Asthma
Conditions
Keywords
Asthma, Severe Persistent Asthma, Subcutaneous injections, Immunology disorder, Breathlesness
Brief summary
The purpose of this study is to evaluate the effectiveness and safety of CNTO 148 (golimumab) in patients with severe persistent asthma.
Detailed description
This is a multicenter, randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), placebo-controlled (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical study), parallel-group (each group of patients will be treated at the same time), dose-ranging study to evaluate the efficacy and safety of CNTO 148. The study will consists of run-in phase (2 weeks), treatment period (52 weeks) and follow up period (24 weeks). The patients inhaled corticosteroids (ICS) medication will be standardized in the run-in phase and the treatment period contains first 24 weeks of treatment, the patients are required to remain on stable doses of concomitant corticosteroids (CS) medication (steroid stable phase). The steroid stable phase is followed by a 28-week steroid taper phase, during which a reduction of concomitant CS medication will be attempted. After completion of the study treatment, patients are to be followed for an additional 24 weeks. Patients will receive subcutaneous injections of 75, 150, or 300 mg of CNTO 148 or placebo every 4 weeks for 52 weeks followed 50,100, or 200 mg every 4 weeks through week 52. The safety of the patient will be monitored throughout the study.
Interventions
DRUGCNTO148
Type=exact type, unit=mg, number=50, 75, 100, 150, 200 and 300, form=injection, route=subcutaneous. Every 4 weeks partciapnts will receive injections in 4 parallel treatment arms
DRUGPlacebo
Type=exact type, unit=mg, form=injection, route=subcutaneous. Placebo will be given from from Week 0 through Week 52.
Sponsors
Centocor BV
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Physician diagnosis of asthma for greater than or equal to 3 years and a diagnosis of severe persistent asthma forgreater than or equal to 1 year prior to screening * Continuous treatment with high dose Inhaled corticosteroids (ICS) and long acting beta-agonist for at least 3 months prior to screening * Have evidence of at least 1 of the following in the 5 years prior to screening or during screening, reversible airway obstruction greater than or equal to 12 percentage change in forced expiratory volume in 1 second (FEV1) postbronchodilator; Diurnal variation in peak expiratory flow rate (PEFR) greater than or equal to 30 percentage change) and airway hyperresponsiveness * Estimated frequency of symptoms on more than one-third of days for at least 3 months prior to screening (eg, wheezing, breathlessness, chest tightness, cough, nocturnal awakening) despite treatment with high dose ICS and long-acting β2-agonist (LABA), with or without continuous oral corticosteroids * Score of greater than or equal to 2 points on the asthma control questionnaire at screening.
Exclusion criteria
* Diagnosis of chronic obstructive pulmoanry disease (COPD), cystic fibrosis, or other significant respiratory disorder * Worsening of asthma symptoms that required treatment with an addition or increase in oral corticosteroids dose (steroid burst) in the 4-week period prior to the screening visit * Life-threatening asthma attack requiring cardiopulmonary support (eg, intubation) in the 6-month period prior to screening * Have ever used alkylating agents (eg, chlorambucil or cyclophosphamide) * Concomitant diagnosis or any history of congestive heart failure (CHF), including medically controlled CHF.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | Baseline and Week 24 | The endpoint is change from baseline in prebronchodilator clinic-measured percent predicted Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) with Last Observation Carried Forward (LOCF) at 6 months. The baseline visit starts at the end of 2 weeks run in phase. |
| Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | Baseline to Week 24 | The endpoint is the average number of severe asthma exacerbations per patient from baseline through 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | Week 24 to Week 52 | The endpoint is the average number of severe asthma exacerbations per patient from Week (Wk) 24 through Wk 52 for the patients who did not discontinue study participation prior to Wk 24 |
| Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | Baseline to Week 24 | The endpoint is the change from baseline in the overall Asthma Quality of Life Questionnaire (AQLQ) score at 6 months. The AQLQ is a validated and self-administered questionnaire to evaluate symptoms and Quality of Life (QOL) in subjects with asthma and it has 32 questions in 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli). Participants were asked to score the importance of each of the positively identified problems on a 7-point scale (7 = not impaired at all - 1 = severely impaired). |
| Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | Baseline to Week 24 | The endpoint is the change from baseline in domiciliary morning PEFR at Week 24. PEFR- Peak Expiratory Flow Rate (PEFR): A measure of the speed of exhalation. The data were collected in the eDiary which was issued to each participant at screening. PEFR was collected morning and evening each day of the study. |
| Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | Baseline and Week 52 | The endpoint is the change from baseline at Week (Wk) 52 in oral corticosteroids (OCS) dose for the randomized patients who received OCS at baseline. |
| Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | Baseline to Week 24 | The endpoint is change from baseline in rescue medication use at Wk 24 where the rescue medication use was based on the average over 7 days prior to visit. |
Countries
Belgium, Bulgaria, Czechia, France, Germany, Hungary, Netherlands, Poland, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 309 patients were randomized into 4 parallel treatment groups at 53 sites (134 patients at 27 sites in the US and 175 patients at 26 sites in Europe). The first patient was consented on 31 Aug 2004, and the last patient completed the study on 17 Jul 2007.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo Placebo subcutaneous (SC) injections every 4 weeks (Wks) from week (Wk) 0 to Wk 52 | 78 |
| Group II: Golimumab 50 mg Golimumab (CNTO148) 75 mg SC injection at Wk 0 followed by 50 mg SC injections every 4 Wks to Wk 52 | 77 |
| Group III: Golimumab 100 mg Golimumab 150 mg SC injection at Wk 0 followed by 100 mg SC injections every 4 Wks to Wk 52 | 76 |
| Group IV: Golimumab 200 mg Golimumab 300 mg SC injection at Wk 0 followed by 200 mg SC injections every 4 Wks to Wk 52 | 78 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 14 | 14 | 11 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 | 1 |
| Overall Study | Other | 2 | 10 | 7 | 5 |
| Overall Study | Sponsor Directive | 22 | 15 | 16 | 21 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 0 | 2 | 4 |
Baseline characteristics
| Characteristic | Group I: Placebo | Group II: Golimumab 50 mg | Group III: Golimumab 100 mg | Group IV: Golimumab 200 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 49.4 years STANDARD_DEVIATION 12.03 | 49.4 years STANDARD_DEVIATION 11.26 | 49.1 years STANDARD_DEVIATION 12.85 | 52.7 years STANDARD_DEVIATION 12.26 | 50.1 years STANDARD_DEVIATION 12.14 |
| Sex: Female, Male Female | 42 Participants | 46 Participants | 39 Participants | 46 Participants | 173 Participants |
| Sex: Female, Male Male | 36 Participants | 31 Participants | 37 Participants | 32 Participants | 136 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 75 / 78 | 68 / 75 | 75 / 78 | 75 / 78 |
| serious Total, serious adverse events | 16 / 78 | 24 / 75 | 24 / 78 | 22 / 78 |
Outcome results
Primary
Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second
The endpoint is change from baseline in prebronchodilator clinic-measured percent predicted Percent-Predicted Forced Expiratory Volume in 1 Second (FEV1) with Last Observation Carried Forward (LOCF) at 6 months. The baseline visit starts at the end of 2 weeks run in phase.
Time frame: Baseline and Week 24
Population: The analysis of this endpoint uses intent-to-treat population. Missing data were imputed using Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Group I: Placebo | Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | 2.44 Percent predicted |
| Group II: Golimumab 50 mg | Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | 0.48 Percent predicted |
| Group III: Golimumab 100 mg | Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | 3.22 Percent predicted |
| Group IV: Golimumab 200 mg | Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | 2.59 Percent predicted |
| Combined: Group III & IV | Change From Baseline in Prebronchodilator Clinic-Measured, Percent-Predicted Forced Expiratory Volume in 1 Second | 2.91 Percent predicted |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that for combined 100 mg and 200 mg golimumab. Assuming a standard deviation of 23%, there is 86% power to detect a 10% difference at a 0.05 significance level.p-value: 0.802ANCOVA
Comparison: This is a secondary analysis.p-value: 0.945ANCOVA
Comparison: This is a secondary analysis.p-value: 0.717ANCOVA
Comparison: This is a secondary analysis.p-value: 0.357ANCOVA
Primary
Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months
The endpoint is the average number of severe asthma exacerbations per patient from baseline through 6 months.
Time frame: Baseline to Week 24
Population: The analysis of this endpoint uses intent-to-treat population. For the dropouts, the worst case in similar patients was used as the number of severe exacerbations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | 0.5 Events per patient through week (Wk) 24 | Standard Deviation 1.07 |
| Group II: Golimumab 50 mg | Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | 0.7 Events per patient through week (Wk) 24 | Standard Deviation 1.18 |
| Group III: Golimumab 100 mg | Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | 0.4 Events per patient through week (Wk) 24 | Standard Deviation 0.85 |
| Group IV: Golimumab 200 mg | Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | 0.5 Events per patient through week (Wk) 24 | Standard Deviation 1.08 |
| Combined: Group III & IV | Number of Severe Asthma Exacerbations Per Patient From Baseline Through 6 Months | 0.5 Events per patient through week (Wk) 24 | Standard Deviation 0.97 |
Comparison: The null hypothesis was that the number of severe exacerbations per patient from baseline through week 24 for placebo is the same as that in the combined 100 mg and 200 mg golimumab. Assuming 1 severe exacerbation over 6 months per patient in the placebo group, there is 79% power to detect a 35% reduction in the combined 100 mg and 200 mg golimumab group at a 0.05 significance level.p-value: 0.718Cochran-Mantel-Haenszel
Comparison: This is a secondary analysis.p-value: 0.779Cochran-Mantel-Haenszel
Comparison: This is a secondary analysis.p-value: 0.649Cochran-Mantel-Haenszel
Comparison: This is a secondary analysis.p-value: 0.256Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients
The endpoint is the change from baseline in the overall Asthma Quality of Life Questionnaire (AQLQ) score at 6 months. The AQLQ is a validated and self-administered questionnaire to evaluate symptoms and Quality of Life (QOL) in subjects with asthma and it has 32 questions in 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli). Participants were asked to score the importance of each of the positively identified problems on a 7-point scale (7 = not impaired at all - 1 = severely impaired).
Time frame: Baseline to Week 24
Population: The analysis of this endpoint uses intent-to-treat population. Missing data were imputed using last observation carried forward.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | 0.42 Points on scale |
| Group II: Golimumab 50 mg | Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | 0.53 Points on scale |
| Group III: Golimumab 100 mg | Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | 0.86 Points on scale |
| Group IV: Golimumab 200 mg | Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | 0.55 Points on scale |
| Combined: Group III & IV | Change From Baseline in Asthma Quality of Life Questionnaire Score at 6 Months; Randomized Patients | 0.66 Points on scale |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that in the combined 100 mg and 200 mg golimumab.p-value: 0.286Wilcoxon (Mann-Whitney)
p-value: 0.742Wilcoxon (Mann-Whitney)
p-value: 0.128Wilcoxon (Mann-Whitney)
p-value: 0.946Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects
The endpoint is the change from baseline in domiciliary morning PEFR at Week 24. PEFR- Peak Expiratory Flow Rate (PEFR): A measure of the speed of exhalation. The data were collected in the eDiary which was issued to each participant at screening. PEFR was collected morning and evening each day of the study.
Time frame: Baseline to Week 24
Population: The analysis of this endpoint uses intent-to-treat population. Missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | 4.730 L/min | Standard Deviation 60.9136 |
| Group II: Golimumab 50 mg | Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | 8.102 L/min | Standard Deviation 58.0602 |
| Group III: Golimumab 100 mg | Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | 3.488 L/min | Standard Deviation 60.1336 |
| Group IV: Golimumab 200 mg | Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | 2.475 L/min | Standard Deviation 59.7923 |
| Combined: Group III & IV | Change From Baseline in Domiciliary Morning Peak Expiratory Flow Rate (PEFR) at 6 Months; Randomized Subjects | 2.975 L/min | Standard Deviation 59.7668 |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that in the combined 100 mg and 200 mg golimumab.p-value: 0.833ANOVA
p-value: 0.814ANOVA
p-value: 0.897ANOVA
p-value: 0.726ANOVA
Secondary
Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline
The endpoint is the change from baseline at Week (Wk) 52 in oral corticosteroids (OCS) dose for the randomized patients who received OCS at baseline.
Time frame: Baseline and Week 52
Population: Analysis of this endpoint includes only pts who received OCS at baseline.Wk 52 OCS dose is the daily OCS dose in the last period, defined as between 2 consecutive visits, in which no change in total daily dose of OCS occurred, prior to Wk 52 visit.Data from Wk 24-52 must be interpreted with caution as study agent was stopped at various timepoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | -5.000 mg/day P. Eq. |
| Group II: Golimumab 50 mg | Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | 0.000 mg/day P. Eq. |
| Group III: Golimumab 100 mg | Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | -4.550 mg/day P. Eq. |
| Group IV: Golimumab 200 mg | Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | -3.750 mg/day P. Eq. |
| Combined: Group III & IV | Change From Baseline in Oral Corticosteroids Dose at Week 52; Randomized Patients Who Received Oral Corticosteroids at Baseline | -4.550 mg/day P. Eq. |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that in the combined 100 mg and 200 mg golimumab.p-value: 0.986Wilcoxon (Mann-Whitney)
p-value: 0.82Wilcoxon (Mann-Whitney)
p-value: 0.858Wilcoxon (Mann-Whitney)
p-value: 0.021Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients
The endpoint is change from baseline in rescue medication use at Wk 24 where the rescue medication use was based on the average over 7 days prior to visit.
Time frame: Baseline to Week 24
Population: The analysis of this endpoint uses intent-to-treat population. Missing data were imputed using last observation carried forward.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | -0.54 Puffs/day |
| Group II: Golimumab 50 mg | Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | -0.71 Puffs/day |
| Group III: Golimumab 100 mg | Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | -0.29 Puffs/day |
| Group IV: Golimumab 200 mg | Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | -0.14 Puffs/day |
| Combined: Group III & IV | Change From Baseline in Rescue Medication Use at 6 Months; Randomized Patients | -0.21 Puffs/day |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that in the combined 100 mg and 200 mg golimumab.p-value: 0.894Kruskal-Wallis
p-value: 0.572Kruskal-Wallis
p-value: 0.731Kruskal-Wallis
p-value: 0.856Kruskal-Wallis
Secondary
Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24
The endpoint is the average number of severe asthma exacerbations per patient from Week (Wk) 24 through Wk 52 for the patients who did not discontinue study participation prior to Wk 24
Time frame: Week 24 to Week 52
Population: Analysis of this endpoint only includes patients (pts) who did not discontinue study participation prior to Wk 24. For the dropouts during the period between Wks 24- 52, worst case in similar pts was used as the number of severe exacerbations. Data from Wk 24-52 must be interpreted with caution as study agent was stopped at various study timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I: Placebo | Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | 0.6 Events per patient from Wk 24 thru Wk 52 | Standard Deviation 1.02 |
| Group II: Golimumab 50 mg | Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | 0.8 Events per patient from Wk 24 thru Wk 52 | Standard Deviation 1.23 |
| Group III: Golimumab 100 mg | Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | 0.9 Events per patient from Wk 24 thru Wk 52 | Standard Deviation 1.18 |
| Group IV: Golimumab 200 mg | Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | 0.8 Events per patient from Wk 24 thru Wk 52 | Standard Deviation 1.01 |
| Combined: Group III & IV | Number of Severe Asthma Exacerbations Per Patient From Week 24 Through Week 52; Randomized Patients Who Did Not Discontinue Study Participation Prior to Week 24 | 0.9 Events per patient from Wk 24 thru Wk 52 | Standard Deviation 1.09 |
Comparison: The null hypothesis was that the endpoint for placebo is the same as that in the combined 100 mg and 200 mg golimumab.p-value: 0.273Cochran-Mantel-Haenszel
p-value: 0.382Cochran-Mantel-Haenszel
p-value: 0.35Cochran-Mantel-Haenszel
p-value: 0.341Cochran-Mantel-Haenszel