Brief Title
Single Dose Azithromycin in the Treatment of Adult Cholera
Official Title
Randomized, Double-Blind, Controlled Clinical Trial to Compare Efficacy of a Single Dose of Azithromycin Versus a Single Dose of Ciprofloxacin in the Treatment of Adults With Clinically Severe Cholera Due to V. Cholerae O1 or O139
Brief Summary
Cholera remains an important cause of diarrhoeal illness and death in Asia, Africa and Latin
America. Antimicrobial therapy is an important adjunct to fluid therapy in the management of
patients with cholera, and should be given to all patients with clinically moderate-to-severe
disease since they can reduce the diarrhoea duration and stool volume by half. Current
therapy for cholera is limited by increasing prevalence of multiply-resistant strains of
Vibrio cholerae O1 or O139. Tetracycline and doxycycline had been the drugs of choice for
treating cholera, but multiply-resistant strains are now present in all areas where cholera
is endemic or epidemic. There is thus a need to identify alternative drugs that are effect in
treating this disease.
Azithromycin, a newer macrolide agent, is active in-vitro against V. cholerae, attains high
concentrations in the gut lumen, has a long half-life, and is better tolerated than
erythromycin, and older macrolide. In this study we will compare efficacy of a single, 1.0 g
oral doses of azithromycin and ciprofloxacin in male patients, aged 18-60 years, with cholera
due to V. cholerae O1 or O139. Patients with typical "Rice watery" stools of cholera, signs
of severe dehydration and characteristic cholera vibrios in a dark-field stool microscopy.
Patients who have coexisting illness which may confound assessment of the efficacy or safety
will not be eligible. Only those patients who have V. cholerae O1 or O139 isolated from their
pre-therapy stool and/or rectal swab culture and remains in the hospital for the entire
duration of the study will be eligible for efficacy evaluation. A written informed consent
will be obtained from each patients for their enrollment in the study.
Patients will be hospitalized for full 5 days, and asked to return for a follow up evaluation
7 days after discharge. After initial rehydration, patients will be observed for 4 hours, and
only those with ³ 20 ml/kg of watery stools during this period will be enrolled for study.
Treatment will be random, and blinded to study staff and patients. Clinical success of
therapy will be defined as resolution of watery stool within 48 hours of administration of
the study drug, and bacteriologic success will be defined as the inability to isolate V.
cholerae O1 or O139 from fecal/rectal swab cultures of patients after 48 hours of therapy,
i.e. on day 3 and on all subsequent days of the study. Patients in whom therapy clinically
fails will be treated for 3 days with an effective alternate drug without opening the study
code. Ninety one evaluable patients will be required in each group to show with a power of
80% and a type I error of 5% that the two treatment regimens are equivalent (i.e. the 95%
confidence interval for the difference in efficacy between the two groups is not greater than
10%).
If single-dose azithromycin therapy is found effective it will provide an important option
for the treatment V. cholerae infections, especially those caused by multiply-resistant
strains.
Detailed Description
A total of 182 evaluable patients (those with a positive stool culture for V. cholerae O1 or
V. cholerae O139 and remain in the study for full 5 days) will be required for this study.
Patients who meet the initial entry criteria will be admitted into the study ward of the
ICDDR,B, weighed (Dehydration Weight), assessed for hydration status and rehydrated using an
intravenous polyelectrolyte solution ("Dhaka Solution" containing 133 mmol/l of sodium, 13
mmol/l of potassium, 98 mmol/l of chloride and 48 mmol/l of bicarbonate) over a 3-hour period
in accordance with the WHO guidelines [53], and re-weighed (Rehydration Weight). Rice-based
oral rehydration salts (ORS) solution (sodium 90 mmol/l, potassium 20 mmol/l, chloride 80
mmol/l, bicarbonate 30 mmol/l, and rice powder 50 gram per litre) will be used as the primary
maintenance fluid once initial rehydration is accomplished, however, intravenous
polyelectrolyte solution will be used as the maintenance fluid for patients with excessive
vomiting (usually > 4 episodes per hour) or with rapid stool losses (usually >10 ml/kg.hour),
or those who are unable to drink enough ORS solution for maintenance of their hydration.
Patients will be allowed to drink plain water ad libitum after the initial rehydration. All
fluid intake and output during rehydration (and throughout the study) will be recorded. A
stool specimen will be collected from the patients for dark-field microscopic examination to
document the presence of V. cholerae.
Following rehydration, stool output will be measured for a 4-hour period in the maintenance
phase, to be called "Observation Period", and those with a stool output of ³ 20 ml/kg during
this period and those who also have V. cholerae demonstrated in their stool dark-field
examination will be considered eligible for enrollment into the study if they provide
voluntary informed consent. This observation period will help establish that patients
enrolled in the study have moderate to severe disease, so that the potential impact of
therapy can be evaluated (as any therapy is likely to appear effective in mild disease).
On final enrollment into the study, a more complete history and physical examination will be
performed, and all findings will be recorded on pre-designed data collection forms.
Patients entered into study will be randomly assigned to receive either a single, 1 gram oral
dose of azithromycin or a single, 1 gram oral dose of ciprofloxacin. Patients entered into
study will be assigned a consecutive study number which will have been previously randomly
assigned to one of the two treatment regimens, and this randomization will be done using a
computer generated random number list with a fixed block length of 4. Study drugs will be
administered after completion of the four-hour observation period, and at least 2 hours after
the last food intake. The time of administering study drug will be considered as the
beginning (the "0" hour) of the study. For patients who vomit within 10 minutes of ingestion
of study drug, the dose of the study drug will be repeated. For this purpose, all study drugs
will be available in duplicate. Such events will be recorded, and data of these patients will
be carefully evaluated. The study drugs will be prepared in identical form to allow for
blinding of treatment. Randomization will be done by Pfizer, USA who will also provide coded
study drugs.
Patients will be hospitalized for 5 complete days to be counted from the time of
administration of the study drug (Each consecutive, 24-period constituting a day). The
following clinical and laboratory evaluations will be done for each of the study patients:
- Body Weight: On initial entry into the study, after initial rehydration, at "0" hour of
the study (which will coincide with administration of the study drug), and at 24 hour
intervals beginning from the time of administration of study drug.
- History and physical examination: On admission, after initial rehydration, at "0" hour
of the study, and at least once daily during hospitalization. This will also include
evaluation for potential adverse events.
- Vital signs: Oral temperature, pulse and respiratory rates, and blood pressures will be
recorded on admission (dehydrated), after rehydration, at the end of the 4-hour
observation period ("0" hour of the study), and every 6 hours after administration of
the study drug.
- Measurement of stool volume: Will be done for the rehydration period, the four hour
observation period, and for each 6-hour period after administration of study drug.
- Characterization of stool: Individual stool will be categorized as either watery or soft
or formed; the worst stool character of each 6 hour study period will be used to
categorize that time period.
- Stool culture for V. cholerae O1, O139 and non-Ol; and Shigella and Salmonella: Will be
done on admission, on study day two and at follow up.
- Rectal swab culture for V. cholerae O1 and O139: Will be done on admission, and on each
study day.
- Hematological studies: Serum electrolytes, creatinine and serum Sp. gr., and haematocrit
will be determined before and after rehydration, and 24 hours after administration of
the study drug (3.0 ml of blood will be required for these tests each time, i.e. a total
of 9.0 ml of blood). Complete blood count, and platelet count will be done just before
administration of the study drug, however, this may also be done subsequently only if
clinically indicated.
- Pharmacokinetic studies: For the first 40 patients enrolled into the study, venous blood
will be obtained for determination of the serum concentration of the study drugs at
either of the following time intervals from administration of the study drug- 3, 12, 24
or 48 hours. An indwelling catheter with two way stop cock will be introduced to avoid
repeated venipuncture which will be taken off 3 hours after administration of the study
drug; all subsequent blood samplings will be done by individual venipunctures. This will
require only 1.0 ml of venous blood, and serum will be separated and stored at -70EC
until assayed. For determination of stool concentration of the study drugs, aliquots of
stool (About 5.0 ml each) will be obtained from stool collected over each 6 hour period
during the first two days of the study, and like serum, will be stored and analyzed.
- Handling of Treatment Failures: If the study treatment is judged to have failed
clinically patients will be treated for 3 days with an agent other than azithromycin or
ciprofloxacin to which the isolate of V. cholerae will be found to be susceptible to.
The treatment code will not be broken for these patients. Patients with microbiological
failure will be treated with a suitable drug as determined by antimicrobial
susceptibility of such isolates.
Study Phase
Phase 3
Study Type
Interventional
Primary Outcome
Clinical success
Secondary Outcome
Rates of clinical and bacteriologic relapse.
Condition
Cholera
Intervention
Azithromycin
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
220
Start Date
December 2002
Completion Date
May 2004
Eligibility Criteria
Inclusion Criteria:
- Age: 18 - 60 years
- Gender: Male (To facilitate accurate measurement of stool and urine, and also due to
the difficulties in hospitalizing women for longer duration)
- Duration of illness: 24 hours or less
- Written informed consent for participation in the study
- Dehydration status: Signs of severe dehydration as determined by World Health
Organization criteria.
- Positive stool dark-field microscopic examination for V. cholerae, and subsequent
isolation of V. cholerae O1 or O139 from an admission culture of a stool or rectal
swab sample.
Exclusion Criteria:
- History of receiving even one dose of an antimicrobial agent effective in the
treatment of cholera, and even a single fose of the drugs under evaluation.
- Concomitant infection requiring antimicrobial therapy other than the study drugs which
may interfere with evaluation of either the efficacy or safety of the study drugs.
- A concomitant illness which may confound evaluation of outcome or is a
contraindication for use of either of the study drugs (chronic heart, lung, of kidney
disease, or instance), or conditions which may confound evaluation of adverse events
of the study drugs.
Gender
All
Ages
18 Years - 60 Years
Accepts Healthy Volunteers
No
Contacts
Debasish Saha, MBBS,MS, ,
Location Countries
Bangladesh
Location Countries
Bangladesh
Administrative Informations
NCT ID
NCT00229944
Organization ID
98-022
Study Sponsor
International Centre for Diarrhoeal Disease Research, Bangladesh
Collaborators
Pfizer
Study Sponsor
Debasish Saha, MBBS,MS, Study Director, International Centre for Diarrhoeal Disease Research, Bangladesh
Verification Date
September 2005