| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Regadenoson will be used as a pharmacologic stress agent in paediatric patients with cardiovascular problems, undergoing a clinically indicated myocardial perfusion MRI |
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| E.1.1.1 | Medical condition in easily understood language |
Regadenoson will be used to study heart problems in children and young adults with existing heart conditions.
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065141 |
| E.1.2 | Term | Vascular diagnostic procedure |
| E.1.2 | System Organ Class | 100000004848 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To characterise the single IV dose PK of regadenoson over a range of doses in three paediatric populations: adolescents aged 12 to <18 years, children aged 2 to <12 years, and infants aged 1 to <24 months;
- To evaluate the safety and tolerability of a single IV bolus dose of regadenoson in paediatric populations with ages 1 month to <18 years
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| E.2.2 | Secondary objectives of the trial |
- To characterise the single IV dose PD of regadenoson on HR and coronary sinus flow over a range of doses in three paediatric populations: adolescents aged 12 to <18 years, children aged 2 to <12 years, and infants aged 1 to <24 months;
- To provide dosing recommendations for potential use of regadenoson in paediatric patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients who are clinically indicated to undergo a diagnostic MPI study using cardiac MRI performed in accordance with the institution’s practice for the paediatric age and condition under evaluation;
2.Male or female, adolescents aged from 12 to <18 years (Part A), children aged from 2 to <12 years (Part B), and infants aged from 1 to <24 months (Part C);
3.Weight >5th percentile and <95th percentile based on age and gender; and a body mass index (BMI) >5th percentile and ≤90th percentile for age and gender;
4.Acceptable range for BP (systolic / diastolic mmHg):
a.For Parts A and B: 85−130/45−90.
b.For Part C: 80−120/40−80.
5.Acceptable range for pulse:
a.For Part A: 55−100 beats per minute (bpm);
b.For Part B: 60−120 bpm;
c.For Part C: 70−1640 bpm.
6.Restriction of dosing with beta blockers (and preferably other cardioactive medications that may impact the ischaemic reaction to stress, e.g., calcium channel blockers, long-acting nitrates, angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], etc.) in accordance with study site’s routine practice for the stress procedure;
7.Patients and those whose parent(s) or legally authorised representative(s) who, in the Investigator's view, are likely to be compliant and complete the study;
8.Negative urine pregnancy test at screening and at pre-dose on the dosing day for post-menarchal female patients;
9.Post-menarchal female patients must be practicing abstinence, or be using an effective form of birth control (e.g., intrauterine device, oral contraceptives, contraceptive implants or injections, diaphragm with spermicide, cervical cap, or consort use of condom) for at least one month before being enrolled in the study and for the duration of the study;
10.Written informed consent and signed age-appropriate paediatric assent (for patients who are able to review and/or read the assent) prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
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| E.4 | Principal exclusion criteria |
1.Exclusions for the use of gadolinium and MRI are:
a.End stage renal failure (estimated glomerular filtration rate [GFR] <30mL/min/1.73m2);
b.Metallic implant or device (e.g. non-conditional pacemaker);
c.Known allergy to magnetic resonance contrast agents;
2.Exclusion criteria according to the use of general anaesthesia , if being applied;
3.Allergy or intolerance to adenosine, to any component of the regadenoson formulation, or to aminophylline or to its components (ethylenediamine and theophylline);
4.In the judgment of the Investigator, any clinically-significant ongoing medical condition (eg myocardial disease, pericardial inflammatory disease, or severe cardiac outflow obstruction, etc.) that might jeopardise the patient’s safety or interfere with the absorption, distribution, metabolism or excretion of the study drug;
5.Use of any experimental or investigational drug or device within 30 days prior to the first dose of study drug;
6.Patients with 2nd or 3rd degree AV block or sick sinus syndrome with or without an artificial pacemaker, and/or with unstable angina that has not been stabilised with medical therapy and/or with severe hypotension and/or with decompensated states of heart failure;
7.Known or suspected bronchoconstrictive and bronchospastic lung disease either being unstable or requiring active treatment (e.g., wheezing noted on physical exam, frequent exacerbations or active treatment with a bronchodilator or corticosteroids);
8.Abnormal sitting or semi-recumbent resting BP or pulse (bpm) at screening. If, upon repeat assessment, the sitting or semi-recumbent resting BP or pulse (bpm) at screening is normal, the patient may be evaluated further for inclusion in the study;
9.Dipyridamole use within 48 hours prior to dosing;
10.Consumption of methylxanthine-containing products such as caffeinated coffee, tea, caffeinated soft drinks, cocoa or chocolate in the 12 hours prior to dosing;
11.Aminophylline or theophylline use within 24 hours prior to dosing;
12.History of alcohol abuse or drug addiction, as determined by the Investigator;
13.Currently smokes more than five cigarettes or equivalent per day, and if eligible for the study, would not be able to abstain from smoking from midnight prior to dosing until the end of the study period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and Tolerability Endpoints
Assessments of heart rate, blood pressure and Adverse Events of a single bolus dose of regadenoson in paediatric populations with ages 1 month to <18 years.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
HR and supine BP (mmHg) (systolic/diastolic). Additional vital signs should be recorded as clinically indicated.
Pre and post-dose vital signs will be recorded as follows:
• Pre-dose: 15 minutes and 5 minutes prior to dosing;
• Post-dose: 1, 3, 6, 10, 15, 30 minutes and 1, 2, and 4-6 hours post dosing.
For post dose vital signs recordings, the time windows are as follows: +/- 0 minutes for minutes 0 through 10, +/- 2 minutes for minutes 15 through 30, and +/- 10 minutes for hours 1 through 6.
Adverse Events will be recorded throughout the trial. |
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| E.5.2 | Secondary end point(s) |
Pharmacokinetic (PK) Outcome Measures, namely, the determination of the PK profile of regadenoson.
Pharmacodynamic (PD) outcome measures: assessment of coronary sinus flow and HR. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For PK outcome measures: for Adolescents aged 12 to <18 years (part A), plasma samples for measurement of regadenoson concentrations are collected pre-dose and at 1, 3, 6, 10, 15, 30 minutes, and then 1, 2, and 4-6 hours post dose. For Children aged 2 to <12 years (part B) and Infants aged 1 to <24 months (part C), population PK modelling will be applied. The frequency, time-points, and/or sampling windows of blood draws for PK will be determined after analysis of the data from Part A, and will be adjusted based on the volume of blood allowed to be drawn from patients in each age group.
For PD outcome measures: assessment of coronary sinus flow and HR. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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