Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary arterial hypertension, imatinib, 6MWD, pulmonary hypertension
Brief summary
This is a multinational, multi center extension study. This study will provide data on the long-term safety, tolerability, and efficacy of imatinib in the treatment of severe pulmonary arterial hypertension.
Interventions
DRUGImatinib
Participants, who received imatinib 200 mg in the core study, CQTI571A2301 (NCT00902174), and completed the core study, received imatinib 200 mg every day (qd) in the extension. Participants, who were randomized to receive imatinib 400 mg in the core study and completed the core study, received imatinib 400 mg qd in the extension. Participants, who terminated early from the core study or who were randomized to placebo and completed the core study, started the extension with imatinib 200 mg qd. After 2 weeks, the dose was increased to 400 mg qd if tolerated.
DRUGPlacebo
To preserve the blind of the core study until the core study, CQTI571A2301 (NCT00902174), was completed, participants received a blinded study drug package containing a 70-tablet bottle of imatinib and a 70-tablet bottle of matching placebo.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who participated in CQTI571A2301 clinical trial and completed the week 24 visit of the study protocol, including all Study Completion assessments * Patients who withdrew from the CQTI571A2301 study prematurely for reasons not related to study drug or not related to a safety issue but performed all Study Completion assessments
Exclusion criteria
* Patients with a pulmonary capillary wedge pressure \> 15 mmHg at time of Study Completion assessments in core protocol CQTI571A2301. If pulmonary capillary wedge pressure is not attainable, then a left atrial pressure measurement may be used in its place. * LVEF \< 45% * Patients with thrombocytopenia, platelet count \< 50E9/L (50E3/µL) * Patients with uncontrolled systemic arterial hypertension, systolic \> 160 mmHg or diastolic \> 90 mmHg * Patients with a QTcF \> 450 ms for males and \> 470 ms for females in the absence of right branch bundle block (based on Visit 1 ECG if required to be performed) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events, Serious Adverse Events and Deaths | 204 weeks | Adverse event monitoring was conducted throughout the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | core study baseline, extension baseline, 12 weeks, 24 weeks, 48 weeks, 72 weeks, 96 weeks, 120 weeks, 144 weeks, 156 weeks, 204 weeks | A six minute walk test (6MWT) was performed in accordance with the guidleines of the American Thoracic Society (2002). |
| Percentage of Participants With Incidence of Clinical Worsening Events | 204 weeks | Clinical worsening events included death, overnight hospitalization for worsening of PAH, worsening of World Health Organization (WHO) functional class by at least one level (drop in WHO ), 15% decrease in the 6MWD as compared to baseline confirmed by two 6MWTs at two consecutive study visits (6MWD reduction), and drop in WHO & 6MWD reduction. Some participants have fulfilled more than one criterion. Therefore, the sum of individual components may be higher than the total number of participants with clinical worsening. |
Countries
Austria, Belgium, Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Core Imatinib Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated. | 66 |
| Core Placebo Depending on the participants randomized treatment in the core study, CQTI571A2301 (NCT00902174), and their completion status in the core study, participants received imatinib at 200 mg qd, 400 mg qd, or 200 mg qd with an increase to 400 mg qd after 2 weeks, if tolerated. | 78 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal test procedure result | 2 | 0 |
| Overall Study | Administrative problems | 25 | 22 |
| Overall Study | Adverse Event | 19 | 26 |
| Overall Study | Death | 5 | 10 |
| Overall Study | Lack of Efficacy | 3 | 4 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol deviation | 0 | 1 |
| Overall Study | Subject no longer requires study drug | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 10 |
Baseline characteristics
| Characteristic | Core Imatinib | Core Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.3 Years STANDARD_DEVIATION 15.52 | 45.7 Years STANDARD_DEVIATION 13.31 | 47.4 Years STANDARD_DEVIATION 14.42 |
| Sex: Female, Male Female | 57 Participants | 63 Participants | 120 Participants |
| Sex: Female, Male Male | 9 Participants | 15 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 66 | 72 / 78 |
| serious Total, serious adverse events | 40 / 66 | 53 / 78 |
Outcome results
Primary
Number of Participants With Adverse Events, Serious Adverse Events and Deaths
Adverse event monitoring was conducted throughout the study.
Time frame: 204 weeks
Population: Safety analysis set: The safety set included all paticipants who received at least one dose of study drug during the extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Core Imatinib | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Adverse events (non-serious and serious) | 62 Participants |
| Core Imatinib | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Serious adverse events | 40 Participants |
| Core Imatinib | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Deaths | 6 Participants |
| Core Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Adverse events (non-serious and serious) | 76 Participants |
| Core Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Serious adverse events | 53 Participants |
| Core Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Deaths | 10 Participants |
Secondary
Change From Core Study Baseline in Six-Minute Walk Distance (6MWD)
A six minute walk test (6MWT) was performed in accordance with the guidleines of the American Thoracic Society (2002).
Time frame: core study baseline, extension baseline, 12 weeks, 24 weeks, 48 weeks, 72 weeks, 96 weeks, 120 weeks, 144 weeks, 156 weeks, 204 weeks
Population: Participants from the Full Analysis Set (FAS), who had values at both core study baseline and the given post-baseline time point, were included in the analysis for that post-baseline time point. The FAS included all participants who received at least one dose of study drug during the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 96 (n=38,35) | 66.64 meters | Standard Deviation 71.08 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Extension baseline (n=61,77) | 42.98 meters | Standard Deviation 55.209 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 120 (n=32,29) | 83.19 meters | Standard Deviation 67.855 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 48 (n=47,42) | 45.81 meters | Standard Deviation 72.15 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 144 (n=27,21) | 67.70 meters | Standard Deviation 64 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 12 (n=58,57) | 48.75 meters | Standard Deviation 60.887 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 156 (n=21,18) | 72.60 meters | Standard Deviation 67.972 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 72 (n=40,39) | 49.54 meters | Standard Deviation 76.019 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 204 (n=4,3) | 96.88 meters | Standard Deviation 42.048 |
| Core Imatinib | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 24 (n=54,53) | 44.71 meters | Standard Deviation 45.506 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 204 (n=4,3) | 4.50 meters | Standard Deviation 25.608 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 12 (n=58,57) | 16.25 meters | Standard Deviation 64.992 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 24 (n=54,53) | 19.34 meters | Standard Deviation 71.675 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 48 (n=47,42) | 29.18 meters | Standard Deviation 65.198 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 72 (n=40,39) | 56.46 meters | Standard Deviation 111.13 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 96 (n=38,35) | 41.03 meters | Standard Deviation 54.495 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 120 (n=32,29) | 37.43 meters | Standard Deviation 60.087 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 144 (n=27,21) | 39.45 meters | Standard Deviation 79.356 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Week 156 (n=21,18) | 30.17 meters | Standard Deviation 66.856 |
| Core Placebo | Change From Core Study Baseline in Six-Minute Walk Distance (6MWD) | Extension baseline (n=61,77) | 4.91 meters | Standard Deviation 62.629 |
Secondary
Percentage of Participants With Incidence of Clinical Worsening Events
Clinical worsening events included death, overnight hospitalization for worsening of PAH, worsening of World Health Organization (WHO) functional class by at least one level (drop in WHO ), 15% decrease in the 6MWD as compared to baseline confirmed by two 6MWTs at two consecutive study visits (6MWD reduction), and drop in WHO & 6MWD reduction. Some participants have fulfilled more than one criterion. Therefore, the sum of individual components may be higher than the total number of participants with clinical worsening.
Time frame: 204 weeks
Population: Full Analysis Set (FAS): The full analysis set included all participants who received at least one dose of study drug during the extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | Total participants with clinical worsening | 50.0 Percentage of participants |
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | Death (all deaths) | 7.6 Percentage of participants |
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | Hospitalization for worsening of PAH | 33.3 Percentage of participants |
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | Drop in WHO | 24.2 Percentage of participants |
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | 6MWD reduction | 12.1 Percentage of participants |
| Core Imatinib | Percentage of Participants With Incidence of Clinical Worsening Events | Drop in WHO and 6MWD reduction | 1.5 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | 6MWD reduction | 19.2 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | Total participants with clinical worsening | 46.2 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | Drop in WHO | 19.2 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | Death (all deaths) | 12.8 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | Drop in WHO and 6MWD reduction | 3.8 Percentage of participants |
| Core Placebo | Percentage of Participants With Incidence of Clinical Worsening Events | Hospitalization for worsening of PAH | 28.2 Percentage of participants |