| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult subjects 18 to 65 years of age with persistent asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adults with chronic asthma |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001705 |
| E.1.2 | Term | Allergic asthma |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 |
1. To demonstrate that MK-1029, compared with placebo, results in dose related improvements in the lung function test: forced expiratory volume in 1 second (FEV1), over the last 6 weeks of the 12-week active-treatment period.
2. To determine the dose-related safety and tolerability of MK-1029 as monotherapy (single medication) and as concomitant dosing with montelukast over 12 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
1. To demonstrate that co-administration of MK-1029 and montelukast, compared with montelukast alone, results in improvement in the lung function test: forced expiratory volume in 1 second (FEV1) over the last 6 weeks of the 12-week active-treatment period.
2. To assess the dose-related efficacy of MK-1029, compared with placebo, on the following endpoints:
Over the last 6 weeks of the 12-week active-treatment period:
- percentage of days with asthma exacerbations
- daytime symptom score
- s-needed short-acting beta agonists (SABA) use
- nocturnal awakenings
- AM and PM peak expiratory flow (PEF)
At Week 12 of the 12-week active-treatment period:
- Asthma Quality of Life Questionnaire with Standardised Activities [AQLQ(S)]
total and individual domain scores
- Asthma Control Questionnaire-6 (ACQ-6) score
Over the entire 12-week treatment period:
- asthma attacks as defined per protocol.
3. To assess the efficacy of co-administration of MK-1029 and montelukast, c |
|
| 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 |
| The sputum sub study protocol is included as appendix 6.10 of the main protocol. No UK sites will be undertaking the sputum sub-study. |
|
| E.3 | Principal inclusion criteria |
Visit 1
1. Subject is a female or male subject between 18 and 65 years of age.
2. Subject is not pregnant (as evidenced by negative serum pregnancy test for subjects of childbearing potential) or breastfeeding and does not plan to become pregnant for the duration of the study and post study follow-up period.
3. A subject who is of reproductive potential agrees to remain abstinent (defined as true abstinence in line with the preferred and usual lifestyle of the subject) or use (or have their partner use) 2 acceptable methods of birth control, as defined per protocol, within the projected duration of the study.
A female subject who is not of reproductive potential, as defined per protocol, is eligible without requiring the use of contraception.
A male subject who is not of reproductive potential, defined per protocol, is eligible without requiring the use of contraception.
4. Subject has a consistent clinical history, for at least one year, of symptoms of persistent asthma that may include, but are not limited to, dyspnea, wheezing, chest tightness, cough, and/or sputum production. Onset of symptoms of asthma must have occured by the age of 45 yrs or sooner.
5. While withholding SABAs for at least 6 hours and long-acting β-agonists (LABAs)for at least 12 hours, subject has a Forced Expiratory Volume in 1 second (FEV1) ≥55% and ≤85% of the predicted value (≥60% and ≤90% of the predicted value if subject is receiving asthma controller medications).
6. While withholding SABAs for at least 6 hours and LABAs for at least 12 hours (at Visit 1 only), subject has evidence of reversibility of airway obstruction defined as an increase of FEV1 of 12% or greater, and at least 200 mL, 10 to 30 minutes after SABA administration, documented once during Visit 1, Visit 2 or Visit 3.
Note: If the reversibility criterion is met for an individual subject at Visit 1 or Visit 2, reversibility will not be performed at subsequent visits.
7. Subject’s asthma treatment must fall into one of two categories:
- The subject must have been using only as-needed inhaled SABAs; have a score between 1 and 6 for Question 6 of the Visit 1 ACQ-6; have an overall Visit 1 ACQ-6 score ≥1.5; and have not been receiving asthma controllr medications for ≥4 weeks prior to Visit 1
OR
- The subject must have been receiving stable doses of low- or medium-dose ICS, combination ICS/LABA, and/or other asthma controller medications, including leukotriene receptor antagonists, and can tolerate tapering of these controllers or discontinuing them during the run in period.
Maximal permitted daily doses of ICS at screening are as follows:
1000 μg beclomethasone CFC
500 μg beclomethasone HFA
800 μg budesonide
2000 μg flunisolide
500 μg fluticasone propionate
<800 μg mometasone furoate
2000 μg triamcinolone acetonide
320 μg ciclesonide
8. Subject has never smoked or is a non-smoker for at least 1 year, with a smoking history of no more than 10 pack-years (i.e., 1 pack [20 cigarettes] per day for 10 years).
9. Subject is able to maintain a constant day/night, awake/sleep cycle.
10. Subject agrees not to change his/her habitual consumption of beverages or foods containing caffeine throughout the study.
11. Subject has a Body Mass Index (BMI) between 15 and 40 kg/m2 inclusive.
12. Subject provides written informed consent for the study. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main study without participating in Future Biomedical Research.
Visit 2
13. Subject is judged to be in stable health (except for his/her asthma) on the basis of medical history, physical examination, and routine laboratory data, and appears able to successfully complete this study.
14. Subjects who are receiving asthma controller medications, will agree to taper over a 2 to 4 week interval or discontinue their asthma controller medications.
Visit 3
15. Subject has an ACQ-6 (questionnaire) score ≥1.5.
16. Subject has a total daytime and nocturnal SABA administration average ≥1 puff per day, as recorded on the subject’s e-Diary for the last 7 days prior to Visit 3.
17. Subject has demonstrated at least 80% compliance with self-administration of study drug and with completion of asthma e-Diary. |
|
| E.4 | Principal exclusion criteria |
Visit 1
1. Subject is, in the opinion of the investigator, mentally or legally incapacitated preventing informed consent from being obtained, unable to read or comprehend written material, or unable to comply with the study procedures or protocol.
2. Subject has a recent history (≤3 months) of myocardial infarction, congestive heart failure, or uncontrolled cardiac arrhythmia prior to Visit 1.
Pulmonary
3. Subject has evidence of another clinically significant, active pulmonary disorder.
4. Subject has been treated in an emergency room for asthma within the 4 weeks prior to Visit 1 or has been hospitalized for asthma within the 8 weeks prior to Visit 1.
5. Subject has had a respiratory tract infection which necessitated treatment with antibiotics within the 8 weeks prior to Visit 1.
6. Subject has evidence of active, clinically significant sinus disease within 1 week prior to Visit 1.
General Medical
7. Subject has a recent history of a clinically significant psychiatric disorder, other than stable depression.
8. Subject has a history of HIV.
9. Subject is hypersensitive or intolerant to inhaled β-agonists, leukotriene antagonists, leukotriene synthesis inhibitors, or any of their formulation components, including lactose and its metabolite, galactose.
10. Subject has a clinically unstable disease of the ophthalmologic, neurological, hepatic, renal, connective tissue, genitourinary, gastrointestinal, cardiovascular or hematologic systems.
11. Subject has cancer (except for successfully treated basal and squamous cell carcinomas of the skin). Subjects with a history of cancer who have been cancer-free for >5 years may be included.
12. Subject has specific abnormalities, defined per protocol, on the Visit 1 laboratory tests.
13. Subject has evidence of uncontrolled hypertension during at least 2 of the first 3 study visits.
14. Subject has a history of any illness that would require treatment with an excluded medication, could be immediately life threatening, would pose a restriction on participation or successful completion of the study, or would pose an additional risk to the subject on administration of study drug.
15. The electrocardiogram obtained at Visit 1 demonstrates clinically significant or unexplained abnormality.
Medications
16. Subject has used any medication with a narrow therapeutic index within the 2 weeks prior to Visit 1 or plans to take such medications during the study.
17. Subject is currently receiving, or plans to take during the study, specified inhibitors or substrates of OATP1B1 and OATP1B3, as defined per protocol.
18. Subject has taken any of the following anti-asthma medications or plans to take such medications during the study:
- Inhaled long- or short-acting anticholinergic agents within the 2 weeks prior to Visit 1;
- Systemic corticosteroids (e.g. oral, intravenous, intramuscular, intra-articular or rectal) within the 4 weeks prior to Visit 1;
- ICS or ICS/LABA following tapering and throughout the remainder of the study;
- Oral asthma controller medications following tapering and throughout the remainder of the study;
- SABAs other than salbutamol throughout the course of the study;
- Omalizumab within the 4 weeks prior to Visit 1.
19. Aspirin and non-steroidal anti-inflammatory medication in subjects known to be sensitive or subjects who have not had previous exposure to these compounds.
20. β-adrenergic receptor blocking agents within the 4 weeks prior to Visit 1.
21. Subject has started immunotherapy within the 6 months prior to Visit 1. If on immunotherapy, the subject must remain on a stable dose of immunotherapy throughout the study.
Visit 2
22. Subject is unable to comply with the study procedures or protocol.
23. Subject is unable to perform acceptable spirometry.
24. Subject experiences a pre-defined clinically significant worsening of their asthma between Visit 1 and Visit 2.
Visit 3
25. Subject is unable to comply with the study procedures or protocol.
26. Subject is unable to perform acceptable spirometry.
27. Subject has required an oral corticosteroid rescue for worsening asthma between Visit 2 and Visit 3.
28. Subject experiences a pre-defined clinically significant worsening of their asthma between Visit 2 and Visit 3. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The average change from baseline in Forced Expiratory Volume in 1 second (FEV1) over the last 6 weeks of the 12-week active-treatment period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The last 6 weeks of the 12-week active treatment period (weeks 8,10 and 12) |
|
| E.5.2 | Secondary end point(s) |
• percentage of days with asthma exacerbations
• daytime symptom score
• as-needed SABA use
• nocturnal awakenings
• AM and PM PEF
• Asthma Quality of Life Questionnaire with Standardised Activities
[AQLQ(S)] total and individual domain scores
• Asthma Control Questionnaire-6 (ACQ-6) score
• asthma attacks |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The various time points include daily or every 2 weeks of the 12-week active treatment period; Week 12 of the 12-week active period and over the entire 12-week active treatment period. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 8 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Canada |
| France |
| Italy |
| Japan |
| Germany |
| United Kingdom |
| United States |
|
| 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
|
| Date that last patient completes final study visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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