NCT03368066

Is Adrenal Insufficiency Under-diagnosed in Hospitalized Cirrhosis Patients?

Completed Phase 3 Results posted Last updated 9 December 2021

What this trial tests

Phase 3 trial testing Cosyntropin in Adrenal Insufficiency in 100 participants. Completed in 12 March 2019.

Timeline

29 January 2018

Primary endpoint
12 March 2019

12 March 2019

Quick facts

Lead sponsor	University of Virginia
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	diagnostic
Enrollment	100
Start date	29 January 2018
Primary completion	12 March 2019
Estimated completion	12 March 2019
Sites	1 location across United States

Drugs / interventions tested

• Cosyntropin — full drug profile →

Conditions studied

• Adrenal Insufficiency — all drugs for Adrenal Insufficiency →
• Cirrhosis — all drugs for Cirrhosis →
• Spur Cell Anemia — all drugs for Spur Cell Anemia →
• Lecithin Acyltransferase Deficiency — all drugs for Lecithin Acyltransferase Deficiency →

Sponsor

University of Virginia

Who can join

Adults 18 to 110, any sex, with Adrenal Insufficiency or Cirrhosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Cholesterol Esterification Deficiency Primary · 24 hours

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.

Group	Value	95% CI
Normal Adrenal Response	10
Relative Adrenal Insufficiency	11

Number of Participants With Spur Cell Anemia Primary · 24 hours

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.

Group	Value	95% CI
Normal Adrenal Response	6
Relative Adrenal Insufficiency	8

Participant Transplant-Free Survival Primary · 6 months

Transplant and Death are considered equivalent outcomes

Group	Value	95% CI
Normal Adrenal Response	41
Relative Adrenal Insufficiency	16

Number of Participants With Relative Adrenal Insufficiency (RAI) Secondary · 24 hours

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.

Group	Value	95% CI
Hospitalized Cirrhosis Patients	37

Number of Participants With Low Free Cortisol Secondary · 24 hours

Patients will have their free cortisol levels measured to assess for deficiency.

Group	Value	95% CI
Normal Adrenal Response	6
Relative Adrenal Insufficiency	1

Number of Participants Who Received Liver Transplantation at 90 Days Secondary · 90 days

Patients who received a liver transplant within 90 days of enrollment

Group	Value	95% CI
Normal Adrenal Response	6
Relative Adrenal Insufficiency	5

Number of Participants Who Received Liver Transplantation at 6 Months Secondary · 6 months

Patients who received a liver transplant within 6 months of enrollment

Group	Value	95% CI
Normal Adrenal Response	8
Relative Adrenal Insufficiency	6

Number of Participants Who Died Within Index Hospitalization Secondary · Within Hospitalization

Patients who died within the same hospitalization as enrollment

Group	Value	95% CI
Normal Adrenal Response	1
Relative Adrenal Insufficiency	1

Number of Participants Who Died at 30 Days Secondary · 30 days

Patients who died within 30 days of enrollment

Group	Value	95% CI
Normal Adrenal Response	4
Relative Adrenal Insufficiency	4

Number of Participants Who Died at 90 Days Secondary · 90 days

Patients who died within 90 days of enrollment

Group	Value	95% CI
Normal Adrenal Response	5
Relative Adrenal Insufficiency	12

Number of Participants Who Died at 6 Months Secondary · 6 months

Patients who died within 6 months of enrollment

Group	Value	95% CI
Normal Adrenal Response	9
Relative Adrenal Insufficiency	15

Adverse events — posted to ClinicalTrials.gov

Time frame: 6 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Hospitalized Cirrhosis Patients

Serious: 25/100 (25%)

Deaths: 25/100

Serious adverse events (2 terms)

Reaction	System	Hospitalized Cirrhosis Pat…
Liver-related death	Hepatobiliary disorders	—
Non-liver-related death	General disorders	—

Other adverse events (1 terms — click to expand)

Reaction	System	Hospitalized Cirrhosis Pat…
Nausea	Gastrointestinal disorders	—

Most-reported serious reactions: Liver-related death, Non-liver-related death.

Data from ClinicalTrials.gov NCT03368066 adverse events section.

Sponsor's own description

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.

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.