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OR16-2 Osilodrostat Treatment in Cushing's Disease (CD): Results from a Phase III, Multicenter, Double-Blind, Randomized Withdrawal Study (LINC 3)

ABSTRACT: Abstract Background: In a Phase II study, osilodrostat, a potent oral 11?-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD (Fleseriu M et al. Pituitary 2016;19:138-48). We report the efficacy and safety of osilodrostat in a large CD patient population in the first randomized withdrawal Phase III study in this rare, serious disorder (clinicaltrials.gov: NCT02180217). Methods: Phase III, multicenter, double-blind, randomized withdrawal study following a 24-week, open-label, single-arm treatment phase. Open-label osilodrostat was initiated at 2 mg bid in 137 adults with CD and mUFC (mean of three 24-h samples) >1.5xULN (ULN=50.0 µg/24h), with dose adjustments every 2 weeks (dose range 1-30 mg bid) up to week (W) 12 based on efficacy (if mUFC >ULN) and tolerability. At W26, 71 eligible patients (mUFC ?ULN at W24 without a dose increase after W12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until W48. Patients who remained on treatment at W26 but were not eligible for randomization continued open-label osilodrostat (n=47). Primary endpoint: patients in each randomized group with mUFC ?ULN at the end of the randomized withdrawal phase (W34) without a dose increase after W26. For all mUFC assessments, patients who discontinued were classed as non-responders at subsequent time points. Results: At baseline, median (range) mUFC was 3.5xULN (0.3-69.6) in enrolled patients. At the end of the randomized withdrawal period (W34), significantly more patients maintained mUFC ?ULN (without a dose increase after W26) in the osilodrostat group than in the placebo group (86% vs 29%; OR 13.7, P<0.001). Other endpoints: at W24, 53% of enrolled patients had mUFC ?ULN without a dose increase after W12 (key secondary endpoint); at W48, 66% of enrolled patients had mUFC ?ULN; 96% of enrolled patients had mUFC ?ULN at least once during the study; median time to first mUFC ?ULN was 41 days. Median (range) duration of osilodrostat exposure was 75 weeks (1-165). By W48, 24 (18%) patients had discontinued the study, 15 (11%) because of AEs. Overall, the most common AEs were nausea (42%), headache (34%) and fatigue (28%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 51% and 42% of patients, respectively. The most common AEs reported in the osilodrostat group during the randomized withdrawal period were nausea (11% vs 0% for placebo), anemia (8% vs 9%), arthralgia (8% vs 0%) and headache (8% vs 0%). Conclusion: Osilodrostat was significantly superior to placebo at maintaining mUFC ?ULN after randomized withdrawal and normalized mUFC in two-thirds of enrolled patients at W48, with few patients discontinuing treatment because of AEs. This randomized withdrawal study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability.

SUBMITTER: Biller B

PROVIDER: S-EPMC6555000 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.MethodsThe multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed.ResultsOf 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports.ConclusionOsilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease.Clinical trial registrationClinicalTrials.gov, identifier NCT02180217.

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:Study objectivesTo evaluate the efficacy and safety of Dimdazenil, a novel partial positive allosteric modulator for GABAA receptor in adults with insomnia disorder.MethodsThis was a 2-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III study of Dimdazenil. The primary efficacy outcome was total sleep time (TST) analyzed by polysomnography (PSG) on day 13/14. Latency to persistent sleep (LPS), sleep efficiency (SE), and wake after sleep onset (WASO) were analyzed in the same way by polysomnography (PSG). The other secondary outcomes including the average subjective sleep latency (sSL), subjective TST (sTST), subjective SE (sSE), subjective WASO (sWASO), and subjective number of awakenings (sNAW) were analyzed from sleep diary data, and the insomnia severity index (ISI) was also assessed. Treatment-emergent adverse events (TEAEs) were monitored throughout the study.ResultsA total of 546 participants with insomnia (age ≥18 years) were randomized (2:1), received treatment with an oral dose of Dimdazenil (2.5 mg) or placebo, and analyzed. Compared to baseline and placebo, Dimdazenil demonstrated significant improvements in PSG measures, increased TST (71.09, 31.68 minutes, respectively; both p < 0.001), increased SE (13.26%, 5.55%, respectively; both < 0.001), reduced WASO (49.67, 20.16 minutes, respectively; both p < 0.001), and reduced LPS (21.65 minutes, p < 0.001; 6.46 minutes, p = 0.023). Compared to placebo, Dimdazenil also improved key self-reported measures of sTST (18.33 minutes, p < 0.001), sWASO (14.60 minutes, p < 0.001), sSL (4.23 minutes, p < 0.001), sSE (2.97%, p < 0.001), and sNAW (0.29, p < 0.001). Participants treated with Dimdazenil reported a significant improvement in ISI. Dimdazenil was well tolerated. The majority of TEAEs were mild or moderate. There were no clinically relevant treatment-related serious AEs and no deaths.ConclusionsDimdazenil of 2.5 mg provided significant benefit on sleep maintenance and sleep onset in individuals with insomnia disorder versus placebo, with a favorable safety profile and was well tolerated.Clinical trial informationA multicenter, randomized, double-blind phase III clinical study evaluating the efficacy and safety of EVT201 capsules compared to placebo in patients with insomnia disorders (http://www.chinadrugtrials.org), with the number of CTR20201068.

Project description:ObjectiveTo evaluate the effect of withdrawing ixekizumab in patients with psoriatic arthritis (PsA) in whom minimal disease activity (MDA) has been achieved after open-label ixekizumab treatment.MethodsSPIRIT-P3 was a multicenter, randomized, double-blind withdrawal study of biologic treatment-naive adult patients with PsA who were treated with open-label ixekizumab for 36 weeks (160 mg at week 0, then 80 mg every 2 weeks). Patients in whom MDA was sustained for >3 consecutive months were randomized 1:1, between weeks 36 and 64, to undergo blinded withdrawal of ixekizumab treatment (placebo) or to continue ixekizumab treatment every 2 weeks up to week 104. The primary efficacy end point was time to relapse (loss of MDA) for randomized patients. Patients who experienced a relapse were re-treated with ixekizumab every 2 weeks up to week 104.ResultsA total of 394 patients were enrolled and received open-label ixekizumab every 2 weeks. Of those patients, 158 (40%) achieved sustained MDA and were randomized to undergo withdrawal of ixekizumab treatment (placebo every 2 weeks; n = 79) or to continue ixekizumab treatment every 2 weeks (n = 79). Disease relapse occurred more rapidly with treatment withdrawal (median 22.3 weeks [95% confidence interval (95% CI) 16.1-28.3]) compared to those who continued treatment with ixekizumab (median not estimable; P < 0.0001). Sixty-seven patients (85%) compared to 30 patients (38%) experienced relapse in the placebo group and the continued treatment group, respectively. Median time to achieving MDA again with re-treatment was 4.1 weeks (95% CI 4.1-4.3); in 64 of 67 patients (96%) who experienced relapse with treatment withdrawal, MDA was achieved again with re-treatment. Safety was consistent with the known safety profile for ixekizumab.ConclusionContinued ixekizumab therapy is superior to ixekizumab withdrawal in maintaining low disease activity in biologic treatment-naive patients with PsA. Re-treatment with ixekizumab following a relapse may restore disease control in cases of treatment interruption.

Project description:Abstract Background: Cushing’s disease (CD) is a rare disease associated with significant morbidity and mortality, with 2-5 new cases per million per year, of which 10% occur in children (Stratakis CA. Endocrinol Metab Clin North Am 2012;41:793-803). In children, CD presents with a combination of weight gain and slowed linear growth. First-line surgery is the treatment of choice for most patients, with a success rate of 60-98% in pediatric patients if performed by an expert pituitary surgeon (Keil MF. J Clin Endocrinol Metab 2013;98:2667-78). When surgery is not successful, patients require additional pharmacologic interventions, which are currently limited in children. Osilodrostat is a potent oral 11β-hydroxylase inhibitor in clinical development for the treatment of CD. This Phase II, multicenter, open-label, non-comparative study will evaluate the pharmacokinetics (PK), pharmacodynamics and safety/tolerability of osilodrostat in patients aged 6-<18 years with Cushing’s disease (clinicaltrials.gov identifier: NCT03708900). Methods: This single-arm study will enroll 12 evaluable patients aged 6-<18 years with confirmed CD for whom pituitary surgery is not an option, for whom surgery has failed, or who are awaiting surgery. CD will be confirmed by the clinical criteria of decreasing growth percentiles with increasing weight (defined by height SDS <0, BMI SDS >0, and a strong clinical suspicion of CD), an abnormal low-dose dexamethasone suppression test, measurable morning ACTH levels, and two 24-hour UFC measurements >1.3 x ULN. This study consists of two phases: a 12-week core phase and an optional 9-month extension period for patients who obtain a clinical benefit from osilodrostat as judged by the investigator. The primary objective is to assess the PK (Cmax and Ctrough) of osilodrostat during the 12-week core study. A secondary objective is to assess the proportion of patients with normal mean UFC (mUFC; determined from two 24-hour UFC samples) at weeks 6 and 12. Other secondary objectives include: assessment of safety and tolerability up to week 12 of the core phase and up to month 12 of the extension phase; assessment of efficacy up to month 12. The starting dose of osilodrostat will be 1 mg once daily and 1 mg twice daily for patients weighing <60 kg and ≥60 kg, respectively. The dose may be titrated based on mUFC response. PK parameter estimates will be calculated by pooling individual plasma osilodrostat concentration-time data and analyzed using non-compartmental analysis. Conclusion: This Phase II, multicenter, open-label, non-comparative study will be the first study of osilodrostat in pediatric patients with CD. The results of this study may allow further clinical development of osilodrostat in children with CD.

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OR16-2 Osilodrostat Treatment in Cushing's Disease (CD): Results from a Phase III, Multicenter, Double-Blind, Randomized Withdrawal Study (LINC 3)

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