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Sponsored by: |
National Heart, Lung, and Blood Institute (NHLBI) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00279708 |
This study will determine if atorvastatin (Lipitor), a widely used cholesterol-lowering drug, can help patients with pulmonary (lung) sarcoidosis and replace or reduce the need for patients to take steroids, such as prednisone. Sarcoidosis is an inflammatory disease that can affect nearly any part of the body. Pulmonary sarcoidosis may resolve on its own or it may progress to irreversible lung damage, disability, and death. Many sarcoidosis patients are treated with prednisone, but the drug is not effective in all patients, and it can cause serious side effects, such as high blood pressure, sugar diabetes, eye cataracts, and bone thinning.
Patients with stage II or III pulmonary sarcoidosis between 18 and 70 years of age who require prednisone may be eligible for this study. Candidates are screened with the tests and procedures described below.
Participants are randomly assigned to one of two treatment groups: one group takes atorvastatin; the other takes a placebo (a look-alike pill that has no active ingredient to fight sarcoidosis). Both groups take the pills by mouth once a day for 12 months. When treatment begins, participants begin to have their prednisone dosage tapered (reduced). The tapering is done over 8 weeks until the dose is reduced by 90 percent. Patients are evaluated periodically to determine if the two groups differ in how long they can remain on the reduced dose of prednisone without having their symptoms recur, requiring an increase in the prednisone dose. A full battery of tests is done at the initial screening visit and at the 26- and 52-week follow-up visits, requiring hospitalization for 3-5 days. Additional interim outpatient assessments are done at 6, 12, 18 and 36 weeks.
The full battery of tests at the initial screening and the 26- and 52-week visits includes the following:
Interim testing at 6, 12, 18 and 36 weeks includes PFT, MIVP, Exhaled NO and CO, CXR, questionnaire, blood tests, and 6MWT.
Six months after completing the study, participants fill out a questionnaire.
Condition | Intervention | Phase |
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Sarcoidosis, Pulmonary |
Drug: Atorvastatin |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Single Group Assignment, Efficacy Study |
Official Title: | Atorvastatin as a Disease Modifying Agent in Stage II and III Pulmonary Sarcoidosis: A Randomized, Double-Blind, Placebo-Controlled Trial |
Estimated Enrollment: | 96 |
Study Start Date: | January 2006 |
Arms | Assigned Interventions |
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1: Placebo Comparator |
Drug: Atorvastatin
Placebo vs. Atorvastatin
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2: Active Comparator |
Drug: Atorvastatin
Placebo vs. Atorvastatin
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Background
Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea and decreased quality of life (QOL). The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-alpha, INF-gamma, IL-2 and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain. Because steroids often produce undesirable side effects, investigations to identify alternative therapies are warranted. There is sufficient evidence to test the proof of concept that pathways targeted by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies, statins blunt Th1-mediated inflammatory responses.
Aims
The study involves a double-blind placebo-controlled, randomized trial which aims to determine if atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment.
Methods
Patients, who are 18-70 years old, with stage II or III pulmonary sarcoidosis, diagnosed by a compatible clinical history and supported by a lung, lymph node, or tissue biopsy, will be enrolled in the study, if they require prednisone therapy. The patients will be randomly assigned to two groups; as prednisone is tapered, one group will receive placebo and the other, atorvastatin. The two study drugs will be administered for twelve months, during which time patients will be periodically evaluated as to their clinical status and prednisone requirements. Pill counts and patient diaries will be used to determine the amount of steroid use during the study period. Patients with pulmonary fibrosis greater than 50 percent of total lung volume or severe co-morbidities will be excluded from the trial.
The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and physiological endpoints are intended to analyze possible anti-inflammatory and beneficial effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four categories of secondary endpoints will be used to characterize the effects of the therapeutic agent on the clinical course of the disease: imaging (high resolution chest CT); quality of life assessments (SF-36, and SGRQ), anti-inflammatory effects (biomarkers and relapse rates), and functional effects (CPET, PFTs). Finally, we will study the utility of exhaled nitric oxide and carbon monoxide in monitoring disease activity.
Ages Eligible for Study: | 18 Years to 70 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Patients are eligible for the trial if they are 18-70 years old with radiographic stages II and III pulmonary sarcoidosis, and are on prednisone, methotrexate, or azathioprine for pulmonary sarcoidosis or who are steroid-requiring. Patients with extra-pulmonary saroidosis (except cardiac and neurosarcoid) may be eligible as long as they have active pulmonary (stage II or III) sarcoidosis.
Steroid-Requiring History:
A steroid-requiring patient is one who was previously stable but who ultimately experiences (a) increased symptoms associated with radiographic deterioration, and/or, (b) met the criteria for relapse and/or functional deterioriation. In addition, patients who were prescribed prednisone for sarcoidosis, but have self-discontinued it (yet still have clinical and symptomatic disease and/or evidence of pulmonary functional deterioration) will be considered steroid-requiring.
This latter group of steroid-requiring patients is eligible for enrollment if they are willing to resume taking their latest stabilizing dose of prednisone for at least four weeks prior to study entry. If their dose cannot be determined, then 40 mg will be used.
Therefore, a history of symptomatic or clinical deterioration leading to therapy initiation, or a history of decline associated with attempts to decrease therapy should be established. Medical records review and discussion with the prescribing physician will be used to establish this history.
Radiographic Stages of Pulmonary Sarcoidosis:
STAGE DESCRIPTION
0 Normal Chest Radiograph
I Bilateral Hilar Lymphadenopathy
II Pulmonary Infiltration and Bilateral Hilar Lymphadenopathy
III Pulmonary Infiltration alone
Steroid-requiring refers to one of three situations:
Patients who meet relapse criteria or functional deterioration.
Functional deterioration criteria that warrants prednisone therapy includes:
If VC fell to 75% of the best recorded value for the patient before any treatment
If VC fell to greater than 50% of predicted value
IF DLCO fell to greater than 60% of the best recorded value prior to their treatment
Patients who are on a previously prescribed systemic steroid, or alternative agent such as methotrexate or azathioprine, primarily for pulmonary sarcoidosis. Alternative agents must first be changed to roughly equivalent anti-inflammatory dose of prednisone and the patient should be stable on this dose for at least four weeks prior to randomization.
Patients who have substantial respiratory symptoms (distressing cough or dyspnea, which interferes with daily activities that would warrant therapy as per the standard of practice in the US.
Extra Pulmonary Sarcoidosis:
Paatients with extra pulmonary sarcoidosis (except neurosarcoid and cardiac sarcoid) may be eligible as long as they have active pulmonary (stage II or III) sarcoidoisis. All patients will be referred to an NIH ophthalmologist. Steroid therapy may be modified based upon the recommendations of the consultants, as well as per the lapse criteria described above.
EXCLUSION CRITERIA:
Patients taking the following preparations will not be allowed to participate in the study unless they agree to discontinue usage at least two weeks prior to randomization and for the duration of the study period: grapefruit juice and herbal remedies that may lead to severe liver injury and/or muscle injury if taken with atorvastatin, including: Skullcap, Chapparal, Germander, Jin Bu Huan, Valerian, Comfrey, and Eucalyptus. Since other products such as St. John's Wort, oat bran, and pectin can reduce the effectiveness of atorvastatin, they and similar agents, should also be discontinued at least two weeks before randomization and for the duration of the study period.
Subjects with inactive hepatitis B will require antiviral prophylaxis with an agent such as lamivudine, while on prednisone therapy.
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 |
Responsible Party: | National Institutes of Health ( Joseph R. Fontana, M.D./National Heart, Lung, and Blood Institute ) |
Study ID Numbers: | 060072, 06-H-0072 |
Study First Received: | January 18, 2006 |
Last Updated: | November 8, 2008 |
ClinicalTrials.gov Identifier: | NCT00279708 |
Health Authority: | United States: Federal Government |
Granulomatous Inflammation Steroid-Sparing Pulmonary Function Sarcoidosis, Pulmonary Statins (Atorvastatin) Biomarkers Nitric Oxide |
Disease Activity Quality of Life Corticosteroids Pulmonary Sarcoidosis Sarcoidosis Granulomatous Inflammation |
Nitric Oxide Lymphatic Diseases Lung Diseases, Interstitial Sarcoidosis, pulmonary Respiratory Tract Diseases Lung Diseases |
Quality of Life Sarcoidosis Lymphoproliferative Disorders Atorvastatin Inflammation Sarcoidosis, Pulmonary |
Antimetabolites Molecular Mechanisms of Pharmacological Action Therapeutic Uses Antilipemic Agents |
Enzyme Inhibitors Anticholesteremic Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Pharmacologic Actions |