Atorvastatin to Treat Pulmonary Sarcoidosis
|ClinicalTrials.gov Identifier: NCT00279708|
Recruitment Status : Completed
First Posted : January 19, 2006
Results First Posted : August 12, 2016
Last Update Posted : May 22, 2017
This study will determine if atorvastatin (Lipitor) 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:
- Medical history, physical examination, blood and urine tests, assessment of disease severity and activity.
- Chest x-ray (CXR) and computed tomography (CT) scan.
- Abdominal ultrasound.
- Six-minute walk test (6MWT)
- Exercise testing and blood gases
- Pulmonary function tests (PFT)
- Maximum incremental ventilatory performance test (MIVP)
- Exhaled nitric oxide and carbon monoxide (Exhaled NO and CO)
- Bronchoscopy and lavage
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 or disease||Intervention/treatment||Phase|
|Sarcoidosis, Pulmonary||Drug: Atorvastatin Other: Placebo Oral Tablet||Phase 2|
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.
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||55 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Atorvastatin as a Disease Modifying Agent in Stage II and III Pulmonary Sarcoidosis: A Randomized, Double-Blind, Placebo-Controlled Trial|
|Study Start Date :||January 2006|
|Primary Completion Date :||December 2015|
|Study Completion Date :||December 2015|
Active Comparator: Intervention Arm (Atorvastatin)
Atorvastatin: Subjects were assigned to the treatment intervention by way of double blind masking. Atorvastatin 80 mg/day was the initial treatment given, as tolerated for a 12 month period. During the study, a 50% dose reduction was applied for subjects meeting pre-specified criteria.
Placebo vs. Atorvastatin
Other Name: Lipitor
Placebo Comparator: Control Arm (Placebo)
Placebo: In a double-blind fashion, subjects were assigned to receive the sham intervention which appeared the same as the intervention agent. For subjects meeting pre-specified criteria, a 50% dose reduction was applied during the 12 month treatment phase of the study: Placebo vs. Atorvastatin
Other: Placebo Oral Tablet
Placebo: Sham Therapy in an oral tablet formulation
Other Name: Placebo
- The Steroid Sparing Period [ Time Frame: 1 year ]The duration of steroid sparing was defined as the date when the target dose of prednisone was reached until the date at which the dose was increased and/or met the relapse (flare) criteria; or until the 12 month study phase ended if no prednisone dose increase was required. The steroid sparing period was measured in units of days. The prednisone target dose was defined as a 90% reduction of the baseline dose or an absolute prednisone dose of 4 mg/day or less.
- Pulmonary Sarcoidosis Flares [ Time Frame: 1 year ]Flare rates and relative risk: Flares (relapses) were defined as the physiological deterioration in pulmonary function due to worsened pulmonary inflammation. The criteria used for a pulmonary flare included: > 15% decline in static function (FEV1 post, FVC post); or (> 20% DLCO adj); or a > 15% decline in walk distance as measured by the six minute walk test, or via a decline in oxygen consumption collected during a cardiopulmonary exercise test (CPET). Additional factors considered included an increase in dyspnea (>15% increase in the dyspnea scale (TDI); and/or significant radiographic worsening. Clinical assessment of the patient's status may have been factored into the criteria for flare determination as well.
- Pulmonary Function Tests [ Time Frame: 12 month treatment period ]Spirometry measurements (FVC and FEV1) obtained post-bronchodilator Diffusion, adjusted for hemoglobin
- Exercise Performance [ Time Frame: 12 month treatment period ]Cardiopulmonary Exercise Tests (VO2 peak, VO2/work, VECO2) Six minute Walk Test (distance, Borg scale)
- Quality of Life and Dyspnea Scales [ Time Frame: 12 month treatment period ]St. George's Respiratory Questionnaire SF-36 Modified MRC Dyspnea Scale
- Chest Imaging [ Time Frame: 12 month treatment period ]HRCT Chest radiographs
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00279708
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Joseph R Fontana, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|