Pulmonary Arterial Hypertension
Conditions
Keywords
Pediatric
Brief summary
The purpose of this study to confirm the selexipag starting dose(s), selected based on pharmacokinetic (PK) extrapolation from adults, that leads to similar exposure as adults doses in children from greater than or equal to (\>=) 2 to less than (˂) 18 years of age with Pulmonary Arterial Hypertension (PAH), by investigating the PK of selexipag and its active metabolite ACT-333679 in this population.
Detailed description
The selection of the starting dose for pediatric participants is based on the PK extrapolation from adults, taking into account the children body weight category, in order to lead to an exposure similar to that in adult PAH participants at a starting dose of 200 micrograms (mcg). As in adults, selexipag will be up-titrated to the individual maximum tolerated dose (iMTD) during the first 12 weeks. Approximately 60 participants will be enrolled in 3 different age cohorts to obtain at least 45 participants with evaluable PK profiles: Cohort 1: \>= 12 to \< 18 years of age, Cohort 2: \>= 6 to \< 12 years of age, Cohort 3: \>= 2 to \< 6 years of age. In each age cohort the starting dose will depend on the body weight. Enrollment will start with both Cohort 1 and Cohort 2. After completion of PK assessments in at least 15 participants from Cohort 1 at Week 12, a first interim analysis will be conducted to establish the dose-exposure relationship using a population PK model. The PK data from any participants in Cohort 2 who have completed their PK assessments at this time will be included in this first interim analysis. Results of this model-based analysis will be used to confirm or adjust the selexipag doses initially selected. Enrollment of Cohort 3 (children \>= 2 to \< 6 years of age) will start once the appropriate doses have been confirmed in a second interim analysis of PK data from Cohorts 1 and 2, and if there is no safety concern based on review by an Independent Data Monitoring Committee (IDMC).
Interventions
DRUGselexipag (Uptravi)
Film-coated tablets for oral administration
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent by the parent(s) or Legally authorized representative(s) AND assent from developmentally capable children * Males or females between greater than or equal to (\>=) 2 and less than (\<) 18 years of age with weight \>= 9 kilograms (kg) * Pulmonary arterial hypertension (PAH) diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before participant's enrollment * PAH with one of the following etiologies: * idiopathic (iPAH), * heritable (hPAH), * associated with congenital heart disease (CHD): PAH with co-incidental CHD; post-operative PAH (persisting/ recurring/ developing \>= 6 months after repair of CHD) * Drug or toxin-induced * PAH associated with HIV * PAH associated with connective tissue disease * Word Health Organization functional class (WHO FC) II to III * Participants treated with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor provided that the treatment dose(s) has been stable for at least 3 months prior to enrollment, or participants who are not candidates for these therapies * Females of childbearing potential must have a negative pregnancy test at Screening and at Enrollment, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) from screening up to study drug discontinuation plus 30 days (EOS) Key
Exclusion criteria
* Participants with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis * Participants with PAH associated with Eisenmenger syndrome * Participants with moderate to large left-to-right shunts * Participants with cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, univentricular heart or pulmonary atresia with ventricular septal defect, as well as Participants with Fontan-palliation * Participants with pulmonary hypertension due to lung disease * Previous treatment with Uptravi (selexipag) within 2 weeks prior to enrollment * Participants having received prostacyclin (epoprostenol) or prostacyclin analogs (that is, treprostinil, iloprost, beraprost) within 2 months prior to enrollment or are scheduled to receive any of these compounds during the trial * Treatment with another investigational drug within 4 weeks prior to enrollment * History, or current suspicion of intussusception or ileus or gastrointestinal obstruction as per investigator's judgment * Uncontrolled thyroid disease as per investigator judgment * Hemoglobin or hematocrit \< 75 percentage (%) of the lower limit of normal range * Known severe or moderate hepatic impairment * Clinical signs of hypotension that in the investigator's judgment would preclude initiation of a PAH-specific therapy * Participants with severe renal insufficiency * Known hypersensitivity to the investigational treatment or to any of the excipients of the drug formulations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCτ, ss, Combined) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) | AUCτ, ss, combined was defined as the area under the plasma concentration-time curve over one dosing interval at steady state. AUCτ,ss,combined was calculated as 1/38 AUCτ,ss,selexipag plus 37/38 AUCτ,ss,ACT-333679. |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Heart Rate | Up to 7 years |
| Change From Baseline Over Time in Height up to EOT+3 Days | EOT+3 days (Up to Week 17) |
| Change From Baseline Over Time in Body Mass Index (BMI) up to EOT + 3 Days | EOT+ 3 days (Up to Week 17) |
| Change From Baseline in Sexual Maturation (Tanner Stage) up to End of Treatment (EOT + 3 Days) | EOT+ 3 days (Up to Week 17) |
| Area Under the Plasma Concentration-time Curve Over a Dose Interval of Selexipag at Steady State (AUCτ,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Area Under the Plasma Concentration-Time Curve Over a Dose Interval of ACT-333679 at Steady State (AUCτ,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Maximum Observed Plasma Concentration of Selexipag at Steady State (Cmax,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Cmax,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Time to Reach the Maximum Observed Plasma Concentration of Selexipag at Steady State (Tmax,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Time to Reach the Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Tmax,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Trough Concentration of Selexipag at Steady State (Ctrough,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Trough Concentration of ACT-333679 at Steady State (Ctrough,ss) | Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12) |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) (End of Treatment [EOT] + 3 Days) | EOT+3 days (Up to Week 17) |
| Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Number of Participants With Adverse Events (AEs) Leading to Permanent Discontinuation of Study Drug | Up to 7 years |
| Number of Participants With Treatment-emergent Deaths (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Change From Baseline in Hematology Parameters (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Change From Baseline in Chemistry Parameters (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 Days) | EOT+3 days (Up to Week 17) |
| Change From Baseline in Blood Pressure | Up to 7 years |
| Change From Baseline in Thyroid Stimulating Hormone (TSH) up to EOT + 3 Days | EOT+3 days (Up to Week 17) |
Countries
Belarus, Belgium, Canada, China, France, Germany, Hungary, Israel, Malaysia, Poland, Russia, Serbia, Taiwan, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORCatherine Boisson
Actelion
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Greater Than or Equal to [>=] 12 Years to Less Than [<] 18 Years) Pediatric participants with pulmonary arterial hypertension (PAH) aged between \>=12 to \<18 years received Selexipag (Uptravi /ACT-293987/JNJ-67896049) orally on Day 1 based on body weight (\>=50 kilograms \[kg\] with a starting dose of 200 micrograms \[mcg\] and up-titrated to individual maximum tolerated dose \[iMTD\] of up to 1,600 mcg; weight \>=25 to \<50 kg: with a starting dose of 150 mcg and up-titrated to the iMTD of up to 1200 mcg; weight \>=9 to \<25 kg at a starting dose of 100 mcg , up titrated to the iMTD of 800 mcg) twice daily during the first 12 weeks. Up-titration was followed by a stable maintenance treatment period from Week 12 up to end of treatment. | 22 |
| Cohort 2 (>=6 to <12 Years) Pediatric participants with PAH aged between \>=6 to \<12 years received Selexipag (Uptravi /ACT-293987/JNJ-67896049) orally on Day 1 based on body weight (\>=50 kilograms \[kg\] with a starting dose of 200 micrograms \[mcg\] and up-titrated to iMTD of up to 1,600 mcg; weight \>=25 to \<50 kg: with a starting dose of 150 mcg and up-titrated to the iMTD of up to 1200 mcg; weight \>=9 to \<25 kg at a starting dose of 100 mcg , up-titrated to the iMTD of up to 800 mcg) twice daily during the first 12 weeks. Up-titration was followed by a stable maintenance treatment period from Week 12 up to end of treatment. | 21 |
| Cohort 3 (>=2 to <6 Years) Pediatric participants with PAH aged between \>=2 to \<6 years received Selexipag (Uptravi /ACT-293987/JNJ-67896049) orally on Day 1 based on body weight (\>=50 kilograms \[kg\] with a starting dose of 200 micrograms \[mcg\] and up-titrated to iMTD of up to 1,600 mcg; weight \>=25 to \<50 kg: with a starting dose of 150 mcg and up-titrated to the iMTD of up to 1200 mcg; weight \>=9 to \<25 kg at a starting dose of 100 mcg , up-titrated to the iMTD of up to 800 mcg) twice daily during the first 12 weeks. Up-titration was followed by a stable maintenance treatment period from Week 12 up to end of treatment. | 20 |
| Total | 63 |
Baseline characteristics
| Characteristic | Cohort 1 (Greater Than or Equal to [>=] 12 Years to Less Than [<] 18 Years) | Total | Cohort 3 (>=2 to <6 Years) | Cohort 2 (>=6 to <12 Years) |
|---|---|---|---|---|
| Age, Continuous | 14.2 years STANDARD_DEVIATION 1.79 | 9 years STANDARD_DEVIATION 4.53 | 3.8 years STANDARD_DEVIATION 1.28 | 8.5 years STANDARD_DEVIATION 1.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 56 Participants | 19 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 16 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 3 Participants | 6 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 39 Participants | 11 Participants | 12 Participants |
| Region of Enrollment BELARUS | 4 Participants | 9 Participants | 3 Participants | 2 Participants |
| Region of Enrollment BELGIUM | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment CHINA | 0 Participants | 8 Participants | 7 Participants | 1 Participants |
| Region of Enrollment FRANCE | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Region of Enrollment GERMANY | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment HUNGARY | 1 Participants | 5 Participants | 2 Participants | 2 Participants |
| Region of Enrollment ISRAEL | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Region of Enrollment MALAYSIA | 3 Participants | 7 Participants | 0 Participants | 4 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 7 Participants | 9 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Serbia | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Region of Enrollment TAIWAN | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment UKRAINE | 1 Participants | 5 Participants | 0 Participants | 4 Participants |
| Region of Enrollment UNITED KINGDOM | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment UNITED STATES | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 15 Participants | 36 Participants | 10 Participants | 11 Participants |
| Sex: Female, Male Male | 7 Participants | 27 Participants | 10 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 22 | 0 / 21 | 3 / 20 |
| other Total, other adverse events | 21 / 22 | 20 / 21 | 17 / 20 |
| serious Total, serious adverse events | 12 / 22 | 4 / 21 | 6 / 20 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCτ, ss, Combined)
AUCτ, ss, combined was defined as the area under the plasma concentration-time curve over one dosing interval at steady state. AUCτ,ss,combined was calculated as 1/38 AUCτ,ss,selexipag plus 37/38 AUCτ,ss,ACT-333679.
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Population: The Pharmacokinetic analysis set included all participants from the safety set who complied with the protocol sufficiently and did not deviate from the protocol in a way that might affect the PK outcome of the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Cohort 1 (Greater Than or Equal to [>=] 12 Years to Less Than [<] 18 Years) | Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCτ, ss, Combined) | 21.56 nanograms*hour per milliliter |
| Cohort 2 (>=6 to <12 Years) | Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCτ, ss, Combined) | 20.40 nanograms*hour per milliliter |
| Cohort 3 (>=2 to <6 Years) | Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCτ, ss, Combined) | 18.57 nanograms*hour per milliliter |
Secondary
Area Under the Plasma Concentration-Time Curve Over a Dose Interval of ACT-333679 at Steady State (AUCτ,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Area Under the Plasma Concentration-time Curve Over a Dose Interval of Selexipag at Steady State (AUCτ,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Change From Baseline in Blood Pressure
Time frame: Up to 7 years
Secondary
Change From Baseline in Chemistry Parameters (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Change From Baseline in Heart Rate
Time frame: Up to 7 years
Secondary
Change From Baseline in Hematology Parameters (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Change From Baseline in Sexual Maturation (Tanner Stage) up to End of Treatment (EOT + 3 Days)
Time frame: EOT+ 3 days (Up to Week 17)
Secondary
Change From Baseline in Thyroid Stimulating Hormone (TSH) up to EOT + 3 Days
Time frame: EOT+3 days (Up to Week 17)
Secondary
Change From Baseline Over Time in Body Mass Index (BMI) up to EOT + 3 Days
Time frame: EOT+ 3 days (Up to Week 17)
Secondary
Change From Baseline Over Time in Height up to EOT+3 Days
Time frame: EOT+3 days (Up to Week 17)
Secondary
Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Cmax,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Maximum Observed Plasma Concentration of Selexipag at Steady State (Cmax,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Number of Participants With Adverse Events (AEs) Leading to Permanent Discontinuation of Study Drug
Time frame: Up to 7 years
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) (End of Treatment [EOT] + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Number of Participants With Treatment-emergent Deaths (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (EOT + 3 Days)
Time frame: EOT+3 days (Up to Week 17)
Secondary
Time to Reach the Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Tmax,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Time to Reach the Maximum Observed Plasma Concentration of Selexipag at Steady State (Tmax,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Trough Concentration of ACT-333679 at Steady State (Ctrough,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary
Trough Concentration of Selexipag at Steady State (Ctrough,ss)
Time frame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)