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

NCT02023450 | Unknown Early Phase 1 DMC

• 1 other identifier: HPI-PAH-0
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (1)

• HMGB1 level

  14 days

Secondary Outcomes (4)

• TNF、IL-1Β、IL-6、NT-ProBNP and CRP level

  14 days

• NYHA/WHO functional class

  14 days

• Brog respiration class

  14 days

• PA pressure and total right heart function measured by echocardiography

  14 days

Other Outcomes (1)

• 6 minute walk distance

  14 days

Study Arms (2)

micro/low dose saquinavir and ritonavir

EXPERIMENTAL

To determine if micro dose and low dose SQV+RIT mediates parameters of chronic inflammation in patients with IPAH.

Drug: saquinavir and ritonavir

standard dose saquinavir and ritonavir

EXPERIMENTAL

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

Interventions

saquinavir and ritonavir DRUG

micro and low dose

micro/low dose saquinavir and ritonavir

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• The Third Xiangya Hospital of Central South University: lead
• Xiangya Hospital of Central South University: collaborator

Study Sites (1)

Xiangya hospital

Changsha, Hunan, China

RECRUITING

Related Publications (1)

• 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.

  PMID: 26401255 DERIVED

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

Saquinavir; Ritonavir

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinolines; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Li Ying, MD

CONTACT

0086-13787184360; lydia0312@csu.edu.cn

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: The Third Xiangya Hospital

Study Record Dates

• First Submitted: December 23, 2013
• First Posted: December 30, 2013
• Study Start: December 1, 2013
• Primary Completion: December 1, 2014
• Study Completion: July 1, 2015
• Last Updated: September 8, 2014

Record last verified: 2014-09

Locations

CN (1)