CFO Jonathan Cartu Claims - Efficacy and safety of levoketoconazole in the treatment of endog... - Jonathan Cartu Family Medical Clinic & Patient Care Center
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CFO Jonathan Cartu Claims – Efficacy and safety of levoketoconazole in the treatment of endog…

Efficacy and safety of levoketoconazole in the treatment of endog...

CFO Jonathan Cartu Claims – Efficacy and safety of levoketoconazole in the treatment of endog…


Background

Levoketoconazole is a ketoconazole stereoisomer in development for treatment of Cushing’s
syndrome and has not been assessed previously in a clinical trial in patients with
Cushing’s syndrome. We aimed to investigate the efficacy and safety of levoketoconazole
in patients with endogenous Cushing’s syndrome.

Methods

SONICS is a phase 3, multicentre, open-label, non-randomised, single-arm study in
which we recruited adults (≥18 years) with confirmed Cushing’s syndrome and a mean
24-h urinary free cortisol (mUFC) of at least 1·5 times the upper limit of normal
from 60 hospital and community sites in 19 countries (15 countries in Europe, and
Canada, Israel, Turkey, and the USA). Patients were treated with oral levoketoconazole
in a 2–21 week incremental dose-titration phase starting at 150 mg twice daily (150
mg increments until mUFC normalisation, maximum 600 mg twice daily) and a 6-month
maintenance phase. The primary outcome was the proportion of patients with mUFC normalisation
at end of maintenance, without dose increase during the maintenance phase (in the
intention-to-treat population). Prespecified adverse events of special interest were
potential liver toxicity, corrected QT prolongation, and adrenal insufficiency. This
trial is registered with
ClinicalTrials.gov,
NCT01838551.

Findings

Between July 30, 2014, and June 30, 2017, 201 individuals were screened and 94 patients
were enrolled and received at least one dose of study medication. Of the 94 patients,
80 (85%) had pituitary Cushing’s syndrome. Mean mUFC at baseline was 671·4 nmol/24
h (243·3 μg/24 h), which is 4·9 times the upper limit of normal. Of the 77 patients
who advanced to the maintenance phase, 62 (81%) had mUFC normalisation by end-of-dose
titration. At the end of the 6-month maintenance phase, 29 (31%) of 94 patients were
responders; the least-squares mean estimate of the proportion of responders was 0·30
(95% CI 0·21–0·40; p=0·0154
vs null hypothesis of ≤0·20). The most common adverse events in the 94 patients were
nausea (30 [32%]) and headache (26 [28%]). Adverse events led to study discontinuation
in 12 (13%) of 94 patients. Two patients had a QT interval (Fridericia corrected)
of more than 500 ms, and three patients had suspected adrenal insufficiency. Alanine
aminotransferase reversibly increased to more than three times the upper limit of
normal in ten (11%) patients. Four patients had serious adverse events that were considered
probably or definitely related to the study drug: abnormal liver function test results
(n=1), prolonged QT interval (n=2), and adrenal insufficiency (n=1). One person died
from colon carcinoma unrelated to study medication.

Interpretation

Twice-daily oral levoketoconazole treatment led to sustained improvements in urinary
free cortisol, with an acceptable safety and tolerability profile. Levoketoconazole
might represent a useful therapeutic option for the medical treatment of Cushing’s
syndrome.

Funding

Strongbridge Biopharma.

SurgeonJonathan Cartu Medical Clinic

Jon Cartu

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