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Study Sponsor: Study Number: 1555 Study Phase: II Clinical Trial Results Synopsis STUDY DESIGN DESCRIPTION Bayer Healthcare AG NCT00000000 Official Study Title: Open, non controlled, non randomised, unicenter pilot study to investigate the long-term efficacy of Adalat drops and Adalat retard 10 mg tablets in children with pulmonary hypertension and with peripheral pulmonary stenosis Test Product Therapeutic Area: Cardiology/Coagulation Name of Test Product: Adalat (Nifedipine, BAYA1040) Name of Active Ingredient: Dose and Mode of Administration: Reference Therapy/Placebo Nifedipine Reference Therapy: Not applicable Dose and Mode of Administration: Subjects weighing <5 kg were treated with Adalat drops 0.5% or 2% and subjects weighing >5 kg were treated with Adalat retard 10 mg tablets. The total daily dosage ranged between 0.5 to 2.0 mg/kg body weight/day. The daily dosage of Adalat drops was divided into 4 to 6 regularly administered doses taken with meals. Adalat retard 10 mg tablets were administered twice per day in 12-hour intervals. Not applicable Duration of Treatment: Each subject had an individual dose titration during an inhospital phase for 5 to 7 days. Endpoints of the treatment period were: normalisation of the pulmonary arterial pressure, termination of treatment owing to serious adverse events, e.g. uncontrollable cardiac insufficiency, hypersensitivity to Adalat, withdrawal of parental consent, after correction of congenital defects by operation and limitation of the post-operative treatment period to 1 to 2 years. Studied period: Date of first subjects first visit: 21 Feb 1990 Date of last subjects last visit: 09 Dec 1992 Study Center: One investigational site treated 33 subjects at one center located in Austria. Methodology: This was a unicenter, long-term, open, non-controlled, non randomized observational pilot study without a comparison group. Stabilisation was achieved during a 5 to 7 day inpatient treatment phase with dose titration dependent on efficacy and side effects. Further treatment was carried out at home by the subjects, who collected the study medication at regular intervals Page 1 of 5
Indication/ Main Inclusion Criteria: Study Objectives: Evaluation Criteria: from the investigator and reported on the progress during the intervening period. Outpatient control examinations were conducted at 3 to 6 monthly intervals by the investigator which included a physical examination, an ECG, a chest X-ray and Doppler echocardiography. In order to assess the hypertrophy of the right ventricle, an M-Mode Doppler echocardiography was performed. In this mode, the diameter of the ventricular septum, the anterior wall of the right ventricle and the right ventricle were also determined. Two-dimensional echocardiography was also performed in cases of elevated right ventricular pressure. In the subjects with pulmonary hypertension, Doppler echocardiography was performed to study the flow profile. Determination of pressure gradients was also done. Neonates and infants who presented with primary pulmonary hypertension, congenital heart disease with pulmonary hypertension (atrial, ventricular, and combined atrio-ventricular septal defect, ductus arteriosus Botalli persistent, Eisenmenger's syndrome), bronchopulmonary dysplasia, peripheral pulmonary stenoses, or persistent fetal circulation in newborns were included. Subjects suffering from congenital vitium and secondary pulmonary hypertension could be included in the study if they were regarded as primarly inoperable or at increased surgery risk. Overall: To investigate the efficacy and tolerance of Adalat drops and Adalat retard 10 mg tablets in the long-term therapy of neonates and infants with primary and secondary pulmonary hypertension and peripheral pulmonary stenoses and in newborns with persistent fetal circulation. Primary: Reduction in the pulmonary hypertension and regression of right ventricular hypertrophy in subjects with bronchopulmonary dysplasia. Secondary: Improvement in the quality of life, enabling of operability and reduction of the surgical risk. Efficacy (Primary): Endpoints of Adalat therapy were normalization of the pulmonary artery pressure (assessed by Doppler echocardiography), corrective heart surgery and post surgical treatment. The following variables were investigated: Left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), shortening fraction (VF%), ventricular septum diameter (SEPT), right ventricular end diastolic diameter (RVEDD), ventricular septum motility (MOTION), acceleration time (TIME), pulmonary artery systolic pressure (PASP), proportion of pre-ejection time to ventricular ejection time (EJECT), ventricular septum defect - gradient (VSD GR), right atrium-right ventricular-gradient (TI), (RA-RV-TI), right Page 2 of 5
Statistical Methods: ventricular-mean pulmonary artery gradient (PI), (RV/MPA-PI), systolic and diastolic blood pressure (BPS)(BPD), heart rate (HR), right ventricular systolic pressure (TI), (RVSP), pulmonary artery diastolic pressure (PI), (PADP) and right ventricular hypertrophy (RVHYP). Efficacy (Secondary): -Ability to drink (newborns), -Shortness of breath, -Pleasure of playing, -Limitation in moving, -Enabling of operability and -Reduction of surgical risk. Safety: Safety of Adalat was evaluated by the adverse events (AEs) and their characteristics (intensity, relationship to the study drug, outcome etc.) which occurred during the study. Efficacy (Primary): The primary efficacy parameters were mostly of quantitative character (except for the septum motility and right ventricular hypertrophy). All relevant quantitative variables were analyzed by basic descriptive characteristics of location and dispersion (mean, median, standard deviation, minimum, maximum). Efficacy (Secondary): All secondary parameters were qualitative (categorical). The data of qualitative variables were described by frequency tables. Safety: The safety analyses included the following descriptions: listing of AEs and listing of deaths. Number of Subjects: A total of 20 subjects were planned to be recruited; 33 subjects were enrolled. Results Summary Subject Disposition and Baseline Study Results A total of 33 subjects (18 males, 15 females) were enrolled in the study. All subjects were Caucasians except one Black subject and one Asian subject. All subjects were included into the intent-to-treat analysis. Due to early heart surgery and some cases with infaust prognosis, 9 subjects were left for long-term therapy with follow-up investigations after 3, 6, 9, and 12 months. Only one subject was available after 21 months. The average age of the subjects was 5 months (0 to 15), average weight 4.4 kg (1-8.5) and average height was 60 cm (47 to 45). In 10 cases, complex congenital heart disease was due to Trisomy 21. Eight subjects were diagnosed to have broncho-pulmonal dysplasia and 8 with ventricular septal defect. The daily dose was increased during the in-hospital titration period from a median of 0.5 to 1.0 mg/kg body weight. During the further stages of therapy (i.e. from 3 to 24 months after study start) the average dosage of the study drug remained constant and oscillated around one mg/kg body weight. After 3 months, 9 subjects continued the study; after 15 months there were only 6 subjects and after 21 months only one subject was left. The average duration of the treatment was 136.2 (3 to 639) days. Page 3 of 5
Results Summary Efficacy The variety of diagnoses and their severity, the differing courses, surgical interventions, failure of measurements due to restlessness, small numbers at the beginning and rare cases with late follow-up investigations did not provide the echocardiographic parameters a sensitive tool in this study. Left ventricular end-systolic diameter (VESD): Average values of LVESD measured after 3 months and after 6 months remained constant and did not differ markedly from the average baseline value (= 12.54 mm). Left ventricular end-diastolic diameter (VEDD): The minimum average value of LVEDD was registered as 19.88 mm after 3 months of therapy. Later investigations showed a tendency of LVEDD to increase to a maximum value of 25.1 mm after 18 months. Shortening fraction (VF): Before the study, after 3 and 6 months the average VF values oscillated around 40%. After that VF decreased, the minimum average value 33.1% was documented after 12 months. Later investigations showed an increase to a maximum value of 52% after 18 months. Ventricular septum diameter (VSD): During the entire treatment, the measured values of VSD remained almost constant and oscillated around 5.5. Right ventricular end-diastolic diameter (RVEDD): The course of RVEDD during the therapy showed a rather irregular pattern with local peaks of 11.57 mm (after 6 months), 12.5 mm (after 12 months), 12.57 mm (after 15 months) and local troughs of 9.57 mm (after 9 months) and 10.0 mm (after 18 months). Septum motility: At baseline, the most frequent categories were "paradoxical" (14 cases), "flattened" (7 cases) and "oblate" (5 cases). In 10 subjects with long term measurements, no change in septum motility was observed. Acceleration Time (AT): Over a period of 12 months from study start, the values of AT increased on the average from 56.6 msec. (before study) to 76.7 msec. (after 12 months). Pulmonary artery systolic pressure (PASP): The average values of PASP decreased monotonously from 63.01 mmhg at baseline to 51.85 mmhg after 12 months. After that the values of PASP indicated a certain increase. Relation of pre-ejection time to right ventricular ejection time (EJECT): During the first 12 months of therapy, the EJECT values decreased slightly and monotonously from 0.34 to 0.24. For the following parameters only a few values were documented: VSD GR, RA-RV-TI, RV-PI, MPA-PI, RVSP and PADP. The available numbers of these parameters were very small and did not allow drawing any conclusion concerning the efficacy. A constant improvement in the secondary efficacy parameters was observed. In 3 children with broncho-pulmonal dysplasia Adalat was stopped after normalization of pulmonary hypertension. In 15 subjects, a corrective operation became feasable by Adalat therapy, leading to a normalized pulmonary circulation in 12 of them. Results Summary Safety A total of 15 AEs was documented in 9 of the 33 subjects: pneumonia (N = 3), cardiac decompensation (N = 2), sepsis (N = 2), anuria for nephrotic syndrome (N = 1), hemorrhagic pneumonia (N = 1), urinary tract infection (N =1), intestinal infection (N = 1), varicella (N = 1), respiratory insufficiency (N = 1), hospitalized in moribund state (N = 1) and severe pulmonary hypertension (N = 1). The relationship to the study drug was assessed as "unlikely" or "not assessable" for all AEs, except one (cardiac decompensation was assessed as "probable"). Seven AEs resolved, 2 remained unchanged, 3 required prolonged hospitalization and 4 caused the subject's Page 4 of 5
death. Eight subjects died during the study or within a short period after the end of the study. Conclusions This study was the first investigation of Adalat in pulmonary hypertension. This observational study showed benefit in clinical markers but failed to verify them by quantitative parameters possibly due to a small total number and varying diagnoses. Date Created or Date Last Updated: 23 Aug 2011 Page 5 of 5