Idiopathic Pulmonary Fibrosis, Pulmonary Fibrosis
Conditions
Brief summary
The purpose of this study is to determine whether combination therapy with sildenafil and losartan can improve function and exercise tolerance in patients with idiopathic pulmonary fibrosis.
Detailed description
It is currently suspected that the fibrosis in IPF is based upon an abnormal reparative process in the lung. Normally, an insult to the endothelium or epithelium of the lung would trigger an inflammatory process to help repair the site of injury; epithelial and endothelial cells then replicate and repair the tissue damage. In pulmonary fibrosis, alterations in this cascade change the balance of the inflammatory products and reduce the regulatory response which can produce continued inflammation. Fibrosis results from continued deposition of collagen by proliferating fibroblasts and lack of collagen breakdown. In addition to fibrosis and microvascular destruction, pulmonary hypertension in IPF patients is a significant contributor to morbidity and mortality. The prevalence ranges from 32-85%, suggesting that pulmonary vascular disease is one of several processes that contribute to severity of disease. We propose use of two therapeutic agents that affect the balance of vasoconstriction and vasodilation to improve basal tone of the vasculature. First, we propose the use of a phosphodiesterase inhibitor. Sildenafil (Viagra, Revatio) is an orally administered vasodilator that prolongs the effect of nitric oxide by inhibiting phosphodiesterase type 5 (PDE-5) which is responsible for degradation of cGMP. Increased cGMP concentration results in pulmonary vasculature relaxation and consequent vasodilation. Second, the use of an angiotensin receptor blocker (ARB) acts to diminish the direct vasoconstrictor effect of angiotensin and endothelin-1 in the vessels. In treatment of systemic hypertension, ARBs have been shown to be associated with a decrease in the amount of circulating endothelin-1 and increase in basal nitric oxide release. They have also been shown to rapidly inhibit the generation of reactive oxygen species by inflammatory cells. We test these interventions in a randomized cross-over trial in IPF patients.
Interventions
DRUGSildenafil
Sildenafil 20mg three times per day for 3 months followed by a one month washout prior to next intervention.
DRUGLosartan
Losartan 25mg two times a day for 3 months followed by a one month washout prior to next intervention.
DRUGSildenafil and Losartan
Sildenafil 20mg three times per day and Losartan 25mg two times per day followed by a one month washout prior to next intervention.
DRUGPlacebo Oral Tablet
Placebo pill three times per day for 3 months followed by a one month washout prior to next intervention.
Sponsors
Pulmonary Fibrosis Foundation
Alicia Gerke
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Participants will receive sildenafil for three months then losartan for three months, then sildenafil and losartan for three months and then placebo for three months in a random order.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-99 * Have not taken any of the study medications in the past 6 weeks * Diagnosed with idiopathic pulmonary fibrosis
Exclusion criteria
* FVC\<50%, DLco \<30% or FEV1/FVC ratio \<65% * Greater amount of emphysema than fibrotic change on chest CT scan * Acute myocardial infarction within the past 6 months * Nitrate use * Contraindications, hypersensitivity, or allergic reaction to any study medication * Presence of aortic stenosis * Life-threatening arrhythmia within 1 month of evaluation * Diabetes requiring insulin therapy * Second-degree or third-degree atrioventricular block on electrocardiogram * Echocardiographic evidence of severe pulmonary hypertension (\>50mmHg) • Severe terminal illness (survival predicted to be less than 1 year) * Severe congestive heart failure * Renal impairment (creatinine \>2.0 mg/dl) * Moderate to severe hepatic impairment * Concurrent treatment with immunosuppressive, cytotoxic, or investigational agents. * Pregnant or Breastfeeding (Women of childbearing age must use effective form of birth control or abstinence during study participation) * History of acute exacerbation of IPF * Current enrollment in another investigational protocol * Acute or chronic impairment other than dyspnea that limits the patient's ability to perform the six minute walk test * Current drug or alcohol dependence * Initiation of pulmonary rehabilitation within 30 days of enrollment. Subjects currently undergoing maintenance pulmonary rehabilitation at study entry will be asked to maintain their levels of rehabilitation for the duration of the trial * Treatment of pulmonary hypertension with prostaglandins, endothelin-1 antagonists, or any other phosphodiesterase inhibitor within 30 days of enrollment * Addition or discontinuation of calcium channel blockers, digitalis, diuretics or vasodilators within 30 days of enrollment. Dosage must be stable for 7 days prior to enrollment (except for diuretics) * Listed for lung transplantation * Due to drug interactions, all of the following agents will be prohibited: alpha-blockers, endothelin-1 antagonists, and CYP3A4 inhibitors * Resting oxygen saturation of \<92% with greater than 6 liters of supplemental oxygen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Six Minute Walk Distance in Meters | At baseline and three months post each intervention. | Change in 6MWD before and after treatment compared to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Forced Vital Capacity (FVC) | At baseline and three months post each intervention. | Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size. |
| Change in Shortness of Breath (SOB) Score | At baseline and three months post each intervention. | Change in symptoms of SOB as determined by St. Georges Respiratory Questionnaire score. This score ranges from 0 to 100 with a higher score indicating more problems breathing. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Study participants are patients that have been diagnosed with idiopathic pulmonary fibrosis (IPF). | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Losartan | Death | 1 |
| Losartan | Withdrawal by Subject | 1 |
| Placebo Oral Tablet | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 1 / 12 | 0 / 9 | 0 / 10 |
| other Total, other adverse events | 7 / 9 | 9 / 12 | 7 / 9 | 5 / 10 |
| serious Total, serious adverse events | 0 / 9 | 1 / 12 | 1 / 9 | 1 / 10 |
Outcome results
Primary
Change in Six Minute Walk Distance in Meters
Change in 6MWD before and after treatment compared to placebo
Time frame: At baseline and three months post each intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Six Minute Walk Distance in Meters | 10.5 meters | Standard Deviation 23.1 |
| Losartan | Change in Six Minute Walk Distance in Meters | 15.8 meters | Standard Deviation 24 |
| Sildenafil and Losartan | Change in Six Minute Walk Distance in Meters | -11.1 meters | Standard Deviation 12 |
| Placebo | Change in Six Minute Walk Distance in Meters | 12.1 meters | Standard Deviation 23.8 |
Secondary
Change in Forced Vital Capacity (FVC)
Change in FVC before and after treatment compared to placebo. FVC is a measure of lung size.
Time frame: At baseline and three months post each intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Forced Vital Capacity (FVC) | -0.04 liters | Standard Deviation 0.13 |
| Losartan | Change in Forced Vital Capacity (FVC) | -0.06 liters | Standard Deviation 0.13 |
| Sildenafil and Losartan | Change in Forced Vital Capacity (FVC) | 0.002 liters | Standard Deviation 0.14 |
| Placebo | Change in Forced Vital Capacity (FVC) | -0.02 liters | Standard Deviation 0.14 |
Secondary
Change in Shortness of Breath (SOB) Score
Change in symptoms of SOB as determined by St. Georges Respiratory Questionnaire score. This score ranges from 0 to 100 with a higher score indicating more problems breathing.
Time frame: At baseline and three months post each intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Change in Shortness of Breath (SOB) Score | 2.1 score on a scale | Standard Deviation 10.3 |
| Losartan | Change in Shortness of Breath (SOB) Score | 1.5 score on a scale | Standard Deviation 5.7 |
| Sildenafil and Losartan | Change in Shortness of Breath (SOB) Score | 3.3 score on a scale | Standard Deviation 11.6 |
| Placebo | Change in Shortness of Breath (SOB) Score | -3.0 score on a scale | Standard Deviation 9.8 |