Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
The purpose of this study is to obtain additional data on efficacy and safety of Rengalin in the treatment of cough in patients with stable obstructive pulmonary disease
Detailed description
Design: multicenter, double-blind, randomized, parallel group placebo-controlled study. The study will enroll men and women (aged 40 to 80 years) with cough associated with stable chronic obstructive pulmonary disease (COPD). Subjects with COPD diagnosed more than 12 months earlier obtaining allowed basic therapy and retaining cough ≥2 points (according to cough severity scale \[CSS\]) despite their therapy should be considered as the study candidates. After signing patient information leaflet (informed consent form) to participate in the clinical study, collection of medical history and objective examination are performed, cough severity is assessed (using CSS; at baseline evaluation of diurnal and nocturnal cough the number of episodes and cough severity in the preceding day is taken into account) as well as intensity of COPD effect on the subject (САТ test), concomitant therapy is recorded, computer spirometry with evaluation of baseline FEV1/FVC and post-bronchodilator FEV1 (where respiratory function cannot be assessed, the results of the previous examination dating no more than 3 months earlier may be used). Females of childbearing potential will undergo pregnancy test. If a patient meets the inclusion criteria and does not demonstrate any of the exclusion criteria at Visit 1 (Day 1), he/she is randomized to one of 2 groups: group 1 patients will receive Rengalin at 2 tablets 3 times a day for 4 weeks; group 2 patients will receive placebo using Rengalin dosing regimen for 4 weeks. The patient will be monitored for 4 weeks (screening, randomization - before day 1, treatment - 4 weeks). During follow-up period two visits are scheduled (Visit 1 (Day 1) and Visit 2 (Week 4) at which objective examination, recording cough severity (using CSS) will be carried out, COPD effect on the subjects (САТ test) and concomitant therapy will be evaluated. At Visit 2 (after 4-week treatment period) compliance will be additionally assessed. At one of the clinical sites (Research Institute of Pulmonology, Russian FMBA), patients will be monitored for cough on a daily basis (using the WHolter™ monitor), with the data used as an additional measure to evaluate efficacy. Subjects are allowed to take basic COPD therapy and medications for their co-morbidities in the course of the study, except for the medicines listed in Prohibited concomitant treatment.
Interventions
DRUGPlacebo
Oral administration.
DRUGRengalin
Oral administration.
Sponsors
Materia Medica Holding
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patients of both sexes aged from 40 to 80 years old. 2. COPD diagnosed (in accordance with the GOLD-2014 guidelines) ≥12 months before inclusion. 3. Stable course of COPD (≥ 6 weeks free of disease progression). 4. Mild, moderate or severe degree of bronchial obstruction (FEV1/FVC \< 0.7; post-bronchodilator FEV1 ≥30% of predicted value). 5. CSS score ≥2. 6. Stable dose of standard therapy within the preceding 4 weeks. 7. Use of and adherence to contraceptive methods by fertile-age patients of both sexes during the study. 8. Availability of a signed patient information sheet (Informed Consent form) for participation in the trial.
Exclusion criteria
1. Earlier diagnosis of intra- or extrathoracic causes of cough (e.g., asthma, malignant neoplasm of lung, tuberculosis, sarcoidosis, α1-antitrypsin deficiency, bronchiectasis, cystic fibrosis, interstitial pulmonary diseases, perennial allergic rhinitis, gastro-oesophageal reflux disease, use of ACE inhibitors, disease of upper respiratory tract, etc.). 2. Cough associated with eating. 3. An exacerbation of COPD, acute upper and/or lower respiratory infection at inclusion or in the previous 4 weeks. 4. Modifications to standard drug therapy (dose escalation, replacement of medicines prescribed or addition of new medications) in the previous 4 weeks. 5. Very severe degree of bronchial obstruction (post-bronchodilator FEV1 \<30% pred or \< 50% and chronic respiratory failure). 6. Haemoptysis. 7. Stroke in the preceding 3 months or stroke with long-term residual neurological deficit within 6 months before study entry. 8. Acute coronary syndrome, myocardial infarction within 6 months before study enrollment. 9. Unstable or life-threatening arrhythmia in the previous 3 months. 10. Acute or chronic heart failure (NYHA (1964) Class III or IV). 11. Presence or suspicion of oncological disease. 12. Body Mass Index (BMI) ≤18 kg/m2 or ≥40 kg/m2. 13. Chronic kidney disease (categories С3-5 А3). 14. Hepatic failure (Child-Pugh class C) 15. Exacerbation or decompensation of a chronic disease that would affect the patient's ability to participate in the clinical trial. 16. For smokers - intention to quit smoking in the next 4 weeks. 17. Allergy/intolerance to any of the components of medications used in the treatment. 18. Course intake of medicines listed in the section 'Prohibited concomitant treatment' for 4 weeks prior to the enrollment in the trial. 19. Participation in other clinical trials within 3 months prior to the enrollment in this study. 20. Patients who, from investigator's point of view, will fail to comply with the observation requirements of the trial or with the dosing regimen of the investigational drug. 21. Other conditions preventing the patient from normal participation (e.g., planned business or other trips). 22. Drug addiction, alcohol use in the amount over 2 units of alcohol a day, mental diseases. 23. Pregnancy, breast-feeding, unwillingness to use contraception during the study. 24. Patient is related to the research staff of the clinical investigative site who are directly involved in the trial or is the immediate family member of the investigator. The immediate family members include husband/wife, parents, children or brothers (or sisters), regardless of whether they are natural or adopted. 25. Patient works for MATERIA MEDICA HOLDING company (i.e., is the company's employee, temporary contract worker or appointed official responsible for carrying out the research or their immediate family).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Positive Treatment Response | in 4 weeks of the treatment | Cough Severity Scale (CSS) total score. Cough intensity according to the scale is assessed in daytime and at night in points where 0 - no cough, 5 - continuous exhausting cough in daytime and at night. Response criterion: ≥1 lower total CSS score compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of Cough After 4 Weeks Compared to Baseline | Baseline and 4 weeks after the treatment | Cough Severity Scale (CSS) total score. Cough intensity according to the scale is assessed in the daytime and at night in points, where 0 - no cough, 5 - continuous exhausting cough in the daytime, and at night. |
| Percentage of Patients With ≥50% Lesser Cough Severity at 4 Weeks | in 4 weeks of the treatment | Number of Participants with a Decrease from Baseline of ≥50% in Cough Severity at 4 weeks. Based on the total Cough Severity Scale (CSS) score. Cough intensity according to the scale is assessed in the daytime and at night in points, where 0 - no cough, 5 - continuous exhausting cough in the daytime and at night. |
| Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | in 4 weeks of the treatment | Based on the total COPD Assessment Test (CAT) score. CAT consists of 8 items. Each item ranges from 0 to 5 balls. The total score ranges from minimum 0 to maximum 40 points. Higher values represent a worse outcome. |
| Percentage of Patients With no Exacerbation of COPD | in 4 weeks of the treatment | COPD exacerbation is defined as an acute event characterized by aggravation of the event within 2-3 or more days. Exacerbation manifests in intensification of respiratory disorders beyond their regular daily fluctuations and require administration of products in addition to the previously prescribed basic therapy as well as a rescue drug for symptom relief (salbutamol). Additional products include antibacterial drugs, systemic corticosteroids and/or emergency therapy (ambulance call) or hospitalization for COPD exacerbation. COPD exacerbation is recorded as an adverse event. If a COPD exacerbation develops within the first week of the subject participation in the study, it will not be considered as a secondary inefficacy criterion |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rengalin Oral administration. Two tablets per intake. The tablet should be held in the mouth until complete dissolution. 2 tablets 3 times a day without food (i.e. 15-30 min prior to meal or 15-30 min after meal).
Rengalin: Oral administration. | 121 |
| Placebo Oral administration. Two tablets per intake. The tablet should be held in the mouth until complete dissolution. 2 tablets 3 times a day without food (i.e. 15-30 min prior to meal or 15-30 min after meal).
Placebo: Oral administration. | 117 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Incorrect inclusion ineligible patient | 5 | 3 |
| Overall Study | Patient has taken no dose of study drug | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Rengalin |
|---|---|---|---|
| Age, Continuous | 64.8 years STANDARD_DEVIATION 8.4 | 64.3 years STANDARD_DEVIATION 8.2 | 63.9 years STANDARD_DEVIATION 7.9 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Russia | 117 Participants | 238 Participants | 121 Participants |
| Sex: Female, Male Female | 23 Participants | 50 Participants | 27 Participants |
| Sex: Female, Male Male | 94 Participants | 188 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 121 | 1 / 116 |
| other Total, other adverse events | 14 / 121 | 11 / 116 |
| serious Total, serious adverse events | 2 / 121 | 1 / 116 |
Outcome results
Primary
Percentage of Patients With a Positive Treatment Response
Cough Severity Scale (CSS) total score. Cough intensity according to the scale is assessed in daytime and at night in points where 0 - no cough, 5 - continuous exhausting cough in daytime and at night. Response criterion: ≥1 lower total CSS score compared to baseline.
Time frame: in 4 weeks of the treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rengalin | Percentage of Patients With a Positive Treatment Response | 97 Participants |
| Placebo | Percentage of Patients With a Positive Treatment Response | 82 Participants |
p-value: 0.0422G-test (Chi-square)
Secondary
Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD)
Based on the total COPD Assessment Test (CAT) score. CAT consists of 8 items. Each item ranges from 0 to 5 balls. The total score ranges from minimum 0 to maximum 40 points. Higher values represent a worse outcome.
Time frame: in 4 weeks of the treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rengalin | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | Initial total score | 19.9 score on a scale | Standard Deviation 6.8 |
| Rengalin | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | Total score after 4 weeks | 16.6 score on a scale | Standard Deviation 6.9 |
| Rengalin | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | ∆ between initial and 4 weeks total scores | 3.3 score on a scale | Standard Deviation 4.2 |
| Placebo | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | Initial total score | 20.3 score on a scale | Standard Deviation 6.6 |
| Placebo | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | Total score after 4 weeks | 17.8 score on a scale | Standard Deviation 6.8 |
| Placebo | Changes in Clinical Symptoms of Chronic Obstructive Pulmonary Disease (COPD) | ∆ between initial and 4 weeks total scores | 2.5 score on a scale | Standard Deviation 4.1 |
p-value: 0.087Wilcoxon (Mann-Whitney)
Secondary
Percentage of Patients With ≥50% Lesser Cough Severity at 4 Weeks
Number of Participants with a Decrease from Baseline of ≥50% in Cough Severity at 4 weeks. Based on the total Cough Severity Scale (CSS) score. Cough intensity according to the scale is assessed in the daytime and at night in points, where 0 - no cough, 5 - continuous exhausting cough in the daytime and at night.
Time frame: in 4 weeks of the treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rengalin | Percentage of Patients With ≥50% Lesser Cough Severity at 4 Weeks | 49 Participants |
| Placebo | Percentage of Patients With ≥50% Lesser Cough Severity at 4 Weeks | 37 Participants |
p-value: 0.1373G-test (Chi-square)
Secondary
Percentage of Patients With no Exacerbation of COPD
COPD exacerbation is defined as an acute event characterized by aggravation of the event within 2-3 or more days. Exacerbation manifests in intensification of respiratory disorders beyond their regular daily fluctuations and require administration of products in addition to the previously prescribed basic therapy as well as a rescue drug for symptom relief (salbutamol). Additional products include antibacterial drugs, systemic corticosteroids and/or emergency therapy (ambulance call) or hospitalization for COPD exacerbation. COPD exacerbation is recorded as an adverse event. If a COPD exacerbation develops within the first week of the subject participation in the study, it will not be considered as a secondary inefficacy criterion
Time frame: in 4 weeks of the treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rengalin | Percentage of Patients With no Exacerbation of COPD | 115 Participants |
| Placebo | Percentage of Patients With no Exacerbation of COPD | 113 Participants |
p-value: 1Fisher Exact
Secondary
Severity of Cough After 4 Weeks Compared to Baseline
Cough Severity Scale (CSS) total score. Cough intensity according to the scale is assessed in the daytime and at night in points, where 0 - no cough, 5 - continuous exhausting cough in the daytime, and at night.
Time frame: Baseline and 4 weeks after the treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rengalin | Severity of Cough After 4 Weeks Compared to Baseline | Initial total score | 4.18 score on a scale | Standard Deviation 1.42 |
| Rengalin | Severity of Cough After 4 Weeks Compared to Baseline | Total score after 4 weeks | 2.56 score on a scale | Standard Deviation 1.35 |
| Rengalin | Severity of Cough After 4 Weeks Compared to Baseline | ∆ between initial and 4 weeks total scores | 1.62 score on a scale | Standard Deviation 1.38 |
| Placebo | Severity of Cough After 4 Weeks Compared to Baseline | Initial total score | 4.12 score on a scale | Standard Deviation 1.42 |
| Placebo | Severity of Cough After 4 Weeks Compared to Baseline | Total score after 4 weeks | 2.78 score on a scale | Standard Deviation 1.16 |
| Placebo | Severity of Cough After 4 Weeks Compared to Baseline | ∆ between initial and 4 weeks total scores | 1.35 score on a scale | Standard Deviation 1.2 |
Comparison: This analysis applies to ∆ between initial and 4 weeks total scores row.p-value: 0.1101Wilcoxon (Mann-Whitney)