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MON-332 Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome (LOGICS): A Double-Blind, Placebo-Controlled, Withdrawal Study

ABSTRACT: Abstract Endogenous Cushing’s syndrome (CS) is a rare, serious disorder caused by chronically elevated cortisol. A phase 3, open-label study (SONICS) of levoketoconazole in adults with CS and mean urinary free cortisol (mUFC) ?1.5 × upper limit of normal (ULN) at baseline demonstrated normalization of mUFC in 62% of those completing 6 months of maintenance treatment (Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7[11]:855-865). LOGICS is an ongoing, phase 3, double-blind, placebo-controlled, randomized-withdrawal study further investigating the safety and efficacy of levoketoconazole in patients who completed the SONICS study, or patients with CS who are levoketoconazole treatment-naive (ClinicalTrials.gov identifier: NCT03277690). The primary objective of LOGICS is to evaluate the effect of withdrawing levoketoconazole treatment to placebo, versus continuing treatment with levoketoconazole, on the cortisol therapeutic response established during open-label levoketoconazole therapy. The study includes (1) a screening phase (up to 13 weeks to allow for washout of CS medications); (2) a dose titration-maintenance phase (150-600 mg BID [dosed as needed to target mUFC normalization]) of ?14 weeks, with at least the final 4 weeks demonstrating mUFC normalization prior to advancing to the randomized-withdrawal (R-W) phase; (3) a double-blind, placebo-controlled R-W phase (levoketoconazole or placebo; up to 8 weeks); and (4) a double-blind restoration phase (levoketoconazole and placebo; 8 weeks). Patients are randomized 1:1 in the R-W phase to continue their therapeutic dose of levoketoconazole, established during the dose titration-maintenance phase, or to receive an equivalent number of placebo tablets. Up to ~54 subjects are targeted for randomization. The primary efficacy endpoint, assessed at the completion of R-W phase, is the proportion of patients with loss of therapeutic response to levoketoconazole (mUFC ?1.5x ULN, >40% above baseline if baseline value is >ULN [SONIC-completer cohort only], or early rescue criterion met) upon withdrawing to placebo, compared with continuing treatment with levoketoconazole, during the R-W phase. Secondary endpoints include changes from baseline to all postbaseline visits in R-W phase for mUFC, late-night salivary cortisol, CS cardiovascular biomarkers (fasting glucose, fasting insulin, hemoglobin A1c, homeostatic model assessment-insulin resistance, total and LDL cholesterol, high-sensitivity C-reactive protein), CS clinical signs and symptoms (acne, hirsutism [women only], and peripheral edema scores), and patient-reported outcomes of QoL (Cushing QoL questionnaire score) and depression (Beck Depression Inventory II). Potential liver toxicity, QT prolongation, and adrenal insufficiency are prespecified adverse events of special interest.

SUBMITTER: Zacharieva S

PROVIDER: S-EPMC7208150 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundInterleukin-23 inhibitors are effective and safe for treating moderate-to-severe plaque psoriasis.ObjectivesTo evaluate the efficacy and safety of mirikizumab in adult patients with moderate-to-severe plaque psoriasis through 52 weeks in a phase III randomized controlled trial.MethodsOASIS-1 (NCT03482011) was a double-blind, placebo-controlled, randomized withdrawal, phase III trial. Patients (n = 530, randomized 4 : 1) received subcutaneous mirikizumab 250 mg or placebo every 4 weeks (Q4W) through week 16. Coprimary endpoints were superiority of mirikizumab vs. placebo on static Physician's Global Assessment (sPGA; score of 0 or 1 with ≥ 2-point improvement) and ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90, responders) at week 16. Mirikizumab responders were rerandomized (1 : 1 : 1) to mirikizumab 250 mg every 8 weeks (Q8W), mirikizumab 125 mg Q8W, or placebo Q8W through week 52. Secondary endpoints were evaluated at weeks 16 and 52. Safety was monitored in all patients.ResultsAll primary and key secondary endpoints were met. At week 16, sPGA(0,1) responses were significantly greater with mirikizumab (293 of 423, 69·3%) than placebo (seven of 107, 6·5%) (P < 0·001). PASI 90 response was also greater with mirikizumab (272 of 423, 64·3%) than placebo (seven of 107, 6·5%) (P < 0·001). Significantly more patients in the mirikizumab arms achieved PASI 75 and PASI 100 (mirikizumab 349, 82·5% and 137, 32·4%; placebo 10, 9·3% and 1, 0·9%, respectively; all P < 0·001). At week 52, PASI 90, PASI 100 and sPGA(0,1) responses were mirikizumab 250Q4W/placeboQ8W (N = 91; 19%, 10%, 18%), mirikizumab 250Q4W/125Q8W (N = 90; 86%, 59%, 86%) and mirikizumab 250Q4W/250Q8W (N = 91; 86%, 60%, 82%; all P < 0·001), respectively. Rates of serious adverse events were similar across treatments (induction: mirikizumab 1·2% vs. placebo 1·9%; maintenance: mirikizumab 250Q4W/125Q8W 1%, mirikizumab 250Q4W/250Q8W 3% vs. placebo 3%). No deaths occurred.ConclusionsMirikizumab was superior to placebo at week 16 and maintained efficacy through week 52, with no new safety signals. What is already known about this topic? Interleukin (IL)-23 is a key cytokine in the pathogenesis of psoriasis. Drugs targeting the p19 subunit of IL-23 have recently been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis. Patients with moderate-to-severe plaque psoriasis achieved significantly greater improvements in skin measures and patient-reported quality-of-life measures after 16 weeks when treated every 8 weeks with mirikizumab compared with placebo in a phase II clinical trial. What does this study add? Compared with placebo, mirikizumab demonstrated high levels of efficacy at week 16 in a large phase III trial; safety profiles were similar between the mirikizumab and placebo arms. After week 16, patients maintained on doses of mirikizumab 250 mg every 8 weeks (Q8W) or 125 mg Q8W showed similar efficacy and favourable safety profiles over 52 weeks, whereas patients switched to placebo gradually lost efficacy over time.

Project description:No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of ?-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy.In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221.Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment.Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy.National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

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MON-332 Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome (LOGICS): A Double-Blind, Placebo-Controlled, Withdrawal Study

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