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A Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin in the Treatment of Plague in Humans

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2012 by Centers for Disease Control and Prevention
Sponsor:
Collaborators:
MRC/UVRI Uganda Research Unit on Aids
Ministry of Health, Uganda
Information provided by (Responsible Party):
Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:
NCT01243437
First received: November 17, 2010
Last updated: September 10, 2012
Last verified: September 2012
  Purpose

Plague is a severe, life-threatening disease. Plague occurs in focal locations worldwide, but over 95% of human cases reported to WHO are by countries in Africa. The most common clinical manifestations of human infection are bubonic, septicemic, and pneumonic plague. Untreated pneumonic or septicemic plague is fatal in over 90% of cases; untreated bubonic plague is fatal in over 50% of cases. Delayed and ineffectual treatment is a main contributor to elevated case fatality rates, which can be as high as 40%, and to the development of pneumonic plague and plague outbreaks.

Streptomycin is considered the treatment of choice, and prompt administration can reduce mortality to 5% or less. However, streptomycin may cause irreversible hearing loss and vestibular damage, reversible renal damage, and it is contraindicated during pregnancy. Tetracyclines, including doxycycline, are considered effective alternatives but they are bacteriostatic and relatively contraindicated for use in children aged < 8 years and pregnant women.

Ciprofloxacin is a relatively newer antimicrobial that is used extensively in clinical practice because of its broad-spectrum antimicrobial activity, excellent tissue and intracellular penetration, suitability for oral administration, and good overall tolerability. In vitro and animal studies suggest equivalent or greater activity of ciprofloxacin against Yersinia pestis when compared with streptomycin or tetracyclines. However, the efficacy of ciprofloxacin for the treatment of human plague has never been demonstrated, nor is it FDA approved for this indication.

Since 2004, CDC has collaborated with the Uganda Ministry of Health (MoH) and the Uganda Virus Research Institute (UVRI) to enhance surveillance, diagnosis, and ecological control of plague in Arua and Nebbi Districts. Through these efforts, we have collected data on over 2,400 cases of clinically diagnosed plague occurring from 1999 through 2009. In 2008, UVRI and CDC staff investigated 163 suspect plague cases: 57 (35%) had laboratory-confirmed plague illness, of which 14 patients (25%) died.

Because plague is a relatively rare disease that mainly affects people living in rural, impoverished areas, it receives limited attention for research and development of affordable and sustainable diagnostic and treatment options. However, because plague cannot be eradicated, and because it causes high case fatality and has the potential for widespread person to person transmission, continued research should not be neglected.

The objective of this clinical trial is to conduct a randomized, open-labeled, non-inferiority study comparing the safety and efficacy of ciprofloxacin to doxycycline, the national treatment standard in Uganda for plague, in patients aged > 8 years. The primary outcome for this trial will be patient outcome 14 days from enrollment and initiation of treatment. Patient outcome will be evaluated only for those patients with laboratory-confirmed plague illness.

Information gathered from this proposed study will help optimize management of naturally occurring plague in humans in many countries of the world, including Uganda and the United States, by providing clinicians with more choices for optimal antimicrobial treatment. This is particularly true in resource limited rural regions such as Uganda where intravenous or intramuscular injections are less available. Ciprofloxacin currently is being used in Uganda and other plague endemic areas of the world for treatment of other infectious conditions, including infectious diarrhea and lower respiratory infections. In Uganda, ciprofloxacin is widely available in health facilities and local drug shops, and is affordable.


Condition Intervention Phase
Plague
Drug: ciprofloxacin
Drug: doxyxcycline
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Non-inferiority, Active Controlled Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin Versus Doxycycline in the Treatment of Plague in Humans

Resource links provided by NLM:


Further study details as provided by Centers for Disease Control and Prevention:

Primary Outcome Measures:
  • all cause mortality [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • time to defervesence [ Time Frame: days to weeks ] [ Designated as safety issue: No ]
  • antimicrobial associated adverse events [ Time Frame: days to weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 200
Study Start Date: December 2010
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ciprofloxacin Drug: ciprofloxacin
  • For adults and children aged > 15 years: 500 mg orally every 12 hours for 10 days or until the patient has been fever-free for 24 hours, whichever is longer;
  • For children aged 8-15 years: 15 mg/kg (maximum 500 mg per dose) orally every 12 hours for 10 days or until the patient has been fever-free for 24 hours, whichever is longer.
Active Comparator: doxycycline Drug: doxyxcycline
  • For adults and children weighing 45 kg or more: 200 mg orally one time as an initial loading dose, followed by 100 mg orally every 12 hours for 10 days or until the patient has been fever-free for 24 hours, whichever is longer;
  • For children weighing less than 45 kg: 4.4 mg/kg orally one time as an initial loading dose, followed by 2.2 mg/kg orally every 12 hours for 10 days or until the patient has been fever-free for 24 hours, whichever is longer.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   8 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Suspect cases of plague will be eligible and will be asked to give consent for study enrollment using the following criteria:

    1. any person, including women and persons who are minorities, who;
    2. must be aged 8 years or older, and;
    3. must have had potential exposure to rodents and/or fleas or contact with a confirmed plague case, and;
    4. must have a fever of at least 38ºC that developed rapidly, and have at least one of the following:
  • One or more buboes, defined as a tender lymph node swelling > 1cm in diameter, or;
  • Clinical suspicion of pneumonic plague (e.g. prostration, cough, increased respiratory rate, hemoptysis and/or purulent sputum), or
  • Clinical suspicion of cutaneous plague (lesion)
  • Clinical suspicion of plague and epidemiologic link with other cases

Exclusion Criteria:

  • Patients with suspected plague illness will be considered ineligible for the study and will be excluded from study enrollment using the following criteria:
  • Any women who is pregnant, or;
  • Any woman who is breast-feeding, or;
  • Any person aged < 8 years of age, or;
  • Any patient with:
  • signs of plague meningitis
  • hypotension unresponsive to fluid therapy
  • an illness severity score of > 16 at time of enrollment (see below)
  • known allergy to ciprofloxacin or doxycycline
  • taken tetracyclines, quinolones, gentamicin, streptomycin, trimethoprim-sulfamethoxazole, or chloramphenicol in the 24 hours preceding study enrollment

Patients who are pregnant, breast-feeding, or aged < 8 years will be excluded because doxycycline has a relative contraindication for use in these populations due to drug deposition in calcifying areas of bones and teeth, enamel hypoplasia, and decreased linear skeletal growth rate. [22, 23] Please see section 10.2 for additional background describing the reasoning to exclude patients from these populations. Please see section 3.5 for the specifics regarding the timing of urine pregnancy testing.

The illness severity score is a composite measure adapted from the APACHE-II and Glasgow Coma scores that estimates the severity of a patient's illness at enrollment. Because most clinic locations are remote with little or no laboratory capacity, the illness severity score utilizes only non-biochemical parameters.

Patients will not be tested for Human Immunodeficiency Virus (HIV), and known or suspected HIV-positive patients will not be excluded.

Because this study will be conducted in a remote region of Uganda where no prisons are located, the enrollment of prisoners is not applicable to our study. If for some unforeseen reason a prisoner presents to a study clinic location for treatment of suspected plague, the prisoner will be excluded from the trial.

All study resources will be available and treatment following the UMOH national plague treatment guidelines will be offered to patients with suspected plague at the UMOH collaborating clinics who are not eligible for enrollment or who declined to consent.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01243437

Contacts
Contact: Kevin S. Griffith, MD, MPH 970-221-6400 ext 4259 kkg8@cdc.gov
Contact: Paul S. Mead, MD, MPH 970-221-6400 ext 6474 pfm0@cdc.gov

Locations
Uganda
Uganda Ministry of Health: selected Arua and Nebbi district health centres Recruiting
Arua and Nebbi district, Uganda
Contact: Kevin S. Griffith, MD, MPH    970-221-6400 ext 4259    kkg8@cdc.gov   
Contact: Paul S Mead, MD, MPH    970-221-6400 ext 6474    pfm0@cdc.gov   
Sponsors and Collaborators
MRC/UVRI Uganda Research Unit on Aids
Ministry of Health, Uganda
Investigators
Principal Investigator: Kevin S. Griffith, MD, MPH Centers for Disease Control and Prevention
Principal Investigator: Edward Mbidde, MD MRC/UVRI Uganda Research Unit on Aids
Principal Investigator: Issa Makumbi, MD Ministry of Health, Uganda
  More Information

No publications provided

Responsible Party: Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier: NCT01243437     History of Changes
Other Study ID Numbers: CDC-NCEZID-5859
Study First Received: November 17, 2010
Last Updated: September 10, 2012
Health Authority: United States: Federal Government (Centers for Disease Control and Prevention)
Uganda: Ministry of Health
Uganda: National Council for Science and Technology
United States: Food and Drug Administration

Keywords provided by Centers for Disease Control and Prevention:
plague, ciprofloxacin

Additional relevant MeSH terms:
Plague
Yersinia Infections
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Ciprofloxacin
Doxycycline
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Infective Agents
Therapeutic Uses
Anti-Bacterial Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on July 23, 2014