Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary arterial hypertension, Imatinib, 6MWD, Borg scale, Pulmonary hypertension
Brief summary
A multinational, multicenter, double blind, placebo-controlled study evaluating the efficacy and safety of imatinib as an add-on therapy in the treatment of patients with severe pulmonary arterial hypertension (PAH).
Interventions
DRUGimatinib mesylate
Two or 4 imatinib mesylate (QTI571) 100 mg film coated tablets once daily.
DRUGPlacebo
Placebo to imatinib 100 mg film coated tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria * Male or female patients ≥18 years of age with a current diagnosis of pulmonary arterial hypertension (PAH) according to the Dana Point 2008 Meeting: World Health Organization (WHO) Diagnostic Group I, idiopathic or heritable (familial or sporadic) PAH, PAH associated with collagen vascular disease including systemic sclerosis, rheumatoid arthritis, mixed connective tissue diseases, and overlap syndrome. PAH following one year repair of congenital heart defect \[Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD) or Posterior Descending Artery (PDA)\], or PAH associated with diet therapies or other drugs * A Pulmonary Vascular Resistance (PVR) ≥ 800 dynes.sec.cm-5 (as assessed by Right Heart Catheterization (RHC) at screening or in the 3 months preceding the screening visit) despite treatment with two or more specific PAH therapies, including Endothelin Receptor Antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE5), or subcutaneous, inhaled, intravenous or oral prostacyclin analogues for ≥ 3 months. Background therapy doses were to be stable for ≥ 30 days except for warfarin and prostacyclin analogues ( ≥ 30 days but doses could vary even within the month before enrollment). * World Health Organization functional Class II-IV. For WHO Functional Class IV, one of the 2 or more specific PAH therapies were to be an inhaled, subcutaneous, intravenous or oral prostacyclin analogue, unless the subject showed intolerance of prostacyclin analogues. * 6MWD ≥ 150 meters and ≤ 450 meters at screening. Distances of two consecutive 6MWTs were to be within 15% of one another. Key
Exclusion criteria
* With a pulmonary capillary wedge pressure \> 15 mm Hg to rule out PAH secondary to left ventricular dysfunction. * With a diagnosis of pulmonary artery or vein stenosis * Left ventricular ejection fraction (LVEF) \< 45% * With Disseminated Intravascular Coagulation (DIC) * With evidence of major bleeding or intracranial hemorrhage * With a history of elevated intracranial pressure * With a history of latent bleeding risk such as diabetic retinopathy, gastrointestinal bleeding due to gastric or duodenal ulcers, or colitis ulcerosa * With a QTcF \> 450 msec for males and \> 470 msec for females at screening and baseline in the absence of right bundle branch block. * With a history of ventricular tachycardia, ventricular fibrillation or ventricular flutter * With a history of Torsades de Pointes * With a history of long QT syndrome * Having undergone atrial septostomy in the 3 months prior to the screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks | 24 weeks | This standardized walk course was 30 meters in length. During the walk the participant was connected to a portable pulse oximeter via a finger probe. Participants were instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. The total distance walked (in meters) was recorded. Results were compared between the 2 groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Right Atrial Pressure | baseline and week 24 | Change from baseline in right atrial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The right atrial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher right atrial pressure number indicates worsening. |
| Change From Baseline in Mean Pulmonary Arterial Pressure | baseline and week 24 | Change from baseline in mean pulmonary arterial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The mean pulmonary arterial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher mean pulmonary arterial pressure number indicates worsening. |
| Change From Baseline in Mean Pulmonary Capillary Wedge Pressure | baseline and week 24 | Change from baseline in mean pulmonary capillary wedge pressure (mmHg)was measured via right heart catheterization according to the local hospital procedures. The right atrial mean pulmonary capillary wedge pressure was assessed when the participant was in a stable hemodynamic rest state. |
| Change From Baseline in Systemic Vascular Resistance | baseline and week 24 | Change from baseline in systemic vascular resistance (dynes\*sec\*cm\^-5) was measured via right heart catheterization according to the local hospital procedures. The systemic vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in mean systemic vascular resistance indicates improvement. |
| Change From Baseline in Pulmonary Vascular Resistance | baseline and week 24 | Change from baseline in pulmonary vascular resistance (dynes\*sec\*cm\^-5) was measured via right heart catheterization according to the local hospital procedures. The pulmonary vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in pulmonary vascular resistance indicates improvement. |
| Change From Baseline in Pulmonary Resistance Index | baseline and week 24 | Change from baseline in pulmonary resistance index (dynes\*sec\*cm\^-5/m2) was measured via right heart catheterization according to the local hospital procedures. The pulmonary resistance index was assessed when the participant was in a stable hemodynamic rest state. A reduction from baseline in pulmonary resistance index indicates improvement. |
| Change From Baseline in Cardiac Output | 24 weeks | Change from baseline in cardiac output (L/min) was measured via right heart catheterization according to the local hospital procedures. The cardiac output was assessed when the participant was in a stable hemodynamic rest state. An increase from baseline (higher number) in cardiac output indicates improvement. |
| Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases | 24 weeks | Clinical worsening per participant was measured by the onset of any adjudicated event (all cause mortality; overnight hospitalization for worsening of Pulmonary Arterial Hypertension (PAH); worsening of WHO functional class by one level; 15% decline in Six Minute Walk Distance (6MWD) measured on two consecutive occasions) at 24 weeks treatment, comparing imatinib to placebo groups. A cox regression analysis model was used. |
| Change From Baseline in Diastolic Arterial Blood Pressure | baseline and week 24 | Change from baseline in diastolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The diastolic arterial blood pressure was assessed when the participant was in a stable hemodynamic rest state. |
| Change From Baseline in Heart Rate | 24 weeks | Change from baseline in heart rate (bpm) was measured via right heart catheterization according to the local hospital procedures. The heart rate was assessed when the participant was in a stable hemodynamic rest state. |
| Change in Borg Dyspnea Score During 6-minute Walk Test | week 24 | Change in Borg scale was measured at different time points at week 24. The Borg Scale consists of scale range of 0 to 10. Participants pointed to indicate their level of dyspnea before and at the end of exercise testing (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). A reduction in this score indicates an improvement. |
| Covariance of End of Study CAMPHOR Score | Week 24 | The CAMPHOR test consists of 65 items and 3 scales. Two scales measure Health Related Quality of Life. 1) Symptoms: consists of 25 items measuring loss or abnormality of psychological, physiological or anatomical structure or function; further sub-divided into 3 subscales (energy, breathlessness and mood), 2) Disability: consists of 15 items measuring any restriction or lack of ability to perform an activity. 3) Quality of Life (QOL): consists of 25 items defining how individuals perceived ability and capacity to satisfy their needs. The 25-item symptom and QOL scales score from 0-25 where a higher score indicates the presence of more symptoms and poor QOL, respectively. The 15-item functioning scale scores 0-30; a higher score indicates poor functioning. |
| Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168 | Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168. The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay. |
| Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168 | Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168. The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay. |
| Change From Baseline in Systolic Arterial Blood Pressure | baseline and week 24 | Change from baseline in systolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The systolic arterial blood was assessed when the participant was in a stable hemodynamic rest state. |
Countries
Austria, Belgium, Canada, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Overall, 326 participants were screened, 202 participants were randomized (103 to Imatinib and 99 to placebo). Out of 202 participants randomized 201 participants received study drug treatment (103 received imatinib mesylate, 98 received placebo). One participant was randomized to the placebo group but did not receive any study treatment.
Pre-assignment details
Participants were randomized in a 1:1 ratio to imatinib mesylate or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Imatinib Mesylate Imatinib mesylate (QTI571) 200 mg once daily for two weeks, increased to 400 mg once daily if well tolerated. If 400 mg dose was not well tolerated, a down titration to 200 mg once daily was permitted. | 103 |
| Placebo Placebo to imatinib mesylate taken once daily. Participants receiving placebo were allowed to receive already approved PAH treatments. | 99 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal labs | 1 | 1 |
| Overall Study | Administration problem | 0 | 1 |
| Overall Study | Adverse Event | 27 | 7 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lack of Efficacy | 1 | 5 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Imatinib Mesylate | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.0 years STANDARD_DEVIATION 15.33 | 46.5 years STANDARD_DEVIATION 13.6 | 48.3 years STANDARD_DEVIATION 14.59 |
| Gender Female | 83 participants | 79 participants | 162 participants |
| Gender Male | 20 participants | 19 participants | 39 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 103 | 80 / 98 |
| serious Total, serious adverse events | 45 / 103 | 29 / 98 |
Outcome results
Primary
Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks
This standardized walk course was 30 meters in length. During the walk the participant was connected to a portable pulse oximeter via a finger probe. Participants were instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. The total distance walked (in meters) was recorded. Results were compared between the 2 groups.
Time frame: 24 weeks
Population: The Full Analysis Set includes all participants who received at least one dose of study drug and completed the 6MWD Six-minute walk test at week 24. Repeated measurement model was used for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks | 382.94 meters | Standard Error 9.79 |
| Placebo | Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks | 351.18 meters | Standard Error 9.834 |
Secondary
Change From Baseline in Cardiac Output
Change from baseline in cardiac output (L/min) was measured via right heart catheterization according to the local hospital procedures. The cardiac output was assessed when the participant was in a stable hemodynamic rest state. An increase from baseline (higher number) in cardiac output indicates improvement.
Time frame: 24 weeks
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Cardiac Output | 1.17 Liters/minute | Standard Error 0.182 |
| Placebo | Change From Baseline in Cardiac Output | 0.29 Liters/minute | Standard Error 0.186 |
Secondary
Change From Baseline in Diastolic Arterial Blood Pressure
Change from baseline in diastolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The diastolic arterial blood pressure was assessed when the participant was in a stable hemodynamic rest state.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Diastolic Arterial Blood Pressure | -3.81 mm Hg | Standard Error 1.958 |
| Placebo | Change From Baseline in Diastolic Arterial Blood Pressure | -1.48 mm Hg | Standard Error 1.909 |
Secondary
Change From Baseline in Heart Rate
Change from baseline in heart rate (bpm) was measured via right heart catheterization according to the local hospital procedures. The heart rate was assessed when the participant was in a stable hemodynamic rest state.
Time frame: 24 weeks
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Heart Rate | 0.38 bpm | Standard Error 12.63 |
| Placebo | Change From Baseline in Heart Rate | 0.73 bpm | Standard Error 2.255 |
Secondary
Change From Baseline in Mean Pulmonary Arterial Pressure
Change from baseline in mean pulmonary arterial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The mean pulmonary arterial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher mean pulmonary arterial pressure number indicates worsening.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Mean Pulmonary Arterial Pressure | -3.54 mm Hg | Standard Error 1.585 |
| Placebo | Change From Baseline in Mean Pulmonary Arterial Pressure | 1.63 mm Hg | Standard Error 1.586 |
Secondary
Change From Baseline in Mean Pulmonary Capillary Wedge Pressure
Change from baseline in mean pulmonary capillary wedge pressure (mmHg)was measured via right heart catheterization according to the local hospital procedures. The right atrial mean pulmonary capillary wedge pressure was assessed when the participant was in a stable hemodynamic rest state.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Mean Pulmonary Capillary Wedge Pressure | 0.92 mm Hg | Standard Error 0.693 |
| Placebo | Change From Baseline in Mean Pulmonary Capillary Wedge Pressure | -0.05 mm Hg | Standard Error 0.701 |
Secondary
Change From Baseline in Pulmonary Resistance Index
Change from baseline in pulmonary resistance index (dynes\*sec\*cm\^-5/m2) was measured via right heart catheterization according to the local hospital procedures. The pulmonary resistance index was assessed when the participant was in a stable hemodynamic rest state. A reduction from baseline in pulmonary resistance index indicates improvement.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Pulmonary Resistance Index | -221.29 dynes*sec*cm^-5/m2 | Standard Error 47.355 |
| Placebo | Change From Baseline in Pulmonary Resistance Index | 21.92 dynes*sec*cm^-5/m2 | Standard Error 48.247 |
Secondary
Change From Baseline in Pulmonary Vascular Resistance
Change from baseline in pulmonary vascular resistance (dynes\*sec\*cm\^-5) was measured via right heart catheterization according to the local hospital procedures. The pulmonary vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in pulmonary vascular resistance indicates improvement.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Pulmonary Vascular Resistance | -366.47 dynes*sec*cm^-5 | Standard Error 67.673 |
| Placebo | Change From Baseline in Pulmonary Vascular Resistance | 12.12 dynes*sec*cm^-5 | Standard Error 68.963 |
Secondary
Change From Baseline in Right Atrial Pressure
Change from baseline in right atrial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The right atrial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher right atrial pressure number indicates worsening.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Right Atrial Pressure | -1.02 mm Hg | Standard Error 0.851 |
| Placebo | Change From Baseline in Right Atrial Pressure | 0.68 mm Hg | Standard Error 0.855 |
Secondary
Change From Baseline in Systemic Vascular Resistance
Change from baseline in systemic vascular resistance (dynes\*sec\*cm\^-5) was measured via right heart catheterization according to the local hospital procedures. The systemic vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in mean systemic vascular resistance indicates improvement.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Systemic Vascular Resistance | -467.84 dynes*sec*cm^-5 | Standard Error 78.577 |
| Placebo | Change From Baseline in Systemic Vascular Resistance | -88.10 dynes*sec*cm^-5 | Standard Error 77.183 |
Secondary
Change From Baseline in Systolic Arterial Blood Pressure
Change from baseline in systolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The systolic arterial blood was assessed when the participant was in a stable hemodynamic rest state.
Time frame: baseline and week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Imatinib | Change From Baseline in Systolic Arterial Blood Pressure | -2.92 mm Hg | Standard Error 2.298 |
| Placebo | Change From Baseline in Systolic Arterial Blood Pressure | -1.15 mm Hg | Standard Error 2.227 |
Secondary
Change in Borg Dyspnea Score During 6-minute Walk Test
Change in Borg scale was measured at different time points at week 24. The Borg Scale consists of scale range of 0 to 10. Participants pointed to indicate their level of dyspnea before and at the end of exercise testing (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). A reduction in this score indicates an improvement.
Time frame: week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib | Change in Borg Dyspnea Score During 6-minute Walk Test | End of test (n= 92 imatinib; 91 placebo) | -0.38 units on a scale | Standard Deviation 2.009 |
| Imatinib | Change in Borg Dyspnea Score During 6-minute Walk Test | End of test - Resting (n= 81 imatinib; 81 placebo) | -0.24 units on a scale | Standard Deviation 1.193 |
| Imatinib | Change in Borg Dyspnea Score During 6-minute Walk Test | 2 min after end (n= 82 imatinib; 81 placebo) | -0.37 units on a scale | Standard Deviation 1.409 |
| Imatinib | Change in Borg Dyspnea Score During 6-minute Walk Test | 2 min after end - end of test (n= 82 ima; 81plb) | -0.07 units on a scale | Standard Deviation 1.533 |
| Imatinib | Change in Borg Dyspnea Score During 6-minute Walk Test | Resting (n= 86 imatinib; 89 placebo) | -0.06 units on a scale | Standard Deviation 1.097 |
| Placebo | Change in Borg Dyspnea Score During 6-minute Walk Test | 2 min after end - end of test (n= 82 ima; 81plb) | -0.03 units on a scale | Standard Deviation 1.743 |
| Placebo | Change in Borg Dyspnea Score During 6-minute Walk Test | Resting (n= 86 imatinib; 89 placebo) | -0.12 units on a scale | Standard Deviation 1.142 |
| Placebo | Change in Borg Dyspnea Score During 6-minute Walk Test | End of test (n= 92 imatinib; 91 placebo) | -0.24 units on a scale | Standard Deviation 2.093 |
| Placebo | Change in Borg Dyspnea Score During 6-minute Walk Test | 2 min after end (n= 82 imatinib; 81 placebo) | -0.18 units on a scale | Standard Deviation 1.55 |
| Placebo | Change in Borg Dyspnea Score During 6-minute Walk Test | End of test - Resting (n= 81 imatinib; 81 placebo) | -0.29 units on a scale | Standard Deviation 1.279 |
Secondary
Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases
Clinical worsening per participant was measured by the onset of any adjudicated event (all cause mortality; overnight hospitalization for worsening of Pulmonary Arterial Hypertension (PAH); worsening of WHO functional class by one level; 15% decline in Six Minute Walk Distance (6MWD) measured on two consecutive occasions) at 24 weeks treatment, comparing imatinib to placebo groups. A cox regression analysis model was used.
Time frame: 24 weeks
Population: The Full Analysis Set included all participants who received at least one dose of study drug and experienced an adjudicated event. A cox regression analysis model was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib | Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases | 35.9 percentage of participants |
| Placebo | Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases | 32.7 percentage of participants |
Secondary
Covariance of End of Study CAMPHOR Score
The CAMPHOR test consists of 65 items and 3 scales. Two scales measure Health Related Quality of Life. 1) Symptoms: consists of 25 items measuring loss or abnormality of psychological, physiological or anatomical structure or function; further sub-divided into 3 subscales (energy, breathlessness and mood), 2) Disability: consists of 15 items measuring any restriction or lack of ability to perform an activity. 3) Quality of Life (QOL): consists of 25 items defining how individuals perceived ability and capacity to satisfy their needs. The 25-item symptom and QOL scales score from 0-25 where a higher score indicates the presence of more symptoms and poor QOL, respectively. The 15-item functioning scale scores 0-30; a higher score indicates poor functioning.
Time frame: Week 24
Population: Participants from the Full Analysis Set, defined as all randomized participants who received at least one dose of study drug, with data available for analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib | Covariance of End of Study CAMPHOR Score | Symptoms score | 7.93 units on a scale | Standard Error 1.372 |
| Imatinib | Covariance of End of Study CAMPHOR Score | Activity score | 8.99 units on a scale | Standard Error 1.177 |
| Imatinib | Covariance of End of Study CAMPHOR Score | Quality of life score | 7.45 units on a scale | Standard Error 1.026 |
| Placebo | Covariance of End of Study CAMPHOR Score | Symptoms score | 9.03 units on a scale | Standard Error 1.431 |
| Placebo | Covariance of End of Study CAMPHOR Score | Activity score | 10.55 units on a scale | Standard Error 1.223 |
| Placebo | Covariance of End of Study CAMPHOR Score | Quality of life score | 7.13 units on a scale | Standard Error 1.066 |
Secondary
Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant
Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168. The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay.
Time frame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168
Population: The Full Analysis Set includes all patients who received at least one dose of study drug with available blood samples for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - predose (n=77 imat; n=77 GCP) | 0 ng/mL | Standard Deviation 0 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - 0-3h post-dose (n=77 imat; n=77 GCP) | 471.9 ng/mL | Standard Deviation 560.1 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - predose (n=18 imat; n=18 GCP) | 579.6 ng/mL | Standard Deviation 384.9 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - 0-3h post-dose (n=19 imat; n=19 GCP) | 1005.7 ng/mL | Standard Deviation 665.6 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - predose (n=20 imat; n=20 GCP) | 658.8 ng/mL | Standard Deviation 450.3 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - 0-3h post-dose (n=19 imat; n=19 GCP) | 1438.6 ng/mL | Standard Deviation 924.4 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168 predose (n=24 imat; n=24 GCP) | 398.6 ng/mL | Standard Deviation 415.5 |
| Imatinib | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168- 0-3h post-dose (n=23 imat; n=23 GCP) | 710.8 ng/mL | Standard Deviation 639.7 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168- 0-3h post-dose (n=23 imat; n=23 GCP) | 166.1 ng/mL | Standard Deviation 103.1 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - predose (n=77 imat; n=77 GCP) | 0 ng/mL | Standard Deviation 0 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - predose (n=20 imat; n=20 GCP) | 228.6 ng/mL | Standard Deviation 121.4 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - 0-3h post-dose (n=77 imat; n=77 GCP) | 61.8 ng/mL | Standard Deviation 77.6 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168 predose (n=24 imat; n=24 GCP) | 126.6 ng/mL | Standard Deviation 83.3 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - predose (n=18 imat; n=18 GCP) | 178.8 ng/mL | Standard Deviation 122.8 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - 0-3h post-dose (n=19 imat; n=19 GCP) | 323.9 ng/mL | Standard Deviation 150.6 |
| Placebo | Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - 0-3h post-dose (n=19 imat; n=19 GCP) | 233.8 ng/mL | Standard Deviation 170.9 |
Secondary
Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant
Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168. The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay.
Time frame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168
Population: The Full Analysis Set includes all patients who received at least one dose of study drug with available blood samples for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - predose (n=12 imat; n=12 GCP) | 0 ng/mL | Standard Deviation 0 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - 0-3h post-dose (n=13 imat; n=13 GCP) | 843.2 ng/mL | Standard Deviation 788.9 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - predose (n=62 imat; n=62 GCP) | 516.5 ng/mL | Standard Deviation 405.2 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - 0-3h post-dose (n=62 imat; n=62 GCP) | 1172.8 ng/mL | Standard Deviation 1088.9 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - predose (n=55 imat; n=55 GCP) | 829.8 ng/mL | Standard Deviation 482.6 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - 0-3h post-dose (n=58 imat; n=58 GCP) | 1335.3 ng/mL | Standard Deviation 817.9 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168 predose (n=36 imat; n=36 GCP) | 869.9 ng/mL | Standard Deviation 407.8 |
| Imatinib | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168- 0-3h post-dose (n=35 imat; n=35 GCP) | 1616.1 ng/mL | Standard Deviation 787.6 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168- 0-3h post-dose (n=35 imat; n=35 GCP) | 348.0 ng/mL | Standard Deviation 119.1 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - predose (n=12 imat; n=12 GCP) | 0 ng/mL | Standard Deviation 0 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - predose (n=55 imat; n=55 GCP) | 248.2 ng/mL | Standard Deviation 125.2 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 1 - 0-3h post-dose (n=13 imat; n=13 GCP) | 109.9 ng/mL | Standard Deviation 132.4 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 168 predose (n=36 imat; n=36 GCP) | 241.4 ng/mL | Standard Deviation 91.9 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - predose (n=62 imat; n=62 GCP) | 155.1 ng/mL | Standard Deviation 101.1 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 28 - 0-3h post-dose (n=58 imat; n=58 GCP) | 320.7 ng/mL | Standard Deviation 154.8 |
| Placebo | Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant | Day 14 - 0-3h post-dose (n=62 imat; n=62 GCP) | 233.7 ng/mL | Standard Deviation 165.6 |