Testing of HIV Protease Inhibitors to Suppress Inflammation and Improve Cardio Pulmonary Hemodynamics in Subjects With Pulmonary Arterial Hypertension

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by The Third Xiangya Hospital of Central South University
Sponsor:
Collaborator:
Xiangya Hospital of Central South University
Information provided by (Responsible Party):
Yuan Hong, The Third Xiangya Hospital of Central South University
ClinicalTrials.gov Identifier:
NCT02023450
First received: December 23, 2013
Last updated: September 4, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: saquinavir and ritonavir
Phase 0

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Resource links provided by NLM:


Further study details as provided by The Third Xiangya Hospital of Central South University:

Primary Outcome Measures:
  • HMGB1 level [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • TNF、IL-1Β、IL-6、NT-ProBNP and CRP level [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • NYHA/WHO functional class [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Brog respiration class [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • PA pressure and total right heart function measured by echocardiography [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • 6 minute walk distance [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: December 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: micro/low dose saquinavir and ritonavir
To determine if micro dose and low dose SQV+RIT mediates parameters of chronic inflammation in patients with IPAH.
Drug: saquinavir and ritonavir
micro and low dose
Experimental: standard dose saquinavir and ritonavir
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.
Drug: saquinavir and ritonavir
standard dose

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02023450

Contacts
Contact: Li Ying, MD 0086-13787184360 lydia0312@csu.edu.cn

Locations
China, Hunan
Xiangya hospital Recruiting
Changsha, Hunan, China
Contact: YU ZAI XIN, PhD    0086-13875873205    yuzaixin@126.com   
Sponsors and Collaborators
The Third Xiangya Hospital of Central South University
Xiangya Hospital of Central South University
  More Information

No publications provided

Responsible Party: Yuan Hong, The Third Xiangya Hospital, The Third Xiangya Hospital of Central South University
ClinicalTrials.gov Identifier: NCT02023450     History of Changes
Other Study ID Numbers: HPI-PAH-0
Study First Received: December 23, 2013
Last Updated: September 4, 2014
Health Authority: China: Food and Drug Administration

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Ritonavir
Saquinavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014