E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Children 5 to 11 years of age with persistent asthma. |
Børn i alderen 5-11 år med vedvarende astma |
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E.1.1.1 | Medical condition in easily understood language |
Children with chronic asthma. |
Børn med kronisk astma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 estimate the effects on HPA axis function for MF/F MDI 50/10 mcg, 100/10 mcg and 200/10 mcg twice daily (BID) in plasma cortisol AUC(0-24 hours) as compared to montelukast 5 mg once daily (QD) (4 mg QD for children 5 years of age) in children 5 to 11 years of age with persistent asthma. |
At vurdere effekten af HPA akse funktion for MF/F MDI 50/10 mikrogram, 100/10 mikrogram og 200/10 mikrogram to gange daglig i plasma kortisol AUC(0-24 timer) sammenlignet med montelukast 5 mg en gang daglig (4 mg en gang daglig for børn på 5 år) til børn i alderen
5-11 år med vedvarende astma |
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E.2.2 | Secondary objectives of the trial |
To compare the log transformed plasma cortisol trough level (Ctrough) at treatment Endpoint (Day 42) evaluation across treatments. |
At evaluere plasma kortisol-trough niveau (Ctrough) på sidste behandlingsdag (dag 42) - sammenligning af alle behandlingerne |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•A subject must have a body weight ≥18 kg.
•Based upon the medical judgment of the investigator: if there is no inherent harm in changing the subject's current asthma therapy, the subject (and subject's legal representative) must be willing to discontinue his/her prescribed ICS or ICS/LABA before beginning montelukast run-in medication.
•At the Screening Visit, the subject's forced expiratory volume in one second (FEV1) must be ≥ 70% of predicted when all restricted medications have been withheld for the appropriate intervals.
•A subject must have been using a low or medium daily dose of ICS (either alone or in combination with a LABA) for at least 12 weeks with no use of oral corticosteroids within 3 months prior to Screening. A subject must have been on a stable asthma regimen (daily dose unchanged) for at least 2 weeks prior to Screening. (Refer to protocol for full details.)
•A subject with a documented positive (at least 12% increase in FEV1) reversibility test, obtained within the 12 months prior to signing the consent form, is eligible for the study. Otherwise, to document the diagnosis of asthma and assure the subject's responsiveness to bronchodilators before randomization will have to be determined at the Screening Visit or at any time prior to the Baseline Visit:
The subject must demonstrate an increase in absolute FEV1 of at least 12% within 30 minutes after administration of 200 mcg to 400 mcg of albuterol/salbutamol or of nebulized short-acting beta-2 agonist (SABA; 2.5 mg).
•The subject must demonstrate ability to use a peak flow meter correctly and to perform spirometry and PEF measurements.
•A subject must demonstrate ability to use an inhaler correctly according to protocol-defined procedures.
•Clinical laboratory tests (complete blood count [CBC], blood chemistries, including urine pregnancy for female subjects of child-bearing potential [i.e., who have started menstruating], and urinalysis) conducted at the Screening Visit must be clinically acceptable to the investigator before the subject is instructed to start using open-label montelukast run-in medication. A female subject of childbearing potential (i.e., who has started menstruating) must have a negative urine pregnancy test at Screening in order to be considered eligible for the open-label montelukast Run-in Period. Rescreening is not permitted for this study.
•The subject must demonstrate a basal plasma/serum cortisol concentration of 10 µ/dL to 25 µ/dL between 7 AM and 10 AM at the Screening Visit.
•The subject (and the subject's legal representative) must be willing to give written informed consent/assent for the trial, and for pharmacogenetic testing and be able to adhere to dose and visit schedules.
Note: Subjects (and subjects' legal representative) who are unwilling to sign the informed consent for pharmacogenetic testing may be included in the trial; howvere, pharmacogenetic samples must not be obtained.
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• Kropsvægt ≥18 kg.
• På baggrund af investigators lægelige skøn: Hvis der ikke er nogen fare ved at ændre forsøgsdeltagerens aktuelle astmabehandling, skal forsøgsdeltageren (og forsøgsdeltagerens værge) være villig til at få seponeret sit ordinerede inhalationssteroid eller inhalationssteroid/langtidsvirkende beta-2-agonist før påbegyndelse af indkøringsmedicinen montelukast.
• Ved screeningsbesøget skal forsøgsdeltagerens FEV1 (forceret eksspiratorisk volumen i det første sekund) være ≥ 70 % af den forventede værdi, når al begrænset medicin er holdt tilbage i de relevante intervaller.
• Forsøgsdeltageren skal have anvendt en lav eller mellemstor dosis inhalationssteroid (enten alene eller i kombination med en langtidsvirkende beta-2-agonist) i mindst 12 uger og må ikke have anvendt perorale glukokortikosteroider i de sidste 3 måneder inden screening. Forsøgsdeltageren skal have fulgt et stabilt astmaregimen (daglig dosis uændret) i mindst 2 uger inden screening (se protokol for alle detaljer)
• Forsøgsdeltagere med en dokumenteret positiv (mindst 12 % stigning i FEV1) reversibilitetstest inden for 12 måneder før underskrivelse af informeret samtykkeerklæring er egnede til forsøget. Ellers kan følgende metode anvendes ved screeningsbesøget eller på et vilkårligt tidspunkt inden baselinebesøget til at dokumentere astmadiagnosen og sikre
forsøgsdeltagerens modtagelighed over for bronkodilatatorer inden randomisering:
o Forsøgsdeltageren skal vise en stigning i FEV1 på mindst 12 % inden for 30 minutter efter indgivelse af 200–400 mcg albuterol/salbutamol eller nebuliseret korttidsvirkende beta-2-agonist (2,5 mg).
• Forsøgsdeltageren skal vise, at han/hun kan bruge et peakflow-meter korrekt og udføre spirometri og PEF-målinger.
• Forsøgsdeltageren skal vise, at han/hun kan bruge en inhalator korrekt i henhold til protokoldefinerede procedurer.
• Kliniske laboratorietest (komplet blodtælling [CBC], blodkemi, herunder uringraviditetstest for kvindelige reproduktionsdygtige forsøgsdeltagere [dvs. er begyndt at menstruere] og urinanalyse) udført ved screeningsbesøget skal være klinisk acceptable for investigator,
inden forsøgsdeltageren bedes om at påbegynde behandling med ikkeblindet montelukast som indkøringsmedicin. Kvindelige reproduktionsdygtige forsøgsdeltagere (dvs. er begyndt at menstruere) skal have en negativ uringraviditetstest ved screeningen for at blive betragtet som egnede til den ikke-blindede indkøringsperiode med montelukast. Ny screening er ikke tilladt i dette forsøg.
• Forsøgsdeltagerne skal vise en basal plasma/serumkortisolkoncentration på 10 μg/dl til 25 μg/dl mellem kl. 7.00 og 10.00 ved screeningsbesøget.
• Forsøgsdeltageren (og forsøgsdeltagerens værge) skal være villig til at give skriftligt samtykke/tilsagn til forsøget og til farmakogenetisk testning og skal være i stand til at overholde doserings- og besøgsplaner.
Bemærk: Forsøgsdeltagere (og forsøgsdeltagerens værge), som ikke er villige til at underskrive den informerede samtykkeerklæring vedr. farmakogenetisk testning, kan godt inkluderes i forsøget, men der kan ikke tages farmakogenetiske prøver |
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E.4 | Principal exclusion criteria |
•A Subject who has taken a high dose of ICS for at least 30 days within the last 6 months prior to Screening Visit. High doses of ICSs are defined in the table above.
•A subject who demonstrates <80% compliance with use of montelukst during the 4-week Run-in Period. Compliance will be determined by counting montelukast tablets in the bottle at Visit 2.
•A subject who requires the use of more than eight inhalations per day of SABA or two or more nebulized treatments per day of 2.5 mg SABA on any 2 consecutive days from the Screening Visit up to and including the Baseline Visit.
•A subject who has a 30% decrease in AM or PM PEF below the Run-in Period stability limit on any 2 consecutive days prior to randomization. To determine the stability limit, the average AM and average PM PEF respective values from the preceding 7 days will be added, divided by the number of non-missing values, and multiplied by 0.70.
•A subject who has an occurrence of clinical deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication (including oral or other systemic corticosteroids, but allowing SABA; see protocol Section 7.4.2.1.1) as judged by the clinical investigator at any time from the Screening Visit up to and including the Baseline Visit.
•A subject with a QTc>440 msec for boys and a QTc>450 msec for girls on ECG at or within 30 days prior to Screening.
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• Forsøgsdeltagere, som har taget en høj dosis inhalationssteroid i mindst 30 dage inden for de sidste 6 måneder inden screeningsbesøget. Høje doser inhalationssteroid er defineret i tabellen ovenfor.
• Forsøgsdeltagere, som udviser < 80 % komplians med montelukast i 4-ugers indkøringsperioden. Komplians bestemmes ved at tælle montelukast-tabletter i glasset ved besøg 2.
• Forsøgsdeltagere, som har behov for mere end 8 inhalationer af kortidsvirkende beta-2-agonister pr. dag eller mindst to nebuliserede behandlinger pr. dag med 2,5 mg korttidsvirkende beta-2-agonister i to på hinanden følgende vilkårlige dage fra screeningsbesøget til og med baselinebesøget.
• Forsøgsdeltagere, som oplever et fald på 30 % i PEF om morgenen eller om aftenen til under stabilitetsgrænsen for indkøringsperioden på 2 på hinanden følgende vilkårlige dage inden randomisering. For at bestemme stabilitetsgrænsen sammenlægges de gennemsnitlige morgen- og aften-PEF-værdier fra de foregående 7 dage, divideres med antallet af ikke-manglende værdier og ganges med 0,70.
• Forsøgsdeltagere, som oplever klinisk astmaforværring, der medfører akut behandling, indlæggelse på grund af astma eller behandling med yderligere, udelukket astmamedicin (herunder perorale eller andre systemiske kortikosteroider, dog er kortidsvirkende beta-2-agonister tilladt) efter den kliniske investigators skøn på et vilkårligt tidspunkt fra screeningsbesøget (besøg 1) til og med baselinebesøget (besøg 2)
• Forsøgsdeltagere med QTc > 440 msek for drenge og QTc > 450 msek for piger på EKG ved eller inden for 30 dage før screening |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary safety endpoint is the mean change from Baseline (Day 1) in log transformed plasma cortisol AUC(0-24 hours) at treatment Endpoint (Day 42). |
Det primære sikkerhedsendepunkt er den gennemsnitlige ændring fra Baseline (dag 1) i log transformed plasma kortisol AUC(0-24 timer) på sidste behandlingsdag (dag 42) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1 and Day 42 |
Dag 1 og dag 42 |
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E.5.2 | Secondary end point(s) |
The secondary safety endpoint is the mean change from Baseline (Day 1) in the log transformed plasma cortisol trough level (Ctrough) at treatment endpoint (Day 42). |
Det sekundære sikkerhedsendepunkt er den gennemsnitlige ændring fra Baseline (dag 1) i log transformed plasma kortisol trough niveau (Ctrough) på sidste behandlingsdag (dag 42) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1 and Day 42 |
Dag 1 og dag 42 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Evaluator-blindet |
Evaluator blind |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Colombia |
Denmark |
Germany |
Guatemala |
Mexico |
Peru |
Puerto Rico |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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Last patient last visit is tentatively set as 11-Sep-2013. |
Sidste patients sidste besøg (forventes at være 11. september 2013) |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |