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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01392469
Registration number
NCT01392469
Ethics application status
Date submitted
10/05/2011
Date registered
12/07/2011
Date last updated
21/06/2021
Titles & IDs
Public title
Pharmacokinetic Effects of QTI571 on Sildenafil and Bosentan in Pulmonary Arterial Hypertension Participants
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Scientific title
A Non-Randomized, Multiple Dose, Three Treatment Period, Open-Label, Single Sequence, Single Group Study to Evaluate the Pharmacokinetic Effect of Two Doses of QTI571 (Imatinib) on the Co-administered Drugs Sildenafil and Bosentan in Pulmonary Arterial Hypertension (PAH) Patients
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Secondary ID [1]
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2010-021344-17
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Secondary ID [2]
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CQTI571A2102
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cardiovascular
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Hypertension
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Imatinib
Treatment: Drugs - Sildenafil
Treatment: Drugs - Bosentan
Experimental: Imatinib + Bosentan + Sildenafil - Participants received treatment with bosentan 125 milligrams (mg) twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan. Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2. Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Treatment: Drugs: Imatinib
Film coated tablets, oral administration
Treatment: Drugs: Sildenafil
Oral Administration
Treatment: Drugs: Bosentan
Oral Administration
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations
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Assessment method [1]
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AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized AUCtau of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
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Timepoint [1]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Primary outcome [2]
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Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations
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Assessment method [2]
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AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized AUCtau of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
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Timepoint [2]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Primary outcome [3]
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Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations
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Assessment method [3]
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Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized Cmax of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
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Timepoint [3]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Primary outcome [4]
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Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations
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Assessment method [4]
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Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized Cmax of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals was then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
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Timepoint [4]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Secondary outcome [1]
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Number of Participants With At Least One or More Adverse Events (AEs)
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Assessment method [1]
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An adverse event was the appearance or worsening of any undesirable sign, symptom, or medical condition that occurred after starting the study drug even if the event was not considered to be related to study drug. Number of participants with AEs were reported by treatment period.
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Timepoint [1]
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From time of first administration of study drug until end of study (up to approximately 18 months)
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Secondary outcome [2]
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Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib)
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Assessment method [2]
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Timepoint [2]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Secondary outcome [3]
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Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib)
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Assessment method [3]
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Timepoint [3]
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Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose
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Eligibility
Key inclusion criteria
- Participants with Pulmonary arterial hypertension (PAH) in World Health Organization
(WHO) Diagnostic Group 1, with pulmonary vascular resistance > 800 dyne*sec*cm^-5,
- On stable doses of bosentan and sildenafil
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Other diagnosis of PAH in World Health Organization (WHO) Diagnostic Group 1 such as
congenital large or small unrepaired systemic to pulmonary shunts, portal
hypertension, Human Immunodeficiency Virus (HIV) infection, glycogen storage disease,
Gaucher's disease, hereditary hemorrhagic teleangiectasia, hemoglobinopathies,
myeloproliferative disorders, veno-occlusive pulmonary disease
- Significant lung diseases not related to PAH
- Significant cardiovascular system disorders, hematological system disorders, liver
insufficiency
- Significant diseases in other organ system.
Other protocol-defined inclusion/exclusion criteria may apply
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
20/04/2011
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
25/10/2012
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Sample size
Target
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Accrual to date
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Final
21
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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Novartis Investigative Site - Darlinghurst
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Recruitment postcode(s) [1]
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2010 - Darlinghurst
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Florida
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Country [2]
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United States of America
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State/province [2]
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New York
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Country [3]
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Belgium
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State/province [3]
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Bruxelles
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Country [4]
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Belgium
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State/province [4]
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Leuven
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Country [5]
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Germany
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State/province [5]
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Berlin
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Country [6]
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Germany
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State/province [6]
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Hannover
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Country [7]
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Italy
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State/province [7]
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RM
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Country [8]
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Lithuania
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State/province [8]
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Vilnius
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Country [9]
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United Kingdom
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State/province [9]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this study was to investigate the effects of QTI571 (imatinib) on
pharmacokinetics of bosentan and sildenafil at steady state when co-administered to
participants with pulmonary arterial hypertension.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01392469
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01392469
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