Danazol for Low Blood Counts in Liver Cirrhosis

Overseen By Caitlin O'Neill, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 24 months

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether danazol, taken daily by mouth, can safely and effectively treat low blood counts (cytopenias) in individuals with liver cirrhosis. Liver cirrhosis can lead to issues like low white blood cells or platelets, impacting overall health. The study aims to determine if danazol can improve these blood problems. Eligible participants have liver cirrhosis (excluding cases from hepatitis B) and experience low blood cell counts, such as frequent low white blood cell or platelet levels. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that danazol is likely to be safe for humans?

Research has shown that danazol, a man-made steroid, has been tested for safety and effectiveness in treating low blood counts. Studies have found that danazol is usually well-tolerated at low-to-medium doses, particularly for conditions like immune thrombocytopenia, which causes low platelet levels. Some patients have experienced improvements in their blood counts without serious side effects.

Danazol has also been used for other medical conditions, providing insight into its safety. However, since this is a phase II study, more information is needed to fully understand its safety in people with liver cirrhosis. This phase aims to gather detailed information on patient responses to the treatment and to closely monitor any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for low blood counts in liver cirrhosis?

Danazol is unique because it offers a novel approach to treating low blood counts in liver cirrhosis patients. Unlike standard treatments that often focus on managing symptoms or addressing underlying liver issues, Danazol directly targets cytopenias (low blood counts) with its action as a synthetic androgen. This hormone-like activity can stimulate blood cell production, potentially providing a more direct and effective way to improve blood counts. Researchers are excited about Danazol because it could offer an alternative to more invasive treatments, such as blood transfusions, with the convenience of oral administration.

What evidence suggests that danazol might be an effective treatment for low blood counts in liver cirrhosis?

Research suggests that danazol, administered to participants in this trial, might improve low blood counts in individuals with liver cirrhosis. While direct evidence for danazol in this specific condition is limited, similar drugs, such as anabolic steroids, have shown promise in boosting blood components. Additionally, danazol has successfully treated low platelet counts (thrombocytopenia) in patients with certain blood disorders. This success indicates it might also address similar blood count issues in liver cirrhosis patients. ^{1 2 4 6 7}

Who Is on the Research Team?

Casey O'Connell, MD

Principal Investigator

Keck Hospital of USC

Are You a Good Fit for This Trial?

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 do not have telomere mutations that increase their function.

- Leukopenia defined as white blood cell count ≤ 3500/mm3 measured on two separate occasions at least 3 months apart within 6 months of enrollment

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Danazol

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.

How Is the Trial Designed?

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

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

Danazol is already approved in United States, European Union for the following indications:

Approved in United States as Danocrine for:

• Endometriosis
• Hereditary Angioedema
• Fibrocystic Breast Disease

Approved in European Union as Danol for:

• Endometriosis
• Hereditary Angioedema
• Fibrocystic Breast Disease

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

Published Research Related to This Trial

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]

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 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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04873102?term=AREA%5BInterventionSearch%5D(DANAZOL)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=6

Danazol for Treatment of Cytopenias in Patients With ... This is a phase II pilot study designed to assess the safety and efficacy of danazol for treatment of cytopenias in patients with CPC A/B cirrhosis.

2. trialx.com trialx.com/clinical-trials/listings/243829/danazol-for-treatment-of-cytopenias-in-patients-with-cirrhosis/

Danazol for Treatment of Cytopenias in Patients With ... This is a phase II pilot study designed to assess the safety and efficacy of danazol for treatment of cytopenias in patients with CPC A/B ...

3. withpower.com withpower.com/trial/phase-3-thrombocytopenia-4-2021-666b8

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 ...

4. clinicaltrial.be clinicaltrial.be/nl/details/19921?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Danazol for Treatment of Cytopenias in Patients With Cirr... Most studies estimate that between 6 and 77% of all patients with cirrhosis have abnormal hematologic indices (AHI), including anemia, thrombocytopenia and ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10047600/

Danazol Treatment for Thrombocytopenia in ... Danazol appears to be a good treatment option for thrombocytopenic MDS patients, particularly in low-risk setting. The rate of response well ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S247503792400133X

Safety and efficacy of danazol in immune thrombocytopenia Danazol at low-to-medium doses was well tolerated and succeeded in improving ITP. Danazol therapy may be helpful in the treatment of chronic ITP that is ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4968696/

Danazol Treatment for Telomere Diseases - PMC Blood counts and the results of liver function tests were monitored monthly, and participants underwent comprehensive evaluations at the National Institutes of ...