Plague Clinical Trial
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
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.
Plague is a life-threatening disease that requires immediate treatment with effective
antimicrobials. Drugs with demonstrated efficacy include streptomycin, doxycycline, and to a
lesser extent, gentamicin. Animal and in vitro studies suggest that fluoroquinolones,
including ciprofloxacin, may be effective agents for treatment of plague. However, with the
exception of a single case report, there are no published instances in which
fluoroquinolones have been used successfully to treat plague in humans. There is a critical
need to evaluate newer antimicrobials that have been shown to be efficacious in vitro and in
animal studies, used extensively in the treatment of other illnesses in humans, work by a
separate mechanism than antimicrobials currently used for treatment, and are widely
available and affordable.
The objective of this study 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. This study is designed to test the following hypothesis: the safety and
efficacy of ciprofloxacin for the treatment of plague in humans is not inferior to
doxycycline. This study will result in a better understanding of the safety and efficacy of
ciprofloxacin for the treatment of plague in humans. Information from this study will be
used to expand the experience and knowledge base for the treatment of plague in humans and
guide national and international treatment guidelines. Information from this study also will
possibly add to the antiquated list of effective antimicrobials used to treat plague and
possibly lead to a reduction in the overall morbidity and mortality caused by plague and its
treatment.
The randomized clinical trial provides the best design to distinguish treatment effects from
other effects such as bias in allocation, observation, and measurement; spontaneous changes
in disease course or healing; and improvement from participating in a study (i.e., placebo
effect). An open-labeled design is being used because the opportunities for investigators or
patients to bias the outcome are limited (i.e., patient randomized after enrollment and
mortality is objective outcome) and a double blind design would greatly increase the
complexity and cost of the trial.
The primary outcome for this trial will be patient outcome 14 days from enrollment and
initiation of treatment, which includes outcomes of patient recovery without complications,
recovery with complications, withdrawal, or death. Patient outcome will be evaluated only
for those patients with laboratory-confirmed plague illness. Time to defervesence and
occurrence of antimicrobial-associated adverse events will be evaluated as secondary
outcomes in patients with laboratory-confirmed plague illness and all enrolled patients,
respectively.
When conducting a non-inferiority study, it is important to consider the appropriate
selection of a comparator treatment, non-inferiority margin (M), and analysis strategy. For
non-inferiority trials, it is critical to select a standard treatment that has proven to be
the best historically or been used in prior randomized clinical trials as the comparator
treatment. Of the possible options, doxycycline is most optimal choice for this trial
because it is the current treatment standard in Uganda (the country location of the proposed
study) and its treatment regimen and side effect profile are the similar to that of
ciprofloxacin. For this trial, the non-inferiority margin (M) is the acceptable difference
between the probability that ciprofloxacin cures plague as compared to the probability that
doxycycline cures plague. Because of the severity of illness and high case fatality rate for
plague in general, and the potential for pneumonic transmission with pneumonic plague, the
choice of an acceptable M should be no more than 10% with a most conservative choice of 2%.
If we assume an overall Type I error rate = 0.05, a power (power = 1 - Type II error rate)
of 80%, πs = 0.90 and we choose M = 0.10, then the number of patients required for each
study arm is well over 1,000 (calculations not shown). From our previous experience with a
similar trial (i.e., The safety and efficacy of gentamicin vs. streptomycin in the treatment
of plague in humans, CDC IRB #3700) and our current experience with surveillance data in
Uganda, we anticipate being able to enroll approximately 100-200 total patients per year.
Therefore, we computed the power using different values of M (0.02, 0.05, 0.10; where 0.02
is the most conservative and 0.10 is the most forgiving but still within the accepted
non-inferiority margin), to represent a range of reported efficacy of the standards (table
not shown). Using the table, we would have approximately 61% power to detect non-inferiority
of ciprofloxacin treatment with a non-inferiority margin, M, = 0.10 if the true efficacy of
the standard is = 90% and if we were to enroll 148 patients total, for example.
This study will attempt to include all suspect cases of plague aged 8 years or older
identified through clinic-based surveillance. Most patients, including plague cases, are
treated at the "level 3" health centers, mainly due to a lack of motorized transport.
Between 3 and 10 "level 3" clinics in Arua and Nebbi Districts, Uganda will be chosen to
participate in this study based on the reported number of cases of plague in the last 5
years and logistic considerations. Only UMOH clinics will be considered for inclusion.
The "level 3" clinics are staffed by 1-2 clinical officers and are very busy, seeing 50-150
patients each day. Because of the excess patient volume, the study collaborators will hire
and train one additional clinical officer for each collaborating clinic to work alongside
the UMOH clinical officer(s) stationed at the collaborating clinic so as not to impair
normal clinic function. The hired clinical officer will be trained on the clinical aspects
of plague and the study protocol, and will be responsible for evaluating suspect plague
patients for study enrollment, consenting patients, and providing patient treatment and
monitoring per the study protocol.
The diagnosis of suspected plague patients who consent and enroll in the study will follow
the national guidelines of the UMOH. The only adaptations are that, after receiving informed
consent, UMOH physicians will collect biologic samples and patients will be randomized and
receive ciprofloxacin or doxycycline. Of note, a urine pregnancy test will be conducted on
every female of child-bearing age at time of enrollment and randomization and antimicrobial
treatment will not be initiated unless the results are negative. Based on our experience
conducting a similar trial in Madagascar, results from the urine pregnancy test are
available in less than 5 minutes so this should not cause any substantial time delays.
Antimicrobial treatment per UMOH national guidelines will be started immediately should
there be instances where there are delays in obtaining consent or collecting biologic
samples, or if the treating physician deems it necessary.
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:
1. One or more buboes, defined as a tender lymph node swelling > 1cm in diameter, or;
2. Clinical suspicion of pneumonic plague (e.g. prostration, cough, increased
respiratory rate, hemoptysis and/or purulent sputum), or
3. Clinical suspicion of cutaneous plague (lesion)
4. Clinical suspicion of plague and epidemiologic link with other cases.
Patients with suspected plague illness will be considered ineligible for the study and will
be excluded from study enrollment using the following criteria:
1. Any women who is pregnant, or;
2. Any woman who is breast-feeding, or;
3. Any person aged < 8 years of age, or;
4. 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.
We will enroll suspected plague cases during the high transmission season between September
and April, 2010 through 2012. Based on enrollment for a similar study performed previously
by these investigators in Madagascar and Uganda (unpublished data, CDC) and given the
existing epidemiological data on plague in Uganda, we anticipate recruitment of between 125
and 200 suspected cases of plague per year, where approximately 40% to 50% of cases will
have a confirmed plague illness, with a 20-30% case-fatality rate.
Patients will be monitored daily. Participants may voluntarily withdraw from this study for
any reason at any time. The protocol and consent forms must be approved by all three
supervising IRBs (i.e., US Centers for Disease Control and Prevention, Uganda Virus Research
Institute Scientific Ethics Committee, and Uganda National Council for Science and
Technology) prior to starting the trial. A Data Safety and Monitoring Board will review all
serious adverse events and interim and final trial data to ensure patient safety and good
trial conduct.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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