Efficacy Study of Fluconazole to Treat Coccidioidomycosis Pneumonia (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. 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:

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.