| ID | Type | Description | Link |
|---|---|---|---|
| TMC125-TiDP35-C213 | Other Identifier | Tibotec Pharmaceuticals, Ireland | |
| 2007-007086-21 | EudraCT Number |
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The purpose of this study is to determine the safety and antiviral activity of etravirine in treatment-experienced human immunodeficiency virus (HIV) infected children and adolescents.
The study design is a single arm treatment (all patients assigned to receive etravirine), open label (patients will know the identity of the treatments they are receiving) safety and antiviral activity of Etravirine (TMC125) in treatment-experienced, HIV infected children and adolescents 6 to 17 years of age. Etravirine is a new drug belonging to the NNRTI (a non-nucleoside reverse transcriptase inhibitor) drug class that slows down the growth of the human immunodeficiency virus (HIV). This drug has been tested for safety and effectiveness in adults, however, there is no data on the drug's long-term safety and antiviral activity in children and adolescents. This study will last for a maximum of 48 weeks. A total of 100 ptients will receive etravirine tablets based on body weight and an investigator selected optimized background regimen (OBR) of at least 2 antiretrovirals (ARVs), consisting of a boosted protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor(s) (NRTI[s]). Use of enfuvirtide is optional. Safety will be monitored throughout the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Etravirine (TMC125) | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Etravirine (TMC125) | Drug | Patients will be dosed by body weight , i.e. 5.2 mg/kg twice daily (b.i.d.) up to a maximum of 200 mg b.i.d. for 48 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | A treatment-emergent adverse event (TEAE) was defined as an event that occurred in the 48-week treatment period during which it emerged (i.e. started or worsened in severity, relation, or other attribute), and not in the subsequent study periods, even if the event continued to be present. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen | 48 weeks |
| The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | The percentage of patients with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged [i.e. started or worsened in severity, relation, or other attribute], and not in the subsequent study periods, even if the event continued to be present] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen | 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) | The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tibotec Pharmaceuticals, Ireland Clinical Trial | Tibotec Pharmaceuticals, Ireland | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mobile | Alabama | United States | ||||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26566161 | Derived | Tambuyzer L, Thys K, Hoogstoel A, Nijs S, Tomaka F, Opsomer M, De Meyer S, Vingerhoets J. Assessment of etravirine resistance in HIV-1-infected paediatric patients using population and deep sequencing: final results of the PIANO study. Antivir Ther. 2016;21(4):317-27. doi: 10.3851/IMP3011. Epub 2015 Nov 13. |
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In total, 41 investigators in 13 countries enrolled patients in study TMC125-C213. A total of 103 patients were documented as being enrolled in the study, however 2 patients were randomized in error. Therefore, 101 patients were enrolled and treated with etravirine (ETR) also known as TMC125 and included in the intent-to-treat (ITT) population.
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| ID | Title | Description |
|---|---|---|
| FG000 | TMC125 | TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Optimized background regimen (OBR) | Drug | An investigator-selected optimized background regimen (OBR) comprising of a low-dose ritonavir (rtv)-boosted protease inhibitor (PI) (either lopinavir [LPV], darunavir [DRV], atazanavir [ATV] or saquinavir [SQV]) in combination with nucleos(t)ide reverse transcriptase inhibitor(s) (N[t]RTIs) to be dosed according to the drugs individual package inserts for 48 weeks. |
|
| Weeks 4-48 |
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h) | Week 48 |
| Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax) | Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit as shown in the table below. | Week 4 |
| Percentage of Patients With Virologic Response at Week 24 | Virologic response was defined as the percentage of patients with plasma viral load < 50 copies/mL at Week 24 calculated according to the non-completer=failure (NC=F) imputation method. | Week 24 |
| Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time | Baseline, Week 48 |
| The Change From Baseline in CD4 Cell Counts Over Time | Baseline, Week 48 |
| The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | Virologic failure (lack of response) was defined as: plasma viral load decline of < 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of <1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load > 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients). | Baseline and Endpoint (up to Week 48) |
| Los Angeles |
| California |
| United States |
| Washington D.C. | District of Columbia | United States |
| New Orleans | Louisiana | United States |
| St Louis | Missouri | United States |
| New Brunswick | New Jersey | United States |
| New York | New York | United States |
| Syracuse | New York | United States |
| The Bronx | New York | United States |
| Philadelphia | Pennsylvania | United States |
| Memphis | Tennessee | United States |
| Dallas | Texas | United States |
| Fort Worth | Texas | United States |
| Buenos Aires | Argentina |
| Belo Horizonte | Brazil |
| Ribeirão Preto | Brazil |
| Rio de Janeiro | Brazil |
| Ottawa | Ontario | Canada |
| Toronto | Ontario | Canada |
| Montreal | Quebec | Canada |
| Lyon | France |
| Nantes | France |
| Paris | France |
| Toulouse Cedex 3 N/A | France |
| Amsterdam-Zuidoost | Netherlands |
| Almada | Portugal |
| Lisbon | Portugal |
| Porto | Portugal |
| Rio Piedras | Puerto Rico |
| San Juan | Puerto Rico |
| Bucharest | Romania |
| Constanța | Romania |
| Dundee | South Africa |
| Durban | South Africa |
| Port Elizabeth | South Africa |
| Barcelona | Spain |
| Esplugues de Llobregat | Spain |
| Madrid | Spain |
| Seville | Spain |
| Bangkok | Thailand |
| Khon Kaen | Thailand |
| Birmingham | United Kingdom |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | TMC125 | TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Age Customized | Number | participants |
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| 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 | The Number of Patients With Treatment-emergent Adverse Events (TEAEs) | A treatment-emergent adverse event (TEAE) was defined as an event that occurred in the 48-week treatment period during which it emerged (i.e. started or worsened in severity, relation, or other attribute), and not in the subsequent study periods, even if the event continued to be present. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen | The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication. | Posted | Number | Patients | 48 weeks |
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| Primary | The Percentage of Patients With Treatment-emergent Adverse Events (TEAEs) | The percentage of patients with a treatment-emergent adverse event (TEAE) (defined as an event that occurred in the 48-week treatment period during which it emerged [i.e. started or worsened in severity, relation, or other attribute], and not in the subsequent study periods, even if the event continued to be present] are provided below. Adverse events were graded from 1 to 4 in severity using the Division of Acquired Immunodeficiency Syndrome severity scale (grade 1 being less severe and grade 4 being more severe). ETR=etravirine/TMC125; OBR=optimized background regimen | The safety analysis was done on the intent-to-treat (ITT) population, which included all patients who received at least one dose of investigational medication. | Posted | Number | Percentage of patients | 48 weeks |
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| Secondary | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Area Under the Plasma Concentration-time Curve Over 12 Hours at Steady-state (AUC12h) | The AUC12h is a Bayesian estimation based on a population pharmacokinetic model and sparse samples collected at each visit over the duration of trial. For each sparse sample taken, the time blood sample was recorded as well as the time of etravirine intake just prior to the time of blood sample. | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for "Overall (children and adolescents combined)." | Posted | Mean | Standard Deviation | ng.h/mL | Weeks 4-48 |
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| Secondary | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Trough Plasma Concentration (C0h) | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken ETR at least once, regardless of their compliance with the protocol was used for this analysis. The table below shows results for "Overall (children and adolescents combined)." | Posted | Mean | Standard Deviation | ng/mL | Week 48 |
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| Secondary | Population Pharmacokinetic (PK) Estimates of Etravirine/TMC125 (ETR): Maximum Plasma Concentration (Cmax) | Etravirine/TMC125 (ETR) Cmax was approximated for each individual using the median value of plasma ETR concentrations taken 4 hours postdose (± 1 hour), when available, on the day of the Week 4 visit as shown in the table below. | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis. | Posted | Mean | Standard Deviation | ng/mL | Week 4 |
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| Secondary | Percentage of Patients With Virologic Response at Week 24 | Virologic response was defined as the percentage of patients with plasma viral load < 50 copies/mL at Week 24 calculated according to the non-completer=failure (NC=F) imputation method. | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis. | Posted | Number | Percentage of Patients | Week 24 |
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| Secondary | Change From Baseline in Human Immunodeficiency Virus - Type 1 (HIV-1) Ribonucleic Acid (RNA) in Plasma Over Time | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis. | Posted | Mean | Standard Error | log10 copies/mL | Baseline, Week 48 |
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| Secondary | The Change From Baseline in CD4 Cell Counts Over Time | The intent-to-treat (ITT) population, i.e. all patients who had been enrolled and taken Etravirine/TMC125 (ETR) at least once, regardless of their compliance with the protocol was used for this analysis. | Posted | Mean | Standard Error | 10E6 cells/L | Baseline, Week 48 |
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| Secondary | The Emergence of Non-nucleoside Reverse Transcriptase Inhibitor Resistance-associated Mutations (NNRTI RAMs) in Patients Classified as Virologic Failures | Virologic failure (lack of response) was defined as: plasma viral load decline of < 0.5 log10 from Baseline by Week 8 and/or plasma viral load decline of <1.0 log10 from Baseline by Week 12. Virologic failure (loss of response) was defined as 2 consecutive measurements of plasma viral load > 0.5 log10 above the nadir after a minimum of 12 weeks of treatment. The table below provides data for 41 viologic failures of which 30 had mutation data available. In the table below, only the 4 most frequently emerging mutations are presented (emerging in at least 3 patients). | The patients in the intent-to-treat (ITT) population classified as virologic failures were used for this analysis. | Posted | Number | Patients | Baseline and Endpoint (up to Week 48) |
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Only subjects who had at least one of the TEAEs listed in the Other (non Serious) AE table are included in the Total no. subjects with Non-Serious Adverse Events.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | TMC125 | TMC125 dosed according to body weight (kg) from 100 mg to 200 mg twice a day | 5 | 101 | 70 | 101 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ulcerative keratitis | Eye disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Drug resistance | General disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Drug toxicity | Injury, poisoning and procedural complications | MedDRA 11.1 | Non-systematic Assessment |
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| Overdose | Injury, poisoning and procedural complications | MedDRA 11.1 | Non-systematic Assessment |
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| Immunoglobulins | Investigations | MedDRA 11.1 | Non-systematic Assessment |
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| Lymphocyte morphology abnormal | Investigations | MedDRA 11.1 | Non-systematic Assessment |
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| Weight decreased | Investigations | MedDRA 11.1 | Non-systematic Assessment |
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| Treatment noncompliance | Social circumstances | MedDRA 11.1 | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctivitis | Eye disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Pyrexia | General disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Oral herpes | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Pharyngitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Rhinitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Sinusitis | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 11.1 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 11.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Director | Tibotec Pharmaceuticals, Ireland | 32 14 641 265 | gdsmedt1@its.jnj.com |
| ID | Term |
|---|---|
| C451734 | etravirine |
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| Title | Measurements |
|---|---|
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| TEAEs that were grade 3 or 4 in severity |
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| TEAEs leading to temporary ETR discontinuation |
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| TEAEs leading to permanent ETR discontinuation |
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| TEAEs possibly related to ETR |
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| TEAEs probably related to ETR |
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| TEAEs very likely related to ETR |
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| TEAEs at least possibly related to ETR |
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| TEAEs possibly related to OBR |
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| TEAEs probably related to OBR |
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| TEAEs very likely related to OBR |
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| TEAEs at least possibly related to OBR |
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| TEAEs of at least grade 2 in severity |
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| TEAEs of at least grade 3 in severity |
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| TEAEs of interest: Skin event |
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| TEAEs of interest: Rash |
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| TEAEs of interest: severe cutaneous reactions |
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| TEAEs of interest: angioedema |
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| TEAEs of interest: neuropsychiatric events |
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| TEAEs of interest: hepatic events |
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| TEAEs of interest: cardiac events |
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| TEAEs of interest: bleeding events |
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| TEAEs of interest: pancreatic events |
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| TEAEs of interest: lipid-related events |
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| TEAEs of interest: neoplasms |
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