Testing of HIV Protease Inhibitors to Suppress Inflammation and Improve Cardio Pulmonary Hemodynamics in Subjects With Pulmonary Arterial Hypertension
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
- HMGB1 level [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- 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 ]
- 6 minute walk distance [ Time Frame: 14 days ] [ Designated as safety issue: No ]
|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)|
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT02023450
|Contact: Li Ying, MDfirstname.lastname@example.org|
|Changsha, Hunan, China|
|Contact: YU ZAI XIN, PhD 0086-13875873205 email@example.com|