A Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin in the Treatment of Plague in Humans
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.
|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|
- all cause mortality [ Time Frame: 14 days ] [ Designated as safety issue: No ]
- 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 ]
|Study Start Date:||December 2010|
|Estimated Primary Completion Date:||June 2013 (Final data collection date for primary outcome measure)|
|Active Comparator: doxycycline||
Show Detailed Description
|Contact: Kevin S. Griffith, MD, MPH||970-221-6400 ext email@example.com|
|Contact: Paul S. Mead, MD, MPH||970-221-6400 ext firstname.lastname@example.org|
|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 email@example.com|
|Contact: Paul S Mead, MD, MPH 970-221-6400 ext 6474 firstname.lastname@example.org|
|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|