T96. RESULTS OF THE HUMMINGBIRD STUDY A MULTICENTRE, PRAGMATIC TRIAL OF A DIGITAL MEDICINE SYSTEM

Abstract Background This was a multicentre, 8-week, single-arm, open-label, pragmatic trial to explore the acceptance and performance of using the Digital Medicine System (DMS) with health care professionals (HCPs) and adult subjects with schizophrenia, schizoaffective disorder (SAD), or first episode psychosis (FEP) on an oral atypical antipsychotic (aripiprazole, olanzapine, quetiapine, or risperidone). Methods Subjects received an initial introduction to the DMS, and had HCP visits at screening/baseline, Week 4, Week 8/early termination (ET), and as directed by the HCP for the duration of the subject’s participation in the trial. Safety and tolerability data was collected and evaluated on an ongoing basis, as assessed by the frequency and severity of serious adverse events (SAEs), and device-related non-serious adverse events (AEs). Subjects were monitored on the DMS technology by the HCPs through review of the HCP dashboard data at a minimum of every 2 weeks and to make changes to the current treatment plan and therapy at their discretion. The study initiated in May 2018 and concluded in September 2019. NCT03568500 Results Fifty-five (55) subjects were screened, and forty-three (43) subjects were treated and included in the sample analysis. Subjects enrolled were on average 34.4 years old. There were twenty-eight (28) male and fifteen (15) female subjects in the study. The most common reasons for discontinuation was subject withdrawal of consent (5 subjects, 11.6%), loss to follow-up (4 subjects, 9.3%), and adverse events (4 subjects, 9.3%). The primary endpoint was the proportion of days with good patch coverage during the trial, calculated by the number of days with good patch coverage divided by the total number of trial days for each subject. Over the duration of the study, subjects had 63.4 % (SD = 26.6%) of days with good patch coverage during the trial time. No notable differences were observed across the disease types, with schizophrenic subject 64.3% (SD=20.2%), FEP subject 62.5% (SD = 27.5%), and SAD subject 63.0% (SD = 37.7%). The secondary endpoint was subject adherence, defined as the proportion of detected ingestible events markers (IEM) over the expected during the trial days with good patch coverage. Overall, subjects had a mean of 86.6% (SD = 14.5%) IEMs detected during the good patch coverage days. The proportion of IEM detected by disease type were: FEP 91.0% (SD = 7.4%), schizophrenic 88.9% (SD = 8.1%), and SAD 72.3% (SD=25.7%). There were nine (9) subjects (20.9%) who had eleven (11) AEs during the study, all were non-serious. Out of all the AEs, nine (9) subjects had nine (9) treatment emergent adverse events (TEAE) that were all reported as medical device site irritation, and four (4) subjects discontinued the study due to AEs. Discussion In conclusion, during the 8-week treatment with the DMS, subjects reported good patch coverage 63.4% of the time on average for this pragmatic study. Using the DMS, subjects’ medication adherence reached 86.6% on average when subjects were having good patch coverage. The acceptance and performance of DMS is considered safe and there were no SAEs associated with its use. Funding This study was supported by Otsuka Pharmaceutical Development & Commercialization, Inc.

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Hummingbird Study: a study protocol for a multicentre exploratory trial to assess the acceptance and performance of a digital medicine system in adults with schizophrenia, schizoaffective disorder or first-episode psychosis

BMJ Open ◽

10.1136/bmjopen-2018-025952 ◽

2019 ◽

Vol 9 (6) ◽

pp. e025952

Author(s):

J Corey Fowler ◽

Nathan Cope ◽

Jonathan Knights ◽

Peter Phiri ◽

Andrew Makin ◽

...

Keyword(s):

Schizoaffective Disorder ◽

Clinical Decision Making ◽

Pragmatic Trial ◽

First Episode Psychosis ◽

Integrated System ◽

First Episode ◽

Technical Requirements ◽

Digital Medicine ◽

Episode Psychosis ◽

And Performance

IntroductionIn patients with schizophrenia, medication adherence is important for relapse prevention, and effective adherence monitoring is essential for treatment planning. A digital medicine system (DMS) has been developed to objectively monitor patient adherence and support clinical decision making regarding treatment choices. This study assesses the acceptance and performance of the DMS in adults with schizophrenia, schizoaffective disorder or first-episode psychosis and in healthcare professionals (HCPs).Methods/AnalysisThis is a multicentre, 8-week, single-arm, open-label pragmatic trial designed using coproduction methodology. The study will be conducted at five National Health Service Foundation Trusts in the UK. Patients 18–65 years old with a diagnosis of schizophrenia, schizoaffective disorder or first-episode psychosis will be eligible. HCPs (psychiatrists, care coordinators, nurses, pharmacists), researchers, information governance personnel, clinical commissioning groups and patients participated in the study design and coproduction. Intervention employed will be the DMS, an integrated system comprising an oral sensor tablet coencapsulated with an antipsychotic, non-medicated wearable patch, mobile application (app) and web-based dashboard. The coencapsulation product contains aripiprazole, olanzapine, quetiapine or risperidone, as prescribed by the HCP, with a miniature ingestible event marker (IEM) in tablet. On ingestion, the IEM transmits a signal to the patch, which collects ingestion and physical activity data for processing on the patient’s smartphone or tablet before transmission to a cloud-based server for viewing by patients, caregivers and HCPs on secure web portals or mobile apps.Ethics and disseminationApproval was granted by London - City and East Research Ethics Committee (REC ref no 18/LO/0128), and clinical trial authorisation was provided by the Medicines and Healthcare products Regulatory Agency. Written informed consent will be obtained from every participant. The trial will be compliant with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and the Declaration of Helsinki.Trial registration numberNCT03568500; EudraCT2017-004602-17; Pre-results.

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Initial Clinical Experience with a New Complex-Shaped Detachable Platinum Coil System for the Treatment of Intracranial Cerebral Aneurysms

Interventional Neuroradiology ◽

10.1177/159101990601200206 ◽

2006 ◽

Vol 12 (2) ◽

pp. 123-130 ◽

Cited By ~ 4

Author(s):

R.T. Higashida ◽

C. Cognard ◽

S. Bracard

Keyword(s):

Adverse Events ◽

Cerebral Aneurysms ◽

Complication Rates ◽

Open Label ◽

Detachable Coil ◽

Serious Adverse Events ◽

Unruptured Aneurysms ◽

Coil System ◽

Aneurysm Occlusion ◽

And Performance

Endovascular coil occlusion of cerebral aneurysms is increasing as a viable treatment for both ruptured and unruptured aneurysms. The purpose of this study was to evaluate the safety and performance of a newer generation of complex-shaped, geometrically conformable, platinum coils, the TRUFILL DCS Detachable Coil System. From September 2000 to December 2002, 112 patients with 116 aneurysms, either ruptured or unruptured, deemed by an attending neuro-in-terventionalist to be acceptable candidates for endovascular coil embolization, were recruited into an open-label, prospective, multi-center, international registry study from 23 centers in Europe. Information on relevant clinical characteristics, device and procedure performance, and angiographic occlusion data were collected for all patients. An Independent Medical Monitor collected and reviewed information on all device- and procedure-related complications resulting in serious adverse events. Angiographic evaluation immediately following treatment of 116 aneurysms showed a mean ± SD percent of aneurysm occlusion of 93.5% ± 14.2, with 90.2% of aneurysms occluded at least 90%. The desired occlusion was achieved in 94.9% of aneurysms. Success was defined as the ability to obtain ≥ 90% aneurysm occlusion. The proportion achieving greater than 90% occlusion was statistically equivalent (at least as good) to the 80% registry standard. Complication rates were 6.9% device-related and 2.6% procedure-related. Only two complications were categorized as serious adverse events. The TRUFILL DCS coil system provided good to excellent complete occlusion of the aneurysm at initial treatment, as compared to other published studies, and proved effective and safe to use in treating both ruptured and unruptured cerebral aneurysms.

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Single-arm, open-label, multicentre first in human study to evaluate the safety and performance of dural sealant patch in reducing CSF leakage following elective cranial surgery: the ENCASE trial

BMJ Open ◽

10.1136/bmjopen-2021-049098 ◽

2021 ◽

Vol 11 (7) ◽

pp. e049098

Author(s):

Tristan Van Doormaal ◽

Menno R Germans ◽

Mariska Sie ◽

Bart Brouwers ◽

Andrew Carlson ◽

...

Keyword(s):

Adverse Events ◽

Primary Endpoint ◽

User Satisfaction ◽

Neurosurgical Procedures ◽

Open Label ◽

Cranial Surgery ◽

Dural Closure ◽

Handling Characteristics ◽

Csf Leakage ◽

And Performance

ObjectiveThe dural sealant patch (DSP) is designed for watertight dural closure after cranial surgery. The goal of this study is to assess, for the first time, safety and performance of the DSP as a means of reducing cerebrospinal fluid (CSF) leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure.DesignFirst in human, open-label, single-arm, multicentre study with 360-day (12 months) follow-up.SettingThree large tertiary reference neurosurgical centres, two in the Netherlands and one in Switzerland.ParticipantsForty patients undergoing elective cranial neurosurgical procedures, stratified into 34 supratentorial and six infratentorial trepanations.InterventionEach patient received one DSP after cranial surgery and closure of the dura mater with sutures.Outcome measuresPrimary composite endpoint was occurrence of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O positive end-expiratory pressure or postoperative wound infection. Overall success was defined as achieving the primary endpoint in no more than two patients. Secondary endpoints were device-related serious adverse events or adverse events (AEs), pseudomeningocele and thickness of dura+DSP. Additional endpoints were reoperation in 30 days and user satisfaction.ResultsNo patients met the primary endpoint. No device-related (serious) AEs were observed. There were two incidences of self-limiting pseudomeningocele as confirmed on MRI. Thickness of dura and DSP were (mean±SD) 3.5 mm±2.0 at day 7 and 2.1 mm±1.2 at day 90. No patients were reoperated within 30 days. Users reported a satisfactory design and intuitive application.ConclusionsDSP, later officially named Liqoseal, is a safe and potentially efficacious device for reducing CSF leakage after intracranial surgery, with favourable clinical handling characteristics. A randomised controlled trial is needed to assess Liqoseal efficacy against the best current practice for reducing postoperative CSF leakage.Trial registration numberNCT03566602.

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Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia

CNS Spectrums ◽

10.1017/s1092852920002643 ◽

2021 ◽

Vol 26 (2) ◽

pp. 164-180

Author(s):

Amanda Wilhelm ◽

Karen E. Anderson ◽

Hubert H. Fernandez ◽

Hadas Barkay ◽

Nayla Chaijale ◽

...

Keyword(s):

Suicidal Ideation ◽

Adverse Events ◽

Tardive Dyskinesia ◽

Dry Mouth ◽

Fixed Dose ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Pharmaceutical Industries ◽

Flexible Dose

AbstractBackgroundDeutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.MethodsSafety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).ResultsIn titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.ConclusionsDeutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

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Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211873 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2065-2070 ◽

Cited By ~ 33

Author(s):

Lisa K Stamp ◽

Peter T Chapman ◽

Murray Barclay ◽

Anne Horne ◽

Christopher Frampton ◽

...

Keyword(s):

Adverse Events ◽

Dose Escalation ◽

Controlled Trial ◽

Serum Urate ◽

Extension Study ◽

Open Label ◽

Serious Adverse Events ◽

Open Label Extension ◽

Randomised Controlled ◽

Kidney Impairment

ObjectivesTo determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout.MethodsPeople, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24.ResultsThe mean (SE) change in SU from month 12 to 24 was −1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups.ConclusionsThe majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment.Trial registration numberACTRN12611000845932

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Achieving blood pressure control targets in hypertensive patients of rural China – A pilot randomized trial

10.21203/rs.2.12264/v3 ◽

2020 ◽

Author(s):

Xiao Huang ◽

Lishun Liu ◽

Yun Song ◽

Lan Gao ◽

Min Zhao ◽

...

Keyword(s):

Adverse Events ◽

Randomized Trial ◽

Real World ◽

Large Scale ◽

Rural China ◽

Standard Group ◽

Open Label ◽

Target Groups ◽

Serious Adverse Events ◽

Hypertensive Patients

Abstract Background This study aimed to test the feasibility and titration methods to achieve specific BP control targets in hypertensive patients of rural China. Methods A randomized, controlled, open-label trial was conducted in Rongcheng, China. We enrolled 105 hypertensive participants aged over 60 years, and who had no history of stroke and cardiovascular disease. The patients were randomly assigned to one of three systolic BP target groups: standard: 140 - < 150mmHg; moderately intensive: 130 - < 140mmHg; and intensive: <130mmHg. Patients were followed for 6 months. Discussion The optimal target for SBP lowering is still uncertain worldwide and such information is critically needed, especially in China. However, in China the rates of awareness, treatment and control are only 46.9%, 40.7% and 15.3%, respectively. It is challenging to achieve BP control in the real world and it is very important to develop population-specific BP control protocols that fully consider the population’s characteristics, such as age, sex, socio-economic status, compliance, education level and lifestyle. This randomized trial showed feasibility and safety of the titration protocol to achieve desirable SBP targets (<150, <140, and <130mmHg) in a sample of rural Chinese hypertensive patients. The three BP target groups had similar baseline characteristics. After 6 months of treatment, the mean SBP measured at an office visit was 137.2mmHg, 131.1mmHg, and 124.2mmHg in the three groups. Home BP and central aortic BP measurements were also obtained. At 6 months, home BP measurements (2 hours after drug administration) showed a mean SBP of 130.9 mmHg in the standard group, 124.9 mmHg in the moderately intense group, and 119.7 mmHg in the intensive group. No serious adverse events were recorded over the 6-month study period. Rates of adverse events including dry cough, palpitations, and arthralgia were low and showed no significant differences between the three groups. This trial gained real world experience and laid the foundation for a future large-scale BP target study.

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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248418788334 ◽

2018 ◽

Vol 23 (6) ◽

pp. 524-531 ◽

Cited By ~ 5

Author(s):

Robert A. Kloner ◽

Coleman Gross ◽

Jinwei Yuan ◽

Ansgar Conrad ◽

Pablo E. Pergola

Keyword(s):

Adverse Events ◽

Serum Potassium ◽

Common Adverse Event ◽

Open Label ◽

Serious Adverse Events ◽

End Point ◽

The Mean ◽

Baseline Characteristics ◽

Raas Inhibitors ◽

Post Hoc

Introduction: Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin–angiotensin–aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. Methods: Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. Results: Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was −0.67 (0.08) mEq/L in patients taking RAASi and −0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. Conclusions: Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.

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Abstract 19503: Durability of Antiplatelet Effect of a Novel Extended-release Formulation of Acetylsalicylic acid, Durlaza in Patients With Diabetes

Circulation ◽

10.1161/circ.132.suppl_3.19503 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Paul A Gurbel ◽

Kevin Blide P. P Bliden ◽

Jeff Patrick Patrick ◽

Katayoon Saadin Saadin ◽

Udaya Tantry

Keyword(s):

Adverse Events ◽

Extended Release ◽

Platelet Reactivity ◽

Cvd Risk ◽

Open Label ◽

Serious Adverse Events ◽

Release Formulation ◽

Antiplatelet Effect ◽

Immature Platelet Fraction ◽

Induced Aggregation

Background: High platelet turnover (HPT) is implicated in incomplete platelet inhibition and high platelet reactivity (HPR) during immediate release aspirin therapy in type II diabetes patients (T2DM). Durlaza is a new, extended-release orally administered aspirin formulation developed to provide 24-hour antithrombotic effects with once-daily dosing. Methods: In this open-label, single-center study, T2DM patients (n=40) and a history of cardiovascular disease (CVD) or multiple CVD risk factors were treated with daily 162.5 mg Durlaza for 14±4 days and adverse events were collected. Antiplatelet effects were determined by conventional aggregation (LTA), Multiplate analyzer, thrombelastography with PlateletMapping, PlateletWorks ,VerifyNow Assay, and serum thromboxane B2 (TxB2) at 1, 12, 16, and 24 hrs after the last dose. HPT was defined as immature platelet fraction of ≥3.0% or MPV≥11.0 fl. Patients exhibiting HPT and/or HPR (based on previously published cutpoints in ≥2 assays) were treated with Durlaza at 325mg for 14± 4 days and platelet function testing was repeated. Results: Prevalence of HPT and HPR was 47% and 27%, respectively. There was no loss of antiplatelet effect at 12, 16 and 24 h versus 1 h by all assays (Table 1). All patients responded to 162.5mg Durlaza as measured by arachidonic acid-induced aggregation with LTA and platelet reactivity levels were low at all timepoints (Table). Serum TxB2 was lower at 12 h (p<0.03) as compared to 1 h after 162.5mg and was lower at all times with the 325 mg vs. the 162.5 mg Durlaza (p < 0.05). HPT did not affect the PD profile of Durlaza (Pts with HPT vs. no HPT, p=NS for all). Patients had no serious adverse events and low treatment related AE rate (<5%). Conclusion: In this first comprehensive assessment, a new, extended-release 162.5 Durlaza provided sustained antiplatelet effects over 24 h in T2DM patients with a favorable safety profile. Doubling the dose further lowered serum TxB2 in pts with HPT and/or HPR.

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A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

BMC Pharmacology and Toxicology ◽

10.1186/s40360-020-00446-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Fabian Lang ◽

Lydia Wunderle ◽

Susanne Badura ◽

Eberhard Schleyer ◽

Monika Brüggemann ◽

...

Keyword(s):

Adverse Events ◽

Acute Leukemia ◽

Phase I ◽

Mtor Inhibitor ◽

Prolonged Treatment ◽

Small Subset ◽

Open Label ◽

Serious Adverse Events ◽

Efficient Treatment ◽

Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

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Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome

American Journal of Nephrology ◽

10.1159/000497064 ◽

2019 ◽

Vol 49 (5) ◽

pp. 377-385 ◽

Cited By ~ 1

Author(s):

Monique E. Cho ◽

Mary H. Branton ◽

David A. Smith ◽

Linda Bartlett ◽

Lilian Howard ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Adverse Events ◽

Idiopathic Nephrotic Syndrome ◽

High Dose ◽

Open Label ◽

Serious Adverse Events ◽

Oral Dexamethasone ◽

Dose Oral ◽

Pulse Dexamethasone ◽

Daily Prednisone

Background: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. Methods: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. Results: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. Conclusion: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

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