| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| 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 |
Primary Efficacy Objective:
To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 100 mcg twice daily, by evaluating lung function during the first 12 weeks of double-blind treatment in children ages 5–11 years with persistent asthma.
Primary Safety Objective:
To characterize the safety and tolerability of MF/F 100/10 mcg twice daily and MF 100 mcg twice daily based on adverse events reported in association with up to 24 weeks of treatment in children ages 5 to 11 years with persistent asthma. |
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| E.2.2 | Secondary objectives of the trial |
To determine the onset of action for the efficacy of MF/F 100/10 mcg twice daily, compared with MF 100 mcg twice daily by evaluating % predicted FEV1 am of Day 1 of dosing analyzed beginning at 4h-postdose, 2h, 60, 30, 15 and 5 minutes post-dose and measured as the change from baseline (AM-predose-Day1).
1.To demonstrate the efficacy of MF/F 100/10 mcg twice daily, compared with MF 100 mcg twice daily, on the change from baseline in AM post-dose %-predicted FEV1 as measured during 4 hours post-dose, at Day 1 and Week 12; on the change from baseline in AM pre-dose % predicted FEV1, averaged over weeks 4, 8, and 12 of treatment; on the change from baseline in total daily short-acting β agonist use across the first 12-weeks of double-blind treatment.
2.To characterize the plasma PK profile of MF and determine PK parameters at steady state after multiple oral inhalations via MDI device in children ages 5-11 years old with persistent asthma. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Future Biomedical Research : Merck will conduct Future Biomedical Research on DNA (buccal swab) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.”
2) Pharmacokinetic Sub-Trial: Subjectsat selected sites (and after signing consent to participate in the main trial) will have the option to sign a separate informed consent to participate in a pharmacokinetic (PK) sub-trial. At Visit 7, blood samples will be collected from approximately 20 subjects, to characterize the plasma concentration-time profile of MF (AUC0 12h, AUC0-last, Cmax, and Tmax) following repeated twice-daily oral inhalations of MF/F or MF.
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| E.3 | Principal inclusion criteria |
1.Be willing to give written informed consent/assent (in accordance with local regulations) prior to Screening; and the subject’s legal representative must also give written informed consent for the subject to participate in the trial. The subject’s legal representative may also provide written informed consent and the subject provide assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
For the PK Sub-trial: subject and the subject’s legal representative must be willing to actively participate in the main trial and indicate understanding and willingness to participate in the sub-trial by signing the sub-trial specific informed consent/assent.
2.Be between 5 and 11 years of age (inclusive) at Visit 1, of either sex, and of any race.
3.Have a diagnosis of asthma according to the international guidelines of at least 6 months prior to Visit 1 (Global Initiative for Asthma [GINA] Guidelines Available from: http://www.ginasthma.org/).
4.Have asthma that is adequately controlled on a stable dose of ICS/LABA combination therapy for at least 4 weeks prior to Visit 1 according to the clinical judgment of the investigator.
5.Demonstrate at Visit 1, an FEV1 >60% and ≤90% predicted when all restricted medications have been withheld for the appropriate intervals.
6.Demonstrate at Visit 1, an increase in absolute FEV1 of at least 12% within 30 minutes after administration of albuterol/salbutamol (must be demonstrated according to the procedure specifically defined in Appendix 12.8). If the 12% reversibility criterion is not met at Visit 1, reversibility must be demonstrated prior to the randomization visit (Visit 3).
7.Demonstrate an ability to follow trial procedures (including use of MDI training inhaler, use of open-label run-in medication, use of PEF meter, and use of eDiary [IVRS/IWRS]) to the satisfaction of the investigator/qualified designee prior to randomization.
8.Have 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 Visit 1 documented to be clinically acceptable to the investigator before beginning the Run-in Period. A female subject of childbearing potential (i.e., who has started menstruating) must have a negative urine pregnancy test at Visit 1 to be considered eligible for the trial.
9. Demonstrate the ability to: use an MDI (without spacer) correctly according to protocol-defined procedures at Visit 1 (Screening Visit) and Visit 2 (Run-in Visit); use a peak flow meter correctly and perform spirometry correctly before Visit 2 (Run-in Visit).
10. Be willing (with consent of their parent(s)/guardian [i.e., caregiver]) to discontinue his/her prescribed asthma medication before beginning the Run-in Period, if based upon the medical judgment of the investigator, there is no inherent harm in changing the subject’s current asthma therapy. |
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| E.4 | Principal exclusion criteria |
1.Requires the use of >8 inhalations per day of albuterol, 100 mcg per actuation (or its equivalent), and/or >2 nebulized treatments per day of 2.5 mg albuterol (or its equivalent), on any 2 consecutive days between the Screening Visit (Visit 1) and the Randomization Visit (Visit 3). If a subject uses both MDI and nebulized formulations of SABA in the same day, then one nebulized treatment is considered equivalent to 4 inhalations of the MDI in order to calculate if the subject has exceeded the equivalent of 8 inhalations in total SABA use for that day.
2.Experiences a clinical worsening of asthma between the Screening Visit (Visit 1) and the Randomization Visit (Visit 3), that results in emergency room visit (for an asthma exacerbation), hospitalization due to asthma, or treatment with additional, excluded asthma medication (other than SABA).
3.Has experienced an upper or lower respiratory tract infection within the 4 weeks prior to Visit 1. If there is evidence of an upper or lower respiratory tract infection at Visit 1 or at Visit 2 (prior to the subject entering the Run-in Period), the subject may be treated as appropriate, and Visit 1 or Visit 2 can be rescheduled to be at least 4 weeks after resolution.
4.Demonstrates <80% compliance with use of trial medication during the 2 week Run-in Period. Compliance will be determined prior to randomization at Visit 3 and will be determined by comparing the change in dose counter readings relative to the duration of treatment as entered on the eCRF.
5.Is considered to have unstable asthma at the end-of the Run-in Period, based on the clinical judgment of the investigator.
6.Has had greater than 4 asthma exacerbations (defined as a worsening of asthma requiring systemic corticosteroid use and/or a 24-hour or longer stay in an emergency department, urgent care center, and/or hospital) within the 52 weeks prior to Visit 1.
7.Has been taking any restricted medications prior to the Screening Visit (Visit 1) without meeting the required washout timeframes.
8.Has a known or suspected hypersensitivity to ICS, beta2 agonists, or any components of the trial medications.
9. Has had a history of life-threatening asthma, including an asthma episode that required intubation and/or was associated with hypercapnia requiring non-invasive ventilatory support. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the AM post-dose %-predicted FEV1 (measured as the change from AM pre-dose %-predicted FEV1). The AM post-dose %-predicted FEV1 is calculated as the area under the curve from zero to 60 minutes (using the trapezoid rule) after a witnessed dose and divided by the time interval (to preserve the unit, % predicted). This method of calculation provides an aggregate bronchodilatory effect during 1 hour post-dose. A separate AM post-dose %-predicted FEV1 measurement is calculated for each visit, and is evaluated as a change from baseline of the mean across Day 1, Week 1, Week 4, Week 8 and Week 12. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1, Week 1, Week 4, Week 8 and Week 12 |
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| E.5.2 | Secondary end point(s) |
| The key secondary endpoint of AM %-predicted FEV1 at each of the 5-, 15-, 30-, and 60-minute, 2- and 4 hour post-dose evaluations on Day 1 of dosing will assess the onset of action of MF/F. Formoterol is characterized by a rapid bronchodilator effect, which may be observed within 5 minutes of administration. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Colombia |
| Guatemala |
| Mexico |
| Peru |
| Russian Federation |
| South Africa |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 21 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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