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

This is the total number of subjects with at least one adverse event (serious or not serious) whether or not causally related to the study drug and presented cumulatively in the FUTURE 3 and FUTURE 3 Extension study. NOTE: FUTURE 3 extension study was exploratory and no primary efficacy and safety endpoints were defined in the protocol. So, this safety outcome measure was selected and reported as primary endpoint here.

Mean extent of exposure to bosentan treatment in months

Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).

Exercise capacity was assessed using the 6MWT. Area used for testing had to be a minimum of 30m in length and 2-3m in width, with 3m gradations. Areas were well ventilated with air temperature controlled. The test was administered at the same time of day and by the same tester throughout the study. The tester measured the distance walked by non-encouraged patients during the timed 6min period. If the test was stopped before 6 minutes, the main reason for stopping the test was recorded. The tester measured the distance walked by patients during the timed 6min period.

Maximal dyspnea during the walk test was assessed by the patient using the Borg dyspnea index. Immediately following each walk test, patients rated perceived maximal breathlessness during the walk test on a 12-point scale (0 \[nothing at all\], 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 \[maximum ever experienced\]).

Disease severity was assessed by WHO classification of PH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA.

An event of clinical worsening was defined as death during the treatment period, a treatment-emergent adverse event that led to permanent discontinuation of study treatment and with outcome death, hospitalization due to worsening pulmonary hypertension, or lung transplantation. Patients are censored at 1 day after the end of treatment or at day of pulmonary endarterectomy if earlier.

In order to compare the growth data with those of healthy children, growth curves are calculated from height data collected throughout the follow-up period. For each patient, height measured at each study visit was converted to a z-score and expressed in standard deviations (SD) from WHO growth standards. The Z-score was calculated according to the following formula: Z-score = (observed value of the study participant - median value of the reference population) / SD value of the reference population

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height.

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure.

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in blood pressure.

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including changes from baseline in pulse rate.

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including laboratory abnormalities related to liver enzymes. Proportion of patients with increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN) is reported here.

The main study objective was to assess the long-term safety and tolerability of bosentan in children with PAH, including hemoglobin abnormalities. Proportion of patients with marked hemoglobin decreases (i.e., decrease of or above 15% of the lower normal limit (LL)) is reported here.

AUCt was assessed at steady state (i.e., after at least 2 weeks of treatment with a same dose of the study drug) over 12 hours .

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

SHAQ evaluates physical disability. Patients were instructed to rate their capacity to perform activities of daily living within the previous 7 days by checking one of the following descriptors: "without any difficulty", "with some difficulty," "with much difficulty," or "unable to do," equivalent to scores of 0, 1, 2, and 3, respectively. Items were categorized into 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities.

Overall hand pain related to finger ulcers was assessed by the patient using a Visual Analogue Scale. Patients were instructed to score their pain by marking on the continuous 10-cm scale, where 0 (left) was no pain and 100 (right) very severe pain, in response to the question, "How much pain have you had because of your finger ulcers in the past week?" The investigator measured the distance in millimeters between 0 and the patient mark with the ruler provided and recorded the distance.

UKFS relates to upper and lower extremity function and muscle weakness. For each item, the patient indicated the responses that best described their current ability: "able to perform in a normal manner," "able to perform with alteration in style," "can only manage with difficulty," and "impossible to achieve." Each response was given an integer from 0 (able to perform in a normal manner) to 3 (impossible to achieve), and the sum of individual responses provided an overall score of 0 to 33. Missing values were replaced with the worst value the patient reported on the other items at that visit.

The total number of new DUs per patient observed by the investigator at planned visits and new transient DUs recorded in the patient diary (a patient diary was used to record DUs that might appear and disappear between two planned visits) were assessed at each clinic visit