SNPMiner Trials by Shray Alag


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Report for Mutation Q12H

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 14 clinical trials

Clinical Trials


1 An Open-Label, Safety and Tolerability, Study Evaluating KNS-760704 in Patients With Amyotrophic Lateral Sclerosis (ALS)

This is an open-label, multi-center study designed to extend the evaluation of the safety, tolerability, and clinical effects of oral administration of KNS-760704 in patients with ALS.

NCT00931944 Amyotrophic Lateral Sclerosis Drug: KNS-760704
MeSH:Motor Neuron Disease Amyotrophic Lateral Sclerosis Sclerosis
HPO:Abnormal anterior horn cell morphology Amyotrophic lateral sclerosis

Eligible patients will receive 1 tablet of KNS-760704 150 mg every 12 hours (Q12H) (300 mg total daily dose) for up to 180 weeks. --- Q12H ---

Primary Outcomes

Measure: The primary objective of the study is to extend the evaluation of long-term safety and tolerability of KNS-760704 300 mg daily.

Time: 180 weeks

Secondary Outcomes

Measure: The secondary objective of the study is to evaluate the long-term effects of KNS-760704 300 mg daily on measures of clinical function.

Time: 180 weeks

2 Randomized, Open Label, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects

Research Hypothesis: Administration of BMS-663068, a prodrug for HIV attachment inhibitor BMS-626529, will result in a mean decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least one dosing regimen that is safe and well tolerated in Clade B HIV-1 infected subjects.

NCT01009814 HIV Infections Drug: BMS-663068 Drug: Ritonavir
MeSH:HIV Infections

Number of participants with any clinically significant abnormalities in laboratory parameters have been presented.. Maximum Observed Plasma Concentration (Cmax) of BMS-626529 Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess Cmax of BMS-626529 following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).. Trough Observed Plasma Concentration (Ctrough) of BMS-626529 Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to access Ctrough of BMS-626529 following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).. Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-626529 Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess AUC (tau) of BMS-626529 following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).. Area Under the Concentration-time Curve Over a 24-hour Period (AUC [0-24]) of BMS-626529 Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess AUC (0-24) of BMS-626529 following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 8.. Accumulation Index (AI) of BMS-626529 Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess Accumulation Index of BMS-626529 following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 8 evening dose (PM).. Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following Q12H Dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented.. Inhibitory Quotient of BMS-626529 by Ctrough Following Q12H Dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented.. Cmax of Ritonavir Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess Cmax of ritonavir following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).. Ctrough of Ritonavir Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to access Ctrough of ritonavir following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).. AUC (Tau) of Ritonavir Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess AUC (tau) of ritonavir following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).. AUC (0-24) of Ritonavir Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess AUC (0-24) of ritonavir following Q12H dosing. --- Q12H ---

Geometric mean and geometric coefficient of variation are presented for Day 8.. Accumulation Index of Ritonavir Following Q12H Dosing. --- Q12H ---

Blood samples were collected at indicated time points to assess Accumulation Index of ritonavir following Q12H dosing. --- Q12H ---

Primary Outcomes

Description: The primary assessment of the antiviral activity of BMS-663068 was assessed on the log10 change from Baseline in HIV RNA to Day 9. Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline value from post-Baseline visit value. An analysis of covariance (ANCOVA) model correcting for Baseline HIV viral load and treatment group was used to test the differences in mean log10 decrease in HIV RNA at Day 9 between 2 regimen groups by antiretroviral treatment history (ARV [antiretroviral] naive, ARV experienced, and combined [ARV naive + ARV experienced]). For the combined group (ARV naive +ARV experienced) an additional ANCOVA was used correcting also for treatment history as an additional covariate. Only Clade B participants were included in the population.

Measure: Mean Logarithm With Base 10 (Log10) Change From Baseline in Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) at Day 9

Time: Baseline and Day 9

Secondary Outcomes

Description: Blood samples were collected for evaluation of CD4+ and CD8+ cells at Baseline (Day 1, pre-dose), Day 8, Day 15 (Follow up) and Day 50 (study discharge). Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline value from post-Baseline visit value.

Measure: Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count and Cluster of Differentiation 8 Positive (CD8+) Cell Count

Time: Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50

Description: Blood samples were collected for evaluation of percent CD4+ and percent CD8+ cells at Baseline (Day 1, pre-dose), Day 8, Day 15 (Follow up) and Day 50 (study discharge). Baseline was the last non-missing observation before first dose (Day 1 pre-dose) and change from Baseline was calculated by subtracting Baseline visit value from post-Baseline visit value.

Measure: Change From Baseline in Percent CD4+ Cell Count and Percent CD8+ Cell Count

Time: Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50

Description: An AE is any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. Any untoward medical occurrence resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent serious outcomes were categorized as SAE. Treatment emergent adverse events (occurred after start of treatment) have been presented.Safety Population comprised of all randomized participants who used the trial medication at least once.

Measure: Number of Participants With Treatment Emergent Non-serious Adverse Event (Non-SAE) and Serious AE (SAE)

Time: Up to 50 days

Description: A complete physical examination included, at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. A brief physical examination included, at a minimum assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Any abnormality found by investigator during physical examination were recorded. Number of participants with any abnormality in physical examination during study have been reported.

Measure: Number of Participants With Any Abnormality in Physical Examination

Time: Up to 50 days

Description: Vital signs including DBP and SBP were recorded. Normal ranges were as following: For DBP, lower limit: value <55 millimeter of mercury (mmHg) and change <-20 mmHg; upper limit: value >90 mmHg and change >20 mmHg). For SBP, lower limit: value <90 mmHg and change <-10 mmHg; upper limit: value >140 mmHg and change >10 mmHg. Number of participants with worst-case abnormalities are presented. Worst-case abnormality was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. (3) Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.

Measure: Number of Participants With Worst-case Abnormalities in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)

Time: Up to 50 days

Description: Vital signs (body temperature, RR, and HR) were recorded. Normal range were: For HR, lower limit: 55 beats per minute (bpm) and change <-15 bpm; upper limit: >100 bpm and change >30 bpm). For temperature, lower limit: 36.0 Celsius; upper limit: >37.5 Celsius or change >1.7 Celsius). For RR, lower limit: 8 breaths per minute; upper limit: >16 breaths per minute or change >10 breaths per minute. Number of participants with worst-case abnormalities are presented. Worst-case abnormality was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. (3) Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.

Measure: Number of Participants With Worst-case Abnormalities in Body Temperature, Respiratory Rate [RR], and Heart Rate [HR]

Time: Up to 50 days

Description: A 12-lead ECG was recorded during the study using an ECG machine that automatically measures ECG parameters. Normal range for ECG parameters were: PR interval (upper: 200 milliseconds [ms]); QRS (lower: 50 ms; upper: 120 ms); Corrected QT interval by Bazett formula (QTcB) (change from Baseline - increases by > 30 ms); Corrected QT interval by Fredericia formula (QTcF) (change from Baseline - increases by > 30 ms). Number of participants with worst-case abnormalities are presented which was defined as: (1) Below Normal: at least one post-Baseline assessment was below normal range, and no post-Baseline assessment was above normal range. (2) Above Normal: at least one post-Baseline assessment was above normal range, and no post-Baseline assessment was below normal range. Within Normal: all post-Baseline assessments were within normal range. It was to be considered as 'Missing' when there were no post-Baseline assessments.

Measure: Number of Participants With Worst-case Abnormalities in Electrocardiogram (ECG) Parameters

Time: Up to 50 days

Description: Laboratory parameters included hematology, clinical chemistry and urine parameters. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Any abnormal laboratory test results which were considered clinically significant by the investigator were recorded on the case report form. Number of participants with any clinically significant abnormalities in laboratory parameters have been presented.

Measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters

Time: Up to 50 days

Description: Blood samples were collected at indicated time points to assess Cmax of BMS-626529 following Q12H dosing. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (Anti Meridiem [AM]), Day 8 evening dose (Post Meridiem [PM]) and Day 8 morning + evening dose (AM+PM). Pharmacokinetic parameter values were derived by non-compartmental methods. Pharmacokinetic (PK) Population was used which comprised of all participants who receive BMS-663068 and provided pharmacokinetic samples.

Measure: Maximum Observed Plasma Concentration (Cmax) of BMS-626529 Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess Cmax of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).

Measure: Cmax of BMS-626529 Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to access Ctrough of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8, Day 8 morning dose (AM) and Day 8 evening dose (PM).

Measure: Trough Observed Plasma Concentration (Ctrough) of BMS-626529 Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose

Description: Blood samples were collected at indicated time points to assess Ctrough of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).

Measure: Ctrough of BMS-626529 Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose

Description: Blood samples were collected at indicated time points to assess AUC (tau) of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM) and Day 8 evening dose (PM).

Measure: Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-626529 Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess AUC (tau) of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).

Measure: AUC (Tau) of BMS-626529 Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to assess AUC (0-24) of BMS-626529 following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.

Measure: Area Under the Concentration-time Curve Over a 24-hour Period (AUC [0-24]) of BMS-626529 Following Q12H Dosing

Time: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess AUC (0-24) of BMS-626529 following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.

Measure: AUC (0-24) of BMS-626529 Following QHS Dosing

Time: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to assess Accumulation Index of BMS-626529 following Q12H dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 morning dose (AM).

Measure: Accumulation Index (AI) of BMS-626529 Following Q12H Dosing

Time: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess Accumulation Index of BMS-626529 following QHS dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 evening dose (PM).

Measure: Accumulation Index of BMS-626529 Following QHS Dosing

Time: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measures were used in evaluating IQ: Cmin and Css,avg. Geometric mean and geometric coefficient of variation are presented.

Measure: Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose

Description: Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measures were used in evaluating IQ: Cmin and Css,avg. Geometric mean and geometric coefficient of variation are presented.

Measure: Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Day 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose

Description: Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measure was used in evaluating IQ: Ctrough. Geometric mean and geometric coefficient of variation are presented.

Measure: Inhibitory Quotient of BMS-626529 by Ctrough Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose

Description: Blood samples were collected at indicated time points to assess IQ of BMS-626529. Inhibitory quotient was calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein binding adjusted EC90 (PBA-EC90). The following in vivo exposure measure was used in evaluating IQ: Ctrough. Geometric mean and geometric coefficient of variation are presented.

Measure: Inhibitory Quotient of BMS-626529 by Ctrough Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose

Description: Blood samples were collected at indicated time points to assess Cmax of ritonavir following Q12H dosing. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM), Day 8 evening dose (PM) and Day 8 morning + evening dose (AM+PM). Pharmacokinetic parameter values were derived by non-compartmental methods. PK Population was used which comprised of all participants who receive ritonavir and provided pharmacokinetic samples.

Measure: Cmax of Ritonavir Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess Cmax of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 evening dose (PM) and Day 8 morning (AM) + evening dose (PM).

Measure: Cmax of Ritonavir Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to access Ctrough of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8, Day 8 morning dose (AM) and Day 8 evening dose (PM).

Measure: Ctrough of Ritonavir Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose

Description: Blood samples were collected at indicated time points to assess Ctrough of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Days 5, 6, 7, 8 and Day 8 evening dose (PM).

Measure: Ctrough of Ritonavir Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose

Description: Blood samples were collected at indicated time points to assess AUC (tau) of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1, Day 8 morning dose (AM) and Day 8 evening dose (PM).

Measure: AUC (Tau) of Ritonavir Following Q12H Dosing

Time: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess AUC (tau) of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 1 and Day 8 evening dose (PM).

Measure: AUC (Tau) of Ritonavir Following QHS Dosing

Time: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to assess AUC (0-24) of ritonavir following Q12H dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.

Measure: AUC (0-24) of Ritonavir Following Q12H Dosing

Time: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess AUC (0-24) of ritonavir following QHS dosing. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8.

Measure: AUC (0-24) of Ritonavir Following QHS Dosing

Time: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours

Description: Blood samples were collected at indicated time points to assess Accumulation Index of ritonavir following Q12H dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 morning dose (AM).

Measure: Accumulation Index of Ritonavir Following Q12H Dosing

Time: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours

Description: Blood samples were collected at indicated time points to assess Accumulation Index of ritonavir following QHS dosing. AI was calculated as ratio of AUC(tau) at steady-state to AUC(tau) after the first dose. Pharmacokinetic parameter values were derived by non-compartmental methods. Geometric mean and geometric coefficient of variation are presented for Day 8 evening dose (PM).

Measure: Accumulation Index of Ritonavir Following QHS Dosing

Time: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours

3 A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK Inhibitor, Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin for Women With Platinum-Sensitive Ovarian Cancer

A study for women with ovarian cancer that has returned at least 6 months after platinum-based chemotherapy.

NCT01663857 Epithelial Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer Drug: LY2228820 Drug: Carboplatin Drug: Placebo Drug: Gemcitabine
MeSH:Ovarian Neoplasms Carcinoma, Ovarian Epithelial Fallopian Tube Neoplasms
HPO:Fallopian tube carcinoma Ovarian neoplasm

The MTD is defined as the highest dose level at which no more than 33% of patients experience a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg Q12H).. Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin. --- Q12H ---

Primary Outcomes

Description: Recommended Phase 2 dose of LY2228820 that could be safely administered in combination with gemcitabine and carboplatin based on defined dose limiting toxicities (DLT) assessment and MTD definition. The MTD is defined as the highest dose level at which no more than 33% of patients experience a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg Q12H).

Measure: Phase 1b: Recommended Phase 2 Dose of LY2228820 in Combination With Gemcitabine and Carboplatin (Maximum Tolerated Dose [MTD])

Time: Cycle 1 (21 Days)

Description: PFS was defined as time from date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred first. Progressive disease (PD) is defined as at least a 20% increase in the sum of the largest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin

Time: Randomization to Date of Disease Progression or Death from any cause (up to 3 years)

Secondary Outcomes

Description: Overall Response Rate was estimated as the percentage of participants with best response of Complete Response (CR) or Partial Response (PR), based on RECIST version 1.1 divided by the total number of randomized participants. CR is defined as disappearance of all target lesions. PR is defined as at least 30% disease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD.

Measure: Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate)

Time: Baseline to Disease Progression (up to 3 years)

Description: Data presented are the median overall survival in months for participants in the Phase 2 treatment arms.

Measure: Phase 2: Overall Survival

Time: Baseline to Date of Death from any cause (up to 5 years)

Description: PK parameters after administration of LY2228820 for both Phase 1b and Phase 2.

Measure: Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820

Time: Phase1b:Cycle(C)1 Day(D)1:Predose(PRD),0.5,1,2,4,6,8 hours(hr)postdose(PD); C1D10:PRD,0.5,1,2,8hrPD; C2D10:PRD,0.5,1,2,4,6,8,12hrPD; C7D3:PRD,0.5,1,2,4,6hrPD; Phase 2: C1D3:PRD,0.5,1,2,4,6,8hrPD; C1D10:PRD,0.5,1,2,4,6,8hrPD; C7D3:PRD,0.5,1,2,4,6,8hrPD

Description: The Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) instrument measures health related quality of life (HRQoL) in participants with ovarian cancer. The instrument is organized into sections of physical, social/family, emotional, functional well-being and ovarian subscales with a 5-point rating scale in which 0 = "not at all" and 4 = "very much." Data presented here are change from baseline at follow-up in the FACT-O Total Score. The total score is the sum of Physical Well Being (PWB) + Social Well-being (SWB) + Emotional Well Being (EWB) + Family Well-being (FWB) + Ovarian Cancer Subscale (OCS). The FACT-O Total score range 0 - 152 with higher scores indicating better quality of life.

Measure: Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score

Time: Baseline, Study Completion (up to 3 years)

4 A Phase 1, Randomized, Double-blind, Placebo-controlled Study To Assess The Safety, Tolerability, And Pharmacokinetics Of Multiple Escalating Oral Doses Of Pf-06427878 Co Administered With And Without Food In Healthy Adult Subjects

PF-06427878 is a new compound proposed for the treatment of hyperlipidemia. The primary purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of multiple oral doses of PF-06427878 in healthy adult subjects.

NCT02391623 Healthy Subjects Drug: PF-06427878 Drug: Placebo Drug: PF-06427878 Drug: Placebo

Maximum Observed Plasma Concentration (Cmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1. null. --- Q12H ---

Maximum Observed Plasma Concentration (Cmax) for PF-06427878during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12. null. --- Q12H ---

Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1. null. --- Q12H ---

Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12. null. --- Q12H ---

Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1. null. --- Q12H ---

Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12. null. --- Q12H ---

Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Plasma Decay Half-Life (t1/2) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Apparent Volume of Distribution (Vz/F) of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Apparent Oral Clearance (CL/F) of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Minimum Observed Plasma Concentration (Cmin) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Peak:Trough ratio of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Accumulation ratio for Maximum Observed Plasma Concentration (Rac(Cmax)) for PF-06427878 on day14 relative to day 1 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD. --- Q12H ---

Amount of PF-06427878 excreted in urine (Ae) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Percent of dose excreted in urine as PF-06427878 (Ae%) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Renal clearance of PF-06427878 (CLr) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14. --- Q12H ---

Primary Outcomes

Measure: Assessment of adverse events (AEs).

Time: 0-25 days

Measure: Assessment of clinical laboratory tests.

Time: 0-25 days

Measure: Assessment of vital signs (including blood pressure and pulse rate).

Time: 0-25 days

Measure: Assessment of cardiac conduction intervals as assessed via 12-lead electrocardiogram (ECG).

Time: 0-25 days

Secondary Outcomes

Measure: Maximum Observed Plasma Concentration (Cmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Maximum Observed Plasma Concentration (Cmax) for PF-06427878during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Maximum Observed Plasma Concentration (Cmax) for PF-06427878 on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12 hours post dose

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 1

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 12

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Area Under the Curve for PF-06427878 during the dosing interval (AUCtau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Plasma Decay Half-Life (t1/2) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Apparent Volume of Distribution (Vz/F) of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Apparent Oral Clearance (CL/F) of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Minimum Observed Plasma Concentration (Cmin) for PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Peak:Trough ratio of PF-06427878 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Accumulation ratio for Maximum Observed Plasma Concentration (Rac(Cmax)) for PF-06427878 on day14 relative to day 1

Time: 0, 1, 2, 3, 4, 6, 8, 12 hours post dose

Measure: Accumulation ratio for Maximum Observed Plasma Concentration (Rac(Cmax)) for PF-06427878 on day14 relative to day 1 during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Accumulation ratio for Area Under the Curve during the dosing interval (Rac(AUCtau)) for PF-06427878 on day14 relative to day 1

Time: 0, 1, 2, 3, 4, 6, 8, 12, 24 hours post dose

Measure: Amount of PF-06427878 excreted in urine (Ae) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0- tau hours post dose

Measure: Percent of dose excreted in urine as PF-06427878 (Ae%) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0- tau hours post dose

Measure: Renal clearance of PF-06427878 (CLr) during the dosing interval (tau), ie, 0-8H for Q8H, 0-12H for Q12H, and 0-24H for QD, on day 14

Time: 0- tau hours post dose

5 A Phase II Study Incorporating Panobinostat, Bortezomib and Liposomal Vincristine Into Re-Induction Therapy for Relapsed Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoma

This is a phase-II study to evaluate the efficacy of a salvage regimen in children with relapsed T-cell ALL or lymphoma. Peg-asparaginase, mitoxantrone, intrathecal triples (IT) (intrathecal methotrexate/hydrocortisone/cytarabine) (ITMHA) and dexamethasone are commonly used drugs to treat relapsed or refractory acute lymphocytic leukemia or lymphoma (ALL). In this study, the investigators want to know if adding three drugs called panobinostat, bortezomib and liposomal vincristine (VSLI) to this regimen will result in remission (no signs or symptoms of leukemia or lymphoma). - Panobinostat has been approved by the FDA for treating adults with multiple myeloma, but it has not been approved for use in children and has not been given together with the other drugs used in this study. It has not been widely studied in children. - VSLI has been approved by the FDA for adults with relapsed or refractory ALL, but has not yet been approved for treating children with leukemia or lymphoma. - Bortezomib has been approved by the FDA for treating adults with a cancer called multiple myeloma and adults with relapsed mantle cell lymphoma; it has not been approved for treating children. PRIMARY OBJECTIVE: - To estimate the complete remission (CR) rate for patients with T-cell lymphoblastic leukemia and lymphoma in first relapse. SECONDARY OBJECTIVES: - To evaluate minimal residual disease (MRD) levels at end of each block of therapy. - To describe the toxicities of vincristine sulfate liposome injection (VSLI) when used in combination with chemotherapy and bortezomib.

NCT02518750 Acute Lymphoblastic Leukemia Lymphoma, Non-Hodgkin's Leukemia, T-Cell Leukemia, B-Cell Drug: Dexamethasone Drug: Panobinostat Drug: Liposomal vincristine Drug: Mitoxantrone Drug: Peg-asparaginase Drug: Bortezomib Drug: Intrathecal Triples Drug: High-dose methotrexate Drug: 6-Mercaptopurine Drug: High-dose cytarabine Drug: Nelarabine Drug: Cyclophosphamide Drug: Etoposide Drug: Clofarabine
MeSH:Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Lymphoma, Non-Hodgkin Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Leukemia, B-Cell Leukemia, T-Cell
HPO:Leukemia Lymphoid leukemia Lymphoma Non-Hodgkin lymphoma T-cell acute lymphoblastic leukemias

Additional ITs on Days 10 and 17 for patients with central nervous system (CNS) 2, 3 or traumatic tap with blasts Block B: approximately 5 weeks - High-dose methotrexate 8 g/m^2 IV over 24 hours (will not be given to patients with prior cranial irradiation) Day 1 - 6-mercaptopurine 50 mg/m^2 PO days 1-14 - ITMHA Day 1 - High-dose cytarabine 3 g/m^2 IV every 12 hours (Q12H) Days 15 and 16 Block C: approximately 3 weeks - Nelarabine 650 mg/m^2/day IV Days 1-5 (Clofarabine 40 mg/m^2/day IV Days 1-5 will be given instead of nelarabine for patients with B-lymphoblastic leukemia and lymphoma in stratum II) - Cyclophosphamide 300 mg/m^2 IV Days 1-5 - Etoposide 100 mg/m^2/day IV Days 1-5 Response evaluation is performed after the end of each treatment block. --- Q12H ---

Primary Outcomes

Description: All participants who start re-induction Block A therapy are considered evaluable. Any patient who at any time point achieves CR and goes to transplant is considered as a success; or any patient who successfully reaches the end of block C and achieves/remains in CR is considered a success; all other cases are considered as failure.

Measure: Complete Remission (CR) Rate

Time: At the end of each remission re-induction block C (approximately 13 weeks after start of therapy)

Secondary Outcomes

Description: MRD will be studied after each cycle of therapy. MRD is considered as positive (i.e., prevalent) if its level is ≥0.01% for ALL. The prevalence of MRD at end of each cycle is defined as proportion of MRD positives; we will estimate these proportions with point and interval estimates.

Measure: Block A Minimal Residual Disease (MRD)

Time: At the end of Block A therapy (approximately 5 weeks after start of therapy)

Description: MRD will be studied after each cycle of therapy. MRD is considered as positive (i.e., prevalent) if its level is ≥0.01% for ALL. The prevalence of MRD at end of each cycle is defined as proportion of MRD positives; we will estimate these proportions with point and interval estimates.

Measure: Block B Minimal Residual Disease (MRD)

Time: At the end of Block B therapy (approximately 10 weeks after start of therapy)

Description: MRD will be studied after each cycle of therapy. MRD is considered as positive (i.e., prevalent) if its level is ≥0.01% for ALL. The prevalence of MRD at end of each cycle is defined as proportion of MRD positives; we will estimate these proportions with point and interval estimates.

Measure: Block C Minimal Residual Disease (MRD)

Time: At the end of Block C therapy (approximately 13 weeks after start of therapy)

Description: The toxicities of liposomal vincristine (VSLI) when used in combination with chemotherapy will be evaluated. Proportions (probabilities) of relevant toxicities will be estimated with point and interval estimates.

Measure: Proportion of Relevant Toxicities

Time: At the completion of therapy (up to approximately 5 months after the start of therapy)

6 A Phase Ib/IIa Single Centre, Double-blind, Double-dummy, Placebo-controlled, Parallel-group Dose Ranging Trial in Adult Participants With Uncomplicated Dengue Fever in Singapore

Dengue fever is an acute febrile illness transmitted by mosquitoes, which affects half the world's population. There are 96 million symptomatic infections, 500,0000 hospitalisations and 25,000 deaths per year attributed to the disease. The economic burden is $12 billion. In Singapore, as elsewhere, the incidence of the disease continues to increase despite aggressive control measures. At present there are no approved medicines for treating dengue fever. Only supportive fluid replacement therapy is used to treat vascular leakage in patients with severe illness. Therefore there is an urgent need to find alternative treatments. Experiments in the laboratory have shown that Celgosivir and modipafant inhibit dengue virus and improve mouse survival. Both drugs have previously been used in humans with good safety records, so investigators are taking this one step further to find out how well it works in dengue patients. Investigators plan to enroll dengue patients within 48 hours of fever onset and assign them to one of four treatment groups over five days. Together with the support from the industry partner, 60°Pharmaceuticals PLC, the investigators will determine the safety and effectiveness of these drugs on acute dengue patients and pave the way forward for dengue antiviral medicines to reach patients.

NCT02569827 Dengue Fever Drug: Celgosivir Drug: Modipafant 50mg Drug: Placebo Drug: Modipafant 100mg
MeSH:Dengue Fever
HPO:Fever

If a signal is detected, a sample size calculation will be undertaken for Part 2. The Sponsor will convene a Scientific Advisory Board (SAB) who will then review unblinded log10 serum viral load AUC for viraemia and platelet count data to recommend which dosing monotherapy dosing regimen to advance to Part 2. If the recommended sample size for Part 2 exceeds the maximum specified for Part 1 and 2 (a total combined sample size of N = 132 participants) for a monotherapy, the Sponsor will submit a major amendment for Institutional Review Board/ Health Science Authority (IRB/HSA) consideration prior to initiating Part 2. For Part 2, up to 60 otherwise healthy participants with uncomplicated dengue fever meeting the inclusion/exclusion criteria will be assigned in a randomised double-blind fashion to: - Cohort 5: (i) celgosivir monotherapy 150 mg Q6H, OR (ii) modipafant monotherapy (either 50 mg Q12H or 100 mg Q12H) - Cohort 6: Placebo extension for 5 days of treatment. --- Q12H ---

If a signal is detected, a sample size calculation will be undertaken for Part 2. The Sponsor will convene a Scientific Advisory Board (SAB) who will then review unblinded log10 serum viral load AUC for viraemia and platelet count data to recommend which dosing monotherapy dosing regimen to advance to Part 2. If the recommended sample size for Part 2 exceeds the maximum specified for Part 1 and 2 (a total combined sample size of N = 132 participants) for a monotherapy, the Sponsor will submit a major amendment for Institutional Review Board/ Health Science Authority (IRB/HSA) consideration prior to initiating Part 2. For Part 2, up to 60 otherwise healthy participants with uncomplicated dengue fever meeting the inclusion/exclusion criteria will be assigned in a randomised double-blind fashion to: - Cohort 5: (i) celgosivir monotherapy 150 mg Q6H, OR (ii) modipafant monotherapy (either 50 mg Q12H or 100 mg Q12H) - Cohort 6: Placebo extension for 5 days of treatment. --- Q12H --- --- Q12H ---

Primary Outcomes

Description: Area under the curve (AUC) for serum viral load from baseline to Study Day 5 of Celgosivir dosing

Measure: Viral load AUC for viremia

Time: Day 1 to Day 5

Description: Lowest platelet count recorded from baseline to Study Day 5 of Modipafant dosing

Measure: Platelet nadir

Time: Day 1 to Day 5

Secondary Outcomes

Description: The time from the start of treatment to the start of the first 24-hour period during which the tympanic or oral temperature remains below 37.5°C

Measure: Fever clearance time (days)

Time: Day 1 to 28

Description: A 24-hour reduction in duration of illness that is treatment related is deemed clinically relevant. Draft criteria to support this include: Absence of fever (< 37.4˚C) for at least 24 hours

Measure: Duration of illness

Time: Day 1 to 28

Description: Determined by comparison of the maximum haematocrit detected in the acute phase as compared to baseline

Measure: Maximum percentage haemoconcentration

Time: Day 1 to 28

Measure: Time to NS1 clearance

Time: Day 1 to 28

7 Comparison of Oral Thiazides vs Intravenous Thiazides vs Tolvaptan in Combination With Loop Diuretics for Diuretic Resistant Decompensated Heart Failure

Broad Objectives: To determine the comparative efficacy of commonly employed strategies to overcome loop diuretic resistance when added to concomitant loop diuretics in hospitalized decompensated heart failure patients with hypervolemia Specific Aims: 1. Compare the 48-hour weight change of either intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in decompensated heart failure 2. Compare the adverse effects of electrolyte depletion and renal function changes between intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure 3. Pharmacoeconomic analysis of the direct costs of intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure The investigators will conduct a dual center, randomized, double-blind, double-dummy, parallel design trial comparing: oral metolazone, intravenous chlorothiazide, or oral tolvaptan, in combination with loop diuretics in 60 patients hospitalized for hypervolemic decompensated heart failure and displaying loop diuretic resistance.

NCT02606253 Heart Failure Drug: tolvaptan Drug: Chlorothiazide Drug: Metolazone
MeSH:Heart Failure
HPO:Congestive heart failure Left ventricular dysfunction Right ventricular failure

Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H ---

Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H ---

Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H --- --- Q12H ---

Patients will be randomized to either intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H or intravenous placebo infusion Q12H + a capsule containing either oral metolazone 5mg PO Q12H or oral tolvaptan 30mg once daily and placebo capsule in the evening dose. --- Q12H --- --- Q12H --- --- Q12H --- --- Q12H ---

Primary Outcomes

Description: The primary outcome will be 48-hour standing scale weight change (kg) from enrollment among the metolazone, intravenous chlorothiazide, and tolvaptan arms, using metolazone group as the comparator group for all other groups.

Measure: Weight Change Over 48 Hours

Time: 48 hours

Secondary Outcomes

Description: Net urine output from enrollment to the end of study at 48 hours measured in liters

Measure: Net Urine Output

Time: 48 hours

Description: Mean change in serum creatinine (mg/dl) from enrollment to end of study at 48 hours

Measure: Mean Change in Serum Creatinine

Time: 48 hours

Description: Mean change in glomerular filtration rate from enrollment to end of study at hospital discharge, an average of 5 days

Measure: Mean Change in Glomerular Filtration Rate at Discharge

Time: hospital discharge an average of 5 days

Description: Mean change in serum potassium (mEq/L) from enrollment to end of study at 48 hours

Measure: Mean Change in Serum Potassium

Time: 48 hours

Description: Cumulative dose of potassium supplementation (mEq) administered from enrollment to end of study at 48 hours

Measure: Potassium Supplementation

Time: 48 hours

Description: Incidence of hypokalemia (serum potassium less than 3.5mEq/L ) from enrollment to end of study

Measure: Number of Patients With Hypokalemia

Time: 48 hours

Description: Provider escalation of loop diuretic dosage at 24 hours for urine output less than 3 L at 24 hours

Measure: Number of Patients With Escalation of Loop Diuretic Therapy

Time: 24 hours

Description: Incidence of new atrial or ventricular arrhythmias from enrollment to end of study at 48 hours

Measure: Number of Patients With Cardiac Arrhythmias

Time: 48 hours

Description: SBP < 85 mmHg plus medical intervention for symptomatic hypotension

Measure: Number of Patients With Symptomatic Hypotension

Time: 48 hours

Description: Change in estimated glomerular filtration rate (ml/min/m2) from baseline to 48 hours

Measure: Change in eGFR From Baseline to 48 Hours

Time: 48 hours

Description: Mean change in serum sodium (mEq/L) from enrollment to end of study at 48 hours

Measure: Mean Change in Serum Sodium

Time: 48 hours

Other Outcomes

Description: Incidence of death from study enrollment to hospital discharge, an average of 5 days

Measure: Number of Patients With In-hospital Mortality

Time: Enrollment to hospital discharge an average of 5 days

Description: Incidence of new initiation of dopamine, dobutamine, or milrinone from enrollment to end of study at 48 hours

Measure: Number of Patients With New Inotrope Utilization

Time: 48 hours

Description: Incidence of Renal replacement therapy utilization (hemodialysis, ultrafiltration) from enrollment to hospital discharge, an average of 5 days

Measure: Number of Patients With Renal Replacement Therapy Utilization

Time: enrollment to hospital discharge an average of 5 days

Description: Diuretic Efficiency is calculated as 48hr urine output/ 48hr Furosemide equivalents in milligrams

Measure: Diuretic Efficiency

Time: 48 hours

Description: Change in serum chloride (mEq/L) from baseline to 48 hrs

Measure: Change in Serum Chloride From Baseline

Time: 48 hours

Description: Participants will score their congestion on a 10cm scale ranging from "Best" (10cm) to "Worst" (0cm). Change in score (units in centimeters) from baseline to 48 hours.

Measure: Change in Patient Congestion Score

Time: 48 hours

8 A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of N91115 in Healthy Subjects

The present study is designed to assess the safety and tolerability of escalating, multiple ascending doses of Cavosonstat (N91115) in healthy subjects.

NCT02934139 Cystic Fibrosis Drug: Cavosonstat Other: Placebo
MeSH:Cystic Fibrosis

Eligible subjects will be randomized in a 3:1 ratio to receive investigational medicinal product (IMP) N91115 (daily [QD] or every 12 hours [Q12H]) or matching placebo (QD or Q12H) for 7 days and will be followed for safety while housed in the clinical research unit (CRU) until discharge on Day 8. Pharmacokinetics will be followed from Study Day 1 through the morning of Study Day 8. --- Q12H ---

Eligible subjects will be randomized in a 3:1 ratio to receive investigational medicinal product (IMP) N91115 (daily [QD] or every 12 hours [Q12H]) or matching placebo (QD or Q12H) for 7 days and will be followed for safety while housed in the clinical research unit (CRU) until discharge on Day 8. Pharmacokinetics will be followed from Study Day 1 through the morning of Study Day 8. --- Q12H --- --- Q12H ---

Primary Outcomes

Description: Safety assessments based on clinical evaluations, laboratory assessments, and adverse events

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: 14 days

Secondary Outcomes

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in urine.

Measure: Pharmacokinetic parameters of N91115 and metabolites (Amount of analyte excreted in the urine [Ae])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in urine.

Measure: Pharmacokinetic parameters of N91115 and metabolites (% analyte excreted in the urine [Fe])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (area under the curve [AUC])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (maximum concentration [Cmax])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in urine and plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (clearance [CL])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (accumulation index [Racc])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (Terminal elimination half-life [t1/2])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (time of maximum concentration [Tmax])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (metabolite to parent exposure ratio [M/P ratio])

Time: 7 days

Description: Pharmacokinetic parameter of N91115 and metabolites will be measured in plasma.

Measure: Pharmacokinetic parameters of N91115 and metabolites (terminal elimination rate constant [lambda z])

Time: 7 days

9 An Interventional, Open Label, and Randomized Controlled Study to Compare the Titration Efficacy and Safety of Control-released Oxycodone and Immediate-released Oxycodone in Opioid-naive Patients With Moderate to Severe Cancer Pain

This study is to evaluate the efficacy and safety of a titration method by selects 10 mg control-released (CR) oxycodone tablet as background drug in combined with immediate-released (IR) oxycodone, compared to conventional titration method with immediate-released (IR) oxycodone in patients with moderate to severe cancer pain in Taiwan.

NCT03176199 Cancer Pain Drug: Oxycodone Drug: Oxycodone
MeSH:Cancer Pain

Meanwhile, the titration with IR oxycodone will be added according to the pain intensity, e.g. if patient receiving 6 tablets of 10 mg CR oxycodone (giving in Q12H frequency for 3 days), 12 capsules of 5mg IR oxycodone will be dispensed for managing acute pain (rescue use) for the first cycle. --- Q12H ---

Primary Outcomes

Description: The change from baseline of NRS pain score and the daily number of breakthrough pain

Measure: To evaluate the variable change of NRS pain score and the number of breakthrough pain to obtain pain control after treatment

Time: Up to 14 days

Secondary Outcomes

Description: The percentage of patients in each titration cycle

Measure: To evaluate the percentage of patients in each titration cycle

Time: Up to 14 days

Description: The number of patients who switched/discontinued therapy due to serious adverse events or lack of pain control

Measure: To evaluate the number of patients who switched/discontinued therapy due to serious adverse events or lack of pain control

Time: Up to 14 days

Description: The total opioid taken within 24 hrs daily from baseline to day 14

Measure: The total opioid taken within 24hrs daily from baseline to day 14

Time: Up to 14 days

Description: Mean daily NRS score of patients from baseline to day 14

Measure: To evaluate the mean daily NRS score of subjects from baseline to day 14

Time: Up to 14 days

Description: The total daily rescue dose taken (immediate-released oxycodone capsule) for treatment of breakthrough pain among patients from baseline to day 14

Measure: To evaluate the total daily rescue dose taken (immediate-released oxycodone capsule) for treatment of breakthrough pain among patients from baseline to day 14

Time: Up to 14 days

Description: The occurrence rate of adverse events and physical examination status

Measure: To evaluate the tolerability and safety of Oxycodone CR and IR in cancer pain patient

Time: Up to 28 days

Description: The change from baseline in questionnaire

Measure: To evaluate the change from baseline in questionnaire

Time: Up to 14 days

10 Non-Steroidal Anti-inflammatory Drugs in Axial Spondyloarthritis: a Pilot Study

This is a 6-week randomized, double-blind trial of 4 different non-steroidal anti-inflammatory drugs in patients with axial spondyloarthritis to compare the change of pain score from baseline at 4 weeks to the change of pain score from baseline at 6 weeks.

NCT03473665 Ankylosing Spondylitis Axial Spondyloarthritis Drug: Indomethacin Drug: Diclofenac Drug: Meloxicam Drug: Celecoxib
MeSH:Spondylitis Spondylitis, Ankylosing Spondylarthritis

Ankylosing Spondylitis Axial Spondyloarthritis Spondylitis Spondylitis, Ankylosing Spondylarthritis Patients with ankylosing spondylitis or axial spondyloarthritis who fulfills the inclusion and exclusion criteria will be randomized into one of the four arms after an initial one week washout period, including: 1) indomethacin 75mg Q12H; 2) diclofenac 75mg Q12H; 3) meloxicam 7.5mg Q12H; 4) celecoxib 200mg Q12H. --- Q12H ---

Ankylosing Spondylitis Axial Spondyloarthritis Spondylitis Spondylitis, Ankylosing Spondylarthritis Patients with ankylosing spondylitis or axial spondyloarthritis who fulfills the inclusion and exclusion criteria will be randomized into one of the four arms after an initial one week washout period, including: 1) indomethacin 75mg Q12H; 2) diclofenac 75mg Q12H; 3) meloxicam 7.5mg Q12H; 4) celecoxib 200mg Q12H. --- Q12H --- --- Q12H ---

Ankylosing Spondylitis Axial Spondyloarthritis Spondylitis Spondylitis, Ankylosing Spondylarthritis Patients with ankylosing spondylitis or axial spondyloarthritis who fulfills the inclusion and exclusion criteria will be randomized into one of the four arms after an initial one week washout period, including: 1) indomethacin 75mg Q12H; 2) diclofenac 75mg Q12H; 3) meloxicam 7.5mg Q12H; 4) celecoxib 200mg Q12H. --- Q12H --- --- Q12H --- --- Q12H ---

Ankylosing Spondylitis Axial Spondyloarthritis Spondylitis Spondylitis, Ankylosing Spondylarthritis Patients with ankylosing spondylitis or axial spondyloarthritis who fulfills the inclusion and exclusion criteria will be randomized into one of the four arms after an initial one week washout period, including: 1) indomethacin 75mg Q12H; 2) diclofenac 75mg Q12H; 3) meloxicam 7.5mg Q12H; 4) celecoxib 200mg Q12H. --- Q12H --- --- Q12H --- --- Q12H --- --- Q12H ---

Primary Outcomes

Description: Change of pain score by numerical rating score from baseline [scale range: 0 (better) -10 (worse)]

Measure: Change of pain score

Time: Week 4 and Week 6

Secondary Outcomes

Description: Change of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) from baseline [scale range: 0 (better) -10 (worse)]

Measure: Change of BASDAI

Time: Week 4 and Week 6

Description: Change of Bath Ankylosing Spondylitis Functional Index (BASFI) from baseline [scale range: 0 (better) -10 (worse)]

Measure: change of BASFI

Time: Week 4 and Week 6

Description: Change of Ankylosing Spondylitis Disease Activity Score (ASDAS) from baseline [composite score: 0 (no disease activity) - 6.5 (very high disease activity)]

Measure: Change of ASDAS

Time: Week 4 and Week 6

Description: Patient's global assessment of effectiveness of a treatment

Measure: Patient Global Assessment of Response to Therapy (PGART)

Time: Week 6

11 An Open-Label, Randomized, Two-Period, Crossover Study to Evaluate the Effect of Oral Doses of SCY-078 (Ibrexafungerp) on the Pharmacokinetics of Dabigatran Administered Orally to Healthy Subjects

This is a Phase 1 open-label, randomized, two-period, crossover study to evaluate the effect of repeated oral doses of SCY-078 (Ibrexafungerp) on the pharmacokinetics of dabigatran administered orally to healthy subjects.

NCT04092725 Pharmacokinetics Drug: DAB Drug: SCY-078 plus DAB

Treatment B: Twice daily (BID), every 12 hours (Q12H) oral doses of SCY-078 750mg on Day and Day 2; and single oral AM doses of SCY-078 750mg on Day 3 and Day. --- Q12H ---

Primary Outcomes

Description: AUC0-48 of DAB when taken with SCY-078

Measure: Pharmacokinetics of DAB administered with SCY-078, AUC

Time: 17 days

Secondary Outcomes

Description: Cmax DAB when taken with SCY-078.

Measure: Pharmacokinetics of DAB administered with SCY-078, Cmax

Time: 17 days

Description: Tmax of DAB when taken with SCY-078.

Measure: Pharmacokinetics of DAB administered with SCY-078, Tmax

Time: 17 days

Description: Half Life of DAB when taken with SCY-078.

Measure: Pharmacokinetics of DAB administered with SCY-078, Half Life

Time: 17 Days

Description: Incidence of treatment-related adverse events (AE) and discontinuations due to (AEs)

Measure: Safety and tolerability of oral dosing of combination of DAB with SCY-078

Time: 7 weeks

12 Phase 2 Clinical Trial for Comprehensive Treatment Program for Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): SL-401 in Combination With HCVAD and VENETOCLAX

This phase II trial studies how well venetoclax, SL-401, and chemotherapy works in treating patients with blastic plasmacytoid dendritic cell neoplasm. Venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. SL-401 is a recombinant protein consisting of IL-3 linked to a toxic agent called DT. IL-3 attaches to IL-3 receptors on tumor cells in a targeted way and delivers DT to kill them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax and SL-401 with chemotherapy may be an effective treatment for patients with blastic plasmacytoid dendritic cell neoplasm.

NCT04216524 Blastic Plasmacytoid Dendritic Cell Neoplasm Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Drug: Mercaptopurine Drug: Methotrexate Drug: Methylprednisolone Drug: Prednisone Biological: Rituximab Biological: Tagraxofusp-erzs Drug: Venetoclax Drug: Vincristine
MeSH:Neoplasms
HPO:Neoplasm

HYPER-CVAD (AGE < 60): Patients receive cyclophosphamide IV over 3 hours every 12 hours (Q12H) on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and doxorubicin IV over 24 hours on day 4. MINI-HYPER-CVD (AGE >= 60): Patients receive cyclophosphamide IV over 3 hour Q12H on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone PO or IV over 30 minutes on days 1-4 and 11-14. --- Q12H ---

HYPER-CVAD (AGE < 60): Patients receive cyclophosphamide IV over 3 hours every 12 hours (Q12H) on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and doxorubicin IV over 24 hours on day 4. MINI-HYPER-CVD (AGE >= 60): Patients receive cyclophosphamide IV over 3 hour Q12H on days 1-3, vincristine IV over 15 minutes on days 1 and 8, dexamethasone PO or IV over 30 minutes on days 1-4 and 11-14. --- Q12H --- --- Q12H ---

Patients may receive rituximab IV over 4-6 hours on days 1 and 8, cytarabine IT on day 5, and/or methotrexate IT on day 8. MTX/ARAC (AGE < 60): Patients receive methotrexate IV over 24 hours on day 1, and cytarabine IV over 3 hours Q12H on days 2 and 3. MINI-MTX/ARAC (AGE >= 60): Patients receive methotrexate IV over 24 hours on day 1, methylprednisolone IV over 2 hours Q12H on days 1-3, and cytarabine IV over 3 hours Q12H on days 2 and 3. ALL CYCLES: Treatment repeats every 28 days for 8 cycles in the absence of disease progression and unacceptable toxicity. --- Q12H ---

Patients may receive rituximab IV over 4-6 hours on days 1 and 8, cytarabine IT on day 5, and/or methotrexate IT on day 8. MTX/ARAC (AGE < 60): Patients receive methotrexate IV over 24 hours on day 1, and cytarabine IV over 3 hours Q12H on days 2 and 3. MINI-MTX/ARAC (AGE >= 60): Patients receive methotrexate IV over 24 hours on day 1, methylprednisolone IV over 2 hours Q12H on days 1-3, and cytarabine IV over 3 hours Q12H on days 2 and 3. ALL CYCLES: Treatment repeats every 28 days for 8 cycles in the absence of disease progression and unacceptable toxicity. --- Q12H --- --- Q12H ---

Patients may receive rituximab IV over 4-6 hours on days 1 and 8, cytarabine IT on day 5, and/or methotrexate IT on day 8. MTX/ARAC (AGE < 60): Patients receive methotrexate IV over 24 hours on day 1, and cytarabine IV over 3 hours Q12H on days 2 and 3. MINI-MTX/ARAC (AGE >= 60): Patients receive methotrexate IV over 24 hours on day 1, methylprednisolone IV over 2 hours Q12H on days 1-3, and cytarabine IV over 3 hours Q12H on days 2 and 3. ALL CYCLES: Treatment repeats every 28 days for 8 cycles in the absence of disease progression and unacceptable toxicity. --- Q12H --- --- Q12H --- --- Q12H ---

Primary Outcomes

Description: The median PFS time will be estimated by Bayesian posterior estimates. Estimated using the Kaplan-Meier method.

Measure: Progression free survival (PFS)

Time: Up to 6 years

Description: Will be reported by type, frequency and severity. Highest toxicity grades per patient per course will be tabulated for selected adverse events and laboratory measurements.

Measure: Incidence of adverse events

Time: Up to 6 years

Description: Overall response rate along with complete remission and complete remission with incomplete hematologic recovery will be estimated along with 95% confidence interval.

Measure: Overall response rate

Time: Up to 6 years

Description: The response rate will be compared between subgroups (e.g. minimal residual disease negativity, etc.) by Fisher's exact test, and Wilcoxon rank test will be used to compare the patient clinical information (e.g., protein expression) between subgroups such as response and non-response.

Measure: Rate of stem cell transplant

Time: Up to 6 years

13 A Phase 3 Randomized Trial for Patients With De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin (GO) to CPX-351 With GO, and the Addition of the FLT3 Inhibitor Gilteritinib for Patients With FLT3 Mutations

This phase III trial compares standard chemotherapy to therapy with CPX-351 and/or gilteritinib for patients with newly diagnosed acute myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as daunorubicin, cytarabine, and gemtuzumab ozogamicin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. CPX-351 is made up of daunorubicin and cytarabine and is made in a way that makes the drugs stay in the bone marrow longer and could be less likely to cause heart problems than traditional anthracycline drugs, a common class of chemotherapy drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene called FLT3. Genes are pieces of DNA (molecules that carry instructions for development, functioning, growth and reproduction) inside each cell that tell the cell what to do and when to grow and divide. FLT3 plays an important role in the normal making of blood cells. This gene can have permanent changes that cause it to function abnormally by making cancer cells grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with standard chemotherapy may work better in treating patients with acute myeloid leukemia compared to standard chemotherapy alone.

NCT04293562 Acute Myeloid Leukemia Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Asparaginase Drug: Asparaginase Erwinia chrysanthemi Behavioral: Cogstate Assessment Battery Drug: Cytarabine Drug: Daunorubicin Hydrochloride Drug: Dexrazoxane Hydrochloride Drug: Etoposide Drug: Gemtuzumab Ozogamicin Drug: Gilteritinib Fumarate Drug: Liposome-encapsulated Daunorubicin-Cytarabine Drug: Methotrexate Drug: Mitoxantrone Hydrochloride Drug: Therapeutic Hydrocortisone

TREATMENT FOR PATIENTS WITHOUT FLT3 MUTATIONS: ARM A LOW RISK GROUP 1: INDUCTION 1: Patients receive cytarabine intravenously (IV) over 1-30 minutes every 12 hours (Q12H) on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H ---

Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. --- Q12H ---

Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. --- Q12H --- --- Q12H ---

INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi intramuscularly (IM) or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM B LOW RISK GROUP 1: INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H ---

Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. --- Q12H ---

INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM A LOW RISK GROUP 2: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H ---

INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM A LOW RISK GROUP 2: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H --- --- Q12H ---

INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15 minutes on days 3-6. --- Q12H ---

INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM B LOW RISK GROUP 2: INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H ---

INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM A HIGH RISK GROUP: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H ---

INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9. ARM A HIGH RISK GROUP: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. --- Q12H --- --- Q12H ---

TREATMENT FOR PATIENTS WITH FLT3/ITD MUTATIONS (ITD AR > 0.1): ARM AC LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally (PO) once daily (QD) on days 11-31. --- Q12H ---

Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO QD on days 11-38. --- Q12H ---

INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-33. --- Q12H ---

INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15 minutes on days 3-6, and gilteritinib PO QD on days 7-34. --- Q12H ---

INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours and asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib PO QD on days 10-37. --- Q12H ---

ARM AC HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally (PO) once daily (QD) on days 11-31. --- Q12H ---

TREATMENT FOR NON-ITD FLT3 ACTIVATING MUTATIONS: ARM AD LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally (PO) once daily (QD) on days 11-31. --- Q12H ---

ARM AD HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally (PO) once daily (QD) on days 11-31. --- Q12H ---

Primary Outcomes

Description: The Kaplan-Meier method will be used to estimate 3-year EFS, defined as the time from study entry until induction failure, relapse, secondary malignancy, or death.

Measure: Event-free survival (EFS)

Time: Up to 3 years

Secondary Outcomes

Description: The Kaplan-Meier method will be used to estimate 3-year OS, defined as the time from study entry until death.

Measure: Overall survival (OS)

Time: Up to 3 years

Description: The proportion of patients MRD+ at end of induction 1 (EOI1) will be estimated as the number of patients MRD+ divided by the number of patients with evaluable EOI1 MRD results along with a corresponding 95% confidence interval determined using a binomial exact method.

Measure: Proportion of patients positive for minimal residual disease (MRD+)

Time: Up to 4 weeks

Description: The proportion of patients who died during protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method.

Measure: Proportion of patients who died during protocol therapy

Time: Up to 2 years

Description: Cumulative incidence estimates will be used to determine the 3 year relapse rate defined as time from study entry to induction failure or relapse where deaths or secondary malignancies are competing events.

Measure: Relapse rate

Time: Up to 3 years

Description: Cumulative incidence estimates will be used to determine the 3 year TRM defined as time from study entry to death where induction failure, relapse or secondary malignancies are competing events.

Measure: Treatment-related mortality rate (TRM)

Time: Up to 3 years

Description: The proportion of patients experiencing at least one grade 3 or higher non-hematologic toxicity and infection while on protocol therapy will be estimated along with the corresponding 95% confidence interval determined using a binomial exact method. Toxicity will be assessed by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

Measure: Incidence of adverse events

Time: Up to 2 years

Other Outcomes

Description: Median and range of the length of course duration will be determined.

Measure: Course duration

Time: Up to 2 years

Description: Median and range of the length of hospitalization time during protocol therapy will be determined.

Measure: Length of hospitalization

Time: Up to 2 years

Description: Cumulative incidence estimates that account for competing events will be used to estimate time to count recovery in days where deaths are competing events.

Measure: Time to count recovery

Time: Up to 2 years

14 Piclidenoson for Treatment of COVID-19 - A Randomized Open Label Pilot Trial

Patients with documented COVID-19 infection will be randomized 1:1 to receive Piclidenoson 2 mg Q12H orally with standard care (intervention arm) or standard care alone (control arm).

NCT04333472 COVID-19 Coronavirus Infection Drug: Piclidenoson
MeSH:Coronavirus Infections Severe Acute Respiratory Syndrome

Piclidenoson for Treatment of COVID-19 Patients with documented COVID-19 infection will be randomized 1:1 to receive Piclidenoson 2 mg Q12H orally with standard care (intervention arm) or standard care alone (control arm). --- Q12H ---

COVID-19 Coronavirus Infection Coronavirus Infections Severe Acute Respiratory Syndrome Upon admission to the hospital, patients with documented COVID-19 infection will be randomized 1:1 to receive Piclidenoson 2 mg Q12H orally with standard care (intervention arm) or standard care alone (control arm). --- Q12H ---

Primary Outcomes

Description: The duration of viral shedding in days since initial diagnosis, as determined by RT-PCR to COVID-19

Measure: Duration of viral shedding in days

Time: 28 days

Description: TTCR is defined as the time (in hours) from initiation of trial treatment until normalization of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours

Measure: Time to clinical recovery (TTCR) in days

Time: 28 days

Description: Proportion of patients experiencing AEs

Measure: Treatment-emergent adverse events (AEs)

Time: 28 days

Secondary Outcomes

Description: Proportion of patients requiring non-invasive or mechanical ventilation

Measure: Requirement for non-invasive or mechanical ventilation

Time: 28 days

Description: Duration of hospital stay

Measure: Length of hospital stay in days

Time: 28 days

Description: Ratio of arterial oxygen partial pressure to fractional inspired oxygen

Measure: Estimated PaO2/FiO2 ratio on day of discharge

Time: 28 days

Description: Proportion of patients who die

Measure: All-cause mortality

Time: 28 days

Description: Proportion of patients reaching undetectable COVID-19 virus levels in respiratory secretions at selected timepoints

Measure: Patients reaching undetectable COVID-19 virus levels in respiratory secretions

Time: 28 days

Description: Duration of symptoms and signs of respiratory infection associated with COVID-19

Measure: Duration of symptoms and signs of respiratory infection in days

Time: 28 days

Description: Proportion of patients who need for supportive respiratory management

Measure: Need for supportive respiratory management

Time: 28 days

Description: COVID-19 viral load in respiratory secretions using a semi-quantitative method

Measure: Viral load

Time: 28 days

Description: Proportion of patients experiencing AEs

Measure: Treatment-emergent serious AEs (SAEs)

Time: 28 days

Description: Rate of AEs leading to early discontinuation of trial treatment

Measure: AEs leading to withdrawal

Time: 28 days

Description: Proportion of patients experiencing treatment-emergent changes in clinical laboratory

Measure: Treatment-emergent abnormalities in clinical laboratory parameters

Time: 28 days


HPO Nodes


HP:0001635: Congestive heart failure
Genes 260
TRNF TF JUP TPM1 EPG5 EPAS1 DNAJC19 PHYH LMNA ND5 TCF4 ATXN7 TRNS2 VCL EYA4 TAZ NDUFAF1 ABCC6 BSCL2 NDUFAF3 MYH7 TTN SCN5A VPS33A SLC25A3 TRNL1 AGPAT2 TNNI3 COX3 MYH7 LIMK1 PRKAG2 SCO2 TBL2 MYSM1 ENG TRNS1 TNNI3K DMD KIF1B DES COG7 GBA JUP BAG3 MST1 TRNF TRNL1 PSMB8 SLC2A10 TMEM43 VHL HADHA SCN1B CDH23 MYH7 PPA2 MDH2 PTEN MYLK2 SGCD CLIC2 LDB3 IKBKG CLIC2 ACAD9 PRKAR1A TMEM70 TRNW HBA1 ND1 DES CYTB SDHB NSMCE2 HBB CAV3 TPI1 HFE COX2 CASR PEX7 AFF4 MECP2 CEP19 SURF1 EFEMP2 TRIP4 SF3B1 SDHC CLIP2 TNNT2 HNRNPA2B1 NDUFB11 FOS ADCY5 EYA4 CP TMEM127 ATP5F1A CACNA1S ELAC2 ND1 TRNQ ACTC1 SLC25A26 HAMP DLST NDUFB8 ADCY5 SMAD4 TRPM4 STAT1 TMEM127 DSP CAV1 SDHD HADHA TRNK FBLN5 TRNS1 FGD1 ALMS1 COX2 ENPP1 HNRNPA1 TUBB RAB3GAP2 TRNK MYL3 FLNA HLA-DRB1 RASA1 ADAMTSL2 GLA RET VHL SELENON SDHB PRKAR1A SLC25A11 CYTB TRNV LMNA LMNA SDHAF2 ACVRL1 GLA GNPTAB PSEN1 BMP2 TRNL1 GDF2 ALMS1 FBN1 DSP HADHB STRADA PNPLA2 SNAP29 PSMB8 GTF2I SDHD TRNW COX3 GJA1 MYH6 BCHE LMNA MYD88 NDUFS2 TRNH ATP6V1A COX1 FH DTNA HBA2 GATAD1 PSEN2 FGFR3 HFE LMNA GLB1 RPS19 FXN GPR35 AGGF1 ND5 SDHD ND4 KCNJ5 TRNQ TRNS2 CAV1 HADHB TRIM37 ELN TET2 KIF1B RBM20 COL1A2 LMNA COX1 RYR1 CAVIN1 CCR6 SCN4A PPARG FLNC BAZ1B CCN2 MYH7 HJV MAX LMNA VHL IRF5 ABCC6 SLC22A5 RET MYPN MYH7 PPARG WRN PLN COL1A1 TRNE MAPRE2 GTPBP3 ACAD9 VCP SLC17A5 SDHB RFC2 GTPBP3 SLC19A2 PLOD1 RET SDHA TTN ND6 DSP LMNA MAX IDS FGF23 ND6 GDNF PRDM16 IFIH1 NKX2-5 XYLT1 XYLT2 ENG GTF2IRD1 GNPTAB TRNC TRNK PRKAR1A GNA11
SNP 0
HP:0001945: Fever
Genes 344
TRNF MEFV SCNN1B TNFAIP3 LPIN2 IL2RG CD247 WT1 TH TLR3 SCNN1A IL2RG NLRP3 TET2 ERCC4 SPINK1 HLA-DRB1 MLX LIPA NGLY1 TCF4 PTS ATP1A3 LPIN2 HAVCR2 KLRC4 DCLRE1C NPM1 NOTCH3 KIF1B H19 NOD2 SPINK1 IL12A CTRC TRNL1 LPIN1 RYR1 LRRC8A PRKAR1A BCL10 CRLF1 GAA NKX2-1 NLRP3 CHD7 FIP1L1 ND4 SLC29A3 PTPN3 LACC1 KRT8 CASK IRAK1 SCYL1 RNASEH2B SPTB MST1 PML MALT1 AQP2 TBL1XR1 IL12A-AS1 ERAP1 SH3KBP1 CD79B LBR SRP54 SLC12A1 IL7R TP53 SPTA1 SLCO1B1 EIF2B4 TRNK FOXP1 IL7R SLC19A3 TRIM28 UNC93B1 ND1 NLRP3 SCNN1G ELP1 RYR1 RANBP2 IFIH1 NAB2 NGF JAK2 WT1 COX2 NCF2 MVK CTRC BCL2 STAT6 ANK1 KRT18 IRF8 ELANE COG6 CYP11B2 CD79A NOD2 CFH RNASEH2A QDPR ADAMTS13 BCR CACNA1A ERCC3 IGH BLNK PSMB9 ND3 HMGCL RMRP TCF3 EIF2B2 SLC29A3 BRCA2 GYPC IGH CACNA1S HLA-B TRNQ CACNA1S HLA-DPB1 SPTB ERCC2 ADAR ADA NCF4 CPT2 TMEM165 MEFV POMP C4A ABL1 STX11 CD27 UBAC2 GALC CALR PTPN22 IRF8 ZFHX2 NTRK1 NLRP3 HLA-DRB1 TSC2 TRNS1 NCF1 TRIP13 TP53 IL23R F5 STAT3 STAT3 RAG2 NLRC4 PRSS1 IBA57 CHEK2 TSC1 ELANE ADA2 BTK EPB41 C1R GFI1 BCAP31 TRNL1 COL1A1 FBP1 POU6F2 TET2 SLC4A1 PRNP PIK3R1 GLA LIFR SLC12A3 CFTR EIF2B3 PRKAR1A AVPR2 DDB2 CYTB TLR4 BIRC3 PEX6 HAVCR2 IRF2BP2 HLA-DPA1 ACAT1 ND1 SPTA1 STAT4 TRAF3 DIS3L2 IL10 EIF2B5 GCH1 ATM TNFRSF1A IGH RB1 RAG1 ND6 XIAP HBB EIF2B1 BCOR ND2 MPL KCNJ1 ND5 TRIM28 STAT4 PSMB8 HLA-B WAS EPB42 NLRP12 AK2 TRNW COX3 HTR1A POLR3A LIFR HMGCL P4HTM TNFRSF1A RNASEH2C STIM1 MYD88 BTNL2 SH2B3 TRNH COX1 CYBA PSMB4 IKZF1 KLHL7 GATA2 JAK2 NLRP1 REST CFHR1 ZBTB16 CALR NLRC4 NUMA1 LIG4 GPR35 AVPR2 ND5 ATP6 RAG1 ND4 SLC11A1 BCL6 TREX1 XPA TRNS2 IL36RN PTPN22 ALPL STAT5B C1QA LYST SAMHD1 ERCC5 RAB27A RAG2 CFHR3 PMM2 AVP XPC NLRP3 NLRP3 CYBB JAK2 TCIRG1 CYP11B2 RYR1 MPL ATP1A2 MEFV IL12B FAS CCR1 MYD88 PSTPIP1 RUNX1 CD3E ABCC2 HLA-DRB1 ORAI1 SPP1 TBK1 TRNV AQP2 COL1A1 CYP21A2 PMP22 TICAM1 HLA-DRB1 EDA STING1 RNF168 GPC3 NABP1 ATP13A2 TREX1 DST PRSS2 UNC13D IFNGR1 CD3D WIPF1 NLRP3 CFTR IGHM CYBC1 STXBP2 ND6 CTLA4 PRTN3 RARA IGLL1 MEFV IL6 NLRC4 CCND1 HLA-B NLRC4 PRSS1 SLCO1B3 G6PD MIF TRNW
SNP 0
HP:0002664: Neoplasm
Genes 1489
WHCR ATP7A PHOX2B KRT17 IL2RG HMGA2 PORCN KRAS TET2 IDH2 FLT3 ERCC4 AR BRCA1 BRCA2 GATA1 TCF4 TCTN3 GPR101 SMAD7 KRT6B PIK3CA KCNJ10 MAP2K2 REST TTC37 MC2R TRPS1 SIX6 ALX4 PIK3CA BRAF TP53 STK11 TSR2 EXT2 EDN1 RNF43 TRNL1 ATM SDHC EXT1 BCL10 BAP1 NF1 OCRL TP53 CHD7 TINF2 ERCC6 NF1 MAFA PMS2 ASXL1 PHOX2B CTNNB1 CR2 RET TCTN3 C11ORF95 PTPN3 PIEZO2 ABCB11 SETBP1 PDCD10 LRP5 LMOD1 MALT1 ASXL1 LZTR1 TINF2 RAD51C RECQL4 MAP2K1 FOXO1 PTCH2 RPS20 FLI1 BMPR1A SMARCAD1 BMPR1A MAP3K8 DNASE1L3 SUFU TP53 FOXP1 PTCH1 PDGFRB ND1 PIK3CA ZSWIM6 SETD2 INS NRAS HBB MEN1 AIP CLCNKB RPS10 HFE COX2 TSC2 DHH CTRC MEN1 EYA1 BRCA1 GINS1 MSH3 GLI2 TRNS1 HABP2 SSX1 SUFU PRKN CD81 TNFSF12 MYH11 KIT VEGFC WWOX H19 SDHD FGF3 TNFRSF1B RMRP XRCC2 HRAS MTM1 EPHB2 PLCD1 NBN CDKN1B TUBB RECQL4 EDNRB VHL ACAN MSH6 CDKN2B DCC TJP2 HRAS CDKN2A VHL REST NKX2-1 ANTXR1 RPL35 DNM2 FGFR3 SNAI2 NLRP1 ACTG2 GNB1 EWSR1 CBFB NSD1 FLCN ERBB2 MLH1 H19 EIF2AK4 RPL10 TMEM107 TRNK RAD54L RAD51C INPP5E NFKB1 CDKN1A KDM6B F13B SLC26A2 TRNS1 RPL26 CYLD H19 PTEN PTPN11 DCLRE1C MPL FLCN NEK1 MITF MSH3 NUTM1 IL7 STAT3 TRNS2 TG ERCC3 MNX1 NRAS MLH3 TSC1 GLI3 CDK4 SDHC NF1 BRCA2 CIB1 ATRX BRCA2 ADAMTS3 ZFPM2 COL2A1 TET2 ZIC2 SLCO2A1 BLM GJA1 MAP3K1 PIK3CA SDHA RTEL1 CDK4 KCNH1 SH2B3 APC ESCO2 FANCC TERT USP9X APC RAD54B NF2 SDHB RPS14 PPP2R1B RPS19 RPL35A MSH2 WRAP53 RASA1 LMNA ACVRL1 POLH SDHB DIS3L2 PIGA GNPTAB CXCR4 MSH2 SLC25A13 BMP2 NNT PSENEN FOXI1 APC IL1RN MITF ACD PTEN MPL RUNX1 ERCC3 ERCC4 DLEC1 CHEK2 BRCA2 JAK2 SBDS BRCA1 SDHD SEMA3D MSH6 HFE TREM2 APC CCDC22 MINPP1 DISP1 FAM20C MAP2K1 ALK BRCA1 STIM1 SLC25A13 RFWD3 HRAS GLI1 TET2 DVL3 COL7A1 HMBS TFAP2A ICOS CALR PTEN UROD DKC1 FDPS LIG4 TXNRD2 SRSF2 ND5 SDHD CHEK2 NRAS BCL6 GPC3 XPC MEN1 ERCC2 AXIN2 MYC RAD51 GBA KIF1B SDHB EXT2 EXT2 NTHL1 SRY RPGRIP1L MPL MTOR CASP8 RB1CC1 IGF2 FANCC ERCC4 WRN PGM3 VHL ING1 PLAG1 WT1 MYLK KLLN PIK3CA G6PC RPS7 MCM4 ANTXR1 POLH BRCA2 DLL1 OGG1 WRN F13A1 SBDS EFL1 TAF15 GLI3 GPC3 KRAS CDKN2B MAPK1 DIS3L2 GPR101 NRTN DKC1 KLLN NSUN2 MAP3K1 ERBB2 PHKG2 SRGAP1 CYLD NBN ALK MAX WT1 ACTB PALB2 TBX18 FIBP CASP10 DVL1 TYR MSH2 RECQL4 PIGL EDN3 WT1 ATP7B RPL27 RET USP8 FGFR2 PDGFRL H19 CCND1 ATM AXIN2 COL7A1 AKT1 TERT MUTYH HOXD13 DICER1 THPO GDF5 CEL SDHB EXT2 SRP72 TERT TRNF TP53 LIN28B APC NPM1 FGFR3 PTEN SMPD1 SLC22A18 SDHC PRDM16 KIT STK11 RPL11 LETM1 CALR SDHC RB1 PIK3CA PLCB4 COL4A5 CASP8 SKI H19 COL1A1 CC2D2A CASP10 GCGR GLI3 PIK3CA RPS29 RSPO1 PTEN MYSM1 BAP1 SRY UBE2T BRCA1 USP8 COL7A1 RNASEH2B KIF1B MN1 RELA SMAD4 VHL SH3KBP1 BCR CD79B SRP54 SRP54 SSX2 CHRNG RPL18 NF1 WWOX RERE LZTS1 WT1 MSH3 TYROBP ASCL1 IKBKG ABCC6 FAH KIT GDNF FANCE TERT BIN1 FANCL KIF11 SDHB WDPCP SLC6A17 TP53 HNF1A KEAP1 POLE HSPA9 SMO PTCH2 PTCH1 PMS1 ELMO2 BCL2 NSD2 EXT1 SRD5A3 STAT6 MVD TERC SF3B1 MNX1 FGFR1 CYSLTR2 POU2AF1 SMARCB1 NOD2 GJB2 SDHC FLT4 KRT9 CDH1 IRF1 SEC23B MYCN MGMT RPL10 RPL5 KIF7 TCF3 KRAS MUTYH TMEM127 KRAS IGH CTSC GNAS CD28 WWOX HNF1A BUB1B MC1R WNT10A CBL WT1 BRAF ADAR GAS1 GTF2E2 SMARCB1 RPS17 PARN TMEM127 BRIP1 SHH SRC GNAI3 STAR GDNF SLC22A18 FOXH1 SNAI2 GPC4 TNFRSF13C KARS1 TBC1D24 BMPR1A TET2 CD27 CASP8 DHCR7 KDSR HNF1A SH3GL1 PNP USB1 TSC2 TRIP13 TMEM67 EDN3 PMS1 PTPN11 GNA11 CREB1 ADA RAG2 PRSS1 KCNQ1 GPR101 PRF1 MTAP FANCA MSH6 TRNQ BRCA2 KRT1 RNASEL POU6F2 ACD SCN9A APC NSD2 INTU BRAF POU6F2 BRCA2 RB1 GTF2H5 PIK3CA FANCM TARS1 BRAF CASR RET VHL GPR143 TRNP GCM2 TMEM231 CPLANE1 RPS15A SOX9 GFI1B EPCAM MEN1 TERT KRAS SDHAF2 NF1 TRIP13 GATA2 SLC26A4 APC MPLKIP SAMD9L IL6 GNAS IGH AKT1 FANCD2 ESR1 SDHA APC MYF6 RASGRP1 SMAD4 MLLT10 LIG4 CPLANE1 BRCA2 MC1R MRE11 DLST SUFU LMO1 SDHB ABCA5 RMRP SDHC NUP214 AKT1 SMARCD2 DLC1 C1S TRNW THPO CHEK2 KIT SLC37A4 BCHE KCNJ11 ARID1B APC2 SAMD9 TMC6 SLX4 TNFRSF13B FGFR1 TRNH RAD21 KCNN3 DKC1 VANGL1 AXIN2 TCOF1 RPS19 SLC26A2 GPR35 CR2 TFAP2A KRAS FGFR3 PRKCD JAK2 EGFR AIP CTNNB1 KCNJ10 FANCI LYST TET2 SLC25A11 TP53 TCTN3 MUTYH ANTXR2 SEMA3C MMP1 AKT1 PDX1 JAK2 TCIRG1 PTCH1 MUC5B EXT1 DNMT3A BMPR1A SERPINA1 FAN1 CDC73 PTCH2 PIK3CA H19 FERMT1 GPC3 RET RET APC PALLD LPP BRD4 GNAS BMPR1B MAPRE2 DICER1 CTC1 TAL1 DICER1 STK11 HRAS GATA1 BCL10 KCNE3 XRCC4 HNF4A BDNF KLF11 SF3B1 MLH3 GNAQ TRPV3 IGLL1 PAX7 CRKL GDNF GATA2 ARL6IP6 ENG PTCH1 NEK9 TSC1 RNF139 ERCC3 PDGFRA IL2RG CTHRC1 WT1 BAP1 ATP7A SRP54 ABCC8 ESCO2 GPC4 OFD1 TNFSF15 APPL1 RNF6 CTSA TNFRSF1B TP53 PHOX2B DCLRE1C DDB2 BCL10 BCR KRT14 ALX3 EVC2 CD70 SMARCB1 AHCY SDHAF2 RAD51D SPINK1 SDHD ATM GABRD WT1 FASLG CTBP1 NOTCH1 NF2 DPM1 ERCC6 STS PHOX2B BUB1 FLT4 L2HGDH LAMC2 NTHL1 STAG3 ENG SDHD CTNNB1 DAXX NRAS MST1 MSTO1 SLC26A4 RAF1 STS FGFR3 EXOC6B VAMP7 NELFA HRAS ANTXR2 LEMD3 TNFSF12 GPC4 MLH1 SMAD4 RAD50 SUFU TRIP13 REST GNAS CBL RHBDF2 ASXL1 SMAD4 TCF4 ERCC6 WT1 BRAF APC TRIM28 TERT DNAJC21 RPL15 PAX3 SETBP1 CDH1 GNAS SMARCB1 AKT1 ASCL1 KRAS NAB2 ERCC5 RECQL4 KRAS DNMT3A EDN3 POLD1 FAM149B1 CDKN1C KRAS TP53 SMARCE1 PTEN PALB2 SEMA4A TEK NBN NHP2 GPC3 ETV6 FGF8 COL11A2 SMAD4 RNASEH2A NRAS MC1R TDGF1 FGFRL1 FGFR1 CTNNB1 IGH DNAJC21 CCND1 RET DIS3L2 DHCR24 CARD14 BRCA2 SQSTM1 NFKB2 TRNQ NDP SFTPA2 PAX4 COL7A1 TP53 RSPRY1 IFNG HMMR PALB2 FAT4 MBTPS2 MDM2 KRAS GNAS C2CD3 POT1 ABL1 WNT5A FANCE ABL1 ICOS SDHD RAD21 NSD1 SOS1 IL12A LIG4 PIK3CA TBXT RAD51 EWSR1 FZD2 FLNA BRCA2 NRAS TWIST1 TET2 TSC1 INHBA CAT CTNNB1 PIGL IRF1 PTCH2 TRNH MLH1 GFI1 CDC73 RET FANCD2 EVC NF2 TNPO3 SOX2 DYNC2H1 HRAS NEK1 CCND1 KRT10 AKT1 KIT PALB2 VHL CYLD IL1B GJC2 MLH1 SDHC FGFR2 CYP2A6 FOXE1 ARMC5 ERCC2 SLC25A11 LAMA3 FLCN BRCA1 BIRC3 MVK TOP2A PDGFB TCF4 RFWD3 ATP6V1B2 GDNF GATA4 CTNNB1 CDKN1B C2CD3 BRCA2 FUZ STK11 AKT1 FGFR2 SHOX TGFBR1 BTK LEMD3 FIBP SF3B1 SUFU PRLR NR5A1 FN1 ERBB2 CD19 RNR1 PTPN11 KIT RAD51 WAS PTEN TGFBR2 RPS24 CYLD RNF113A MYO1H ALX3 JAK2 BLM CTNNB1 CDKN2A PARN SH2B3 POLD1 CHEK2 COX1 KRT1 EXT1 BRAF PRCC MSH2 GATA2 REST NRAS RB1 TINF2 BMPR1A NR4A3 AGGF1 SIX3 RAG1 ND4 COL2A1 CDKN2A SDHD TREX1 WNT10A SEC23B XPA MET TP53 CDKN1B RPS27 PCNA HMBS RPS26 KIT FGFR2 TRIM37 HPGD ERCC5 PAX6 SLX4 PICALM PSAP FCN3 BMPR1A USF3 XPC DNAJC21 KRT16 BUB3 H19-ICR GPC6 STAC3 RPS28 FANCA RNF43 AP2S1 PDGFB DYNC2LI1 CYP11B1 ABCA5 PTCH1 TERF2IP KRAS DYNC2LI1 CDH1 CDC73 TERC SPRED1 PDGFB TRNF MTMR14 MAD2L2 FOXI1 ERCC2 GJB4 KAT6B MSH6 FASLG KRAS SEC23A RUNX1 CD19 WASHC5 KIT HLA-DRB1 WRAP53 FLT3 CEP57 KDR TREX1 TMEM216 PDGFRA ERCC3 KIT NOTCH3 WIPF1 TERC CTLA4 NQO2 CDKN2A RSPO1 STK4 PTPN11 GJB2 KRAS MET SPINK1 PDGFRB RHOH BUB1 ND6 CDKN2C TFE3 EP300 CHIC2 HNF1B NUMA1 BRCA1 SRY FLCN MLH3 SCN10A GNPTAB KRAS NODAL TGFBR2 PPM1D DOCK8 EPAS1 PHOX2B OCA2 KCNQ1OT1 CYP2D6 ITK DICER1 PRKCD ASPSCR1 SUFU IDH1 RUNX1 ATRX FOXC2 MFN2 SAMD9L SCN4A KIF1B DHH POLE VHL POLR1D KCNAB2 BRAF SLC12A3 CARMIL2 ENPP1 NRAS LRRC8A KIT SH2B3 MST1R CEBPA NRAS MRAP TP53 ND5 FH LAMB3 CALR SLC37A4 PERP KLHDC8B FH SFTPC TGIF1 CHEK2 SLC17A9 SLC22A18 TERT CDH23 MDH2 KRT17 PTEN FGFR3 RB1 YY1 ELANE EP300 SPRTN GJB3 XPA IDH2 MAGT1 ATR GNA14 OFD1 IL7R GREM1 ESCO2 HRAS PRKAR1A MMP1 TP53 KRT17 COL14A1 RHBDF2 MPL OFD1 RYR1 IFIH1 SCN11A IDH1 JAK2 WT1 TP53 ARSA LIG4 CCBE1 FANCG KCNH1 ELANE COL18A1 HACE1 NUP214 MYC CD79A AR CDH1 BRIP1 WT1 BCR BUB1B ERCC3 KRIT1 NBN IGF2 FANCF PDGFRA BLNK PCGF2 MSH6 MEN1 FAS BRIP1 PTH1R SIX1 RNF6 BRAF DHCR7 BMPER BUB1B TP53 RET CTLA4 HABP2 ARHGAP26 DLST GCK ERCC2 RAD54L POLE HSPG2 GNA11 ADA SMAD4 BCL10 RB1 STAT1 TAF1 RPS14 BCR IL12RB1 IRF5 TMC8 TNFRSF13B CYP26C1 CALR POT1 MINPP1 POLR1C CD28 ATP7A HNF1B ERCC2 ACVR1 RPL31 VANGL1 TP63 ERCC4 SLC45A2 OFD1 LMX1B PIK3CA ASCC1 TET2 IGF2R BARD1 TUBB IGF2 BTK MSTO1 CIB1 PHB CDKN2A TNFRSF10B KIAA0753 TBX2 FOXE1 EPCAM TNFRSF13C SLC26A2 ATRX MGAT2 SKIV2L CXCR4 PIK3R1 RTEL1 TSC1 HAX1 SDHB PRKAR1A DDB2 GFI1 CDH23 XRCC3 PMVK TP53 PIK3CA GJB2 NF2 KLF6 AR ZSWIM6 SDHB CDC73 PIK3CA CCND1 GJB6 ATM SOS1 NOTCH3 DDX41 TSC2 FLT4 FGFR3 RASA1 GDF2 F5 PMS2 PTEN HBB TSC2 CASP10 ADA2 AIP WT1 LETM1 PNP COMP TRIM28 TP53 PALB2 RAD51C CCL2 CDC73 SH2D1A COX3 ZAP70 PIK3CA CYP11B2 PDGFRB PTPN11 PHOX2B FH KIT HNF4A RNASEH2C MYD88 PDE6D JAG1 TYR SEC23A FH NPM1 PHKA2 DICER1 PIK3CA HFE GNAQ DMRT3 MS4A1 MYH8 VANGL2 SHOX PUF60 GATA2 BAP1 B3GALT6 TRNS2 HRAS HDAC4 FANCG SAMHD1 GATA2 LIG4 AXIN1 TNFRSF4 OPCML PRKN FGFR2 ECM1 TGFBR2 LMNA WDPCP KCNQ1OT1 BLK GCM2 ALX1 NRAS KIT AAGAB FAH MAX RARA NEUROD1 TGFBR2 MYD88 PHF21A IDH1 MLH1 FANCB CPLX1 SMARCA4 EXTL3 AIP TERT BCL10 XIAP IGF2 SASH1 PIK3R1 PTEN NAGS TMC6 NBEAL2 NOP10 JAK2 SDHB MSH2 ECE1 BARD1 APC PMS2 CCM2 JAK2 MMEL1 RET SDHA SDHD IGHM CACNA1S FAS NR0B1 POT1 SPIB TAL2 NF2 CDON WT1 TET2 PTPRJ CD96 TRNL1 DOCK8 DCC MPL GNAQ CREBBP CDKN2A TRNK MSR1 KRT5 PRKAR1A ERBB3