Efficacy Study of Fluconazole to Treat Coccidioidomycosis Pneumonia (Valley Fever)
Condition: Coccidioidomycosis
MeSH terms: Pneumonia; Coccidioidomycosis; Coccidiosis
Intervention: Fluconazole; Placebo
Intervention description: Fluconazole is a synthetic triazole antifungal agent. It will be supplied as 200 mg over encapsulated tablets. Each gelatin capsule will contain two-100 mg fluconazole tablets and microcrystalline cellulose for overfill.; Placebo will be supplied as matching gelatin capsules containing microcrystalline cellulose only. Capsules are the same size, weight, and color as capsules containing fluconazole tablets.
Intervention MeSH terms: Fluconazole
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: CAP; Coccidioidomycosis; Community Acquired Pneumonia; FLEET; Fluconazole; Parent Study of 16-0008; Pneumonia; Valley Fever

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Aged > / = 18 years and presenting for clinical care in coccidioidomycosis endemic
             areas.

          2. Have a health care provider who has decided to treat community acquired pneumonia with
             antibacterials.

          3. Be able to take and tolerate oral antibacterials/antifungals.

          4. Able to understand the study and provide informed consent.

          5. Willing and able to comply with study procedures and complete study visits.

          6. Willing to allow access to medical records, and medical records are available to the
             study team.

          7. The first dosage of study drug will be administered within 72 hours of presentation
             for care.

          8. Able to swallow large pills.

          9. 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.

         10. Non-pregnant female subjects of childbearing potential must have a negative pregnancy
             test within 24 hours prior to enrollment and at Visits 02 - 03.

         11. 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:

          1. 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).

          2. Present clinical diagnosis of hospital acquired pneumonia (HAP).

          3. Documented microbiologically- or serologically-confirmed past infection with
             coccidioidomycosis.

          4. Clinical diagnosis of coccidioidal infection that is of sufficient certainty as to
             exclude the need for antibacterial therapy.

          5. 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.

          6. Have a history of systemic antifungal treatment within the 4 weeks prior to
             enrollment.

               -  A single dose of fluconazole (ex. treatment of vulvovaginal candidiasis) is
                  acceptable and should not exclude subject from study.

          7. 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

          8. 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.

          9. History of a solid organ or bone marrow transplant.

         10. 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.

         11. 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.

         12. On hemo or peritoneal dialysis or have a creatinine of > / = 2.0 mg/dL or estimated
             CrCl < /= 50 mL/min.

         13. History of hypokalemia defined as less than 3.5 mEQ/L on more than one occasion during
             the 4 weeks prior to enrollment.

         14. 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.

         15. 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.

         16. Pregnant or lactating females.

         17. History of azole intolerance or allergy.

         18. Individuals for whom study participation would not be in their best interest, as
             determined by the clinical investigator.

         19. Are taking medications that are contraindicated with concurrent use of fluconazole.

         20. Positive point of care HIV test at Day 1 visit consistent with new HIV diagnosis.