A Randomized, Double-blind, Placebo-controlled Clinical Trial of Fluconazole as Early Empiric Treatment of Coccidioidomycosis Pneumonia (Valley Fever) in Adults Presenting With Community Acquired Pneumonia (CAP) in Endemic Areas (FLEET-Valley Fever)
A Randomized, Double-blind, Placebo-controlled Clinical Trial of Fluconazole as Early Empiric Treatment of Coccidioidomycosis Pneumonia (Valley Fever) in Adults Presenting With Community Acquired Pneumonia (CAP) in Endemic Areas (FLEET-Valley Fever)
This is a Phase IV randomized, double-blinded, placebo-controlled study in 1000 individuals aged 18 years or older, with community acquired pneumonia (CAP) who meet all eligibility criteria in endemic regions. This study is designed to provide data on the effectiveness of early antifungal treatment (Fluconazole, 400 mg/day) for coccidioidomycosis pneumonia (also referred to as Valley Fever (VF) Pneumonia or acute onset valley fever) vs. placebo in subjects with coccidioidomycosis pneumonia. Patients who are prescribed antibacterials by their health care provider for acute CAP will be randomized to receive either placebo or 400 mg/day of fluconazole for 42 days. The primary objective is to assess the clinical response of early empiric antifungal therapy with fluconazole at Day 22 in subjects with coccidioidomycosis pneumonia and are compliant with the study intervention.
This is a Phase IV randomized, double-blinded, placebo-controlled study in 1000 individuals, aged 18 years or older, with community acquired pneumonia (CAP) who meet all eligibility criteria in endemic regions. This study is designed to provide data on the effectiveness of early antifungal treatment (Fluconazole, 400 mg/day) for coccidioidomycosis pneumonia (also referred to as Valley Fever (VF) Pneumonia or acute onset valley fever) vs. placebo in subjects with coccidioidomycosis pneumonia. Patients who are prescribed antibacterials by their health care provider for acute CAP will be randomized to receive either placebo or 400 mg/day of fluconazole for 42 days. Blood work for serologic determination of coccidioidomycosis infection will be drawn at the time of randomization (Day 1), and again on Days, 22, 29, and 43. On Day 43, subjects will be informed of their treatment assignment and results of serologic testing from Days 1, 22 and 29. At Day 43, those subjects who did not meet the protocol defined case definition for CAP caused by acute coccidioidomycosis and who did not receive fluconazole will be dismissed from the study and referred to a health care provider with the results of their serology testing and their treatment assignment. All subjects who received fluconazole will be evaluated for safety follow up at Day 49. At Day 49, those subjects who did not meet the protocol defined case definition for CAP caused by acute coccidioidomycosis will be dismissed from the study and referred to a health care provider with the results of their serology testing and their treatment assignment. Subjects who did meet the protocol defined case definition for CAP caused by acute coccidioidomycosis infection will be referred to a healthcare provider with the results of their serology testing and their treatment assignment for further treatment as indicated and will be contacted by telephone on Days 90 and 180. The study duration will be approximately 72 months, and the subject participant duration will be from 42 days to approximately 6 months. The primary objective is to assess the clinical response of early empiric antifungal therapy with fluconazole at Day 22 in subjects with coccidioidomycosis pneumonia who are adherent to the study intervention. The secondary objectives are: 1) To assess the clinical response of early empiric antifungal therapy with fluconazole at Day 22 in subjects with coccidioidomycosis pneumonia regardless of adherence with the study intervention; 2) To assess the clinical response of early empiric antifungal therapy with fluconazole at Day 43 in subjects with coccidioidomycosis pneumonia regardless of adherence with the study intervention; 3) To compare the clinical response and its individual components over time, by treatment group, in subjects with coccidioidomycosis pneumonia; 4) To assess the impact of early empiric antifungal therapy with fluconazole on days lost from work or school and responses to the SF-12v2 and PROMIS Item Bank v2.0 - Ability to Participate in Social Roles and Activities - Short Form 4a in subjects with coccidioidomycosis pneumonia; 5) To assess the effect of early empiric antifungal therapy with fluconazole through Day 43 in subjects with coccidioidomycosis pneumonia on all-cause mortality by treatment group; and 6) To assess whether early empiric antifungal therapy with fluconazole at Day 22 is non-inferior to placebo as defined by clinical response at Day 22 in all randomized subjects, regardless of coccidioidomycosis pneumonia status or adherence with study intervention, with baseline and follow-up FLEET-CAP scores.
Inclusion Criteria:
Aged > / = 18 years and presenting for clinical care in coccidioidomycosis endemic areas.
Have a health care provider who has decided to treat community acquired pneumonia with antibacterials.
Be able to take and tolerate oral antibacterials/antifungals.
Able to understand the study and provide informed consent.
Willing and able to comply with study procedures and complete study visits.
Willing to allow access to medical records, and medical records are available to the study team.
The first dosage of study drug will be administered within 72 hours of presentation for care.
Able to swallow large pills.
Sexually active female subjects must be of non-childbearing potential* or, if of childbearing potential, must use a highly effective method of birth control**(captured on the appropriate data collection form).
*Non-childbearing potential is defined as being post-menopausal for at least 18 months or surgically sterile via bilateral oophorectomy or hysterectomy.
**Female subjects must avoid becoming pregnant by using one of the following acceptable methods of birth control for 30 days prior to study drug dosing and must be maintained for 30 days after last dose of study drug: i. Intrauterine contraceptive device; OR ii. Oral contraceptives; OR iii. Implanon, Nexplanon, DepoProvera, contraceptive skin patch or NuvaRing; OR iv. Tubal ligation; OR v. Exclusively same-sex relationships.
Non-pregnant female subjects of childbearing potential must have a negative pregnancy test within 24 hours prior to enrollment and at Visits 02 - 03.
Subjects receiving any of the drugs reported to have manageable drug interactions with fluconazole are allowed to be enrolled based on PI clinical judgment.
Exclusion Criteria:
Have recently received an experimental agent* or participating in or planning to participate in a study involving an experimental agent** while in the active drug administration phase of this study.
*defined as within 30 days prior to enrollment in this study.
**(e.g., vaccine, drug, biologic device, blood product, or medication).
Present clinical diagnosis of hospital acquired pneumonia (HAP).
Documented microbiologically- or serologically-confirmed past infection with coccidioidomycosis.
Clinical diagnosis of coccidioidal infection that is of sufficient certainty as to exclude the need for antibacterial therapy.
Have a history of systemic antibacterial treatment for this current CAP care episode occurring greater than 4 weeks prior to enrollment*.
*Receipt of systemic antimicrobial therapy for indications other than respiratory tract infection is permitted.
Have a history of systemic antifungal treatment within the 4 weeks prior to enrollment.
Long term use* of high dose oral or parenteral glucocorticoids**; or high-dose inhaled steroids*** taken within the 4 weeks prior to enrollment.
*defined as > 8 weeks of daily use.
**high dose defined as prednisone > / = 20 mg total daily dose, or equivalent dose of other glucocorticoids.
***high dose defined as > 800 mcg/day of beclomethasone dipropionate or equivalent
Have confirmed or suspected immunosuppression as a result of an underlying illness [other than well controlled HIV infection], primary immunodeficiency, or treatment, or induction/maintenance use of immunosuppressive agents*.
*including anti-neoplastic chemotherapy or cytotoxic radiation therapy for cancer, anti-TNF medications, or other immunomodulating agents.
History of a solid organ or bone marrow transplant.
Have poorly controlled HIV-infection or HIV-infection treated with Lopinavir, Tipranavir, Etravirine or Didanosine. Poorly controlled HIV is defined as HIV RNA > 50 copies/mm^3 (or greater than the lower limit of quantification [LLOQ] of the local HIV RNA assay if the LLOQ is > 50) in the 6 months prior to current care episode regardless of whether patient is on antiretroviral therapy or CD4 < 250 cell/mm^3.
Current diagnosis and/or treatment of active liver disease including abnormal baseline liver function tests as defined as: total bilirubin greater than or equal to 3.0 mg/dL AND either AST greater than or equal to 135 IU/L OR ALT greater than or equal to 150 IU/L.
On hemo or peritoneal dialysis or have a creatinine of > / = 2.0 mg/dL or estimated CrCl < /= 50 mL/min.
History of hypokalemia defined as less than 3.5 mEQ/L on more than one occasion during the 4 weeks prior to enrollment.
History of cardiovascular disease with increased risk for torsades de pointes as defined as: i. NYHA Heart Failure Criteria III or greater; OR ii. History of atrial or ventricular dysrhythmias; OR iii. History of structural heart disease (including previously repaired); OR iv.Personal or family history of congenital long QT syndrome.
A marked baseline prolongation of the QT/QTc interval defined as a QTc interval > 450 milliseconds (ms) for male subjects or > 470ms for female subjects with repeated demonstration*.
*Subjects without a history of prolonged QTc and an abnormal baseline QTc interval should undergo repeat ECG assessment within screening period prior to randomization (72 hours) to confirm prolongation. If the repeat ECG QTc is within normal limits and less than the parameters above, the subject may be considered for enrollment.
Pregnant or lactating females.
History of azole intolerance or allergy.
Individuals for whom study participation would not be in their best interest, as determined by the clinical investigator.
Are taking medications that are contraindicated with concurrent use of fluconazole.
Positive point of care HIV test at Day 1 visit consistent with new HIV diagnosis.
Phoenix, Arizona 85006, United States
Phoenix, Arizona 85013, United States
Tucson, Arizona 85724-0001, United States
Bakersfield, California 93301, United States
Fresno, California 93701, United States