Interstitial Lung Disease, IPF

General Information

Interstitial Lung Disease Research Program is an NIH designated clinical research site focusing on research for IPF.

Idiopathic Pulmonary Fibrosis (IPF), also described as cryptogenic fibrosing alveolitis, is one of a family of Interstitial Lung Diseases (ILD) also know as Idiopathic Interstitial Pneumonia (IIP).  These disorders share clinical characteristics of shortness of breath, diffuse pulmonary infiltrates evident radiographically, and different degrees of inflammation, fibrosis, or both on lung biopsy. 

There are different types of IIP, but the term IPF should be referred to patients who have Usual Interstitial Pneumonia (UIP) histopathology and lack any evidence of an associated connective tissue disorder.  IPF is characterized by patchy, irreversible fibrosis as result of chronic lung injury with scarring and honeycombing of the lungs, and presence of prominent fibroblast foci as a result of acute lung injury.  To date, there are no proven therapies for IPF. 

Based on new pathophysiological concepts of IPF, there are different investigational agents under preclinical and clinical trials and with the increasing number of on going trials there are hopes for an effective therapeutic agent discovery. 

The multi-center clinical trials described below, either as completed or ongoing trials raise the hope for future new strategies which may help to improve the quality of life and prognosis of disease in this group of patients in the near future.

Contact Information: 

Marilyn K. Glassberg, M.D., Principal Investigator

Robert M Jackson, M.D.

Emmanuelle Simonet, B.A., M.S., C.C.R.P.

Roshel Bautista, Study Coordinator

Carol Ramos M.D., Study Coordinator

 

The Interstitial Lung Disease Program, located at:

University of Miami Miller School of Medicine

1400 NW 10^th Avenue, Suite 901

Miami, Florida 33136

Phone: 305-243-3728

Fax:     305-243-3738

Email: esimonet@med.miami.edu

Listing of Upcoming Trials (pending regulatory review and final site activation):

- Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP in IPF), a randomized, double-blind, placebo-controlled trial.

Purpose of the Research Study

- to test that treatment with sildenafil will improve exercise capacity and quality of life in subjects with advanced IPF.

Inclusion Criteria

Only subjects with a screening DLco (adjusted for hemoglobin) < 35% predicted and a diagnosis of IPF are eligible for this study. A diagnosis of IPF is defined in section 5.2.

Elevation of the serum BNP level, while useful in identifying moderate-to-severe PH, is not a widely validated surrogate marker and is of unclear sensitivity and specificity in subjects with more moderate PH. Therefore, BNP will not be used as one of the inclusion criteria.

Subjects must be able to complete two consecutive pre-enrollment 6MWTs with distances within 15% of one another. Subjects will be walked at screening, to ensure ability to walk the minimum distance of 50m and to set the oxygen flow for future walks. At the enrollment visit, subjects will undergo two 6MWTs with a minimum of an hour’s rest between the two. If the difference between the two distances is greater than 15%, the subject is not eligible for enrollment. If the distance of either walk is less than 50m, the subject is not eligible for enrollment.

Exclusion Criteria

• 1.      Current enrollment in another investigational protocol
• 2.      Screening or enrollment 6MWD of < 50 meters
• 3.      Difference > 15% between first and second enrollment 6MWD
• 4.      Acute or chronic impairment other than dyspnea (eg, angina pectoris, intermittent claudication) limiting  the ability to comply with walk test or other study requirements
• 5.      Forced expiratory volume1/FVC ratio < 0.65 after administration of bronchodilator
• 6.      Extent of emphysema greater than the extent of fibrotic change (honeycombing, reticular changes) on HRCT scan
• 7.      Acute myocardial infarction within the past 6 months
• 8.      Nitrate use
• 9.      Hypersensitivity to sildenafil or any component of the formulation
• 10.  Presence of aortic stenosis (AS)
• 11.  Life-threatening arrhythmia within 1 month of evaluation
• 12.  Poorly controlled diabetes mellitus requiring insulin therapy
• 13.  Second-degree or third-degree atrioventricular (AV) block on electrocardiogram
• 14.  Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25%
• 15.  Presence of idiopathic hypertrophic subaortic stenosis (IHSS)
• 16.  Hypotension (systolic blood pressure [SBP] < 100 mm Hg or diastolic blood pressure [DBP] < 50 mm Hg); (symptomatic orthostatic hypotension)
• 17.  Uncontrolled systemic hypertension (SBP > 180 mm Hg or DBP > 100 mm Hg)
• 18.  Known penile deformities or conditions (eg, sickle cell anemia, multiple myeloma, leukemia) that may predispose to priapism
• 19.  Aspartate aminotransferase (AST)/serum glutamic pyruvic transaminase (SGPT) or alanine aminotransferase (ALT)/serum glutamic oxaloacetic transaminase (SGOT) > 3 times the upper limit of normal ranges
• 20.  Renal impairment: creatinine clearance < 30 mL/minute
• 21.  Current drug or alcohol dependence
• 22.  Retinitis pigmentosa
• 23.  History of vision loss
• 24.  History of nonarteritic ischemic optic neuropathy
• 25.  Recently initiated pulmonary rehabilitation within 30 days of enrollment. Subjects will be prohibited from starting pulmonary rehabilitation during the trial. Subjects who are currently undergoing maintenance pulmonary rehabilitation at study entry will be asked to maintain their levels of rehabilitation for the duration of the trial.
• 26.  Any investigational therapy as part of a clinical trial for any indication, within 30 days of enrollment
• 27.  Start or change in dose of treatment for IPF investigational agent (interferon γ-1b, pirfenidone, etanercept, N-acetylcysteine, and any other investigational agent intended to treat IPF), corticosteroids, or cytotoxic agents, within 30 days of enrollment
• 28.  Due to drug-drug interactions, the following agents will be prohibited: bosentan. Subjects taking strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, iclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine,  ropofol, protease inhibitors, quinidine, telithromycin, troleandomycin, verapamil not an inclusive list) will be asked to stop taking the CYP3A4 inhibitor at least 30 days prior to enrollment. However, if the subject requires the CYP3A4 inhibitor (PI judgment), as long as the dose is not changed throughout the study, the subject will be allowed to concurrently take the CYP3A4 inhibitor.
• 29.  Treatment for PH with prostaglandins (eg, epoprostenol, treprostinil), endothelin-1 antagonists (eg, bosentan, sitaxsentan, ambrisentan), or any other hosphodiesterase inhibitor (eg, tadalafil, vardenafil) within 30 days of enrollment 30. The 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).
• 30.  Listed for lung transplantation
• 31.  Supplementation with L-arginine
• 32.  Concurrent use of grapefruit juice or St. John's wort
• 33.  Pregnant or lactating women
• 34.  Resting SpO₂ (oxygen saturation measured using pulse oximetry) < 92% with 6 liters of supplemental oxygen
• - CNTO 888

A phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluating the efficacy and safety of CNTO 888 administered intravenously in subjects with Idiopathic Pulmonary Fibrosis.

Purpose of the Research Study

• -         to determine the efficacy (as measured by pulmonary function) and safety of CNTO 888 in subjects with IPF
• -         to assess the effect of CNTO 888 on physiologic manifestations of disease progression, dyspnea scores, and other functional capacity measurements.
• -         to assess the effect of CNTO 888 on health-related quality of life in subjects with IPF.
• -         to assess the PK and PD of CNTO 888 in subjects with IPF.

Inclusion Criteria

To be eligible for the trial, subjects must meet all of the following criteria:

• Aged 40 to 80, inclusive.

To be eligible for the trial, subjects must meet all of the following criteria:

1. Aged 40 to 80, inclusive.
2. Physician diagnosis of IPF (adapted from ATS/ERS criteria) within 4 years of screening.

Subjects must meet all of the following major criteria:

Major criteria

• a.       Exclusion of other known causes of interstitial lung disease, such as certain drug toxicities, environmental exposures, and connective tissue diseases.
• b.      Abnormal pulmonary function studies that include evidence of restriction (reduced vital capacity, often with an increased FEV1/FVC ratio) and impaired gas exchange (increased alveolar-arterial oxygen gradient [P(A-a)O2] or evidence of desaturation at rest or exercise or decreased DLCO).
• c.       Bibasilar reticular abnormalities with minimal ground-glass opacities on HRCT scans.

and 3 of the 4 minor criteria

Minor Criteria

• a.       Age > 50 years.
• b.      Insidious onset of otherwise unexplained dyspnea on exertion.
• c.       Duration of illness > 3 months.
• d.      Bibasilar, inspiratory crackles (dry or “Velcro”-type in quality).

3. Symptomatic or have evidence of disease activity despite current treatment. IPF disease activity, for the purposes of this protocol, is defined as having 1 or more of the following within the past 12 months:

• a.       Relative decrease of ≥ 5% in FVC, or
• b.      Relative decrease of ≥ 15% in DLCO/transfer factor of the lung for carbon monoxide (TLCO), or
• c.       Evidence of clinically significant worsening on HRCT (eg, development of honeycombing, increase in opacities), or
• d.      Significant worsening of dyspnea at rest or with exertion.

4. Evidence of recent stability of percent predicted FVC (defined as not having changed > 15% between the screening and the baseline visit).
5. Have HRCT or surgical lung biopsy available for review or surgical lung biopsy evidence of UIP within 3 months of screening.

• a.       HRCT must be available for review if lung biopsy evidence is absent.

6. FVC ≥ 50% of the predicted value.
7. Women of childbearing potential and all men must be using adequate birth control measures and must agree to continue to use such measures and not become pregnant or plan a pregnancy until 12 months after receiving the last infusion of study agent.
8. Are considered eligible according to the following TB screening criteria:

• a.       Have no history of latent or active TB prior to screening.
• b.      Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
• c.       Have had no recent close contact with a person with active TB.
• d.      Within 2 months prior to the first administration of study agent, have negative diagnostic TB test results (defined as a negative QuantiFERON-TB Gold test).
• e.       Have a chest radiograph (both posterior-anterior and lateral views) or HRCT taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no clear evidence of current active TB or old inactive TB.

9. Capable of understanding subject assessment forms.
10. Have provided signed, written, informed consent before receiving any protocol specific procedures.
11. Willing to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria

Subjects meeting any of the following criteria may not be enrolled in the study:

1. Have evidence of interstitial pneumonia other than IPF.
2. Partial pressure of oxygen in arterial blood (PaO2) < 55 mmHg (sea level) or 50 mmHg (altitude) at rest on room air. If arterial blood gas results are not available, an oxygen saturation via pulse oximetry (SpO2) < 88% with O2 supplementation.
3. Known clinically significant pulmonary hypertension requiring vasodilator therapy.
4. Have a diagnosis of other significant respiratory disorder (eg, asthma, TB, sarcoidosis, aspergillosis, chronic obstructive pulmonary disease [COPD], or cystic fibrosis).
5. Have obstruction on prebronchodilator PFTs (defined as FEV1/FVC < 0.7) at screening.
6. Have a predicted life expectancy less than 1 year.
7. Previous treatment with an investigational drug within 6 weeks, or within 5 t1/2 of the investigational agent, whichever is longer, prior to screening or are participating in another investigative study.
8. Current treatment with sildenafil, IFN-γ, mycophenolate, or endothelin receptor antagonists.
9. Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, cardiac, neurologic, or cerebral disease, or any laboratory abnormality which would pose/suggest a risk to the subject during participation in the study.
10. Known to be seropositive for HIV, known active hepatitis A, B, or C infection, or ALT/SGPT and/or AST/SGOT > 2 times the upper limit of normal at screening.
11. Within 3 months prior to screening, has had a clinically important, serious infection (eg, hepatitis, pneumonia, or pyelonephritis), has been hospitalized for an infection, or has been treated with IV antibiotics for an infection. Less serious infections (eg, acute upper respiratory tract infection or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator.
12. Opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii) within 6 months prior to screening.
13. Received any live virus vaccination within 3 months prior to screening or are expected to receive any live virus or bacterial vaccinations during the trial or up to 3 months after the last dose of the study agent.
14. Serious concomitant illness that could interfere with the subject’s participation in the study.
15. History of substance abuse (drugs or alcohol) within the 3 years prior to screening, history of noncompliance to medical regimens, or other condition/circumstance that could interfere with the subject’s adherence to protocol requirements (eg, psychiatric disease, lack of motivation, travel).
16. Major surgery within 1 month prior to screening.
17. Currently listed for lung transplantation.
18. Have any known malignancy or have a history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that has been treated with no evidence of recurrence for at least 3 months).
19. Has a transplanted organ (with the exception of a corneal transplant > 3 months prior to screening).
20. Known allergies or clinically significant reactions to murine, chimeric, or human proteins.
21. Significant bleeding diathesis or excessive risk of bleeding, including chronic anticoagulant therapy.

Listing of Ongoing Trials:

CAPACITY and RE-CAP (Pirfenidone)  

A randomized, double-blinded, placebo-controlled, three-arm, multicenter, phase III study of Pirfenidone in patients with IPF (PIPF-004). Up to 325 patients globally are assigned randomly in a three arm study (2:2:1) to receive 2403 mg/d of Pirfenidone (n = 130 patients), placebo equivalent (n = 130 patients), or 1197 mg/d of pirfenidone (n = 65 patients) in divided doses TID.

This trial is closing in October 2008 and followed by an extension open-label study (PIPF-012) for the subjects who have completed PIPF-004. No new subjects will be enrolled.

Purpose of the Research Study

The primary objective is to assess the safety of Pirfenidone compared to placebo in patients with IPF.  The secondary objective is to measure the efficacy of Pirfenidone by absolute change in percent predicted FVC from Baseline to Week 60.  Other outcome measures include the 6-minute walk test, shortness of breath, percentage predicted DLCO/TLC, and survival-adjusted quality of life. 

Publications:

Bhatt N, Baran CP, Allen J, Magro C, Marsh CB.  Promising pharmacologic innovations in treating pulmonary fibrosis.  Curr Opin Pharmacol.  2006 Jun; 6(3):284-92. Epub 2006 May 2.

Flaherty KR, Andrei AC, Murray S, Fraley C, Colby TV, Travis WD, Lama V, Kazerooni EA, Gross BH, Toews GB, Martinez FJ.  Idiopathic Pulmonary Fibrosis: Prognostic Value of Changes in Physiology and Six Minute Hallwalk.  Am J Respir Crit Care Med.  2006 Jul 6; [Epub ahead of print]

Sildenafil (VA)

A double blinded, randomized, placebo controlled study of Sildenafil citrate given orally 20 mg TID.  The study involves 30 subjects per year from VA Medical Center with idiopathic IPF and Pulmonary Hypertension.  The duration of the study for each individual is 6 months; the pilot study could require up to 3 years in order to recruit patients, complete the protocol, and analyze the results.

Purpose of the Research Study

The primary objective is to assess the possible therapeutic benefit of a vasodilator, Sildenafil, on exercise tolerance and dyspnea in IPF patients.  The secondary objective is to assess and compare changes from baseline in pre- and post-exercise markers of oxidant stress in Sildenafil and placebo control groups.

The long term goal of the study is to improve both exercise ability and the feeling of shortness of breath in patients with IPF and Pulmonary Hypertension. 

Inclusion Criteria                       

- Age 21 – 85 years

- IPF within 36 months, and > 3 months

- HRCT definite UIP/IPF

- HRCT probable plus BAL (non diagnostic) or

- VATS lung biopsy of UIP for patients age 21 - 40                                         

- PAP sys 25 – 50 mmHg

- FVC 40 – 90% or DLCO 30 – 90%

- 6MWT distance of 150 – 500 m

            - Within the past year: > 10% decrease in percent predicted FVC

            - Within the past year worsening of dyspnea at rest or exertion

 

Exclusion Criteria

            - Sever heart failure (NYHA class III or IV or LVEF < 25%)                                      

            - Sever Pulmonary Hypertension (PAsys > 50 mmHg) on echocardiogram

- FEV1/FVC < 50% after BD

- 6MWT < 150m or >500m

- Residual Volume (RV) > 120% of predicted value

- Other conditions that causes PF

- Corticosteroids or other treatment in the past 30 days

- O2 sat < 80% on room air

- Creatinine > 1.5 ULN

- Abnormal CBC or LFT’s

- Treatment with nitroglycerin, CYP3A4 inhibitors (ritonavir or indinavir,                     

   ketoconazol), bosentan, sildenafil  for another reason

- Current treatment with Pirfenidone, Interferon gamma or beta, anti TNF therapy,

   endothelin receptor blockers.

- History of unstable or deteriorating cardiac or neurological disease

- Pregnancy or lactation

LISTING OF COMPLETED TRIALS:

ACTIMMUNE (GIPF007)

A randomized, double-blinded, multinational, Phase III study of the safety and efficacy of 200 micrograms SC Interferon Gamma 1b in patients with Idiopathic Pulmonary Fibrosis (IPF). A total number of 826 study subjects are enrolled.

Purpose of the Research Study

To evaluate the overall survival time from the time of randomization.  Other outcome measures include changes from baseline in the followings: 6minute walk test, shortness of breath, percentage predicted FVC, percentage predicted DLCO/TLC, total days of hospitalization, and survival-adjusted quality of life.             Enrollment: Closed

Gleevec

Phase II, randomized, double-blinded, placebo controlled study of the safety and clinical effects of Gleevec (Imatinib mesylate) administered orally to patients with Idiopathic Pulmonary Fibrosis (IPF).

Purpose of the Research Study

To gain information about the safety and effectiveness of Gleevec in comparison to a placebo (an active substance that contains no medication) in patients with idiopathic pulmonary fibrosis (IPF) who have not responded to standard therapy.  Secondary purposes are to evaluate the quality of life while involved in this study.

The duration is approximately 96 weeks

Enrollment: Closed

CoTherix (C200-300)

A randomized, double-blinded, placebo-controlled, multinational, phase II study to evaluate the safety and efficacy of Iloprost inhalation solution in subjects with abnormal Pulmonary Arterial Pressure (PAP)  and exercise limitation associated with IPF.

Purpose of the Research Study

The primary goal is to assess the safety of Iloprost inhalation solution in subjects with IPF and abnormal PAP.  The secondary objective is to evaluate the efficacy of inhaled Iloprost as measured by improvement in 6-minute walk test (6MWT) and Borg dyspnea and  fatigue scale, reduction in exercise-associated oxygen desaturation, and clinical status.            Enrollment: Closed

ACTIMMUNE GIPF 001

A randomized, double-blinded, placebo-controlled, multinational, phase III study of safety and efficacy of IFN gamma-1b in patients with IPF, who were unresponsive to steroid. A total number of 330 subjects with mild-to-moderate IPF were enrolled.

Purpose of the Research Study

The primary objective was to determine the safety and efficacy of 200 microgram IFN gamma 1b administered subcutaneously for up to 3 years.  The secondary objective was to evaluate survival time, quality of life, and changes from baseline in the followings: shortness of breath, percentage predicted FVC, percentage predicted DLCO/TLC, and survival-adjusted quality of life.

Publications:

Lynch DA, David Godwin J, Safrin S, Starko KM, Hormel P, Brown KK, Raghu G, King TE Jr, Bradford WZ, Schwartz DA, Richard Webb W; Idiopathic Pulmonary Fibrosis Study Group.  High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis.  Am J Respir Crit Care Med.  2005 Aug 15; 172 (4): 488-93. Epub 2005 May 13.

Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group.  A placebo-controlled trial of interferon gamma-1b in patients with idiopathic fibrosis.  N Engl J Med.  2004 Jan 8;350(2):125-33.

King TE Jr, Safrin S, Starko KM, Brown KK, Noble PW, Raghu G, Schwartz DA.  Analyses of efficacy end point in a controlled trial of interferon gamma-1b for idiopathic pulmonary fibrosis.  Chest. 2005 jan;127(1):171-7.

Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK; IPF Study Group.  The clinical course of patients with idiopathic pulmonary fibrosis.  Ann Intern Med.  2005 Jun 21;142(12 Pt 1):963-7.

ACTIMMUNE GIPF 002

A randomized, double-blinded, placebo controlled, multicenter, phase II study of safety and efficacy of IFN gamma-1b in patients with IPF for 26 weeks, followed by open-label SC IFN gamma-1b and an additional 26 weeks.

Open-label therapy was administered up to 220 patients, following completion of either InterMune Protocol GIPF-002 Part B or Protocol GIPF-004, to assess the long-term safety of subcutaneous Interferon gamma-1b.

Purpose of the Research Study

The goals of the study were to assess the effects of IFN gamma-1b on lung tissue transcription levels of TGF and CTFT, as well as on the other biological markers, clinical parameters, and survival-adjusted quality of life.

Publications:

Strieter RM, Starko KM, Enelow RI, Noth I, Valentine VG; Idiopathic Pulmonary Fibrosis Biomarkers Study Group. Effects of interferon gamma-1b on biomarker expression in patients with idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med.  2004 Jul 15;170(2):133-40.  Epub 2004 Mar 24.

ACTIMMUNE GIPF 004

GIPF-004 study, a 48-week open-label safety study of interferon gamma-1b in IPF patients, was conducted to assess the risk of acute respiratory decompensation following initiation of treatment. This association had been suggested in a previous literature report based on observations in 4 patients. All patients completing GIPF-001, a randomized, placebo-controlled, Phase III trial of interferon gamma-1b, were offered participation in the GIPF-004 safety study.

ACTIMMUNE GIPF 006

A study of open-label therapy of IFN gamma-1b, administered subcutaneously to 220 patients following completion of either Protocol GIPF 002 Part B or Protocol GIPF-004. The objective of this study was to assess the long term safety of subcutaneous IFN gamma-1b administered in doses of 200 microgram three times per week.

ENBREL

A double-blinded, parallel, placebo-controlled, randomized study of the efficacy and safety of Enbrel in patients with Idiopathic Pulmonary Fibrosis (IPF).

Purpose of the Research Study

To gain information about the safety and effectiveness of etanercept in comparison to a placebo (inactive substance) in subjects with IPF who had not responded to standard therapy.  Secondary purposes were to evaluate the quality of life and the way the body uses etanercept.  The duration of this study was approximately 54 weeks.

BOSENTAN: BUILD I STUDY

A double-blinded, randomized, placebo-controlled, multi-center study to assess the efficacy, safety, and tolerability of Bosentan in patients with Idiopathic Pulmonary Fibrosis (IPF).

Purpose of the Research Study

To evaluate the effect of long-term (12 months) Bosentan therapy in patients with IPF, who had not improved with normal treatment, by evaluating an increase in their exercise capacity.  Secondary purposes were to evaluate the effect of Bosentan treatment on lungs function, patient’s quality of life, and improvement of disease symptoms.

The duration of this study was 12-24 weeks.

 

CT scan of chest showing honeycombing of the lung typical for advanced IPF