Mycobacterium avium complex (MAC) are ubiquitous organisms that cause isolated pulmonary disease in otherwise healthy patients with yet undefined susceptibilities. Patients typically present with a history of chronic cough, eventually progressing to hemoptysis, fever, and hypoxia. With half or more of all patients failing standard three-drug therapy, this is an insidious disease with a poor prognosis. Under the natural history protocol of nontuberculous mycobacterial infection (NTM; #01-I-0202), 46 patients with diagnosed pulmonary MAC disease are being studied. Numerous studies have suggested that a dysregulation in cytokine production may make these patients susceptible to mycobacterial infection. cytokines are particularly important in the activaction of macrophages, which help to clear mycobacterial infection. Interferon gamma 1b (Actimmune) and GM-CSF (Leukine) are two cytokine therapies that have been approved in the treatment of chronic granulomatous disease and post-transplantation hematopoietic reconstitution, respectively. A number of in vitro studies suggest that either or both of these therapies may help to clear MAC infection. Given the poor outcomes of therapy and the persistent, debilitating nature of the disease, nes therapies are desperately needed, and many are being tried without benefit of scientific foundation. Currently, there are no prospective trials that show any effect of these drugs in the lung delivered subcutaneously. This protocol proposes to perform a pilot study to evaluate the effects, if any, of these macrophage stimulating cytokines in the context of ongoing pulmonary MAC infection.

1.2 Aims

To determine the local and systemic effect, if any, of adjuvant IFNy and GM-CSF in pulmonary MAC patients.

1.3 Methods

Fifteen patients will be randomized into three treatment groups of five patients each. The first group will receive a standard drug regimen, based on the 1997 ATS guidlines. The second and third groups, in addition to receiving the standard therapy, will also receive three months of IFNy and GM-CSF, respectively. All patients will undergo bronchoscopy with bronchoalveolar lavage (BAL) at the beginning of the study, after, after three months, and at six months.

In addition to obtaining traditional subjective and objective clinical measures, both proteomic and genomic analysis of the BAL will be performed to determine if cytokine therapy effects any detectable change in the lungs, In vitro studies on type II alveolar macrophages culled from these patients before and after cytokine therapy will also be performed.

Phase
Phase I

Further Study Details: 

Expected Total Enrollment:  25

Mycobacterium avium complex (MAC) are ubiquitous organisms that cause isolated pulmonary disease in otherwise healthy patients with yet undefined susceptibilities. Patients typically present with a history of chronic cough, eventually progressing to hemoptysis, fever, and hypoxia. With half or more of all patients failing standard three-drug therapy, this is an insidious disease with a poor prognosis. Under the natural history protocol of nontuberculous mycobacterial infection (NTM; #01-I-0202), 46 patients with diagnosed pulmonary MAC disease are being studied. Numerous studies have suggested that a dysregulation in cytokine production may make these patients susceptible to mycobacterial infection. cytokines are particularly important in the activaction of macrophages, which help to clear mycobacterial infection. Interferon gamma 1b (Actimmune) and GM-CSF (Leukine) are two cytokine therapies that have been approved in the treatment of chronic granulomatous disease and post-transplantation hematopoietic reconstitution, respectively. A number of in vitro studies suggest that either or both of these therapies may help to clear MAC infection. Given the poor outcomes of therapy and the persistent, debilitating nature of the disease, nes therapies are desperately needed, and many are being tried without benefit of scientific foundation. Currently, there are no prospective trials that show any effect of these drugs in the lung delivered subcutaneously. This protocol proposes to perform a pilot study to evaluate the effects, if any, of these macrophage stimulating cytokines in the context of ongoing pulmonary MAC infection.

1.2 Aims

To determine the local and systemic effect, if any, of adjuvant IFNy and GM-CSF in pulmonary MAC patients.

1.3 Methods

Fifteen patients will be randomized into three treatment groups of five patients each. The first group will receive a standard drug regimen, based on the 1997 ATS guidlines. The second and third groups, in addition to receiving the standard therapy, will also receive three months of IFNy and GM-CSF, respectively. All patients will undergo bronchoscopy with bronchoalveolar lavage (BAL) at the beginning of the study, after, after three months, and at six months.

In addition to obtaining traditional subjective and objective clinical measures, both proteomic and genomic analysis of the BAL will be performed to determine if cytokine therapy effects any detectable change in the lungs, In vitro studies on type II alveolar macrophages culled from these patients before and after cytokine therapy will also be performed.

Genders Eligible for Study:  Female

Criteria

INCLUSION CRITERIA:
To be eligible for this protocol, a patient must meet the following criteria:
Diagnosed with M. avium complex (MAC) lung disease based on the 1997 version of American Thoracic Society (ATS) diagnostic criteria and have positive AFB smear or culture for MAC at least three months prior to the date of enrollment. Patients with only histological evidence of mycobacterial infection without positive smear or culture will not qualify for this protocol even if they meet the ATS diagnostic criteria for nontuberculous mycobacterial lung infection.
A patient must have radiographic evidence on jigh resolution computerized tomography of changes that are consistent with pulmonary MAC infection. These include, but are not limited to: multiple small nodules (less than 5 mm), cylindrical bronchiectasis.
The patient must be on a treatment regimen based on ATS guidelines that has been stable for at least three months. By stable, we mean that the patient has been tolerating the regimen without any significant adverse reactions, and that no new agents have been begun in the last three months.
The patient must be female and post-menopausal (either through natural menopause or surgical removal of her ovaries). She must not be under 40 years at the time of enrollment in the study.
The patient must be enrolled in protocol # 01-I-0202 ("Natural History, Genetics, Phenotype, and treatment of Non-Tuberculoid Mycobacterial Infections").
EXCLUSION CRITERIA:
Patients with pulmonary MAC disease who do not meet the above entry criteria.
Patients with any of the following preexisting medical conditions:
a) HIV positive
b) asthma
c) active cancer requiring treatment
d) hepatic disease (defined as either a history of cirrhosis, or grade 3 or 4 hepatic toxicity by the Toxicity Table in Appendix II)
Patients who are unable to tolerate bronchoscopy. This will be defined by the following criteria:
a) A PaO2 pressure of less than 100 cmH20 when given supplemental oxygen at 100% FiO2.
b) Clinically significant reactive airway disease that does not respond to bronchodilators.
Patients with the following laboratory abnormalities:
a) creatinine greater than 1.5 mg/dL
b) Hemoglobin less than 9 mg/dL
c) WBC less than 3,000
d) Platelets less than 150,000
e) ALT greater than 82 U/L, or AST greater than 78 U/L.
f) Bilirubin greater than 2.0 mg/dL
g) Alkaline phosphates greater than 232 U/L
Patients with a preexisting allergy or history of allergic reactions to study or protocol medications. These include, but are not necessarily limited to: IFNy, GM-CSF, azithromycin/ clarithromycin, ethambutol, rifampin/ rifabutin, anesthetic agents employed in bronchoscopy, or any yeast-derived products.
Patients who are unable to maintain the described follow up schedule. Likewise, patients who are unable to give informed consent are excluded from the study.
Patients with a history of a sputum culture that was positive for Pseudomonas aeruginosa.
Patients with known cystic fibrosis mutations (per CFTR sequencing performed under protocol # 01-I-0202), whether they be homozygotes, heterozygotes, or compound heterozygotes.
Patients who are either currently smoking, or have a previous history of smoking that exceeds 20 pack years.
Patients currently taking any estrogen-based hormone replacement therapies.
Patients with prior treatment with either IFNy or GM-CSF within the last three months.
Patients with known history of cardiac, endocrine, neurologic or other medical conditions that the principle investigator deems dangerous or unsuitable for enrollment will be excluded.
Patients who are either pregnant or lactating. Also, patients who refuse to use appropriate barrier forms of contraception during this trial will also be excluded.
Patients who, at any time during this trial, have an active lung infection caused by either Staphylococcus or a gram negative rod are excluded from this trial until this infection has been successfully treated.

Please refer to this study by ClinicalTrials.gov identifier  NCT00111397

Maryland
      National Institute of Allergy and Infectious Diseases (NIAID), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050156; 05-I-0156
Record last reviewed:  May 8, 2005
Last Updated:  May 19, 2005
Record first received:  May 19, 2005
ClinicalTrials.gov Identifier:  NCT00111397
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-05-24