Single Dose Azithromycin in the Treatment of Adult Cholera

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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