臨床研究等提出・公開システム

Real-life effectiveness of Indacaterol/Glycopyrronium/Mometasone for symptomatic relief of cough after switching from ICS/LABA therapy in patients with asthma

REACH Study

118

The mean age (SD) at enrollment was 50.8 (15.7) years old in the study product group and 50.4 (14.2) years old in the comparator group. The breakdown by sex was 31.6% male and 68.4% female in the study product group and 34.6% male and 65.4% female in the control drug group. The mean BMI (SD) was 23.67 (4.04) in the study product group and 23.25 (4.49) in the comparator group. The proportion of subjects with smoking history was 12.3% in the study product group and 19.2% in the control group. The mean duration of asthma (SD) was 8.28 (9.99) years in the study product group and 10.22 (10.59) years in the control group, indicating that the duration of asthma tended to be longer in the control group than in the study product group. The severity of asthma in the study product group was mild persistent (12.3%), moderate persistent (86.0%), and severe persistent (1.8%), while that in the control group was mild persistent (25.0%), moderate persistent (67.3%), and severe persistent (7.7%), showing that there were more patients with moderate persistent asthma in both groups. In the study product group, asthma tended to be more concentrated in patients with moderate persistent asthma, while that in the control group tended to be distributed over a relatively wide range from mild persistent asthma to severe persistent asthma.

Of the 125 subjects who provided informed consent, 7 subjects dropped out before enrollment, and 118 subjects were enrolled. Enrolled patients were assigned to study product group (59 patients), comparator group (1) (FF/VI) (30 patients), and comparator group (2) (BUD/FM) (29 patients) (59 patients in all comparator groups). All enrolled subjects received protocol therapy, and 11 subjects (4 in the study product group, 3 in the comparator group (1) [FF/VI], and 4 in the comparator group (2) [BUD/FM]) discontinued the study.

The incidences of adverse events were 32.2% in the study product group and 22.0% in the control group. Adverse events that occurred in the study product group were bronchitis (8.5%), asthma (5.1%), dysphonia and thirst (3.4% each), acute sinusitis, gingivitis, oral candidiasis, retinal degeneration, oropharyngeal pain, pruritus, back pain, facial pain, and heat illness (1.7% each). On the other hand, adverse events that occurred in the control group were influenza, nasopharyngitis, COVID-19, insomnia, dizziness, headache, tremor, hypertension, asthma, abdominal pain, nausea, stomatitis, muscle spasms, Sjogren's syndrome, pyrexia, and vaccination site bruising (1.7% each). No serious adverse events or adverse events were assessed as severe. The incidence of adverse events assessed as moderate in severity was 8.5% in the study product group and included asthma (3.4%) and retinal degeneration, dysphonia, and pruritus (1.7% each). Hypertension, 5.1% asthma, abdominal pain, and nausea (1.7% each). All other adverse events were assessed as mild. The incidences of adverse reactions were 10.2% in the study product group and 5.1% in the control group. Adverse drug reactions that occurred in the study product group were dysphonia and thirst (3.4% each), and oral candidiasis and oropharyngeal pain (1.7% each). Adverse reactions that occurred in the control group were tremor, stomatitis, and muscle spasms (1.7% each). The only adverse reaction assessed as moderate was dysphonia (1.7%) in the study product group, and no such adverse reaction occurred in the control drug group. Thus, there were no noteworthy events in the safety evaluation in this study.

The change from baseline in the J-LCQ total score at Week 8 of treatment, the primary endpoint (STEP1), was 1.99+-3.48 in the study product group and 2.50+-4.28 in the control group, showing no statistically significant difference between the groups, failing to demonstrate superiority (p=0.5037). Therefore, the study did not proceed to STEP2 and the superiority verification was completed. Because all analyses were planned to be performed even if the superiority could not be verified in STEP1, verification of each STEP was performed. The change from baseline in the cough VAS score (while awake), a key secondary endpoint (STEP2A), at Week 8 was -21.4+-22.4 in the study product group and -26.6+-28.5 in the control group, with no statistically significant difference between the groups (p=0.2986). The change from baseline in the total score of the J-LCQ, the primary endpoint (STEP2B), at Week 8 was 1.99+-3.48 in the study product group, 2.11+-4.59 in the comparator group (1) (FF/VI), and 2.91+-3.97 in the comparator group (2) (BUD/FM), with no statistically significant difference between the study product group and the comparator group (1) (FF/VI) or between the study product group and the comparator group (2) (BUD/FM) (p=0.9882 and p=0.5343, respectively). The change from baseline to Week 8 in the cough VAS score (while awake), one of the key secondary endpoints (STEP3), was -21.4+-22.4 in the study product group, -23.4+-27.9 in the comparator (1) group (FF/VI), and -30.1+-29.4 in the comparator (2) group (BUD/FM), with no statistically significant difference between the study product group and the comparator (1) group (FF/VI) or between the study product group and the comparator (2) group (BUD/FM) (p=0.9317 and p=0.2861, respectively). The change in J-LCQ total score from baseline to Week 4 was 1.22+-2.89 in the study product group and 2.32+-2.99 in the control group, and no statistically significant difference was noted between the groups (p=0.0546). The proportion of patients who achieved the minimal clinically important change (MCID) of 1.3 in J-LCQ was 40.4% in the study product group and 61.5% in the control group at Week 4, and 52.7% in the study product group and 57.7% in the control group at Week 8. The proportion of patients who showed significant improvement in the control group compared with the study product group at Week 4 was higher, but there was no significant difference between the two groups at Week 8 (Week 4 p=0.0271, Week 8 p=0.6058). The change from baseline in the evaluation of cough VAS (while awake) was -13.0+-23.6 in the study product group and -22.3+-24.1 in the control group at Week 4, showing a significant improvement in the control group compared to the study product group (p=0.0448). On the other hand, the scores at Week 8 were -21.4+-22.4 in the study product group and -26.6 +-28.5 in the control group, showing no statistically significant difference between the groups (p=0.2986). The change from baseline in cough VAS assessment (while sleeping) was -7.2 +- 24.8 in the study product group and -11.2 +- 23.5 in the control group at Week 4, and -11.6 +- 29.0 in the study product group and -17.6 +- 23.2 in the control group at Week 8, showing no statistically significant difference between the groups (p=0.3891 and p=0.2388, respectively). The percentage of patients who achieved an improvement of 15 mm in cough VAS score from baseline to Week 4 or 8 with a cough VAS score of < 40 mm (Waking or sleeping) was 40.4% in the study product group and 50.0% in the control drug group during waking hours at Week 4, 58.2% in the study product group and 55.8% in the control drug group at Week 8, and 29.8% in the study product group and 28.8% in the control drug group during sleeping hours at Week 4, and 36.4% in the study product group and 36.5% in the control drug group at Week 8. No statistically significant difference was noted between the groups (p=0.3118, p=0.8011, p=0.9108, p=0.9850, respectively). Changes from baseline in respiratory function (FEV1, FVC, FEF25 -75,% FEV1, FEV1%) at Week 8 were as follows: FEV1 was 0.044 +- 0.181 in the study product group and 0.044 +- 0.147 in the control drug group; FVC was 0.040 +- 0.194 in the study product group and 0.052 +- 0.174 in the control drug group; FEF25-75 was 0.12 +- 0.44 in the study product group and 0.31 +- 1.70 in the control drug group;% FEV1 was 2.14 +- 6.79 in the study product group and 1.99 +- 6.44 in the control drug group; and FEV1% was 0.42 +- 3.77 in the study product group and 0.16 +- 3.04 in the study product group. No statistically significant differences were observed between the groups (p=0.9870, p=0.7240, p=0.4394, p=0.9101, p=0.7004, respectively). The change in exhaled nitric oxide concentration (FeNO) from baseline to Week 8 was 3.1 +- 17.3 in the study product group and -5.4 +- 20.6 in the control group, showing a significant improvement in the control group compared to the study product group (p=0.0230). The changes in blood eosinophils from baseline were -1.8 +- 141.3 in the study product group and -58.8 +- 131.4 in the control drug group at Week 4 of treatment and 9.3 +- 118.6 in the study product group and -54.8 +- 132.5 in the control drug group at Week 8 of treatment, showing a significant decrease in the control drug group as compared with the study product group (p=0.0328 and p=0.0101, respectively). Changes in blood neutrophils from baseline were -362.5 +- 1380.2 in the study product group and 140.0 +- 1246.0 in the control group at Week 4, and -384.4 +- 1395.8 in the study product group and 256.5 +- 1244.3 in the control group at Week 8. No statistically significant differences were observed between the groups at Week 4, but the levels decreased significantly in the study product group compared to the control group at Week 8 (p=0.0504 and p=0.0141, respectively). The change from baseline in ACQ-6 score was -0.17 +- 0.67 in the study product group and -0.56 +- 0.75 in the control drug group at Week 4 of administration, and -0.53 +- 0.69 in the study product group and -0.70 +- 1.04 in the control drug group at Week 8 of administration. The change was significantly greater in the control drug group than in the study product group at Week 4, but there was no statistically significant difference between the groups at Week 8 (p=0.0059 and p=0.3276, respectively). The proportion of subjects with a reduction in ACQ-6 score of 0.5 from baseline was 31.6% in the study product group and 57.7% in the control group at Week 4 of treatment, and 49.1% in the study product group and 69.2% in the control group at Week 8 of treatment, showing significant improvement in the control group compared with the study product group (p=0.0061 and p=0.0343, respectively). The change in CASA-Q total score from baseline was 4.0 +- 14.3 in the study product group and 10.8 +- 12.1 in the control drug group at Week 4 of administration, and 8.3 +- 14.3 in the study product group and 11.1 +- 17.1 in the control drug group at Week 8 of administration. The change significantly improved in the control drug group compared to the study product group at Week 4, but there was no significant difference between the groups at Week 8 (p=0.0082 and p=0.3685, respectively). Because of the limited number of patients who underwent a capsaicin cough receptor sensitivity test and the VitaloJAK cough monitor, the study product group and the control drug group were not compared.

Although the superiority of the intermediate-dose IND/GLY/MF group to the high-dose ICS/LABA group could not be confirmed, it was confirmed that the intermediate-dose IND/GLY/MF group produced a sustained antitussive effect. No clinically significant adverse drug reactions occurred in either group, but long-term use of high-dose ICS is associated with a risk of adverse drug reactions. Taking this point into account, addition of LABA may be preferable to long-term administration of high-dose ICS.

July. 08, 2024

No

Not applicable

https://jrct.mhlw.go.jp/latest-detail/jRCTs041220003

Niimi Akio

Nagoya City University Hospital

1,Kawasumi,Mizuho-chou,Mizuho-ku,Nagoya,Aichi

a.niimi@med.nagoya-cu.ac.jp

Niimi Akio

Nagoya City University Hospital

1,Kawasumi,Mizuho-chou,Mizuho-ku,Nagoya,Aichi

+81-52-853-8216

a.niimi@med.nagoya-cu.ac.jp

Complete

April. 14, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1. Patients whose written consent has been obtained prior to the initiation of any procedure related to this study.
2. Male or female, between 20 and 80 years of age at the time of consent.
3. Patients must have a diagnosis record of asthma at least 3 months prior to Visit 0.
4. Patients who have been receiving moderate doses of FF/VI or BUD/FM for at least one month prior to Visit 0.
5. Patients with a cough VAS (awake) of 40 mm or greater at both Visit 0 and Visit 1 (or Visit 1 pre).
6. Patients who are willing to not receive SMART therapy during the study period.

1. Patients who have smoked (including e-cigarettes) within 12 months prior to Visit 0, or who have smoked at least 10 pack-years in the past (Note: 1 pack is equivalent to 20 cigarettes. 10 pack-year = 1 pack/day x 10 years, or 1/2 pack/day x 20 years).
2. Patients who quit smoking within 6 months prior to Visit 0.
3. Patients who have used central antitussives within 1 months prior to Visit 0. (e.g Codeine phosphate, etc.)
4. Patients who have used antitussive herbal medicines within 1 months prior to Visit 0.
5. Patients who have used amitriptyline for neuropathic pain treatment or antitussive purposes within 3 months prior to Visit 0. (Examples opioids, gabapentin, pregabalin, etc.)
6. Patients who have used ACE inhibitors within 3 months prior to Visit 0.
7. Patients who have used anticholinergic drugs (LAMA, SAMA, oral drugs) and tricyclic antidepressants or first-generation antihistamine with anticholinergic effects within 1 months prior to Visit 0.
8. Patients who started or changed controllers for asthma except medium-dose ICS/LABA within 1 months prior to Visit 0. (However, patients who started or changed anti-IgE, anti-IL-5, anti-IL-5 receptor alpha, anti-IL-4 receptor alpha, or anti-TSLP antibody preparations within 3 months prior to Visit 0 are excluded.)
9. Patients who received SMART therapy within 3 months prior to Visit 0.
10. Patients with upper or lower respiratory tract infections or significant changes in lung function within 1 month prior to Visit 0 or from Visit 0 to the date of administration (Visit1).
11. Patients with abnormal findings on chest radiographs taken within 12 months prior to Visit 0 that could cause cough.
12. Patients with a history of chronic lung diseases other than asthma. These chronic lung diseases include (but are not limited to) chronic obstructive pulmonary disease (COPD), sarcoidosis, interstitial lung disease, cystic fibrosis, bronchiectasis, and active infections such as pulmonary tuberculosis.
13. Patients with a history of malignancy under treatment.
14. Patients with angle closure glaucoma.
15. Patients with dysuria due to prostatic hypertrophy, etc.
16. Patients who cannot or are not willing to use the electronic diary record device.
17. Patients participating in interventional trials (including clinical trials) other than this study.
18. Patients who are pregnant, lactating or may be pregnant.
19. Patients who have previously experienced a safety issue with the study drug or any of its active ingredients.
20. Other patients who are judged by the principal investigator or sub-investigator to be inappropriate as research subjects.

Both

asthma

Enerzair group (IND/GLY/MF)
: Subjects will inhale medium-dose capsule of ENERZAIR (150 microgram of indacaterol, 50 microgram of glycopyrronium, and 80 microgram of mometasone furan carboxylate ester) once daily for 8 weeks from Visit 1 to Visit 3 using an inhalation device designed specifically for this drug.
Control group (1) (FF/VI)
Subjects will receive an inhaled dose of LELVEA 200 Ellipta (25 microgram of vilanterol and 200 microgram of fluticasone furan carboxylate) once daily for 8 weeks from Visit 1 to Visit 3.
Control group (2) (BUD/FM)
Subjects will receive four inhalations of BUD/FM (Total 8 inhalations: 1280 microgram as budesonide and 36 microgram as formoterol fumarate hydrate) twice daily for eight weeks from Visit 1 to Visit 3. (However, the dosage may be reduced to three inhalations twice daily only if there is a safety concern associated with an increase in the dosage of formoterol fumarate hydrate.)

asthma

Change from baseline at 8 weeks in J-LCQ

[Important secondary endpoints]
Change from baseline in cough VAS ( awake ) assessment at 8 weeks

[Other secondary endpoints]
1. J-LCQ
:Change from baseline at 4 weeks of treatment
:Percentage of patients achieving a minimum clinically important difference (MCID) of 1.3 or greater from baseline at 4 and 8 weeks.
2. Cough VAS assessment (awake and asleep)
:Change from baseline at 4 weeks of treatment
:Change from baseline at 4 and 8 weeks of treatment
:Percentage of patients who achieve a cough VAS improvement of at least 15 mm from baseline and a cough VAS of less than 40 mm at 4 or 8 weeks of treatment
3. Capsaicin cough receptor sensitivity test
:Change in cough receptor sensitivity from baseline to 8 weeks of treatment
4. VitaloJAK cough monitor
:Change in cough frequency from baseline to 8 weeks of treatment
:Cough frequency in 24 hours (frequency per hour)
:Change in cough frequency (frequency per hour) during waking hours (from 6:00 AM to 10:00 PM)
:Change in cough frequency (frequency per hour) during sleeping hours (from 10 PM to 6 AM the next day)

5. Respiratory function (spirometry)
:Change in respiratory function (FEV1, FVC) from baseline at 8 weeks of treatment
:Change in FEF25-75 (effort expiratory flow rate during exhalation of 25-75% of FVC) from baseline at 8 weeks of treatment
6. Exhaled nitric oxide concentration (FeNO)
:Change from baseline at 8 weeks of treatment
7. Biomarkers (blood eosinophils, blood neutrophils)
:Change from baseline at 4 weeks and 8 weeks of treatment
8. ACQ-6
:Change from baseline at 4 weeks and 8 weeks of treatment
9. CASA-Q
:Change from baseline at 4 weeks and 8 weeks of treatment

+81-52-853-8346

Feb. 09, 2022

none