ENDO 2021 Roundup: COVID-19 Risk With Adrenal Insufficiency, Cushing’s Death Risk, Jatenzo Liver Data, and More

Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society’s virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rateshyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights:

More Safety Data on Jatenzo

In a study of 81 men with hypogonadism — defined as a serum testosterone level below 300 ng/dL — oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study.

After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range.

And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study — including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL).

Throughout the trial, only one participant had elevation of liver function tests.

“Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration,” said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement.

In addition, for many men with hypogonadism, “an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children,” he said. “Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage.”

Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history.

COVID-19 Risk With Adrenal Insufficiency

Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%).

These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001).

Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries.

“It’s really important that you take your hydrocortisone medications and start stress dosing as soon as you’re sick,” study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children’s in Little Rock, explained during a press conference. “This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids.”

And with kids starting to return back to in-person schooling, “parents should also be reeducated about using the emergency injections of hydrocortisone,” Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well.

Cushing’s Death Risk

In a systematic review and meta-analysis of 87 studies — including data on 17,276 patients with endogenous Cushing’s syndrome — researchers found that these patients face a much higher death rate than those without this condition.

Overall, patients with endogenous Cushing’s syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing’s disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%).

And those with adrenal Cushing’s syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%).

The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels,” said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement.

From https://www.medpagetoday.com/meetingcoverage/endo/91808

Etomidate Found Effective in Severe Cushing’s Syndrome

Etomidate — a steroid synthesis blocker — is an effective treatment for patients with severe Cushing’s syndrome who do not respond to ketoconazole, according to a new case report from Mexico.

The report, “Etomidate in the control of severe Cushing’s syndrome by neuroendocrine carcinoma,” appeared in the journal Clinical Case Reports.

The investigators reported the case of a 51-year-old woman with ectopic Cushing’s syndrome caused by a pancreatic tumor. Ectopic Cushing’s refers to cases of excess secretion of adrenocorticotropin hormone (ACTH) outside the pituitary or adrenal glands.

The patient underwent distal pancreatectomy — the surgical removal of the bottom half of the pancreas — in 2015 due to an ACTH-secreting tumor. Although she had a good initial response, liver metastasis was evident by 2016.

Compared to measurements in 2016, morning blood cortisol, 24-hour urinary-free cortisol, and ACTH levels significantly increased in 2017. The patient also showed low levels of the luteinizing and follicle-stimulating hormones, which the scientists attributed to her severe hypercortisolism (excess cortisol levels).

The woman was being treated with ketoconazole to lower her cortisol values and later received chemoembolization — a method to reduce blood supply and deliver chemotherapy directly to a tumor — for her liver metastasis.

Although ketoconazole is generally the treatment of choice for the control of hormone production in the adrenal glands, its effectiveness is often limited and is associated with side effects, clinicians noted.

In April 2017, the patient arrived at the emergency room with sepsis — a potentially life-threatening complication of an infection — that originated in the gut.

Because ketoconazole had failed to lower cortisol levels, the patient started receiving infused etomidate, an inhibitor of the enzyme 11‐beta‐hydroxylase that prevents cortisol synthesis.

This treatment was stopped one day before the bilateral removal of the adrenal glands as a definitive treatment for the elevated production of cortisol.

While the patient experienced decreased levels of potassium, calcium, and magnesium with an initial dose of 0.04 mg per kg body weight an hour of etomidate, a gradual decrease of etomidate — depending on her cortisol levels — corrected these alterations.

After surgery, the patient showed a significant improvement in her general health, including control of her sepsis. She is currently taking hydrocortisone and fludrocortisone, with treatment for liver metastasis pending.

“Etomidate is a very effective drug in severe Cushing’s syndrome that is refractory to ketoconazole,” the researchers wrote.

“Control of the serum cortisol levels in ectopic Cushing’s syndrome can be obtained with infusion rates much lower than those used in anesthesia, without respiratory side effects,” they added.

The authors recommend an initial dose of etomidate of 0.04 mg/kg per hour, daily monitoring of 24-hour urinary cortisol and cortisol levels, and a gradual decrease of the etomidate dose according to daily measurements of metabolites.

From https://cushingsdiseasenews.com/2018/05/17/severe-cushings-syndrome-case-study-finds-etomidate-effective-therapy/

Clinical Trial for Cortendo

Cortendo Clinical Trial

 

About the Study

OBJECTIVE:

The purpose of this study is to test the effects of different doses of COR-003 on people with endogenous Cushing’s syndrome, primarily by measuring the cortisol levels in urine and secondarily by measuring other health parameters such as blood pressure, weight, liver function, etc. This study is also being conducted to find out if COR-003 is safe to use. This study is open-label, which means both the health providers and the participants in the study are aware of the drug or treatment being given.

STUDY DESIGN:

  • The study will begin with a screening period to make sure subjects are eligible to participate in the study.
  • After the screening period, subjects who are eligible for participation will each be given several different doses of COR-003, to be taken by mouth in tablet form.
  • After an individualized dose has been selected, participants will take COR-003 for 6 months.
  • Finally, participants will continue in the study for an additional 6 months at doses to be determined by the study doctor.
  • Throughout the study, participants will meet regularly with a study doctor and will take part in a variety of medical tests to make sure they are doing well and to see if COR-003 is working.
  • Participants in the study should be sure they have the time to participate. Participants will generally be followed for over a year.

See if you may be eligible for this clinical study. By providing your contact information, you will receive more information about the study and your eligibility.

About Cortendo

Cortendo is the sponsor of this study. This means Cortendo planned and organized this study. Cortendo will also collect and analyze the data from the study.

Cortendo is a global pharmaceutical company primarily focused on researching and providing treatments for rare diseases in endocrinology, such as Cushing’s syndrome. The company was founded in Sweden and its worldwide headquarters is located just outside of Philadelphia.

Fill out this form for more information: https://www.cushingssyndromestudy.com/registration.aspx

Research Study: An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R-ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

Objectives:         

The purpose of this study is to test the effects of different doses of COR-003 on people with Cushing’s syndrome (CS) primarily by measuring the cortisol levels in urine and secondarily by measuring other health parameters such as blood pressure, weight, and liver function. This study is also being conducted to see if there is any harm caused when using COR-003.

This study is an open label study. That means both the health providers and the participants in the study are aware of the drug or treatment being given.

Eligibility:

Adult Subjects (18 years or older) with elevated levels of cortisol due to endogenous CS.

Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if subjects are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).

Women who are pregnant or lactating are not eligible for this study.

Individuals with other health conditions or diagnoses may not be eligible for this study.

These and other eligibility criteria are best reviewed with a doctor who is participating in the study. You can also get more detailed eligibility information about the study by clicking here to visit http://www.clinicaltrials.gov.

Study Design:

  • The study will begin with a screening period to make sure subjects are eligible to participate in the study.
  • After the screening period, subjects who are eligible for participation will each be given several different doses of COR-003, to be taken orally in tablet form.
  • After an individualized dose has been selected, participants will take COR-003 for six months.
  • Finally, participants will continue in the study for an additional six months at doses to be determined by the study doctor.

 

Throughout the study, participants will meet regularly with a study doctor and will take part in a variety of medical tests to make sure they are doing well and to see if COR-003 is working.

Participants in the study should be sure they have the time to participate. Participants will generally be followed for over a year:

Study Locations

The study is currently taking place in several places around the world (United States, Belgium, France, Israel, Netherlands, Spain, and Sweden).
Additional information on the study can be found at clinicaltrials.gov through this link.

Study sponsor: Cortendo AB

For more information, please contact:

Jim Ellis at Cortendo AB tel: +1 (610) 254-9245 or jellis@cortendo.com

 

Rare neuroendocrine tumours may be misdiagnosed as Cushing’s disease

By Eleanor McDermid, Senior medwireNews Reporter

Ectopic tumours secreting corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are very rare in children and can result in a misdiagnosis of Cushing’s disease (CD), say researchers.

Three of the patients in the reported case series had pituitary hyperplasia and underwent transsphenoidal surgery for apparent CD before the tumour that was actually causing their symptoms was located. The hyperplasia was probably caused by release of CRH from the ectopic tumour, which stimulated the pituitary gland, giving the impression of an ACTH-secreting pituitary adenoma, explain Maya Lodish (National Institutes of Health, Bethesda, Maryland, USA) and study co-authors.

These three patients were part of a series of seven, which Lodish et al describe as “a relatively large number of patients, considering the infrequency of this disease.”

The patients were aged between 1.8 and 21.3 years. Three had neuroendocrine tumours located in the pancreas ranging in size from 1.4 to 7.0 cm, two had thymic carcinoids ranging from 6.0 mm to 11.5 cm, one patient had a 12.0 cm tumour in the liver and one had a 1.3 cm bronchogenic carcinoid tumour of the right pulmonary lobe.

Four of the patients had metastatic disease and, during up to 57 months of follow-up, three died of metastatic disease or associated complications and two patients had recurrent disease.

“Our series demonstrates that these are aggressive tumors with a high mortality rate,” write the researchers in the Journal of Clinical Endocrinology & Metabolism. “It is important to follow the appropriate work up, regarding both biochemical and imaging tests, which can lead to the correct diagnosis and to the most beneficial therapeutic approach.”

The team found the CRH stimulation test to be helpful, noting, for example, that none of the patients had a rise in cortisol that was consistent with CD, with all patients showing smaller responses ranging from 2% to 15%. Likewise, just one patient had an ACTH rise higher than 35% on CRH administration, and four patients had a “flat” response, which has previously been associated with ectopic neuroendocrine tumours.

Of note, six patients had normal or high plasma CRH levels, despite all having high cortisol levels, which would be expected to result in undetectable plasma CRH due to negative feedback, implying another source of CRH production. Five patients had blunted diurnal variation of both cortisol and ACTH levels consistent with Cushing’s syndrome.

The patients also underwent a variety of imaging procedures to identify the source of ACTH/CRH production, some of which, such as octreotide scans, are specialist and not available in most hospitals, the researchers note, potentially contributing to inappropriate diagnosis and management.

From http://www.news-medical.net/news/20141030/Rare-neuroendocrine-tumours-may-be-misdiagnosed-as-Cushinge28099s-disease.aspx

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