Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension, Nilotinib, 6MWD, Pulmonary Hypertension
Brief summary
The purpose of this trial was to establish the safety, tolerability and PK of nilotinib in this population and to test the hypothesis that 6 months treatment with nilotinib will significantly reduce pulmonary artery resistance.
Detailed description
The purpose of this trial was to establish the safety, tolerability and PK of nilotinib in this population and to test the hypothesis that 6 months
Interventions
DRUGNilotinib
Nilotinib capsules for oral administration at 50 mg, 150 mg twice a day and 300 mg (2 capsules of 150 mg) twice a day.
DRUGPlacebo to nilotinib
Placebo to nilotinib capsules for oral administration to match 50 mg, 150 mg and 300 mg capsules twice a day
Sponsors
Novartis Pharmaceuticals
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
* World Health Organization (WHO) Functional Class II or III * 6MWD ≥ 150 m and ≤ 450 m at screening * Current diagnosis of PAH according to Dana Point 2008 Meeting * Inadequate clinical response on one or more class(es) of PAH drug * Stabilization of pulmonary hypertension medications for ≥ 2 months on approved therapeutic dose of at least one PAH drug and still symptomatic with WHO functional Class II or III performance.
Exclusion criteria
* Women of child-bearing potential not practicing birth control * In treatment with chronic nitric oxide therapy * Pre-existing lung disease * Use of drugs prolonging the QT interval or strong CYP3A4 inhibitors * Long QT syndrome or QTc \> 450 ms males; \> 470 ms females. * WHO Class IV * Pulmonary capillary wedge pressure \> 15 mm Hg * Other diagnosis of PAH in WHO Diagnostic Group 1 * PAH associated with: venous hypertension (WHO Diagnostic Group II), hypoxia (WHO Diagnostic Group III), chronic pulmonary thromboembolic disease (WHO Diagnostic Group IV) or other miscellaneous causes (WHO Diagnostic Class V, which includes sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels) * Thrombocytopenia \< 50 x109/L (50 x 103/µL) * Uncontrolled systemic arterial hypertension, systolic \> 160 mm Hg or diastolic \>90 mm Hg * Any advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Vascular Resistance (PVR) | 168 days | Change in pulmonary vascular resistance is measured via right heart catheter assessment according to local hospital procedures. It assesses several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Vascular Resistance (PVR). Study was prematurely terminated and not powered for efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Six-Minute Walk Distance (6MWD) From Baseline | Baseline, 168 days | During standardized walk course participants are connected to a portable pulse oximeter via a finger probe and instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. Study was prematurely terminated and efficacy data were not analyzed or summarized |
| Total Number of Adverse Events and Serious Adverse Events | 168 days | Adverse events were summarized by the number of patients having any adverse event overall and presented in the safety section. Study was prematurely terminated. |
Countries
Canada, Germany, Singapore, South Korea, Switzerland, United States
Participant flow
Recruitment details
23 participants were enrolled into the study (15 in cohort 1; 8 in cohort 2) 8 participants completed cohort 1 and 6 of these participants moved into cohort 1expansion. Of the 5 participants that completed Cohort 1 expansion; 3 participants went into an Extension. None of the participants completed treatment as trial was terminated
Pre-assignment details
Participants were randomized 6:1 ratio to nilotinib and placebo
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Nilotinib Participants were assigned to receive nilotinib 50 mg during 14 days, followed by 150 mg during 14 days, followed by 300 mg during 140 days. | 12 |
| Cohort 1: Placebo Participants were assigned to receive placebo to nilotinib to match 50 mg and 150 mg capsules during 168 days. | 3 |
| Cohort 2: Nilotinib Participants were assigned to receive nilotinib 300 mg during 168 days | 4 |
| Cohort 2: Placebo Participants were assigned to receive placebo to match 50mg and / or 150mg capsules during 168 days | 4 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Cohort 1 & Cohort 2 | Administrative problems | 0 | 0 | 2 | 4 |
| Cohort 1 & Cohort 2 | Adverse Event | 3 | 1 | 1 | 0 |
| Cohort 1 & Cohort 2 | Death | 0 | 0 | 1 | 0 |
| Cohort 1 & Cohort 2 | Withdrew consent | 2 | 0 | 0 | 0 |
| Cohort 1 & Cohort 2 | Withdrew consent without EOS 1 visit | 0 | 1 | 0 | 0 |
| Cohort 1 & Cohort 2 Expansion | Death | 1 | 0 | 0 | 0 |
| Extension | The study was terminated | 3 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Nilotinib | Cohort 1: Placebo | Cohort 2: Nilotinib | Cohort 2: Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52 Years STANDARD_DEVIATION 13.1 | 60 Years STANDARD_DEVIATION 6.1 | 31 Years STANDARD_DEVIATION 14.6 | 33 Years STANDARD_DEVIATION 10.2 | 32 Years STANDARD_DEVIATION 11.8 |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 4 Participants | 3 Participants | 20 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 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 | 12 / 12 | 1 / 3 | 3 / 4 | 4 / 4 |
| serious Total, serious adverse events | 7 / 12 | 1 / 3 | 2 / 4 | 1 / 4 |
Outcome results
Primary
Change in Pulmonary Vascular Resistance (PVR)
Change in pulmonary vascular resistance is measured via right heart catheter assessment according to local hospital procedures. It assesses several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Vascular Resistance (PVR). Study was prematurely terminated and not powered for efficacy.
Time frame: 168 days
Secondary
Change in Six-Minute Walk Distance (6MWD) From Baseline
During standardized walk course participants are connected to a portable pulse oximeter via a finger probe and instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. Study was prematurely terminated and efficacy data were not analyzed or summarized
Time frame: Baseline, 168 days
Secondary
Total Number of Adverse Events and Serious Adverse Events
Adverse events were summarized by the number of patients having any adverse event overall and presented in the safety section. Study was prematurely terminated.
Time frame: 168 days