SPHERIC-1. Sildenafil and Pulmonary HypERtension In COPD

Study Overview
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Brief Summary
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Although pulmonary hypertension (PH) is a quite frequent complication of advanced pulmonary diseases, and it is an independent prognostic factor, until now no evidence-based treatment approach exists for those patients. This study will address if the drug sildenafil can lower pulmonary vascular resistance in patients with significant pulmonary hypertension (high blood pressure in the lungs) associated to chronic obstructive pulmonary disease (COPD). It will see if this treatment can improve effort capacity, quality of life without causing a deterioration in pulmonary gas exchange (mainly arterial oxygenation). Patients 18 years of age and older with moderate COPD and pulmonary hypertension (mean pulmonary arterial pressure >30 mmHg) may be eligible for this study. Participants are randomly assigned to receive sildenafil or placebo (pill with no drug) for 16 weeks. Before starting treatment (baseline), and a the end of the study, the patients have a comprehensive assessment including: a chest x-ray and CT scan (only at baseline); pulmonary function tests to measure how much air the patient can breathe in and out, and the capacity of diffusion of gases; arterial blood gases analysis (for safety reason this examination is performed at baseline, before the randomization after one hour from the administration of a tablet (20 mg) of sildenafil, and every month) an echocardiogram (heart ultrasound) (only at baseline); a 6-minute walk test to measure exercise capacity; a quality-of-life assessment (SF-36 questionnaire) a right heart catheterization to evaluate the severity of hypertension At the end of the 16-week period, patients may opt to continue to receive sildenafil and monitoring in an open-label phase of the study for up to 1 year.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study Evaluating the Effect of Sildenafil in the Treatment of Patients With Pulmonary Hypertension Associated to Chronic Obstructive Lung Disease

Conditions
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Pulmonary Hypertension, COPD

Intervention / Treatment
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* Drug: Sildenafil citrate
* Drug: Sugar pills


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient affected by stable COPD under optimal treatment, chronic oxygen therapy in patients with hypoxia, with PaO2 at rest ≥ 60 mmHg and PaCO2≤ 55 mmHg, aged between 18 and 80 years old: Group 1: BPCO GOLD I-III (post bronchodilator FEV1 ≥ 30%, FEV1/FVC ≤ 0,7 , TLC ≥ 70%) + PAPm ≥ 30 mmHg and PCP <15 mmHg Group 2: BPCO GOLD IV (post bronchodilator FEV1 <30%, FEV1/FVC ≤ 0,7 , TLC ≥ 70%) + PAPm ≥ 35 mmHg and PCP <15 mmHg Exclusion Criteria: Different types of pulmonary hypertension (chronic, thromboembolic pulmonary hypertension, pulmonary arterial hypertension etc.) Significant left cardiac disease (LVEF <45%, cardiomyopathy, valvulopathy, unstable coronaropathy) Treatment with nitrates in the last 10 days, or in need of other nitrate therapy for different diseases Treatment with other specific drugs for arterial pulmonary hypertension (less than 4 weeks) Significant systemic disease other than COPD Recent exacerbations of chronic bronchitis (< 4 weeks) Pregnancy or breastfeeding, or women without an adequate contraceptive method for the whole study duration History of anaphylaxis or allergic reactions to 5-phosphodiesterase inhibitors Cancers within the last 5 years with the exception of localized cancers of the skin or of the cervix Hepatic insufficiency or chronic renal failure or hemoglobinemia < 10 g/dL during the screening phase Contraindications to subministration as per SPC Mental disorder, alcohol abuse, chronic alcoholism, drug abuse Subjects unable to sign the informed consent form Subjects unable to walk

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sildenafil citrate<br>20 mg t.i.d. | Drug: Sildenafil citrate<br>* sildenafil 20 mg t.i.d. compared to placebo 20 mg t.i.d - 16 weeks treatment<br>* Other names: Revatio;|
| Placebo Comparator: Sugar pill<br> | Drug: Sugar pills<br>* placebo t.i.d.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary vascular resistance (PVR) | PVR are measured by right cath study as the following formula: PVR= (mean pulmonary arterial pressure-pulmonary arterial wedge pressure)/cardiac output | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial blood gas analysis |  | 16 Weeks | 
| Pulmonary function - Borg scale | The dyspnea is assessed by an analogic scale from 0 (no dyspnea) to 10 (very severe dyspnea) | 16 Weeks | 
| Pulmonary function - Bode Index | The BODE Index is a composite marker of disease taking into consideration the systemic nature of COPD: FEV1% pred = predicted amount as a percentage of the forced expiratory lung volume in one second; 6MWD = six minute walking distance; MMRC = modified medical research council dyspnea scale; BMI = body mass index. | 16 Weeks | 
| Functional capacity - Quality of Life | Quality of Life is assessed by a standardized questionnaire (SF-36 questionnaire) at baseline and the end of study | 16 Weeks | 
| Functional capacity testing - 6 Minutes walking test | The six-minute walk test is performed in a straight corridor (length 25-30 meters) in the same environmental conditions | 16 Weeks |