IPF Research
Idiopathic Pulmonary Fibrosis (IPF):
Why Early Referral is Critical—
Even if Your Patient is Not Eligible for a Clinical Trial
Management of IPF requires a confident diagnosis and prompt consideration for the latest treatment strategies and lung transplantation. Access to clinical trials of new treatments can be key to improved outcomes.
Even if a patient is not eligible for a clinical trial, early referral of patients with potential IPF to a specialty center, such as the Fibrotic Lung Disease Program at the Temple Lung Center, remains critical. While survival rates after diagnosis vary widely, in general the rates are highest when the disease is diagnosed at a young age, in an early stage, and when the initial response to medications may be good.
The Temple Lung Center has the expertise to make prompt and accurate diagnosis of IPF and to manage difficult-to-treat cases of fibrotic lung disease. Temple currently has one of the largest lung transplant programs in the Mid-Atlantic region. Fully 40% of our recently waitlisted patients for lung transplantation had IPF as their primary disease.
Temple is currently enrolling IPF patients in clinical trials involving anti-fibrotics and in a regional registry. Detailed information on the registry and two of the newest IPF clinical trials is provided here.
Linking IPF patients into large referral programs with active transplantation and research programs is essential. Not only does this referral potentially allow patients to benefit from new therapies, it also offers them education, social support, exhaustive examinations by experts, and highly personalized assistance from a large team of professionals in maintaining a high standard of care.
Pennsylvania Idiopathic Pulmonary Fibrosis Registry (PA-IPF Registry)
Ambrisentan in Early Idiopathic Pulmonary Fibrosis (ARTEMIS)
CNTO 888, a Chemokine Blocker, in Idiopathic Pulmonary Fibrosis
Temple Research Focus:
Pennsylvania Idiopathic Pulmonary Fibrosis State Registry (PA-IPF Registry)
Investigators: Gerard Criner, MD; Francis Cordova, MD
Coordinator: Kathy Cucuel-Lautensack
Pennsylvania is the first state to create a registry for patients with IPF. The Temple Lung Center is one of five Pennsylvania institutions in this Pennsylvania Idiopathic Pulmonary Fibrosis Registry (PA-IPF Registry).
The registry will not only help researchers learn more about IPF natural history, prevalence, and best methods of medical and surgical care but, equally important, will help patients learn more about their condition and improve their access to advanced specialty care, including transplantation and clinical trials.
The PA-IPF Registry is aimed at generating information that will be useful in understanding this disease and its burden and, ultimately, in improving treatment. For example, new research indicates that mutations in the gene encoding telomerase—the enzyme that keeps the “cap ends” of the chromosome in place—are associated not only with a rare form of lung fibrosis called dyskeratosis congenita, but also with familial IPF. [Armanios et al. New Engl J Med 2007;356:1317-1326] This is exactly the type of new clue that PA-IPF will be in better position to explore once more patients enroll in the registry.
The registry will also be extremely useful in expanding the number of IPF patients involved in clinical trials with novel combination regimens and experimental antifibrotic agents. Such trials are critical because most patients with IPF will not respond to standard steroid or cytotoxic therapies and the transplantation option is limited by the shortage of donated organs.
Please encourage all patients with IPF who reside in Delaware, New Jersey, Pennsylvania and West Virginia to enroll in the PA-IPF Registry. Patients with IPF can contact the Registry staff: By filling out a Patient Contact Request at the website: www.paipf.medicine.pitt.edu or by calling the registry: 1-866-922-4473. Registry researchers will then coordinate collection of the demographic, diagnostic, and clinical information that will become the core of the database. More information and blood samples may also be requested periodically as part of the patient’s routine care. Patients will receive information aboutthe disease, support groups, and care close to where they live via the website and a quarterly newsletter.
Temple Research Focus:
Ambrisentan in Early Idiopathic Pulmonary Fibrosis (ARTEMIS)
Investigators: Francis Cordova, MD
Coordinator: Kathy Cucuel-Lautensack
This is a Phase 3 randomized, double-blind, placebocontrolled study to evaluate the safety and effectiveness of ambrisentan (LetairusTM, Gilead Sciences) in early IPF.
Ambrisentan is an endothelin receptor antagonist that is selective for the type A endothelin receptor (ETA). It was approved by the U.S. Food and Drug Administration in mid-2007 for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to improve exercise capacity and delay clinical worsening. [Galiè N et al. Circulation. 2008;117:3010-3019] The drug had been used for the PAH indication as an orphan drug since 2004.
In IPF, as in PAH, researchers hypothesize that ambrisentan will block ETA receptors and thereby negate the consequences of chronically elevated lung levels of ET-1. Endothelin 1 is known to be a potent vasoconstrictor and smooth muscle mitogen, promoting fibrosis, cell proliferation and remodeling, and inflammation. Ambrisentan will be administered in an attempt to neutralize the multiple pathways and mediators involved in IPF [Laurent GJ et al. R. Proc Am Thorac Soc. 2008;5:311-315] and perhaps also to diminish the secondary impacts of pulmonary hypertension. People who have been diagnosed early in the disease process may be more responsive to treatment and therefore the study will focus on patients who are in the earlier stages of IPF. Bosentan, which inhibits both A and B ET receptors, is also being evaluated in IPF; the clinical significance of selective versus nonselective inhibition of ET in IPF is currently unclear.
Inclusion:
-Male or female between 40 and 80 years of age
-Diagnosed with IPF in the last 3 years
-Honeycombing on HRCT scan of less than or equal to 5%
-Willing and able to have 2 right heart catheterizations performed
-Willing to have monthly lab tests
-Able to perform the 6-minute walk test
-Must meet lung function requirements
-Normal liver function tests
Exclusion:
-Restrictive lung disease (other than IPF)
-Obstructive lung disease
-Recent or active respiratory exacerbations
-Recent hospitalization for an IPF exacerbation
-Recent history of alcohol abuse
-Pregnant or breast-feeding
-Unwilling to follow contraceptive measures per protocol if applicable
-Chronic sildenafil (or same drug class) use for pulmonary hypertension
-Chronic treatment with certain medications for IPF within
-30 days of randomization
-Other serious medical conditions
After screening and enrollment, patients will be randomized 2:1 to receive either ambrisentan (5 mg or 10 mg tablet by mouth once a day) or placebo (i.e., participants have a 2 out of 3 chance of receiving ambrisentan, 1 out of 3 chance of receiving placebo). Serious side effects of ambrisentan include possible liver injury and birth defects. The most common side effects seen in clinical trials for PAH included reduced red blood cell count, peripheral edema, nasal congestion and sinusitis, palpitations, headache, and others.
Patients will be asked to continue in the trial for up to 3 years. In addition to taking the assigned treatment every day, clinical visits occur every 3 months and laboratory checks are needed every month. All patients will receive education about their disease, extensive diagnostic testing, and ongoing evaluations for disease progression or treatment effects. The primary outcome measured during the trial is time to death or disease progression. A secondary outcome is the proportion of subjects with disease progression at the designated timepoint of 48 weeks.
Temple Research Focus:
CNTO 888, a Chemokine Blocker, in Idiopathic Pulmonary Fibrosis
Investigators: Francis Cordova, MD
Coordinator: Kathy Cucuel-Lautensack
In this Phase 2 study, an agent currently being tested in cancer patients will be evaluated for the first time in patients with IPF. The randomized double-blind study will test the safety and effectiveness of once-monthly intravenous infusions of CNTO 888 (3 different doses) compared to placebo over a 48-week treatment period.
CNTO 888 (Centocor, Inc) is an experimental monoclonal antibody that blocks a protein called CC-Chemokine Ligand 2 (CCL2). This agent has not been approved by any regulatory authority for use in patients with any condition. Chemokines are multifunctional cytokines involved in regulating angiogenesis and vascular remodeling, promoting activity of fibrocytes, and influencing the action and movement of leukocytes. Recently, an excessive localized release of CCL2 in the pulmonary epithelium has been associated with the pathogenesis of pulmonary fibrosis. [Mercer PF et al. Am J Respir Crit Care Med. 2009 Jan 22. [Epub ahead of print]; Baran CP et al. Am J Respir Crit Care Med. 2007;176:78-89; Murray LA et al. Int J Biochem Cell Biol. 2008;40:2174-2182.] Thus it is hoped that an antagonist of CCL2 binding such as CNTO 888 will control the progression of IPF.
The study will be conducted at approximately 28 sites globally. Patients can remain on usual accepted treatment for IPF while enrolled in the study. However, participating in other experimental studies or taking other experimental medications while participating in this study will not be allowed.
Inclusion:
-Male or female between 40 and 80 years of age
-FVC ³ 50% predicted at screening
-Abnormal lung function test results that include evidence of restriction and impaired gas exchange, or evidence of desaturation at rest or exercise or decreased DLCO
-Bibasilar reticular abnormalities with minimal ground-glass opacities on HRCT
-Surgical lung biopsy evidence of usual interstitial pneumonia and/or HRCT scan-based diagnosis of IPF
-Relative decrease of ³ 10% in FVC, or relative decrease of ³ 15% in DLCO, or evidence of clinically significant worsening on HRCT (e.g., development of honeycombing, increase in opacities), or significant worsening of dyspnea at rest or with exertion
Exclusion:
-Evidence of interstitial pneumonia other than IPF
-Diagnosis of IPF unconfirmed by HRCT or lung biopsy results
-PaO2 < 55 mmHg (sea level) or 50 mmHg (altitude) at rest on room air
-Diagnosis of other significant respiratory disorder (e.g., asthma, tuberculosis (TB), sarcoidosis, aspergillosis, chronic obstructive pulmonary disease [COPD], or cystic fibrosis)
-Obstruction on prebronchodilator PFTs (defined as FEV1/FVC< 0.7) at screening demonstrated increase in FEV1 ³ 12% postbronchodilator
All patients must pass a 1-to-4 week screening phase to determine eligibility for the study
After screening, patients will be randomized to placebo or1 mg/kg, 5 mg/kg, or 15 mg/kg CNTO 888. The IV infusions are administered over 90 minutes every 4 weeks. The first 20 patients enrolled will receive treatment and special monitoring as part of an up-front safety evaluation. Only after careful review of this safety pre-study will an additional 100 patients be allowed to enroll and begin treatment. Patients will receive study agent until Week 48 and will continue to be followed through Week 72 for assessment of safety and any other effects after discontinuation of therapy.
The primary objective is to determine the efficacy (as measured by pulmonary function) and safety of CNTO 888 in subjects with IPF. Secondary outcomes to be measured include the effect of CNTO 888 on disease progression, patient reported outcomes, functional capacity and health-related quality of life, and the pharmacokinetics and pharmacodynamics of CNTO 888 in IPF.
Temple University Hospital has one of the most active and truly multidisciplinary lung transplant centers in the nation. Temple accepts patients with complex illnesses and rapidly assesses their suitability for transplant. Temple’s recognized strengths in caring for the most acutely ill pulmonary patients.