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Open-label, individual dose titration study to evaluate safety, tolerability and pharmacokinetics of riociguat in children from 6 to less than 18 years of age with pulmonary arterial hypertension (PAH)

Riociguat in children with pulmonary arterial hypertension (PAH)

24

PATENT-CHILD targeted pediatric patients with pulmonary arterial hypertension (PAH). Among the 24 subjects in the safety analysis set, the most common type of PAH was idiopathic PAH (18 [75.0%] subjects). 6 subjects were >=6 to <12 years old and 18 subjects were >=12 to <18 years old. 15 subjects were on endothelin receptor antagonist (ERA)-only and 9 subjects were on ERA+ prostacyclin analogue (PCA). No subjects were included in the PCA only group.

A total of 26 subjects were screened in 16 study centers in 9 countries or regions. 2 subjects did not pass the screen of inclusion/exclusion criteria.24 subjects entered the treatment period and received riociguat. 21 (87.5%) subjects completed the 24-week main treatment period and entered the optional long-team extension phase. 3 (12.5%) subjects did not complete the main treatment period and the reason for non-completion was adverse events. Of the 3 subjects, 1 subject completed the safety follow-up visit and 2 subjects did not complete the safety follow-up visit.

Treatment-emergent adverse events (TEAEs): The most common TEAEs in total by MedDRA PT were headache (29.2% of subjects), abdominal pain, nasopharyngitis and upper respiratory tract infection (16.7% each). The TEAE frequencies and the ranking of the most frequent TEAEs were generally comparable across equivalent treatment doses. Deaths: No death occurred during the main treatment period of the study. Serious TEAEs: Serious TEAEs were reported for 4 (16.7%) subjects in total. The most common serious TEAEs in total by MedDRA PT were right ventricular failure (reported for 2 [8.3%] subjects), and asthma, pain of skin, skin swelling, and hypotension (reported for 1 [4.2%] subject, each).

The primary aim of this single-arm, open-label study was to evaluate the safety, tolerability and pharmacokinetics of oral riociguat treatment in subjects of >=6 and <18 years of age and with idiopathic pulmonary arterial hypertension (PAH), hereditable PAH or PAH associated with connective tissue disease or congenital heart disease with shunt closure. All efficacy variables were evaluated in an exploratory manner. Primary variables Safety Adverse events: Refer to the column above. Laboratory safety parameters. Overall, laboratory safety parameters, mean and median changes between baseline and subsequent study visits were small and comparable across age and concomitant PAH medication subgroups. No clinically significant abnormalities of laboratory parameters were reported. Other safety data. As expected with the known pharmacological mechanism of action of riociguat, mean systolic blood pressure (SBP) decreased under riociguat treatment. Mean diastolic blood pressure decreased in the study with similar trends as observed in SBP. No clinically meaningful changes in heart rate, weight, or electrocardiogram parameters were identified. Overall, no clinically significant transition in bone age and bone morphology was observed at Week 24. No clinically significant difference was observed across age and concomitant PAH medications subgroups. In summary, the TEAEs reported were consistent with the study population with underlying PAH and frequent comorbidities, and with previous observations in the use of riociguat in adults with this indication. The results of the safety analyses in PATENT-CHILD indicate that the administration of body weight adjusted riociguat (tablets or suspension) is safe and well tolerated when given to subjects between >=6 and <18 years of age with idiopathic PAH, hereditable PAH or PAH associated with connective tissue disease or congenital heart disease with shunt closure. Primary variables Clinical pharmacology Pharmacokinetics(PK): Plasma concentrations of riociguat and the main metabolite M1 in pediatric population were in the range of riociguat plasma concentrations observed in adult studies with riociguat. PK results confirmed riociguat dosing strategy established in the PATENT-CHILD attained adult exposures.

Secondary variables Efficacy 6MWD: For 6MWD, an improvement with a mean change of 23.01 m was seen between baseline and Week 24. WHO functional class: For WHO functional class, the majority of subjects (18 [75.0%]) had a WHO functional class of II at baseline. No change was seen between baseline and Week 24. NT-proBNP: For NT-proBNP, an improvement with a median change of -12.05 pg/mL (a mean change of -65.77 pg/mL) was seen between baseline and Week 24. Between baseline and Week 24, BNP values increased with a median change of 1.25 pg/mL (a mean change of 7.45 pg/mL). Echocardiographic parameters: For echocardiographic parameters, evaluation of the mean changes in the small population did not allow to identify trends across all parameters. Clinical worsening: Clinical worsening was observed in 2 (8.3%) subjects in total who were reported with hospitalization for right heart failure.

Overall, there has been no safety concern identified in the main study part of PATENT-CHILD. The PK results confirmed riociguat dosing strategy established in this study attained adult exposures. The efficacy data suggested a positive trend in some of the secondary endpoints, indicating that subjects between >=6-<18 years of age with PAH may benefit from the treatment with body weight adjusted riociguat.

Oct. 06, 2023

July. 01, 2022

https://onlinelibrary.wiley.com/doi/10.1002/pul2.12133

No

Myoishi Masashi

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

byl_ct_contact@bayer.com

Dedicated contact

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

+81-6-6133-6363

byl_ct_contact@bayer.com

completed

May. 31, 2017

Interventional

No Blinding, Shingle arm study

treatment purpose

3

- Children aged >=6 to <18 years
- Diagnosed with PAH :
- Idiopathic (IPAH)
- Hereditable (HPAH)
- PAH associated with (APAH)
- Connective tissue disease
- Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery)
- Diagnosis of PAH confirmed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
- Pulmonary arterial hypertension confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) >=25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) =<15 mmHg, and pulmonary vascular resistance (PVR) >240 dynseccm-5 (i.e., >=3.0 wood unitsm2)
- Patients must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit.
Two groups of patients will be included:
-Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) who need additional treatment (discretion of the investigator)
-Incident: Treatment naive patients initiated on PAH medication (allowing ERA and/or PCA) and then riociguat added once patients are stable on standard of care
- WHO functional class I-III
- Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to use adequate contraception when sexually active. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 6 weeks after the last study drug administration.
- Young men must agree to use adequate contraception when sexually active.
-Written inform consent provided and if applicable child assent provided

- Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in any form
- Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1
- Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening
- Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004)
- History of left-sided heart disease, including valvular disease or heart failure
- Pulmonary hypertension related to conditions other than specified in the inclusion criteria
- Pulmonary veno-occlusive disease
- Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN)
- Severe restrictive lung disease
- Severe congenital abnormalities of the lung, thorax, and diaphragm
- Clinically relevant hepatic dysfunction (especially Child Pugh C)
- Renal insufficiency (glomerular filtration rate <35 mL/min e.g. calculated based on Cockroft formula)
- PH associated with idiopathic interstitial pneumonia (PH-IIP)

Both

Hypertension, pulmonary

investigational material(s)
Generic name etc : Riociguat (Adempas, BAY63-2521)
INN of investigational material : Riociguat
Therapeutic category code : 219 Other cardiovascular agents
Dosage and Administration for Investigational material : The individual optimal (maintenance) dose is to be determined based on patients monitoring of systolic blood pressure, well-being and clinical status.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
pharmacokinetics
Change in incidence of treatment-emergent adverse events
Change in incidence of treatment-emergent serious adverse events
Change in heart rate
Change in blood pressure
Change in bone age x-ray of left hand
Plasma concentration of riociguat
Baseline to week 24
Day 0, Day 1 (0.5, 1.5 and 2.5h), Day 28, Day 56

efficacy
Change in 6-Minute Walking Distance (6MWD)
Change in WHO functional class
Change in NT-proBNP (N-terminal pro-brain natriuretic peptide)
Changes in echocardiograph from baseline
Time to clinical worsening
Change in Quality of Life scores as assessed by patient questionnaire and PedsQL generic score
Questionnaire to assess both taste and texture of pediatric formulation(s)
Baseline to week 24

Aug. 04, 2016

Aug. 04, 2016