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)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 24
- 试验地点
- 24
- 主要终点
- Change in Heart Rate From Baseline
研究概览
简要总结
This study was designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of riociguat at age-, sex- and body-weight-adjusted doses of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID in children from ≥6 to less than 18 years with pulmonary arterial hypertension (PAH) group 1. The study design consisted of a main study part followed by an optional long-term extension part. The main treatment period consisted of two phases: titration phase up to 8 weeks and a maintenance phase up to 16 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children from 6 years to less than 18 years of age with pulmonary arterial hypertension (PAH)
- •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)
- •Regardless of the type of PAH, the following findings are not exclusionary:
- •--- Patent foramen ovale (PFO) and asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 cm (both confirmed by echocardiogram) and not associated with hemodynamic alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 are not exclusionary
- •PAH diagnosed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
- •PAH 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 dyn•sec•cm^-5 (i.e., ≥3.0 wood units•m^2)
- •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 naïve 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 receive sexual counseling and use effective contraception as applicable. 'Effective contraception' is defined as progestogen-only hormonal contraception associated with inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or any combination of adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to use contraception is required from the signing of the informed consent form up until 4 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
排除标准
- •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
- •The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion.
- •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
- •WHO functional class IV
- •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 (estimated glomerular filtration rate <30 mL/min/1.73m^2 e.g. calculated based on Schwartz formula)
- •PH associated with idiopathic interstitial pneumonia (PH-IIP)
研究组 & 干预措施
Riociguat
Participants with age ≥6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 1.0 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration (up to 0.5 mg) of the dose for safety reasons was allowed at any time.
干预措施: Riociguat (Adempas, BAY63-2521) (Drug)
结局指标
主要结局
Change in Heart Rate From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Mean change in heart rate from baseline is reported.
Change in Clinical Chemistry (eGFR) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. eGFR = estimated glomerular filtration rate
Plasma Concentration of Riociguat at Week 0
时间窗: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week.
Plasma Concentration of Riociguat at Week 8
时间窗: Week 8 (pre-dose)
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Change in Blood Pressure From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.
Change in Hematology Parameters (Platelets) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Plasma Concentration of BAY60-4552 at Week 4
时间窗: Week 4 (pre-dose)
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Plasma Concentration of BAY60-4552 at Week 8
时间窗: Week 8 (pre-dose)
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Number of Participants With Any Treatment-emergent Adverse Events
时间窗: From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a participant administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs).
Change in Clinical Chemistry (Sodium) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Plasma Concentration of Riociguat at Week 4
时间窗: Week 4 (pre-dose)
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Change in Respiratory Rate From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Mean change in respiratory rate from baseline is reported.
Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age
时间窗: Baseline and Week 24 (plus/minus 5 days)
X-ray of left hand was performed for each participant and bone age was determined centrally by a specialist. For each participant, the bone age was compared to the chronological age and assigned to one of the categories - "delayed", "in accordance" or "advanced", indicating the advancement or delay in the growth of the bone. Number of participants who transitioned to another category different from baseline was calculated and is reported.
Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Urea) From Baseline
时间窗: Baseline and Week 24 (plus/minus 5 days)
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Plasma Concentration of BAY60-4552 at Week 0
时间窗: Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week
次要结局
- Change in Right Ventricular Cardiac Output From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Atrial Diastolic Area From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Atrial Diastolic Area Index From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in NT-proBNP From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in BNP From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Pericardial Effusion From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Cardiac Index From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Atrial Systolic Area Index From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Fractional Area Change From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Systolic Pulmonary Artery Pressure From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Quality of Life Evaluated by PedsQL Scale(Baseline and Week 24 (plus/minus 5 days))
- Number of Subjects With Clinical Worsening(Up to Week 24 (plus/minus 5 days))
- Change in Left Ventricular Eccentricity Index From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Pulmonary Artery Acceleration Time From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in 6-minute Walking Distance From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Number of Subjects With Change in WHO Functional Class From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Estimated Right Atrial Pressure From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Diastolic Area From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Systolic Area From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Atrial Systolic Area From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Diastolic Area Index From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Tricuspid Regurgitation Peak Velocity From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Tricuspid Annular Plane Systolic Excursion From Baseline(Baseline and Week 24 (plus/minus 5 days))
- Change in Right Ventricular Systolic Area Index From Baseline(Baseline and Week 24 (plus/minus 5 days))