Testing of HIV Protease Inhibitors to Suppress Inflammation and Improve Cardio Pulmonary Hemodynamics in Subjects With Pulmonary Arterial Hypertension
Primary Purpose
Pulmonary Arterial Hypertension
Status
Unknown status
Phase
Early Phase 1
Locations
China
Study Type
Interventional
Intervention
saquinavir and ritonavir
saquinavir and ritonavir
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Arterial Hypertension
Eligibility Criteria
Inclusion Criteria:
- Age 18-60
- Idiopathic pulmonary arterial hypertension
- Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study
- Had the diagnosis of PAH confirmed by a cardiac catheterization:Mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg (at rest),a pulmonary capillary wedge pressure equal or less than 15mmHg, and a normal or reduced cardiac output
- Stable PAH therapy for at least 3 months
Exclusion Criteria:
- Baseline systemic hypotension, defined as MAP less than 50 mmHg
- Required intravenous inotropes within 30 days prior to study participation
- Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mm Hg or sitting diastolic blood pressure >100 mm Hg at screening
- Has a history of portal hypertension or chronic liver disease, including cirrhosis, chronic alcoholism, hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as moderate to severe hepatic impairment (Child-Pugh Class B-C)
- Has chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL at screening or requires dialysis support
- Has a hemoglobin concentration <9 g/dL at Screening
- History of atrial septostomy
- Repaired or unrepaired congenital heart disease (CHD)
- Pericardial constriction
- Restrictive or congestive cardiomyopathy
- Left ventricular ejection fraction 40% by multiple gated acquisition scan (MUGA), angiography or echocardiography
- Symptomatic coronary disease with demonstrable ischemia
- Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
- Has a psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 30 days prior to study screening Day 1 and for the duration of the study
- Poorly controlled asthma defined by active wheezing and/or cough with FEV1 < 70% predicted, responsive to inhaled BD (>15% increase in FEV1 with BD)
- Clinically significant intercurrent illness (including lower respiratory tract infection) or clinically significant surgery within 4 weeks before the administration of study drug
- History of hypersensitivity or idiosyncratic reaction to drugs from multiple drug classes
- Receipt of an investigational product or device, or participation in a drug research study within a period of 15 days (or 5 half lives of the drug, whichever is longer) before the first dose of study drug
- Blood loss or blood donation >550mL within 90 days or plasma donation >500 mL within 14 days before administration of study drug;
- Patients with a QTc interval > 450 msec
- Has diabetes mellitus as defined by symptoms of hyperglycemia and serum fasting plasma glucose level≥7.0mmol/l or casual plasma glucose≥11.1mmol/l at screen
- Has a hyperlipidemia as TC≥6.22 mmol/L, LDL-C ≥4.14 mmol/L or TG ≥2.26 mmol/L
- History of crohn's disease, ulcerative colitis (UC) and etc. Inflammatory bowel disease (IBD)
- Patients who are not willing to take contraceptive measures during the study
- Patients who are taking certain other medication will need to be evaluated for possible exclusion based on the potential for adverse drug interactions
Sites / Locations
- Xiangya hospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
micro/low dose saquinavir and ritonavir
standard dose saquinavir and ritonavir
Arm Description
To determine if micro dose and low dose SQV+RIT mediates parameters of chronic inflammation in patients with IPAH.
To determine if short-term use of SQV+RIT reduces parameters of chronic inflammation and PA pressure of IPAH based on echocardiographic parameters. Safety issue also evaluated at the same time.
Outcomes
Primary Outcome Measures
HMGB1 level
Secondary Outcome Measures
TNF、IL-1Β、IL-6、NT-ProBNP and CRP level
NYHA/WHO functional class
Brog respiration class
PA pressure and total right heart function measured by echocardiography
Full Information
NCT ID
NCT02023450
First Posted
December 23, 2013
Last Updated
September 4, 2014
Sponsor
The Third Xiangya Hospital of Central South University
Collaborators
Xiangya Hospital of Central South University
1. Study Identification
Unique Protocol Identification Number
NCT02023450
Brief Title
Testing of HIV Protease Inhibitors to Suppress Inflammation and Improve Cardio Pulmonary Hemodynamics in Subjects With Pulmonary Arterial Hypertension
Study Type
Interventional
2. Study Status
Record Verification Date
September 2014
Overall Recruitment Status
Unknown status
Study Start Date
December 2013 (undefined)
Primary Completion Date
December 2014 (Anticipated)
Study Completion Date
July 2015 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Third Xiangya Hospital of Central South University
Collaborators
Xiangya Hospital of Central South University
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Study Rationale:There is recent evidence that HIV protease inhibitors (HIV-PI) can improve pulmonary hemodynamics in experimental models of pulmonary arterial hypertension (PAH). There is also experimental evidence that both TLR4 and high mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension. A recent high throughput screen for inhibitors of HMGB1 induced macrophage activation yielded HIV-protease inhibitors (PIs) as potent inhibitors of HMGB1 induced cytokine production. Based on the experimental evidence we propose a trial to determine whether HIV-PIs will alter the pathobiology of PAH.
Study Objectives:The main objective of this study is to determine whether saquinavir and ritonavir (SQV+RIT) which have a well-characterized safety profile in humans will reduce bio markers of inflammation and pulmonary artery pressures in patients with PAH.
Study Hypothesis:We hypothesize that the HIV-PI, SQV+RIT, will reduce circulating parameters of inflammation including HMGB1, IL1-beta, IL-6, IL-8, IL-10, TNF-alpha and CRP. Our end points will be changes in these parameters from baseline over the duration of the study.We hypothesize that treatment with SQV+RIT will reduce pulmonary artery(PA) pressure of patients with PAH as measured by echocardiography.
Study Design:This is a single center open label phase 0 study to evaluate the effect of SQV +RIT in patients with IPAH. Subjects with IPAH(N=20) will be enrolled into a study, which will be divided into 3 cohorts and entail the administration of HIV protease inhibitors in three doses. The first cohort (n=3) will receive a starting dose of SQV 0.3 mg/kg twice daily in combination with RIT 0.03 mg/kg twice daily. If the first dose is well-tolerated, the second cohort (n= 3 ) with IPAH will be given doses of SQV 3 mg/kg and RIT 0.3 mg/kg twice daily. If the second dose is well-tolerated, the last cohort (n= 14 ) with IPAH will be given doses of SQV 15 mg/kg and RIT 1.5 mg/kg twice daily.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
micro/low dose saquinavir and ritonavir
Arm Type
Experimental
Arm Description
To determine if micro dose and low dose SQV+RIT mediates parameters of chronic inflammation in patients with IPAH.
Arm Title
standard dose saquinavir and ritonavir
Arm Type
Experimental
Arm Description
To determine if short-term use of SQV+RIT reduces parameters of chronic inflammation and PA pressure of IPAH based on echocardiographic parameters. Safety issue also evaluated at the same time.
Intervention Type
Drug
Intervention Name(s)
saquinavir and ritonavir
Intervention Description
micro and low dose
Intervention Type
Drug
Intervention Name(s)
saquinavir and ritonavir
Intervention Description
standard dose
Primary Outcome Measure Information:
Title
HMGB1 level
Time Frame
14 days
Secondary Outcome Measure Information:
Title
TNF、IL-1Β、IL-6、NT-ProBNP and CRP level
Time Frame
14 days
Title
NYHA/WHO functional class
Time Frame
14 days
Title
Brog respiration class
Time Frame
14 days
Title
PA pressure and total right heart function measured by echocardiography
Time Frame
14 days
Other Pre-specified Outcome Measures:
Title
6 minute walk distance
Time Frame
14 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18-60
Idiopathic pulmonary arterial hypertension
Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study
Had the diagnosis of PAH confirmed by a cardiac catheterization:Mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg (at rest),a pulmonary capillary wedge pressure equal or less than 15mmHg, and a normal or reduced cardiac output
Stable PAH therapy for at least 3 months
Exclusion Criteria:
Baseline systemic hypotension, defined as MAP less than 50 mmHg
Required intravenous inotropes within 30 days prior to study participation
Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mm Hg or sitting diastolic blood pressure >100 mm Hg at screening
Has a history of portal hypertension or chronic liver disease, including cirrhosis, chronic alcoholism, hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as moderate to severe hepatic impairment (Child-Pugh Class B-C)
Has chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL at screening or requires dialysis support
Has a hemoglobin concentration <9 g/dL at Screening
History of atrial septostomy
Repaired or unrepaired congenital heart disease (CHD)
Pericardial constriction
Restrictive or congestive cardiomyopathy
Left ventricular ejection fraction 40% by multiple gated acquisition scan (MUGA), angiography or echocardiography
Symptomatic coronary disease with demonstrable ischemia
Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
Has a psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study. This includes subjects with a recent history of abusing alcohol or illicit drugs 30 days prior to study screening Day 1 and for the duration of the study
Poorly controlled asthma defined by active wheezing and/or cough with FEV1 < 70% predicted, responsive to inhaled BD (>15% increase in FEV1 with BD)
Clinically significant intercurrent illness (including lower respiratory tract infection) or clinically significant surgery within 4 weeks before the administration of study drug
History of hypersensitivity or idiosyncratic reaction to drugs from multiple drug classes
Receipt of an investigational product or device, or participation in a drug research study within a period of 15 days (or 5 half lives of the drug, whichever is longer) before the first dose of study drug
Blood loss or blood donation >550mL within 90 days or plasma donation >500 mL within 14 days before administration of study drug;
Patients with a QTc interval > 450 msec
Has diabetes mellitus as defined by symptoms of hyperglycemia and serum fasting plasma glucose level≥7.0mmol/l or casual plasma glucose≥11.1mmol/l at screen
Has a hyperlipidemia as TC≥6.22 mmol/L, LDL-C ≥4.14 mmol/L or TG ≥2.26 mmol/L
History of crohn's disease, ulcerative colitis (UC) and etc. Inflammatory bowel disease (IBD)
Patients who are not willing to take contraceptive measures during the study
Patients who are taking certain other medication will need to be evaluated for possible exclusion based on the potential for adverse drug interactions
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Li Ying, MD
Phone
0086-13787184360
Email
lydia0312@csu.edu.cn
Facility Information:
Facility Name
Xiangya hospital
City
Changsha
State/Province
Hunan
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
YU ZAI XIN, PhD
Phone
0086-13875873205
Email
yuzaixin@126.com
12. IPD Sharing Statement
Citations:
PubMed Identifier
26401255
Citation
Li Y, Li XH, Yu ZX, Cai JJ, Billiar TR, Chen AF, Lv B, Chen ZY, Huang ZJ, Yang GP, Song J, Liu B, Yuan H. HIV protease inhibitors in pulmonary hypertension: rationale and design of a pilot trial in idiopathic pulmonary arterial hypertension. Pulm Circ. 2015 Sep;5(3):538-46. doi: 10.1086/682426.
Results Reference
derived
Learn more about this trial
Testing of HIV Protease Inhibitors to Suppress Inflammation and Improve Cardio Pulmonary Hemodynamics in Subjects With Pulmonary Arterial Hypertension
We'll reach out to this number within 24 hrs