A Pilot Study of Norfloxacin for Hepatopulmonary Syndrome
Condition: Hepatopulmonary Syndrome
MeSH terms: Hepatopulmonary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      The hepatopulmonary syndrome (HPS)and pre-HPS is a disease seen in patients with chronic
      liver disease, whereby patients develop dilations in the blood vessels of the lungs,
      resulting in low oxygen levels and shortness of breath.

      In this study, each HPS and pre-HPS subject will be treated with a commonly used antibiotic
      called "norfloxacin" (approved for use in the treatment of gonorrhea, prostatitis and urinary
      tract infections) for a 4-week period. In order to ensure that any observed improvement was
      indeed due to norfloxacin, each subject will also be treated with a separate 4-week course of
      an identical placebo. There will also be a 4 week wash-out period (no study
      medication/placebo) between the 2 courses of treatment.

      The primary aim of the study will be to measure improvements in oxygen levels while on
      norfloxacin, although a number of secondary parameters will also be followed.
    

Detailed description: 
      Research Question:

      This is a pilot study; the fundamental research question is:

      Does norfloxacin administration reduce Alveolar-arterial oxygen gradient (AaDO2) in patients
      with HPS and pre-HPS?

      However, for this particular pilot study, the research question is:

      What is the magnitude and standard deviation of the change in A-a gradient with norfloxacin
      treatment in subjects with HPS and pre-HPS ?

      This is in order to enable accurate sample size estimations for a future large
      randomized-controlled trial of norfloxacin administration in the treatment of HPS and
      pre-HPS.

      Significance:

      HPS and pre-HPS is a disease that carries a high morbidity and an alarmingly high mortality.
      Orthotopic liver transplantation (OLT) is the only effective treatment, and in itself
      threatens a significant operative mortality in these patients.

      A growing body of literature has built an elegant and compelling case for the role of gut
      bacterial translocation and secondary pulmonary nitric oxide (NO) overproduction in the
      pathophysiology of HPS.

      A sophisticated rat model and a case report in a human subject have supported the potential
      for norfloxacin, a widely available, cheap and non-toxic antibiotic, to mitigate these
      effects and improve oxygenation, which is the most important contributor to both morbidity
      and mortality in HPS.

      Given the dismal prognosis of this disease, the biological plausibility of the hypothesis,
      and the minimal foreseeable deleterious consequences of the intervention, it behooves the
      scientific community to formally test this theory.

      A. Objectives

        -  to evaluate the magnitude and standard deviation of the change in AaDO2 with norfloxacin
           treatment in subjects with HPS and pre-HPS, to enable accurate sample size estimations
           for a future large randomized-controlled trial of norfloxacin administration in the
           treatment of HPS

        -  to evaluate subject recruitment and retention, in order to determine the feasibility of
           a future large randomized-controlled trial of norfloxacin administration in the
           treatment of HPS and pre-HPS

        -  to qualitatively evaluate the usefulness of a number of new measures that have never
           been utilized in this subject population (baseline dyspnea index (BDI), transitional
           dyspnea index (TDI), Chronic Respiratory Disease Questionnaire (CRQ)

        -  to evaluate the hypothesized role of alveolar NO (measured by exhaled NO) as an
           intermediary in the relationship between norfloxacin administration and AaDO2

      Methods

      i. Overview of Study Design - intervention and maneuver

      This is a single-university center (University of Toronto), randomized, controlled pilot
      study with a crossover design. The intervention is exposure to norfloxacin (400 mg po bid)
      for a 4-week period, compared to an identical placebo treatment. In the crossover design, all
      subjects will receive both norfloxacin and the placebo medication, but the order of treatment
      will be randomized, as detailed in the study maneuver, below.

      Study maneuver:

      Eligible subjects will be identified by Drs. Faughnan and Gupta. They will subsequently be
      recruited by the respirology research coordinator (see details below). Next, the hospital
      pharmacist will provide each subject with a 4-week supply of either norfloxacin 400 mg po
      bid, or an identical placebo, according to the pre-determined computerized randomization
      scheme. The pharmacist will be the only person aware of the treatment allocation throughout
      the study (subjects, research coordinator, treating physicians and outcome assessors will be
      blinded). After the initial 4-week treatment, there will be a 4-week washout period, after
      which the pharmacist will provide each subject with a 4-week supply of the alternative agent
      (crossover) (see figure 2).

      ii. Measurements - outcomes Outcomes

      The primary endpoint in this study is the difference in the change in AaDO2 over the
      treatment course, between treatment and placebo groups. The secondary endpoints include
      partial pressure of arterial oxygen (paO2), exhaled NO, diffusion lung capacity for carbon
      monoxide (DLCO), cardiac output (CO), total peripheral resistance (TPR), pulmonary artery
      systolic pressure (PAP) (on echocardiogram), endotoxin levels, endothelin-1 (ET-1) levels,
      MELD score (model for end-stage liver disease) (based on creatinine, bilirubin and INR),
      baseline dyspnea index (BDI), transitional dyspnea index (TDI), and Chronic Respiratory
      Disease Questionnaire (CRQ).

      Assessment of Outcomes Please see attached "procedure table," and "data collection sheet."

      Once randomized, subjects will undergo initial assessment at time 0 (week 0), with:

        1. ABG (pO2, AaDO2)

        2. pulmonary function tests: exhaled NO, DLCO

        3. BP, echocardiogram: CO, TPR, PAP

        4. blood tests: INR, bilirubin, creatinine (MELD score), liver enzymes (ALT, AST, ALP,
           bilirubin), albumin, endotoxin level, ET-1 levels

        5. questionnaires: BDI/TDI, CRQ

        6. history and physical exam by study physician

      All of these measures will be repeated after 4 weeks (end of first treatment course), 8 weeks
      (before start of next treatment course), and 12 weeks (end of second treatment course). In
      addition, ABG and exhaled NO alone will be repeated at 2 weeks and 10 weeks (midway through
      each treatment period). Finally, blood (40 ml) will be drawn at time 0, 4, 8, 12 weeks and
      stored for measurement of future variables.
    

Intervention name(s): Norfloxacin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 400 mg po bid; Placebo 400 mg po bid
Intervention MeSH terms: Norfloxacin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: norfloxacin; hepatopulmonary syndrome