A Phase 3 interventional study of Cosyntropin in Adrenal Insufficiency, Cirrhosis and Spur Cell Anemia, sponsored by University of Virginia. Completed at 1 site in United States. Open to participants aged 18 Years to 110 Years. Per ClinicalTrials.gov, last updated 2021-12-09.
Sponsored by University of Virginia · Phase 3, Interventional, and Diagnostic
The hepatoadrenal syndrome has been well described in the literature and is known to be associated with poorer outcomes in both stable and critically ill cirrhotic patients. In chronic liver disease, adrenal (and more specifically cortisol) insufficiency is thought to be a byproduct of altered lipid metabolism that results in decreased HDL production and thus decreased delivery of cholesterol to the adrenal for subsequent corticosteroid production. Studies to date have implicated lecithin-cholesterol acetyltransferase (LCAT) as the key enzyme which is deficient in some cirrhotic patients, leading to an impaired ability to esterify cholesterol and thus a loss of normal cellular functioning and membrane stability. The investigators seek to quantify this LCAT deficiency in a cohort of cirrhotic patients and demonstrate its association with various abnormal physiologies associated with chronic liver disease, including spur cell anemia, low HDL levels, and adrenal insufficiency.
Hospitalized cirrhotic patients at UVA that meet study eligibility criteria will be approached by a member of the study team to obtain consent for participation. If a patient agrees to become a study subject, they will have an approximate total of 35ml of blood drawn the following morning. Lab tests to be performed include: peripheral blood smear, lipid panel, free cortisol, cortisol binding globulin, serum cholesterol esters (surrogate for LCAT enzyme activity), and a standard-dose cortisol stimulation test. The latter involves blood drawn with the initial collection, administration of an intravenous 250mcg dose of synthetic ACTH, and then repeat small-volume blood draws at 30 minutes and 60 minutes later.
Subjects will be classified as adrenally sufficient or insufficient on the basis of as standard-dose cortisol stimulation test. Variables of interest for comparison between the groups include MELD score, Child-Turcotte-Pugh (CTP) classification, high-density lipoprotein (HDL) levels, presence of spur cell anemia, serum cholesterol ester percentage (surrogate for LCAT enzymatic activity), cortisol binding globulin levels, and free cortisol levels. Student's t-test and Chi Square tests will be utilized to determine significance; a p \<0.05 value will be used as our threshold for significance. If multiple factors are found to be significantly different in a univariate fashion between classification groups, a multivariate logistic regression analysis will be performed for adjusted analysis. The investigators will also seek to define any correlations between variables. Furthermore, the investigators will assess correlation between MELD score and serum cholesterol ester percentage, spur cell anemia, HDL levels, cortisol binding globulin levels, and free cortisol levels; similar correlate analysis will be done using CTP classification instead of MELD score.
136 studies on the registry are indexed under Adrenal Insufficiency; 27 are open to participants now.
This study's enrollment of 100 is above the median of 44 across 71 interventional studies indexed under Adrenal Insufficiency.
Browse Adrenal Insufficiency studies →University of Virginia is the lead sponsor of 675 studies on the registry; 138 are open to participants now.
Of its 61 completed or terminated interventional studies of FDA-regulated products, 42 (69%) have results posted.
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Exclusion Criteria:
Administration of cortisol stimulation test to assess for presence or absence of adrenal insufficiency
Drug: Cosyntropin
Administer 250mcg cosyntropin to hospitalized cirrhosis patients to assess for the presence of adrenal insufficiency
Number of Participants With Cholesterol Esterification Deficiency
A percent quantification of serum cholesterol esterification will be measured via blood draw. Low values represent deficiency in esterification, which is a surrogate measure of lecthicin-cholesterol acetyltransferase (LCAT) enzymatic deficiency.
Time frame: 24 hours
Number of Participants With Spur Cell Anemia
A peripheral blood smear will be obtained and assessed for presence of acanthocytes (spur cells). Spur cell anemia is defined as a serum hemoglobin \< 10g/dL and the presence of \>= 5% spur cells on blood smear.
Time frame: 24 hours
Participant Transplant-Free Survival
Transplant and Death are considered equivalent outcomes
Time frame: 6 months
Number of Participants With Relative Adrenal Insufficiency (RAI)
A baseline total cortisol level will be obtained and then patients will receive a standard-dose synthetic ACTH (250mcg of Cosyntropin) stimulation test to assess for the presence of adrenal insufficiency. RAI is defined as a change in the total cortisol level in response to the stimulation test of \<9mcg/dL when measured 60 minutes after the Cosyntropin is administered.
Time frame: 24 hours
Number of Participants With Low Free Cortisol
Patients will have their free cortisol levels measured to assess for deficiency.
Time frame: 24 hours
Number of Participants Who Received Liver Transplantation at 90 Days
Patients who received a liver transplant within 90 days of enrollment
Time frame: 90 days
Number of Participants Who Received Liver Transplantation at 6 Months
Patients who received a liver transplant within 6 months of enrollment
Time frame: 6 months
Number of Participants Who Died Within Index Hospitalization
Patients who died within the same hospitalization as enrollment
Time frame: Within Hospitalization
Number of Participants Who Died at 30 Days
Patients who died within 30 days of enrollment
Time frame: 30 days
Number of Participants Who Died at 90 Days
Patients who died within 90 days of enrollment
Time frame: 90 days
Number of Participants Who Died at 6 Months
Patients who died within 6 months of enrollment
Time frame: 6 months
| Milestone | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Started | 58 | 37 |
| Completed | 58 | 37 |
| Not completed | 0 | 0 |
A percent quantification of serum cholesterol esterification will be measured via blood draw. Low values represent deficiency in esterification, which is a surrogate measure of lecthicin-cholesterol acetyltransferase (LCAT) enzymatic deficiency.
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants With Cholesterol Esterification Deficiency | 10 | 11 |
A peripheral blood smear will be obtained and assessed for presence of acanthocytes (spur cells). Spur cell anemia is defined as a serum hemoglobin \< 10g/dL and the presence of \>= 5% spur cells on blood smear.
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants With Spur Cell Anemia | 6 | 8 |
Transplant and Death are considered equivalent outcomes
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Participant Transplant-Free Survival | 41 | 16 |
A baseline total cortisol level will be obtained and then patients will receive a standard-dose synthetic ACTH (250mcg of Cosyntropin) stimulation test to assess for the presence of adrenal insufficiency. RAI is defined as a change in the total cortisol level in response to the stimulation test of \<9mcg/dL when measured 60 minutes after the Cosyntropin is administered.
| Participants | Hospitalized Cirrhosis Patients |
|---|---|
| Number of Participants With Relative Adrenal Insufficiency (RAI) | 37 |
Patients will have their free cortisol levels measured to assess for deficiency.
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants With Low Free Cortisol | 6 | 1 |
Patients who received a liver transplant within 90 days of enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Received Liver Transplantation at 90 Days | 6 | 5 |
Patients who received a liver transplant within 6 months of enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Received Liver Transplantation at 6 Months | 8 | 6 |
Patients who died within the same hospitalization as enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Died Within Index Hospitalization | 1 | 1 |
Patients who died within 30 days of enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Died at 30 Days | 4 | 4 |
Patients who died within 90 days of enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Died at 90 Days | 5 | 12 |
Patients who died within 6 months of enrollment
| Participants | Normal Adrenal Response | Relative Adrenal Insufficiency |
|---|---|---|
| Number of Participants Who Died at 6 Months | 9 | 15 |
Collected over 6 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Hospitalized Cirrhosis Patients | 25/100 (25%) | 25/100 (25%) | 1/100 (1%) |
| Event | Hospitalized Cirrhosis Patients |
|---|---|
| Liver-related deathHepatobiliary disorders | 24/100 |
| Non-liver-related deathGeneral disorders | 1/100 |
| Event | Hospitalized Cirrhosis Patients |
|---|---|
| NauseaGastrointestinal disorders | 1/100 |
| Age, Continuous(years) | Hospitalized Cirrhosis Patients |
|---|---|
| Median | 58 (52 to 66) |
| Sex: Female, Male(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| Female | 39 |
| Male | 56 |
| Race and Ethnicity Not Collected(Participants) | Hospitalized Cirrhosis Patients |
|---|
| Region of Enrollment(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| United States | 95 |
| Etiology of Cirrhosis(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| Alcohol | 33 |
| Non-alcoholic steatohepatitis | 22 |
| Hepatitis C | 9 |
| Cryptogenic | 14 |
| Other | 17 |
| Decompensation(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| Ascites | 88 |
| Hepatic Encephalopathy | 55 |
| Esophageal Varices | 68 |
| Hepatocellular Carcinoma(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| Count of participants | 11 |
| Aldosterone Antagonist Use(Participants) | Hospitalized Cirrhosis Patients |
|---|---|
| Count of participants | 55 |
17 further baseline measures are reported on the registry.
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Jan 2018 to primary completion in Mar 2019, 13 months.
Results were first posted in Dec 2021, 2 years 8 months after primary completion.
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Studies of the drug tested here: Cosyntropin