Single Dose Azithromycin in the Treatment of Adult Cholera
|First Submitted Date ICMJE||September 29, 2005|
|First Posted Date ICMJE||September 30, 2005|
|Last Update Posted Date||July 21, 2006|
|Start Date ICMJE||December 2002|
|Primary Completion Date||Not Provided|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00229944 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Single Dose Azithromycin in the Treatment of Adult Cholera|
|Official Title ICMJE||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|
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.
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 , 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:
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Primary Purpose: Treatment
|Intervention ICMJE||Drug: Azithromycin|
|Study Arms||Not Provided|
|Publications *||Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish ML. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med. 2006 Jun 8;354(23):2452-62.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Estimated Completion Date||May 2004|
|Primary Completion Date||Not Provided|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 60 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Bangladesh|
|Removed Location Countries|
|NCT Number ICMJE||NCT00229944|
|Other Study ID Numbers ICMJE||98-022|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Not Provided|
|Study Sponsor ICMJE||International Centre for Diarrhoeal Disease Research, Bangladesh|
|PRS Account||International Centre for Diarrhoeal Disease Research, Bangladesh|
|Verification Date||September 2005|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP