- ICH GCP
- Registro degli studi clinici negli Stati Uniti
- Sperimentazione clinica NCT02023450
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.
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Tipo di studio
Iscrizione (Anticipato)
Fase
- Prima fase 1
Contatti e Sedi
Contatto studio
- Nome: Li Ying, MD
- Numero di telefono: 0086-13787184360
- Email: lydia0312@csu.edu.cn
Luoghi di studio
-
-
Hunan
-
Changsha, Hunan, Cina
- Reclutamento
- Xiangya Hospital
-
Contatto:
- YU ZAI XIN, PhD
- Numero di telefono: 0086-13875873205
- Email: yuzaixin@126.com
-
-
Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
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
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Nessuno (etichetta aperta)
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
---|---|
Sperimentale: 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.
|
micro and low dose
standard dose
|
Sperimentale: 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.
|
micro and low dose
standard dose
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Lasso di tempo |
---|---|
HMGB1 level
Lasso di tempo: 14 days
|
14 days
|
Misure di risultato secondarie
Misura del risultato |
Lasso di tempo |
---|---|
TNF、IL-1Β、IL-6、NT-ProBNP and CRP level
Lasso di tempo: 14 days
|
14 days
|
NYHA/WHO functional class
Lasso di tempo: 14 days
|
14 days
|
Brog respiration class
Lasso di tempo: 14 days
|
14 days
|
PA pressure and total right heart function measured by echocardiography
Lasso di tempo: 14 days
|
14 days
|
Altre misure di risultato
Misura del risultato |
Lasso di tempo |
---|---|
6 minute walk distance
Lasso di tempo: 14 days
|
14 days
|
Collaboratori e investigatori
Pubblicazioni e link utili
Studiare le date dei record
Studia le date principali
Inizio studio
Completamento primario (Anticipato)
Completamento dello studio (Anticipato)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Stima)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Stima)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Termini MeSH pertinenti aggiuntivi
- Malattia cardiovascolare
- Malattie vascolari
- Malattie delle vie respiratorie
- Malattie polmonari
- Ipertensione, polmonare
- Ipertensione
- Ipertensione arteriosa polmonare
- Ipertensione Polmonare Primaria Familiare
- Meccanismi molecolari dell'azione farmacologica
- Agenti antinfettivi
- Agenti antivirali
- Inibitori enzimatici
- Agenti anti-HIV
- Agenti antiretrovirali
- Inibitori della proteasi
- Inibitori del citocromo P-450 CYP3A
- Inibitori dell'enzima del citocromo P-450
- Inibitori della proteasi dell'HIV
- Inibitori virali della proteasi
- Ritonavir
- Saquinavir
Altri numeri di identificazione dello studio
- HPI-PAH-0
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .
Prove cliniche su saquinavir and ritonavir
-
International Antiviral Therapy Evaluation CenterGilead Sciences; Hoffmann-La RocheCompletato
-
AbbottCompletatoInfezioni da HIVSpagna, Regno Unito, Stati Uniti, Canada, Francia, Polonia, Argentina, Brasile, Italia, Porto Rico
-
Hoffmann-La RocheCompletatoInfezioni da HIVSpagna, Tailandia, Argentina
-
The HIV Netherlands Australia Thailand Research...Roche Pharma AG; Kirby Institute; International Antiviral Therapy Evaluation CenterCompletato
-
Germans Trias i Pujol HospitalFundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción...Completato
-
Boehringer IngelheimCompletatoInfezioni da HIVOlanda, Germania, Canada, Stati Uniti, Francia, Regno Unito, Svizzera, Danimarca, Australia, Grecia, Portogallo, Belgio, Italia
-
Royal Free Hampstead NHS TrustRoche Pharma AGCompletato
-
Hoffmann-La RocheCompletato
-
Hoffmann-La RocheCompletatoInfezioni da HIVCanada, Stati Uniti, Porto Rico
-
Germans Trias i Pujol HospitalFundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción...Completato