Ignite Creation Date:
2024-05-05 @ 5:00 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00362752
Status:
COMPLETED
Last Update Posted:
2016-12-07
First Post:
2006-08-08
Brief Title:
A Pilot Study of Norfloxacin for Hepatopulmonary Syndrome
Sponsor:
Unity Health Toronto
Organization:
Unity Health Toronto
Study Overview
Official Title:
A Pilot Study of Norfloxacin for Hepatopulmonary Syndrome
Status:
COMPLETED
Status Verified Date:
2016-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The hepatopulmonary syndrome HPSand 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 medicationplacebo 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
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 medicationplacebo 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 BDITDI 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
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 BDITDI 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None