Trial Outcomes & Findings for Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension (NCT NCT01223352)

Last Updated: 2025-02-04

Results Overview

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) \[AUC(0-24c)\].

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

64 participants

Primary outcome timeframe

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

Results posted on

2025-02-04

Participant Flow

Forty-five expert pediatric centers were initiated but only thirty of them enrolled children with pulmonary arterial hypertension (PAH)

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	31	33
Overall Study COMPLETED	31	33
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bosentan 2 mg/kg t.i.d. n=31 Participants 2 mg/kg bosentan (dispersible tablets) was administered orally three times a day (t.i.d.) for a planned duration of 24 weeks	Bosentan 2 mg/kg b.i.d. n=33 Participants 2 mg/kg bosentan (dispersible tablets) was administered orally twice daily (b.i.d.) for a planned duration of 24 weeks	Total n=64 Participants Total of all reporting groups
Age, Continuous	5.2 Years STANDARD_DEVIATION 3.81 • n=5 Participants	4.5 Years STANDARD_DEVIATION 3.35 • n=7 Participants	4.8 Years STANDARD_DEVIATION 3.57 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	18 Participants n=7 Participants	28 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	15 Participants n=7 Participants	36 Participants n=5 Participants
Region of Enrollment Australia	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Belarus	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment China	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment Czech Republic	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment France	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment Germany	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment Hungary	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment India	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment Israel	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Italy	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment Mexico	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment Poland	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment Russia	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment Serbia	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment South Africa	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment Spain	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment USA	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment Ukraine	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Etiology of pulmonary arterial hypertension (PAH) Idiopathic	15 Participants n=5 Participants	14 Participants n=7 Participants	29 Participants n=5 Participants
Etiology of pulmonary arterial hypertension (PAH) Heritable	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Etiology of pulmonary arterial hypertension (PAH) PAH-Congenital heart disease	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Etiology of pulmonary arterial hypertension (PAH) Associated PAH	13 Participants n=5 Participants	11 Participants n=7 Participants	24 Participants n=5 Participants
Etiology of pulmonary arterial hypertension (PAH) Missing data	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
World Health Organization functional class (WHO FC) FC I	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
World Health Organization functional class (WHO FC) FC II	15 Participants n=5 Participants	12 Participants n=7 Participants	27 Participants n=5 Participants
World Health Organization functional class (WHO FC) FC III	6 Participants n=5 Participants	12 Participants n=7 Participants	18 Participants n=5 Participants
PAH-specific therapy at baseline Bosentan (adult tablet formulation)	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
PAH-specific therapy at baseline Prostanoid	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
PAH-specific therapy at baseline Phosphodiesterase type-5 (PDE-5) inhibitor	13 Participants n=5 Participants	10 Participants n=7 Participants	23 Participants n=5 Participants
PAH-specific therapy at baseline Bosentan / PDE-5 inhibitor combination	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
PAH-specific therapy at baseline Bosentan /PDE-5 inhibitor /Prostanoid combination	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants
PAH-specific therapy at baseline None	9 Participants n=5 Participants	13 Participants n=7 Participants	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=27 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=31 Participants 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.
Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan	7275.1 h*ng/mL Interval 5468.2 to 9679.0	8535.4 h*ng/mL Interval 6936.0 to 10503.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

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).

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=27 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=31 Participants 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.
Dose-corrected Maximum Plasma Concentration [Cmaxc] of Bosentan	527.9 ng/mL Interval 386.0 to 721.9	742.8 ng/mL Interval 572.8 to 963.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=27 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=31 Participants 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.
Time to Reach Cmax [Tmax] of Bosentan	3 hours Interval 1.0 to 8.0	3 hours Interval 0.0 to 7.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

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) \[AUC(0-24c)\].

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=27 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=31 Participants 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.
Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) AUC(0-24C) for Ro 478634	173.2 h*ng/mL Interval 126.2 to 237.6	200.4 h*ng/mL Interval 152.2 to 263.9
Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) AUC(0-24C) for Ro 485033	968.8 h*ng/mL Interval 723.3 to 1297.7	1352.5 h*ng/mL Interval 1073.4 to 1704.0
Dose-corrected Daily Exposure [AUC(0-24c)] to Bosentan Metabolites (Ro 478634, Ro 485033, Ro 641056) AUC(0-24C) for Ro 641056	716.2 h*ng/mL Interval 543.5 to 943.8	1014.1 h*ng/mL Interval 801.2 to 1283.6

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, up to Week 24 on average

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=31 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=33 Participants 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.
Change From Baseline in WHO Functional Class at End of Study Worsened WHO FC	1 Participants	1 Participants
Change From Baseline in WHO Functional Class at End of Study Unchanged WHO FC	27 Participants	25 Participants
Change From Baseline in WHO Functional Class at End of Study Improved WHO FC	3 Participants	7 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, up to Week 24 on average

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=31 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=33 Participants 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.
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Worsened as per physician evaluation	2 Participants	2 Participants
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Worsened as per parents evaluation	4 Participants	3 Participants
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Unchanged as per physician evaluation	24 Participants	24 Participants
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Unchanged as per parents evaluation	19 Participants	19 Participants
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Improved as per physician evaluation	5 Participants	7 Participants
Change From Baseline in Global Clincial Impression Scale (GCIS) at End of Study Improved as per parents evaluation	8 Participants	11 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, up to Week 24

Population: All randomized patients who received at least one dose of study drug and with available data.

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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=30 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=33 Participants 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.
Number of Patients With Treatment-emergent Liver Function Abnormalities ALT > 3 x ULN	1 Participants	0 Participants
Number of Patients With Treatment-emergent Liver Function Abnormalities AST > 3 x ULN	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, up to Week 24

Population: All randomized patients who received at least one dose of study drug and with available data.

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.

Outcome measures

Outcome measures
Measure	Bosentan 2 mg/kg t.i.d. (PK Set) n=30 Participants 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.	Bosentan 2 mg/kg b.i.d. (PK Set) n=33 Participants 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.
Number of Patients With Treatment-emergent Hemoglobin Abnormalities Hemoglobin decrease with values < 10 g/dL	1 Participants	3 Participants
Number of Patients With Treatment-emergent Hemoglobin Abnormalities Hemoglobin decrease with values < 8 g/dL	0 Participants	0 Participants

Adverse Events

Bosentan 2 mg/kg t.i.d

Serious events: 6 serious events

Other events: 18 other events

Deaths: 0 deaths

Bosentan 2 mg/kg b.i.d

Serious events: 4 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

clinical trial disclosure desk

Actelion Pharmaceuticals Ltd

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bosentan 2 mg/kg t.i.d n=31 participants at risk 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	Bosentan 2 mg/kg b.i.d n=33 participants at risk Patients received 2 mg/kg of bosentan twice daily (morning and evening) for at least 6 weeks and up to 26.4 weeks
Surgical and medical procedures ATRIAL SEPTAL DEFECT REPAIR	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Investigations BODY TEMPERATURE INCREASED	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Infections and infestations BRONCHOPNEUMONIA	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Cardiac disorders CARDIAC FAILURE	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 2 • 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)
Surgical and medical procedures CARDIAC OPERATION	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
Immune system disorders DRUG HYPERSENSITIVITY	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
Infections and infestations GASTROENTERITIS	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Infections and infestations INFECTION	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
Nervous system disorders LOSS OF CONSCIOUSNESS	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
Metabolism and nutrition disorders METABOLIC DISORDER	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
General disorders MULTI-ORGAN FAILURE	0.00% 0/31 • 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)	3.0% 1/33 • Number of events 1 • 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)
Investigations OXYGEN SATURATION DECREASED	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Respiratory, thoracic and mediastinal disorders PULMONARY ARTERIAL HYPERTENSION	3.2% 1/31 • Number of events 1 • 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)	3.0% 1/33 • Number of events 1 • 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)
General disorders PYREXIA	3.2% 1/31 • Number of events 2 • 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)	0.00% 0/33 • 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)
Respiratory, thoracic and mediastinal disorders RESPIRATORY DISTRESS	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Infections and infestations RESPIRATORY TRACT INFECTION VIRAL	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)
Infections and infestations VIRAL INFECTION	3.2% 1/31 • Number of events 1 • 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)	0.00% 0/33 • 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)

Measure	Bosentan 2 mg/kg t.i.d n=31 participants at risk 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	Bosentan 2 mg/kg b.i.d n=33 participants at risk Patients received 2 mg/kg of bosentan twice daily (morning and evening) for at least 6 weeks and up to 26.4 weeks
Infections and infestations BRONCHITIS	3.2% 1/31 • Number of events 1 • 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)	6.1% 2/33 • Number of events 2 • 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)
Gastrointestinal disorders CONSTIPATION	6.5% 2/31 • Number of events 2 • 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)	3.0% 1/33 • Number of events 1 • 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)
Respiratory, thoracic and mediastinal disorders COUGH	9.7% 3/31 • Number of events 3 • 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)	0.00% 0/33 • 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)
Gastrointestinal disorders DIARRHOEA	12.9% 4/31 • Number of events 5 • 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)	6.1% 2/33 • Number of events 2 • 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)
Respiratory, thoracic and mediastinal disorders EPISTAXIS	9.7% 3/31 • Number of events 3 • 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)	0.00% 0/33 • 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)
Vascular disorders FLUSHING	6.5% 2/31 • Number of events 2 • 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)	0.00% 0/33 • 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)
Infections and infestations NASOPHARYNGITIS	9.7% 3/31 • Number of events 4 • 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)	15.2% 5/33 • Number of events 8 • 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)
Infections and infestations OTITIS MEDIA	0.00% 0/31 • 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)	6.1% 2/33 • Number of events 2 • 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)
Respiratory, thoracic and mediastinal disorders PULMONARY ARTERIAL HYPERTENSION	0.00% 0/31 • 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)	6.1% 2/33 • Number of events 2 • 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)
General disorders PYREXIA	19.4% 6/31 • Number of events 7 • 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)	12.1% 4/33 • Number of events 7 • 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)
Skin and subcutaneous tissue disorders RASH	6.5% 2/31 • Number of events 2 • 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)	3.0% 1/33 • Number of events 1 • 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)
Infections and infestations RESPIRATORY TRACT INFECTION	3.2% 1/31 • Number of events 2 • 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)	6.1% 2/33 • Number of events 3 • 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)
Blood and lymphatic system disorders THROMBOCYTOPENIA	0.00% 0/31 • 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)	6.1% 2/33 • Number of events 2 • 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)
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	35.5% 11/31 • Number of events 13 • 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)	18.2% 6/33 • Number of events 8 • 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)
Gastrointestinal disorders VOMITING	12.9% 4/31 • Number of events 7 • 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)	3.0% 1/33 • Number of events 1 • 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)