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The primary objective of AC-052-373 was to assess the pharmacokinetic (PK) profile of two dosing regimens of the pediatric formulation of bosentan in children with pulmonary arterial hypertension (PAH) <12 years of age.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bosentan 2 mg/Kg t.i.d. | Experimental | 2 mg/kg bosentan administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks |
|
| Bosentan 2 mg/Kg b.i.d. | Experimental | 2 mg/kg bosentan administered twice daily (morning and evening) for a planned duration of 24 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| bosentan | Drug | 32 mg quadrisected dispersible tablet. The dosage of bosentan (2 mg/Kg) was adjusted according to the patient's body weight at initiation of the study treatment. Dosage readjustment was permitted after 12 weeks of treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan | Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours [AUC(0-24)]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)]. | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
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| Measure | Description | Time Frame |
|---|---|---|
| Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan | Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc). |
Inclusion Criteria:
PAH diagnosis confirmed with right heart catheterization (RHC):
World Health Organization functional Class (WHO FC) I, II or III
Male or female ≥ 3 months and < 12 years of age (maximum age at randomization is 11.5 years)
Body weight ≥ 3.5 kg
Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)
Baseline PAH-therapy (Calcium channel blocker, bosentan, prostanoid, phosphodiesterase type-5 inhibitor) if present, has to be stable for at least 3 months prior to screening. During the study, all background treatments should remain stable
Signed informed consent by the parents or legal representatives
Exclusion Criteria:
PAH etiologies other than listed above
Non-stable disease status
Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost
Systolic blood pressure < 80% of the lower limit of normal range
Aspartate aminotransferase and/or alanine aminotransferase values > 1.5 times the upper limit of normal range.
Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal range.
Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible Tracleer tablet
Treatment with forbidden medication within 2 weeks or at least 5 times the half-life prior to randomization, whichever is the longest:
Treatment with another investigational drug within 1 month prior to randomization or planned treatment
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| Name | Affiliation | Role |
|---|---|---|
| Andjela Kusic-Pajic, MD | Actelion | Study Director |
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Forty-five expert pediatric centers were initiated but only thirty of them enrolled children with pulmonary arterial hypertension (PAH)
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| ID | Title | Description |
|---|---|---|
| FG000 | Bosentan 2 mg/kg t.i.d. | 2 mg/kg bosentan (dispersible tablets) was administered orally three times a day (t.i.d.) for a planned duration of 24 weeks |
| FG001 | Bosentan 2 mg/kg b.i.d. | 2 mg/kg bosentan (dispersible tablets) was administered orally twice daily (b.i.d.) for a planned duration of 24 weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Bosentan 2 mg/kg t.i.d. | 2 mg/kg bosentan (dispersible tablets) was administered orally three times a day (t.i.d.) for a planned duration of 24 weeks |
| BG001 | Bosentan 2 mg/kg b.i.d. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | This is the age reported at the screening visit which had to be performed within 4 weeks prior to randomization |
| 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 | Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan | Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours [AUC(0-24)]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)]. | Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. | Posted | Geometric Mean | 95% Confidence Interval | h*ng/mL | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
From the first dose of study treatment on Day 1 up to 7 days after treatment discontinuation, i.e. up to Week 25 on average
One patient in group 2 mg/kg t.i.d. experienced a serious adverse event (SAE) (adenoviral gastroenteritis) that was reported to the investigator by the parents about 2 months after database closure. Therefore this SAE is not included in the safety summary of FUTURE 3 but is displayed in the cumulative safety data of the FUTURE 3 Extension (AC-052-374)
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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 | Bosentan 2 mg/kg t.i.d | Patients received 2 mg/kg of bosentan 3 times a day (morning, afternoon, evening) for at least 0.4 week and up to 28.7 weeks |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ATRIAL SEPTAL DEFECT REPAIR | Surgical and medical procedures | MedDRA 16.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| BRONCHITIS | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| clinical trial disclosure desk | Actelion Pharmaceuticals Ltd | clinical-trials-disclosure@actelion.com |
| ID | Term |
|---|---|
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000077300 | Bosentan |
| ID | Term |
|---|---|
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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|
| 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
| Time to Reach Cmax [Tmax] of Bosentan | Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations. | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
| Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) | Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint. AUC(0-24c) was corrected to 2 mg/kg (target dose) [AUC(0-24c)]. | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
| Change From Baseline in WHO Functional Class at End of Study | The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension (PH): Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class IIII (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined. | Baseline, up to Week 24 on average |
| Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study | The GCIS is an assessment tool providing a single global assessment of the patient's current overall clinical condition: Very Good, Good, Neither Good or Bad, Bad and Very Bad. The assessment was performed both by the physician and the parents / legal representatives independently. Global clinical impression (GCI) at end of study was compared to GCI at baseline and the number of patients with clinical condition considered as worsened, improved or unchanged are determined. | Baseline, up to Week 24 on average |
| Number of Patients With Treatment-emergent Liver Function Abnormalities | Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date. | Baseline, up to Week 24 |
| Number of Patients With Treatment-emergent Hemoglobin Abnormalities | Number of patients with marked hemoglobin decreases (absolute values below 10 g/dL). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date. | Baseline, up to Week 24 |
2 mg/kg bosentan (dispersible tablets) was administered orally twice daily (b.i.d.) for a planned duration of 24 weeks
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | Participants |
|
| Etiology of pulmonary arterial hypertension (PAH) | Children included in the study had a diagnosis of PAH belonging to one of the following categories:
| Count of Participants | Participants |
|
| World Health Organization functional class (WHO FC) | The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension: Class I (FC I): No limitation of physical activity; Class II (FC II): Slight limitation of physical activity; Class IIII (FC III): Marked limitation of physical activity; Class IV (FC IV): Inability to carry out any physical activity without symptoms. WHO FC at Day 1, before first study drug administration, are reported as baseline values here. | Number | Participants |
|
| PAH-specific therapy at baseline | PAH-specific therapy at Day 1, before first study drug administration, are reported as baseline values here. | Number | Participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Bosentan 2 mg/kg t.i.d. (PK Set) | Patients randomized to the bosentan 2 mg/kg t.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. |
| OG001 | Bosentan 2 mg/kg b.i.d. (PK Set) | Patients randomized to the bosentan 2 mg/kg b.i.d. group who received at least one oral dose of bosentan and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. |
|
|
|
| Other Pre-specified | Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan | Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc). | Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. | Posted | Geometric Mean | 95% Confidence Interval | ng/mL | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
|
|
|
|
| Other Pre-specified | Time to Reach Cmax [Tmax] of Bosentan | Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations. | Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. | Posted | Median | Full Range | hours | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
|
|
|
| Other Pre-specified | Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) | Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint. AUC(0-24c) was corrected to 2 mg/kg (target dose) [AUC(0-24c)]. | Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint. | Posted | Geometric Mean | 95% Confidence Interval | h*ng/mL | 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment |
|
|
|
| Other Pre-specified | Change From Baseline in WHO Functional Class at End of Study | The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension (PH): Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class IIII (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined. | All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set. | Posted | Number | Participants | Baseline, up to Week 24 on average |
|
|
|
| Other Pre-specified | Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study | The GCIS is an assessment tool providing a single global assessment of the patient's current overall clinical condition: Very Good, Good, Neither Good or Bad, Bad and Very Bad. The assessment was performed both by the physician and the parents / legal representatives independently. Global clinical impression (GCI) at end of study was compared to GCI at baseline and the number of patients with clinical condition considered as worsened, improved or unchanged are determined. | All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set. | Posted | Number | Participants | Baseline, up to Week 24 on average |
|
|
|
| Other Pre-specified | Number of Patients With Treatment-emergent Liver Function Abnormalities | Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date. | All randomized patients who received at least one dose of study drug and with available data. | Posted | Number | Participants | Baseline, up to Week 24 |
|
|
|
| Other Pre-specified | Number of Patients With Treatment-emergent Hemoglobin Abnormalities | Number of patients with marked hemoglobin decreases (absolute values below 10 g/dL). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date. | All randomized patients who received at least one dose of study drug and with available data. | Posted | Number | Participants | Baseline, up to Week 24 |
|
|
|
| 6 |
| 31 |
| 18 |
| 31 |
| EG001 | Bosentan 2 mg/kg b.i.d | Patients received 2 mg/kg of bosentan twice daily (morning and evening) for at least 6 weeks and up to 26.4 weeks | 4 | 33 | 18 | 33 |
| BODY TEMPERATURE INCREASED | Investigations | MedDRA 16.0 | Systematic Assessment |
|
| BRONCHOPNEUMONIA | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| CARDIAC FAILURE | Cardiac disorders | MedDRA 16.0 | Systematic Assessment |
|
| CARDIAC OPERATION | Surgical and medical procedures | MedDRA 16.0 | Systematic Assessment |
|
| DRUG HYPERSENSITIVITY | Immune system disorders | MedDRA 16.0 | Systematic Assessment |
|
| GASTROENTERITIS | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
|
| INFECTION | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
|
| LOSS OF CONSCIOUSNESS | Nervous system disorders | MedDRA 16.0 | Systematic Assessment |
|
| METABOLIC DISORDER | Metabolism and nutrition disorders | MedDRA 16.0 | Systematic Assessment |
|
| MULTI-ORGAN FAILURE | General disorders | MedDRA 16.0 | Systematic Assessment |
|
| OXYGEN SATURATION DECREASED | Investigations | MedDRA 16.0 | Systematic Assessment |
|
| PULMONARY ARTERIAL HYPERTENSION | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
|
| PYREXIA | General disorders | MedDRA 16.0 | Systematic Assessment |
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| RESPIRATORY DISTRESS | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
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| RESPIRATORY TRACT INFECTION VIRAL | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| VIRAL INFECTION | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| CONSTIPATION | Gastrointestinal disorders | MedDRA 16.0 | Systematic Assessment |
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| COUGH | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
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| DIARRHOEA | Gastrointestinal disorders | MedDRA 16.0 | Systematic Assessment |
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| EPISTAXIS | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
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| FLUSHING | Vascular disorders | MedDRA 16.0 | Systematic Assessment |
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| NASOPHARYNGITIS | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| OTITIS MEDIA | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| PULMONARY ARTERIAL HYPERTENSION | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
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| PYREXIA | General disorders | MedDRA 16.0 | Systematic Assessment |
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| RASH | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Systematic Assessment |
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| RESPIRATORY TRACT INFECTION | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| THROMBOCYTOPENIA | Blood and lymphatic system disorders | MedDRA 16.0 | Systematic Assessment |
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| UPPER RESPIRATORY TRACT INFECTION | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| VOMITING | Gastrointestinal disorders | MedDRA 16.0 | Systematic Assessment |
|
The only agreement between the sponsor and the investigators is that any study-related article or abstract written independently by investigators must be submitted to the sponsor for review at least 60 days prior to submission for publication or presentation.
| D001555 |
| Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| AUC(0-24C) for Ro 641056 |
|
| Improved WHO FC |
|
| Unchanged as per physician evaluation |
|
| Unchanged as per parents evaluation |
|
| Improved as per physician evaluation |
|
| Improved as per parents evaluation |
|