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| ID | Type | Description | Link |
|---|---|---|---|
| MK3475 KEYNOTE KN163 | Other Identifier | Merck Sharp & Dohme Corp. |
Not provided
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Not provided
Based on a futility analysis, the data monitoring committee recommended to stop enrollment.
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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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An ascending dose study in patients with solid tumors to evaluate the safety, tolerability, pharmacodynamics and efficacy of birinapant when given in combination with pembrolizumab. A dose expansion phase of 4 cohorts will also be included.
This study will be conducted in two phases. The Phase 1 portion of the study will employ a sequential group dose-escalation design to determine the dose-limiting toxicity (DLT) and recommended Phase 2 dose (RP2D) of birinapant administered in combination with 200 mg pembrolizumab, both administered as a 30-minute intravenous (IV) infusion. The following proposed doses of birinapant are to be evaluated: 5.6, 11, 17, and 22 mg/m2.
The Phase 2 portion, the dose expansion phase, will compromise 4 cohorts of 26-30 patients.
The 4 cohorts will include the following:
A Simon's 2-stage design will be used for each of the cohorts in colorectal cancer, ovarian cancer and cervical cancer. A predefined interim analysis allowing stopping each of these cohorts for futility and safety will be conducted in the first stage to limit undue exposure before further inclusion into a given cohort. The design of the various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of enrolled patient to five in each tumor type.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Birinapant in combination with pembrolizumab | Experimental | Birinapant in combination with pembrolizumab |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Birinapant | Drug | Birinapant intravenous (IV) on Days 1 and 8 of each 21-Day Cycle. The following escalating doses of birinapant to be studied: 5.6, 11, 17, and 22 mg/m2. In the expansion phase the assigned recommended phase two dose will be administered in all cohorts |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through blood pressure. | Baseline and up to 2 yrs (follow-up) |
| Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through electrocardiogram. | Baseline and up to 2 yrs (follow-up) |
| Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through amylase and lipase. | Baseline and up to 2 yrs (follow-up) |
| Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through thyroxine free. | Baseline and up to 2 yrs (follow-up) |
| Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through Thyrotropin. | Baseline and up to 2 yrs (follow-up) |
| Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through hemoglobin. |
| Measure | Description | Time Frame |
|---|---|---|
| Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | Analysis of progression-free survival (PFS); time to progression, where progressive disease (PD) corresponds to ≥20% increase in the sum of the longest diameter of target lesions. | Every 9 weeks; up to 2 yrs |
| Measure | Description | Time Frame |
|---|---|---|
| Assess Tumor Activity | To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST) | Baseline and up to 2 yrs (follow-up) |
| Translational Biomarker Assessments Obtained From Blood |
Inclusion Criteria:
Dose Expansion phase specific additional inclusion criteria:
Exclusion Criteria:
Exclusion criteria apply to all phases and cohorts in the study unless otherwise stated
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Banner MD Anderson Cancer Center | Gilbert | Arizona | 85234 | United States | ||
| Cedars-Sinai Medical Center |
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| ID | Title | Description |
|---|---|---|
| FG000 | Phase 1 - 5.6 mg | Dose escalation (Phase 1): 5.6 mg birinapant + pembrolizumab |
| FG001 | Phase 1 - 11 mg | Dose escalation (Phase 1): 11 mg birinapant + pembrolizumab |
| FG002 | Phase 1 - 17 mg | Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab |
| FG003 | Phase 1 - 22 mg | Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab |
| FG004 | Phase 2 - 22 mg | Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Phase 1 - 5.6 mg | Dose escalation (Phase 1): 5.6 mg birinapant + pembrolizumab |
| BG001 | Phase 1 - 11 mg | Dose escalation (Phase 1): 11 mg birinapant + pembrolizumab |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through blood pressure. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | mmHg | Baseline and up to 2 yrs (follow-up) |
|
Up to 2 years
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phase 1 - 5.6 mg | Dose escalation (Phase 1): 5.6 mg birinapant + pembrolizumab |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anxiety | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
The dose escalation (Phase 1) part was analyzed per the protocol. Based on data from the interim analysis of the colorectal cancer cohort (dose expansion [Phase 2] part), the study was closed early due to futility on recommendation by the data monitoring committee (DMC).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Medical Officer | Medivir AB | +46854683100 | info@medivir.com |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 16, 2018 | Sep 2, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 13, 2018 | Sep 2, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C582429 | birinapant |
| C582435 | pembrolizumab |
Not provided
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| Pembrolizumab | Drug | 200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle |
|
|
| Baseline and up to 2 yrs (follow-up) |
| Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through physical exam. | Baseline and up to 2 yrs (follow-up) |
| Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. A responder was a patient who showed best overall response of complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the sum of the longest diameter of target lesions), which was confirmed again at least 4 weeks after the initial assessment. | Baseline and up to 2 yrs (follow-up) |
| Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) |
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through blood pressure. |
| Baseline and up to 2 yrs (follow-up) |
| Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through electrocardiogram. | Baseline and up to 2 yrs (follow-up) |
| Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through amylase and lipase. | Baseline and up to 2 yrs (follow-up) |
| Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyroxine free. | Baseline and up to 2 yrs (follow-up) |
| Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyrotropin. | Baseline and up to 2 yrs (follow-up) |
| Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through hemoglobin. | Baseline and up to 2 yrs (follow-up) |
| Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab assessed through physical exam. | Baseline and up to 2 yrs (follow-up) |
Measured by inhibitor of apoptosis proteins (IAPs), cytokines, tumor infiltrating lymphocytes (TILs) cluster of differentiation (CD)3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts
| Day 1 through Day 8 |
| Translational Biomarker Assessments of Tumor Biopsy Samples | Measured by: Programmed death ligand 1 (PD-1L), programmed cell death protein 1 receptor (PD-1) and related proteins, genome analysis, IAP gene copy number and TILs cluster of differentiation (CD)3, CD4, CD8 and CD19 | Baseline and up to 2 yrs (follow-up) |
| Pharmacokinetics of Birinapant in Plasma | The plasma concentrations of birinapant was to be measured and summarized descriptively | Day 1 through Day 8 |
| Los Angeles |
| California |
| 90048 |
| United States |
| UCLA Dept of Medicine-Hematology/Oncology | Santa Monica | California | 90404 | United States |
| Mid Florida Hematology and Oncology Center | Orange City | Florida | 32763 | United States |
| The Sidney Kimmel Comprehensive Cancer Center at John Hopkins | Baltimore | Maryland | 21287 | United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| Thomas Jefferson University Sidney Kimmel Cancer Center | Philadelphia | Pennsylvania | 19107 | United States |
| Mary Crowley Cancer Research | Dallas | Texas | 75251 | United States |
| MD Anderson Cancer Center, The University of Texas | Houston | Texas | 77030 | United States |
| Withdrawal by Subject |
|
| Radiological progression |
|
| Clinical progression |
|
| BG002 | Phase 1 - 17 mg | Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab |
| BG003 | Phase 1 - 22 mg | Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab |
| BG004 | Phase 2 - 22 mg | Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 | Phase 1 - 17 mg | Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab |
| OG003 | Phase 1 - 22 mg | Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab |
|
|
| Primary | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through electrocardiogram. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | ms | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through amylase and lipase. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | U/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through thyroxine free. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | nmol/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through Thyrotropin. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | mU/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through hemoglobin. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | g/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through physical exam. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Count of Participants | Participants | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Primary | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. A responder was a patient who showed best overall response of complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the sum of the longest diameter of target lesions), which was confirmed again at least 4 weeks after the initial assessment. | For phase 2, only the colorectal cancer (CRC) cohort was analyzed for overall response rate. Patients were not recruited to the ovarian cancer or cervical cancer cohorts due to early termination of the study. | Posted | Count of Participants | Participants | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | Analysis of progression-free survival (PFS); time to progression, where progressive disease (PD) corresponds to ≥20% increase in the sum of the longest diameter of target lesions. | Posted | Median | Inter-Quartile Range | Weeks | Every 9 weeks; up to 2 yrs |
|
|
|
| Secondary | Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through blood pressure. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | mmHg | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through electrocardiogram. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | ms | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through amylase and lipase. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | U/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyroxine free. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | nmol/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyrotropin. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | mU/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through hemoglobin. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Mean | Standard Deviation | g/L | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Secondary | Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab assessed through physical exam. | As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed. | Posted | Count of Participants | Participants | Baseline and up to 2 yrs (follow-up) |
|
|
|
| Other Pre-specified | Assess Tumor Activity | To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST) | Tumor activity according to iRECIST was not analyzed due to early termination of the study. | Posted | Baseline and up to 2 yrs (follow-up) |
|
|
| Other Pre-specified | Translational Biomarker Assessments Obtained From Blood | Measured by inhibitor of apoptosis proteins (IAPs), cytokines, tumor infiltrating lymphocytes (TILs) cluster of differentiation (CD)3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts | Biomarkers in blood were not analyzed due to early termination of the study. | Posted | Day 1 through Day 8 |
|
|
| Other Pre-specified | Translational Biomarker Assessments of Tumor Biopsy Samples | Measured by: Programmed death ligand 1 (PD-1L), programmed cell death protein 1 receptor (PD-1) and related proteins, genome analysis, IAP gene copy number and TILs cluster of differentiation (CD)3, CD4, CD8 and CD19 | Biomarkers in tumor biopsy samples were not analyzed due to early termination of the study. | Posted | Baseline and up to 2 yrs (follow-up) |
|
|
| Other Pre-specified | Pharmacokinetics of Birinapant in Plasma | The plasma concentrations of birinapant was to be measured and summarized descriptively | Birinapant pharmacokinetics was not analyzed due to early termination of the study. | Posted | Day 1 through Day 8 |
|
|
| 0 |
| 3 |
| 2 |
| 3 |
| 3 |
| 3 |
| EG001 | Phase 1 - 11 mg | Dose escalation (Phase 1): 11 mg birinapant + pembrolizumab | 0 | 3 | 1 | 3 | 3 | 3 |
| EG002 | Phase 1 - 17 mg | Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab | 1 | 6 | 4 | 6 | 6 | 6 |
| EG003 | Phase 1 - 22 mg | Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab | 0 | 7 | 3 | 7 | 7 | 7 |
| EG004 | Phase 2 CRC - 22 mg | Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab in colorectal cancer cohort | 1 | 15 | 5 | 15 | 15 | 15 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Transient ischaemic attack | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | MedDRA (20.0) | Systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Death | General disorders | MedDRA (20.0) | Systematic Assessment | The event leading to death (the underlying cause) was unknown and therefore reported by the Investigator as preferred term 'Death' |
|
| Hip fracture | Injury, poisoning and procedural complications | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Brain oedema | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonia staphylococcal | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Upper gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Malignant ascites | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonitis bacterial | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Portal hypertension | Hepatobiliary disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Smal intestinal obstruction | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Metastases to central nervous system | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
|
| Duodenal perforation | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Increased bronchial secretion | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
|
| Lipase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Amnesia | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Weight increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pharyngitis streptococcal | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | MedDRA (20.0) | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Gastric hypomotility | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pancreatic failure | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Vitamin D deficiency | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Intertrigo | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Vulvovaginal mycotic infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Dry eye | Eye disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Eye pain | Eye disorders | MedDRA (20.0) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Foreign body sensation in eye | Eye disorders | MedDRA (20.0) | Systematic Assessment |
|
| Goitre | Endocrine disorders | MedDRA (20.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hyposmia | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Madarosis | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Photophobia | Eye disorders | MedDRA (20.0) | Systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Viral upper respiratory tract infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA (20.0) | Systematic Assessment |
|
| Bloody discharge | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash macular | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pollakiuria | Renal and urinary disorders | MedDRA (20.0) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Gingivitis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Skin cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hyperbilirubinaemia | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Abnormal loss of weight | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hemiparesis | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Mental status changes | Psychiatric disorders | MedDRA (20.0) | Systematic Assessment |
|
| Renal injury | Renal and urinary disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Amylase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Chapped lips | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rash papular | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Haematochezia | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rheumatoid arthritis | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Chills | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Hiccups | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Venous thrombosis | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA (20.0) | Systematic Assessment |
|
| Malignant ascites | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (20.0) | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA (20.0) | Systematic Assessment |
|
| Blood thyroid stimulating hormone increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Thyroxine free decreased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Appetite disorder | Metabolism and nutrition disorders | MedDRA (20.0) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dermatitis allergic | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | MedDRA (20.0) | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | MedDRA (20.0) | Systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Drug eruption | Skin and subcutaneous tissue disorders | MedDRA (20.0) | Systematic Assessment |
|
| Paranasal sinus discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Thyroiditis | Endocrine disorders | MedDRA (20.0) | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (20.0) | Systematic Assessment |
|
| Anal incontinence | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Pyelonephritis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
|
| Pain | General disorders | MedDRA (20.0) | Systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA (20.0) | Systematic Assessment |
|
The Investigator must submit any proposed publication or presentation to the Sponsor, along with information about the scientific journal or presentation forum, at least 30 days before submission of the publication or presentation (2 weeks for abstracts). The Investigator will comply with Sponsor requests to delete confidential information (other than the study results) and to withhold publication or presentation for an additional 60 days in order to obtain patent protection if necessary.
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| Electrocardiogram QT interval at follow-up |
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| Amylase at follow-up |
|
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| Lipase at baseline |
|
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| Lipase at follow-up |
|
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|
| Thyroxine free at last assessment |
|
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| Thyrotropin at last assessment |
|
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| Hemoglobin at follow-up |
|
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| Clinically significant physical exam abnormalities - last assessment |
|
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| Diastolic blood pressure at baseline |
|
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| Diastolic blood pressure at follow-up |
|
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| Lipase at baseline |
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| Lipase at follow-up |
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