts. It aims to enroll 10 patients including those without telomere mutations.

Participant Groups

Group I: Danazol in Treatment of Cytopenias Experimental Treatment 1 Intervention

AGENT: Danazol 600mg, Oral, Daily for 24 months

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

Findings from Research

Demeclotetracycline, an ADH antagonist, was effective in improving water clearance and increasing sodium levels in 8 out of 9 patients with liver cirrhosis, indicating its potential efficacy in treating hyponatremia associated with this condition.

When combined with Spironolactone, demeclotetracycline maintained its anti-ADH effects, leading to positive free water clearance in 5 out of 10 patients, while only causing minimal decreases in sodium levels, suggesting a safe profile for use in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of demeclotetracycline in the treatment of hyponatremia in cirrhotic ascitis]. Delavelle, F., Becchio, J., Fries, D.[2013]

Patients with cirrhosis experience significant hemodynamic changes, including increased plasma volume and decreased systemic vascular resistance, which contribute to low blood pressure and a hyperkinetic circulation.

Various vasodilators, such as nitric oxide and adrenomedullin, may play a role in the abnormal blood flow seen in cirrhosis, indicating a complex interplay of neurohumoral factors that could influence disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulatory abnormalities in cirrhosis with focus on neurohumoral aspects. Møller, S., Henriksen, JH.[2022]

In a study of 30 patients with decompensated cirrhosis, simvastatin treatment for one year significantly reduced cirrhosis severity, particularly in patients who improved from Child-Pugh class B to A, indicating its potential efficacy in managing cirrhosis.

Patients who responded positively to simvastatin also experienced improved health-related quality of life and fewer hospitalizations for cirrhosis complications, suggesting that simvastatin may have beneficial anti-inflammatory effects in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients. Muñoz, AE., Pollarsky, F., Marino, M., et al.[2023]

In a study of 23 patients with cirrhosis, the combination of atorvastatin and propranolol significantly reduced portal pressure more than propranolol alone, with a decrease in hepatic venous pressure gradient (HVPG) of 4.81 mmHg compared to 2.58 mmHg for propranolol alone.

The combination treatment resulted in a higher proportion of HVPG responders (90.91% in the atorvastatin group versus 50.00% in the propranolol group), suggesting that atorvastatin may enhance the effectiveness of propranolol in managing portal hypertension in cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof-of-concept study. Bishnu, S., Ahammed, SM., Sarkar, A., et al.[2018]

In a study of 15 patients with compensated cirrhosis, treatment with 200 mg of metenolone enanthate per week for four weeks significantly increased the turnover of albumin, which was previously reduced in these patients.

The anabolic steroid's effect on albumin turnover was more pronounced in patients who had a greater initial reduction, suggesting that it may help improve protein metabolism in individuals with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of an anabolic steroid (methenolone enanthate) on the intra- and extravasal albumin pool in liver cirrhosis]. Knöbel, H., Becker, K.[2013]

In a study involving ten alcoholic patients with uncomplicated Laennec's cirrhosis and ten healthy subjects, the measurement of marrow granulocyte reserve (MGR) showed no significant differences in response to etiocholanolone, indicating that MGR remains normal in these cirrhotic patients.

Acute alcohol ingestion did not affect the MGR in cirrhotic patients, suggesting that their bone marrow response is not impaired by alcohol, which contrasts with previous studies that used bacterial endotoxin to assess granulocyte reserve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alcohol and marrow granulocyte reserve response to etiocholanolone. Chelazzi, G., Verna, E., Mandelli Contegni, GM., et al.[2013]

In patients with liver cirrhosis and thrombocytopenia (64 subjects studied), there was a significant increase in immature blood cells, including reticulocytes, granulocytes, and immature thrombocytes, indicating altered hematopoiesis.

The study identified new diagnostic markers, such as increased levels of fragmentary erythrocytes and delta-hemoglobin, which can enhance laboratory monitoring and understanding of hemolysis in patients with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The characteristics of the new indices of hemogram under liver cirrhosis]. Baranovskaya, IB., Zentsova, OA., Sysoieva, IP.[2019]

In cirrhotic patients, lower levels of thrombopoietin are associated with thrombocytopenia, as evidenced by significantly reduced thrombopoietin concentrations in patients with low platelet counts compared to those with normal counts.

After liver transplantation, thrombopoietin levels significantly increase, particularly in patients who had low platelet counts before the procedure, suggesting that restoring thrombopoietin production can help resolve thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation. Goulis, J., Chau, TN., Jordan, S., et al.[2019]

In a study of 60 patients with decompensated cirrhosis, adding Erythropoietin (EPO) to granulocyte-colony stimulating factor (G-CSF) significantly improved liver function scores and reduced mortality compared to G-CSF alone.

The combination therapy also led to fewer complications such as acute kidney injury and encephalopathy, and was more effective in patients with less severe liver disease (MELD < 16) and a healthier bone marrow stem cell reserve.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis. Anand, L., Bihari, C., Kedarisetty, CK., et al.[2020]

In patients with liver cirrhosis, while serum thrombopoietin levels remain normal, the production of thrombopoietin mRNA in the liver decreases as the disease progresses, indicating a reduction in platelet production.

Thrombocytopenia in liver cirrhosis is attributed to both increased platelet destruction in the spleen and decreased production of platelets due to lower thrombopoietin levels in the liver, suggesting a dual mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis. Ishikawa, T., Ichida, T., Matsuda, Y., et al.[2019]

References

1. France pubmed.ncbi.nlm.nih.gov

[Use of demeclotetracycline in the treatment of hyponatremia in cirrhotic ascitis]. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Circulatory abnormalities in cirrhosis with focus on neurohumoral aspects. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Baseline Severity and Inflammation Would Influence the Effect of Simvastatin on Clinical Outcomes in Cirrhosis Patients. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof-of-concept study. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

[Effect of an anabolic steroid (methenolone enanthate) on the intra- and extravasal albumin pool in liver cirrhosis]. [2013]

6. France pubmed.ncbi.nlm.nih.gov

Alcohol and marrow granulocyte reserve response to etiocholanolone. [2013]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The characteristics of the new indices of hemogram under liver cirrhosis]. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis. [2020]

10. Australia pubmed.ncbi.nlm.nih.gov

Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis. [2019]